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Sample records for adrenergic receptor immunoreactivity

  1. Human myometrial adrenergic receptors: identification of the beta-adrenergic receptor by [3H]dihydroalprenolol binding

    International Nuclear Information System (INIS)

    Hayashida, D.N.; Leung, R.; Goldfien, A.; Roberts, J.M.

    1982-01-01

    The radioactive beta-adrenergic antagonist [ 3 H] dihydroalprenolol (DHA) binds to particulate preparations of human myometrium in a manner compatible with binding to the beta-adrenergic receptor. The binding of DHA is rapid (attaining equilibrium in 12 minutes), readily reversible (half time = 16 minutes), high affinity (K/sub D/ = 0.50 nM), low capacity (Bmax = 70 fmoles/mg of protein), and stereoselective ([-]-propranolol is 100 times as potent as [+] -propranolol in inhibiting DHA binding). Adrenergic agonists competed for DHA binding sites in a manner compatible with beta-adrenergic interactions and mirrored β 2 pharmacologic potencies: isoproterenol > epinephrine >> norepinephrine. Studies in which zinterol, a β 2 -adrenergic agonist, competed for DHA binding sites in human myometrial particulate indicated that at least 87% of the beta-adrenergic receptors present are β 2 -adrenergic receptors. Binding of DHA to human myometrial beta-adrenergic receptors provides a tool which may be used in the examination of gonadal hormonal modification of adrenergic response in human uterus as well as in the analysis of beta-adrenergic agents as potentially useful tocolytic agents

  2. Rat hepatic β2-adrenergic receptor: structural similarities to the rat fat cell β1-adrenergic receptor

    International Nuclear Information System (INIS)

    Graziano, M.P.

    1984-01-01

    The mammalian β 2 -adrenergic receptor from rat liver has been purified by sequential cycles of affinity chromatography followed by steric-exclusion high performance liquid chromatography. Electrophoresis of highly purified receptor preparations on polyacrylamide gels in the presence of sodium dodecyl sulfate under reducing conditions reveals a single peptide M/sub r/ = 67,000, as judged by silver staining. Purified β 2 -adrenergic receptor migrates on steric-exclusion high performance liquid chromatography in two peaks, with M/sub r/ = 140,000 and 67,000. Specific binding of the high affinity, β-adrenergic receptor antagonists (-)[ 3 H]dihydroalprenolol and (-)[ 125 I]iodocyanopindolol to purified rat liver β-adrenergic receptor preparations displays stereoselectivity for (-)isomers of agonists and a rank order of potencies for agonists characteristics of a β 2 -adrenergic receptor. Radioiodinated, β 1 -adrenergic receptors from rat fat cells and β 2 -adrenergic receptors from rat liver purified in the presence of protease inhibitors comigrate in electrophoretic separations on polyacrylamide gels in the presence of sodium dodecyl sulfate as 67,000-M/sub r/ peptides. Autoradiograms of two dimensional partial proteolytic digests of the purified, radioiodinated rat liver β 2 -adrenergic receptor, generated with α-chymotrypsin, S. aureus V8 protease and elastase reveal a pattern of peptide fragments essentially identical to those generated by partial proteolytic digests of the purified, radioiodinated β 1 -adrenergic receptor from rat fat cells, by these same proteases. These data indicate that a high degree of homology exists between these two pharmacologically distinct mammalian β-adrenergic receptor proteins

  3. Adrenergic receptors are a fallible index of adrenergic denervation hypersensitivity

    DEFF Research Database (Denmark)

    Dejgaard, Anders; Liggett, S B; Christensen, N J

    1991-01-01

    In view of evidence that neither interindividual nor induced intra-individual variations of adrenergic receptor status are related to metabolic or haemodynamic sensitivity to adrenaline in vivo, we took an alternative approach to assessment of the relevance of adrenergic receptor measurement...... by measuring these in a group of subjects with well-documented adrenergic denervation hypersensitivity, patients with diabetic autonomic neuropathy. Mononuclear leukocyte beta 2-adrenergic receptor densities (and binding affinities), measured with 125I-labelled pindolol, and isoproterenol-stimulated cyclic AMP...... accumulation, in samples from patients with insulin-dependent diabetes mellitus (IDDM) with diabetic autonomic neuropathy (n = 8), were no different from those in samples from patients with IDDM without neuropathy (n = 8), or from non-diabetic subjects (n = 8). In addition, platelet alpha 2-adrenergic receptor...

  4. Reduced beta-adrenergic receptor activation decreases G-protein expression and beta-adrenergic receptor kinase activity in porcine heart.

    OpenAIRE

    Ping, P; Gelzer-Bell, R; Roth, D A; Kiel, D; Insel, P A; Hammond, H K

    1995-01-01

    To determine whether beta-adrenergic receptor agonist activation influences guanosine 5'-triphosphate-binding protein (G-protein) expression and beta-adrenergic receptor kinase activity in the heart, we examined the effects of chronic beta 1-adrenergic receptor antagonist treatment (bisoprolol, 0.2 mg/kg per d i.v., 35 d) on components of the myocardial beta-adrenergic receptor-G-protein-adenylyl cyclase pathway in porcine myocardium. Three novel alterations in cardiac adrenergic signaling as...

  5. Adrenergic receptors are a fallible index of adrenergic denervation hypersensitivity

    DEFF Research Database (Denmark)

    Dejgaard, Anders; Liggett, S B; Christensen, N J

    1991-01-01

    In view of evidence that neither interindividual nor induced intra-individual variations of adrenergic receptor status are related to metabolic or haemodynamic sensitivity to adrenaline in vivo, we took an alternative approach to assessment of the relevance of adrenergic receptor measurement...... densities (and binding affinities), measured with 3H-labelled yohimbine, and adrenaline-induced suppression of cyclic AMP contents did not differ among the three groups. Thus, in contrast to idiopathic autonomic failure, there is no generalized increase in adrenergic receptors in autonomic failure due...

  6. Human myometrial adrenergic receptors during pregnancy: identification of the alpha-adrenergic receptor by [3H] dihydroergocryptine binding

    International Nuclear Information System (INIS)

    Jacobs, M.M.; Hayashida, D.; Roberts, J.M.

    1985-01-01

    The radioactive alpha-adrenergic antagonist [ 3 H] dihydroergocryptine binds to particulate preparations of term pregnant human myometrium in a manner compatible with binding to the alpha-adrenergic receptor (alpha-receptor). [ 3 H] Dihydroergocryptine binds with high affinity (KD = 2 nmol/L and low capacity (receptor concentration = 100 fmol/mg of protein). Adrenergic agonists compete for [ 3 H] dihydroergocryptine binding sites stereo-selectively ([-]-norepinephrine is 100 times as potent as [+]-norepinephrine) and in a manner compatible with alpha-adrenergic potencies (epinephrine approximately equal to norepinephrine much greater than isoproterenol). Studies in which prazosin, an alpha 1-antagonist, and yohimbine, and alpha 2-antagonist, competed for [ 3 H] dihydroergocryptine binding sites in human myometrium indicated that approximately 70% are alpha 2-receptors and that 30% are alpha 1-receptors. [ 3 H] dihydroergocryptine binding to human myometrial membrane particulate provides an important tool with which to study the molecular mechanisms of uterine alpha-adrenergic response

  7. β-Adrenergic receptor-mediated suppression of interleukin 2 receptors in human lymphocytes

    International Nuclear Information System (INIS)

    Feldman, R.D.; Hunninghake, G.W.; McArdle, W.L.

    1987-01-01

    Adrenergic receptor agonists are know to attenuate the proliferative response of human lymphocytes after activation; however, their mechanism of action is unknown. Since expression of interleukin 2 (IL-2) receptors is a prerequisite for proliferation, the effect of β-adrenergic receptor agonists on lymphocyte IL-2 receptors was studied on both mitogen-stimulated lymphocytes and IL-2-dependent T lymphocyte cell lines. In both cell types the β-adrenergic receptor agonist isoproterenol blocked the expression of IL-2 receptors, as determined with the IL-2 receptor anti-TAC antibody. To determine the effect of β-adrenergic agonists on expression of the high affinity IL-2 receptors, [ 125 I]IL-2 binding studies were performed at concentrations selective for high affinity sites. No significant effect of β-adrenergic agonists on high affinity IL-2 receptor sites could be detected. The data demonstrate that β-adrenergic receptor agonists down-regulate IL-2 receptors primarily affecting low affinity sites

  8. Muscle Plasticity and β2-Adrenergic Receptors: Adaptive Responses of β2-Adrenergic Receptor Expression to Muscle Hypertrophy and Atrophy

    OpenAIRE

    Shogo Sato; Ken Shirato; Kaoru Tachiyashiki; Kazuhiko Imaizumi

    2011-01-01

    We discuss the functional roles of β2-adrenergic receptors in skeletal muscle hypertrophy and atrophy as well as the adaptive responses of β2-adrenergic receptor expression to anabolic and catabolic conditions. β2-Adrenergic receptor stimulation using anabolic drugs increases muscle mass by promoting muscle protein synthesis and/or attenuating protein degradation. These effects are prevented ...

  9. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to "Biased Opioids"?

    Science.gov (United States)

    Root-Bernstein, Robert; Turke, Miah; Subhramanyam, Udaya K Tiruttani; Churchill, Beth; Labahn, Joerg

    2018-01-17

    Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists.

  10. Do receptors get pregnant too? Adrenergic receptor alterations in human pregnancy.

    Science.gov (United States)

    Smiley, R M; Finster, M

    1996-01-01

    In this review we discuss adrenergic receptor number and function during pregnancy, with emphasis on evidence that pregnancy results in specific receptor alterations from the nonpregnant state. Changes in adrenergic receptor function or distribution in vascular smooth muscle may be in part responsible for the decreased vascular responsiveness seen in human pregnancy, and the lack of the normal alterations may be a part of the syndromes of gestational hypertension, including preeclampsia-eclampsia. The onset of labor may be influenced by adrenergic modulation, and receptor or postreceptor level molecular alterations may trigger or facilitate normal or preterm labor. Human studies are emphasized when possible to assess the role of adrenergic signal transduction regulation in the physiology and pathophysiology of normal and complicated human pregnancy.

  11. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to “Biased Opioids”?

    Science.gov (United States)

    Turke, Miah; Subhramanyam, Udaya K. Tiruttani; Churchill, Beth; Labahn, Joerg

    2018-01-01

    Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists. PMID:29342106

  12. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to “Biased Opioids”?

    Directory of Open Access Journals (Sweden)

    Robert Root-Bernstein

    2018-01-01

    Full Text Available Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists.

  13. β-Adrenergic Receptor Mediation of Stress-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Roles for β1 and β2 Adrenergic Receptors

    Science.gov (United States)

    Vranjkovic, Oliver; Hang, Shona; Baker, David A.

    2012-01-01

    Stress can trigger the relapse of drug use in recovering cocaine addicts and reinstatement in rodent models through mechanisms that may involve norepinephrine release and β-adrenergic receptor activation. The present study examined the role of β-adrenergic receptor subtypes in the stressor-induced reinstatement of extinguished cocaine-induced (15 mg/kg i.p.) conditioned place preference in mice. Forced swim (6 min at 22°C) stress or activation of central noradrenergic neurotransmission by administration of the selective α2 adrenergic receptor antagonist 2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole (BRL-44,408) (10 mg/kg i.p.) induced reinstatement in wild-type, but not β- adrenergic receptor-deficient Adrb1/Adrb2 double-knockout, mice. In contrast, cocaine administration (15 mg/kg i.p.) resulted in reinstatement in both wild-type and β-adrenergic receptor knockout mice. Stress-induced reinstatement probably involved β2 adrenergic receptors. The β2 adrenergic receptor antagonist -(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI-118,551) (1 or 2 mg/kg i.p.) blocked reinstatement by forced swim or BRL-44,408, whereas administration of the nonselective β-adrenergic receptor agonist isoproterenol (2 or 4 mg/kg i.p.) or the β2 adrenergic receptor-selective agonist clenbuterol (2 or 4 mg/kg i.p.) induced reinstatement. Forced swim-induced, but not BRL-44,408-induced, reinstatement was also blocked by a high (20 mg/kg) but not low (10 mg/kg) dose of the β1 adrenergic receptor antagonist betaxolol, and isoproterenol-induced reinstatement was blocked by pretreatment with either ICI-118,551 or betaxolol, suggesting a potential cooperative role for β1 and β2 adrenergic receptors in stress-induced reinstatement. Overall, these findings suggest that targeting β-adrenergic receptors may represent a promising pharmacotherapeutic strategy for preventing drug relapse, particularly in cocaine addicts whose drug use is stress

  14. Amiloride interacts with renal α- and β-adrenergic receptors

    International Nuclear Information System (INIS)

    Howard, M.J.; Mullen, M.D.; Insel, P.A.

    1987-01-01

    The authors have used radioligand binding techniques to assess whether amiloride and certain analogues of amiloride (ethylisopropyl amiloride and benzamil) can bind to adrenergic receptors in the kidney. They found that amiloride could compete for [ 3 H]rauwolscine (α 2 -adrenergic receptors), [ 3 H]prazosin (α 1 -adrenergic receptors), and [ 125 I]iodocyanopindolol (β-adrenergic receptors) binding in rat renal cortical membranes with inhibitor constants of 13.6 /plus minus/ 5.7, 24.4 /plus minus/ 7.4, and 8.36 /plus minus/ 13.5 μM, respectively. Ethylisopropyl amiloride and benzamil were from 2- to 25-fold more potent than amiloride in competing for radioligand binding sites in studies with these membranes. In addition, amiloride and the two analogues competed for [ 3 H]prazosin sites on intact Madin-Darby canine kidney cells and amiloride blocked epinephrine-stimulated prostaglandin E 2 production in these cells. They conclude that amiloride competes for binding to several classes of renal adrenergic receptors with a rank order of potency of α 2 > α 1 > β. Binding to, and antagonism of, adrenergic receptors occurs at concentrations of amiloride that are lower than previously observed nonspecific interactions of this agent

  15. β1-adrenergic receptor stimulation by agonist Compound 49b restores insulin receptor signal transduction in vivo

    Science.gov (United States)

    Jiang, Youde; Zhang, Qiuhua; Ye, Eun-Ah

    2014-01-01

    Purpose Determine whether Compound 49b treatment ameliorates retinal changes due to the lack of β2-adrenergic receptor signaling. Methods Using retinas from 3-month-old β2-adrenergic receptor-deficient mice, we treated mice with our novel β1-/β2-adrenergic receptor agonist, Compound 49b, to assess the effects of adrenergic agonists acting only on β1-adrenergic receptors due to the absence of β2-adrenergic receptors. Western blotting or enzyme-linked immunosorbent assay (ELISA) analyses were performed for β1- and β2-adrenergic receptors, as well as key insulin resistance proteins, including TNF-α, SOCS3, IRS-1Ser307, and IRTyr960. Analyses were also performed on key anti- and proapoptotic proteins: Akt, Bcl-xL, Bax, and caspase 3. Electroretinogram analyses were conducted to assess functional changes, while histological assessment was conducted for changes in retinal thickness. Results A 2-month treatment of β2-adrenergic receptor-deficient mice with daily eye drops of 1 mM Compound 49b, a novel β1- and β2-adrenergic receptor agonist, reversed the changes in insulin resistance markers (TNF-α and SOCS3) observed in untreated β2-adrenergic receptor-deficient mice, and concomitantly increased morphological integrity (retinal thickness) and functional responses (electroretinogram amplitude). These results suggest that stimulating β1-adrenergic receptors on retinal endothelial cells or Müller cells can compensate for the loss of β2-adrenergic receptor signaling on Müller cells, restore insulin signal transduction, reduce retinal apoptosis, and enhance retinal function. Conclusions Since our previous studies with β1-adrenergic receptor knockout mice confirmed that the reverse also occurs (β2-adrenergic receptor stimulation can compensate for the loss of β1-adrenergic receptor activity), it appears that increased activity in either of these pathways alone is sufficient to block insulin resistance–based retinal cell apoptosis. PMID:24966659

  16. Beta adrenergic receptors in human cavernous tissue

    Energy Technology Data Exchange (ETDEWEB)

    Dhabuwala, C.B.; Ramakrishna, C.V.; Anderson, G.F.

    1985-04-01

    Beta adrenergic receptor binding was performed with /sup 125/I iodocyanopindolol on human cavernous tissue membrane fractions from normal tissue and transsexual procedures obtained postoperatively, as well as from postmortem sources. Isotherm binding studies on normal fresh tissues indicated that the receptor density was 9.1 fmoles/mg. with a KD of 23 pM. Tissue stored at room temperature for 4 to 6 hours, then at 4C in saline solution for 19 to 20 hours before freezing showed no significant changes in receptor density or affinity, and provided evidence for the stability of postmortem tissue obtained within the same time period. Beta receptor density of 2 cavernous preparations from transsexual procedures was not significantly different from normal control tissues, and showed that high concentrations of estrogen received by these patients had no effect on beta adrenergic receptor density. Displacement of /sup 125/iodocyanopindolol by 5 beta adrenergic agents demonstrated that 1-propranolol had the greatest affinity followed by ICI 118,551, zinterol, metoprolol and practolol. When the results of these displacement studies were subjected to Scatfit, non- linear regression line analysis, a single binding site was described. Based on the relative potency of the selective beta adrenergic agents it appears that these receptors were of the beta 2 subtype.

  17. β2-Adrenergic Receptor Knockout Mice Exhibit A Diabetic Retinopathy Phenotype

    Science.gov (United States)

    Jiang, Youde; Zhang, Qiuhua; Liu, Li; Tang, Jie; Kern, Timothy S.; Steinle, Jena J.

    2013-01-01

    There is considerable evidence from our lab and others for a functional link between β-adrenergic receptor and insulin receptor signaling pathways in retina. Furthermore, we hypothesize that this link may contribute to lesions similar to diabetic retinopathy in that the loss of adrenergic input observed in diabetic retinopathy may disrupt normal anti-apoptotic insulin signaling, leading to retinal cell death. Our studies included assessment of neural retina function (ERG), vascular degeneration, and Müller glial cells (which express only β1 and β2-adrenergic receptor subtypes). In the current study, we produced β2-adrenergic receptor knockout mice to examine this deletion on retinal neurons and vasculature, and to identify specific pathways through which β2-adrenergic receptor modulates insulin signaling. As predicted from our hypothesis, β2-adrenergic receptor knockout mice display certain features similar to diabetic retinopathy. In addition, loss of β2-adrenergic input resulted in an increase in TNFα, a key inhibitor of insulin receptor signaling. Increased TNFα may be associated with insulin-dependent production of the anti-apoptotic factor, Akt. Since the effects occurred in vivo under normal glucose conditions, we postulate that aspects of the diabetic retinopathy phenotype might be triggered by loss of β2-adrenergic receptor signaling. PMID:23894672

  18. Topical administration of adrenergic receptor pharmaceutics and nerve growth factor

    Directory of Open Access Journals (Sweden)

    Jena J Steinle

    2010-06-01

    Full Text Available Jena J SteinleDepartments of Ophthalmology and Anatomy and Neurobiology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USAAbstract: Topical application of nerve growth factor (NGF and adrenergic receptor pharmaceutics are currently in use for corneal ulcers and glaucoma. A recent interest in the neuroprotective abilities of NGF has led to a renewed interest in NGF as a therapeutic for retinal and choroidal diseases. NGF can promote cell proliferation through actions of the TrkA receptor or promote apoptosis through receptor p75NTR. This understanding has led to novel interest in the role of NGF for diseases of the posterior eye. The role of β-adrenergic receptor agonists and antagonists for treatments of glaucoma, diabetic retinopathy, and their potential mechanisms of action, are still under investigation. This review discusses the current knowledge and applications of topical NGF and adrenergic receptor drugs for ocular disease.Keywords: NGF, β-adrenergic receptor agents, α-adrenergic receptor agents, retina, cornea, glaucoma

  19. Alpha 2-adrenergic receptor turnover in adipose tissue and kidney: irreversible blockade of alpha 2-adrenergic receptors by benextramine

    International Nuclear Information System (INIS)

    Taouis, M.; Berlan, M.; Lafontan, M.

    1987-01-01

    The recovery of post- and extrasynaptic alpha 2-adrenergic receptor-binding sites was studied in vivo in male golden hamsters after treatment with an irreversible alpha-adrenoceptor antagonist benextramine, a tetramine disulfide that possesses a high affinity for alpha 2-binding sites. The kidney alpha 2-adrenergic receptor number was measured with [ 3 H]yohimbine, whereas [ 3 H]clonidine was used for fat cell and brain membrane alpha 2-binding site identification. Benextramine treatment of fat cell, kidney, and brain membranes reduced or completely suppressed, in an irreversible manner, [ 3 H] clonidine and [ 3 H]yohimbine binding without modifying adenosine (A1-receptor) and beta-adrenergic receptor sites. This irreversible binding was also found 1 and 2 hr after intraperitoneal administration of benextramine to the hamsters. Although it bound irreversibly to peripheral and central alpha 2-adrenergic receptors on isolated membranes, benextramine was unable to cross the blood-brain barrier of the hamster at the concentrations used (10-20 mg/kg). After the irreversible blockade, alpha 2-binding sites reappeared in kidney and adipose tissue following a monoexponential time course. Recovery of binding sites was more rapid in kidney than in adipose tissue; the half-lives of the receptor were 31 and 46 hr, respectively in the tissues. The rates of receptor production were 1.5 and 1.8 fmol/mg of protein/hr in kidney and adipose tissue. Reappearance of alpha 2-binding sites was associated with a rapid recovery of function (antilipolytic potencies of alpha 2-agonists) in fat cells inasmuch as occupancy of 15% of [ 3 H]clonidine-binding sites was sufficient to promote 40% inhibition of lipolysis. Benextramine is a useful tool to estimate turnover of alpha 2-adrenergic receptors under normal and pathological situations

  20. β1-adrenergic receptors activate two distinct signaling pathways in striatal neurons

    Science.gov (United States)

    Meitzen, John; Luoma, Jessie I.; Stern, Christopher M.; Mermelstein, Paul G.

    2010-01-01

    Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP Response Element Binding Protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. Norepinephrine-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which norepinephrine and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how norepinephrine and β1-adrenergic receptors may affect striatal physiology. PMID:21143600

  1. Central alpha2 adrenergic receptors in the rat cerebral cortex: repopulation kinetics and receptor reserve

    International Nuclear Information System (INIS)

    Adler, C.H.

    1986-01-01

    The alpha 2 adrenergic receptor subtype is thought to play a role in the mechanism of action of antidepressant and antihypertensive drugs. This thesis has attempted to shed light on the regulation of central alpha 2 adrenergic receptors in the rat cerebral cortex. Repopulation kinetics analysis allows for the determination of the rate of receptor production, rate constant of degradation, and half-life of the receptor. This analysis was carried out using both radioligand binding and functional receptor assays at various times following the irreversible inactivation of central alpha 2 adrenergic receptors by in vivo administration of N-ethoxycarbonyl-2-ethyoxy-1,2-dihydroquinoline (EEDQ). Both alpha 2 agonist and antagonist ligand binding sites recovered with a t/sub 1/2/ equal to approximately 4 days. The function of alpha 2 adrenergic autoreceptors, which inhibit stimulation-evoked release of 3 H-norepinephrine ( 3 H-NE) and alpha 2 adrenergic heteroreceptors which inhibit stimulation-evoked release of 3 H-serotonin ( 3 H-5-HT) were assayed. The t/sub 1/2/ for recovery of maximal autoreceptor and heteroreceptor function was 2.4 days and 4.6 days, respectively. The demonstration of a receptor reserve is critical to the interpretation of past and future studies of the alpha 2 adrenergic receptor since it demonstrates that: (1) alterations in the number of alpha 2 adrenergic receptor binding sites cannot be extrapolated to the actual function of the alpha 2 adrenergic receptor; and (2) alterations in the number of alpha 2 receptors is not necessarily accompanied by a change in the maximum function being studied, but may only result in shifting of the dose-response curve

  2. Adrenal medullary regulation of rat renal cortical adrenergic receptors

    International Nuclear Information System (INIS)

    Sundaresan, P.R.; Guarnaccia, M.M.; Izzo, J.L. Jr.

    1987-01-01

    The role of the adrenal medulla in the regulation of renal cortical adrenergic receptors was investigated in renal cortical particular fractions from control rats and rats 6 wk after adrenal demedullation. The specific binding of [ 3 H]prazosin, [ 3 H]rauwolscine, and [ 125 I]iodocyanopindolol were used to quantitate α 1 -, α 2 -, and β-adrenergic receptors, respectively. Adrenal demedullation increased the concentration of all three groups of renal adrenergic receptors; maximal number of binding sites (B max , per milligram membrane protein) for α 1 -, and α 2 -, and β-adrenergic receptors were increased by 22, 18.5, and 25%, respectively. No differences were found in the equilibrium dissociation constants (K D ) for any of the radioligands. Plasma corticosterone and plasma and renal norepinephrine levels were unchanged, whereas plasma epinephrine was decreased 72% by adrenal demedullation, renal cortical epinephrine was not detectable in control or demedullated animals. The results suggest that, in the physiological state, the adrenal medulla modulates the number of renal cortical adrenergic receptors, presumably through the actions of a circulating factor such as epinephrine

  3. Beta-adrenergic receptors of lymphocytes in children with allergic respiratory diseases

    International Nuclear Information System (INIS)

    Bittera, I.; Gyurkovits, K.; Falkay, G.; Eck, E.; Koltai, M.

    1988-01-01

    The beta-adrenergic receptor binding sites on peripheral lymphocytes in children with bronchial asthma (n = 16) and seasonal allergic rhinitis (n = 8) were examined in comparison with normal controls (n = 18) by means of 124 I-cyanopindolol. The number of beta-adrenergic receptors was significantly lower in the asthmatic group (858 +/- 460/lymphocyte) than in the controls (1564 +/- 983/lymphocyte). The value (1891 +/- 1502/lymphocyte in children with allergic rhinitis was slightly higher than that in healthy controls. Of the 24 patients suffering from allergic diseases of the lower or upper airways, the bronchial histamine provocation test was performed in 21; 16 gave positive results, while 5 were negative. No difference in beta-adrenergic receptor count was found between the histamine-positive and negative patients. Neither was there any correlation between the number of beta-adrenergic receptors and the high (16/24) and low (8/24) serum IgE concentrations found in allergic patients. The significant decrease in beta-adrenergic receptor count in asthmatic children lends support to Szentivanyi's concept. Further qualitative and quantitative analysis of lymphocyte beta-adrenergic receptors may provide an individual approach to the treatment of bronchial asthma with beta-sympathomimetic drugs

  4. α-2 adrenergic receptor: a radiohistochemical study

    International Nuclear Information System (INIS)

    Unnerstall, J.R.

    1984-01-01

    α-2 adrenergic agents have been shown to influence blood pressure, heart rate and other physiological and behavioral functions through interactions with adrenergic pathways within the central nervous system. Pharmacologically relevant α-1 adrenergic receptors were biochemically characterized and radiohistochemically analyzed in intact tissue sections of the rat and human central nervous system. The anatomical distribution of the α-2 receptors, labeled with the agonist [ 3 H]para-aminoclonidine, verified the concept that α-2 receptors are closely associated with adrenergic nerve terminals and that α-2 agents can influence autonomic and endocrine function through an action in the central nervous system. Since α-2 agonists can influence sympathetic outflow, α-2 binding sites were closely analyzed in the intermediolateral cell column of the thoracic spinal cord. The transport of putative presynaptic α-2 binding sites in the rat sciatic nerve was analyzed by light microscopic radiohistochemical techniques. Finally, in intact tissue section of the rat central nervous system, the biochemical characteristics of [ 3 H]rauwolscine binding were analyzed. Data were also shown which indicates that the synthetic α-2 antagonist [ 3 H]RX781094 also binds to α-2 receptors with high-affinity. Further, the distribution of [ 3 H]RX781094 binding sites in the rat central nervous system was identical to the distribution seen when using [ 3 H]para-aminoclonidine

  5. The role of adrenergic receptors in nicotine-induced hyperglycemia ...

    African Journals Online (AJOL)

    The role of adrenergic receptors in nicotine-induced hyperglycaemia has not been well studied in amphibians. Thus, this study investigates the effects of alpha and beta adrenergic receptor blockers in nicotine-induced hyperglycaemia in the common African toad Bufo regularis. Toads fasted for 24 h were anaesthetized with ...

  6. Anxiety and beta-adrenergic receptor function in a normal population.

    Science.gov (United States)

    Kang, Eun-Ho; Yu, Bum-Hee

    2005-06-01

    Many studies have shown a close relationship between anxiety and beta-adrenergic receptor function in patients with anxiety disorders. This study examined the relationship between beta-adrenergic receptor function and anxiety levels in a normal population. Subjects for this study included 36 men and 44 women between the ages of 20 and 40 years whose Body Mass Index (BMI) was between 18 and 26. All of them were healthy subjects who had no previous history of medical or psychiatric illnesses. The authors measured the Spielberger State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), and Chronotropic 25 Dose (CD25) of isoproterenol, previously developed to assess in vivo beta-adrenergic receptor sensitivity. We also examined correlations between log normalized CD25 and mood states. The mean of CD25 was 2.64+/-1.37 mug and the mean of CD25 in men was significantly higher (i.e., lower beta-adrenergic receptor sensitivity) than that of women (3.26+/-1.35 vs. 2.14+/-1.17 microg; t = 3.99, p anxiety (r = -0.344, p = 0.002), trait anxiety (r = -0.331, p = 0.003), and BDI (r = -0.283, p = 0.011). CD25 was positively correlated with BMI (r = 0.423, p anxiety, and BMI. The sensitivity of beta-adrenergic receptors increased as anxiety levels became higher in a normal population. Thus, the relationship between anxiety and beta-adrenergic receptor function in healthy subjects may be different from that of patients with anxiety disorders.

  7. Postsynaptic alpha-adrenergic receptors potentiate the beta-adrenergic stimulation of pineal serotonin N-acetyltransferase.

    OpenAIRE

    Klein, D C; Sugden, D; Weller, J L

    1983-01-01

    The role played by postsynaptic alpha-adrenergic receptors in the stimulation of pineal N-acetyltransferase (EC 2.3.1.5) and [3H]melatonin production was investigated in the rat. In vivo studies indicated that phenylephrine, an alpha-adrenergic agonist, potentiated and prolonged the effects of isoproterenol, a beta-adrenergic agonist. Similar observations were made in organ culture with glands devoid of functional nerve endings. In addition, a combination of 1 microM prazosin, an alpha 1-adre...

  8. Cloning and expression of a human kidney cDNA for an α2-adrenergic receptor subtype

    International Nuclear Information System (INIS)

    Regan, J.W.; Kobilka, T.S.; Yang-Feng, T.L.; Caron, M.G.; Lefkowitz, R.J.; Kobilka, B.K.

    1988-01-01

    An α 2 -adrenergic receptor subtype has been cloned from a human kidney cDNA library using the gene for the human platelet α 2 -adrenergic receptor as a probe. The deduced amino acid sequence resembles the human platelet α 2 -adrenergic receptor and is consistent with the structure of other members of he family of guanine nucleotide-binding protein-coupled receptors. The cDNA was expressed in a mammalian cell line (COS-7), and the α 2 -adrenergic ligand [ 3 H]rauwolscine was bound. Competition curve analysis with a variety of adrenergic ligands suggests that this cDNA clone represents the α 2 B-adrenergic receptor. The gene for this receptor is on human chromosome 4, whereas the gene for the human platelet α 2 -adrenergic receptor (α 2 A) lies on chromosome 10. This ability to express the receptor in mammalian cells, free of other adrenergic receptor subtypes, should help in developing more selective α-adrenergic ligands

  9. Peripheral adrenergic receptors in hypertension

    NARCIS (Netherlands)

    Michel, M. C.; Brodde, O. E.; Insel, P. A.

    1990-01-01

    Increased sympathoadrenal activity appears to play an important role in the development or maintenance of elevated blood pressure in hypertensive patients and various animal models of hypertension. Alterations of adrenergic receptor number or responsiveness might contribute to this increased

  10. Synthesis of fluorine-18 fluoroalkyl pindolol derivatives: Ligands for the β-adrenergic receptor

    International Nuclear Information System (INIS)

    Tewson, T.J.; Kinsey, B.M.; Franceschini, M.P.

    1990-01-01

    [I-125]Iodocyanopindolol, an antagonist for the β-adrenergic receptor, has been shown to accumulate in vivo in areas rich in β-adrenergic receptors, presumably through saturable receptor mediated binding. In order to perform PET studies of the β-adrenergic receptor in the heart and lung the authors have prepared fluoroalkyl analogs of iodocyanopindolol and are evaluating these compounds for this purpose

  11. beta-Adrenergic and cholinergic receptors in hypertension-induced hypertrophy

    International Nuclear Information System (INIS)

    Vatner, D.E.; Kirby, D.A.; Homcy, C.J.; Vatner, S.F.

    1985-01-01

    Perinephritic hypertension was produced in dogs by wrapping one kidney with silk and removing the contralateral kidney 1 week later. Mean arterial pressure rose from 104 +/- 3 to 156 +/- 11 mm Hg, while left ventricular free wall weight, normalized for body weight, was increased by 49%. Muscarinic, cholinergic receptor density measured with [ 3 H]-quinuclidinyl benzilate, fell in hypertensive left ventricles (181 +/- 19 fmol/mg, n = 6; p less than 0.01) as compared with that found in normal left ventricles (272 +/- 16 fmol/mg, n = 8), while receptor affinity was not changed. The beta-adrenergic receptor density, measured by binding studies with [ 3 H]-dihydroalprenolol, rose in the hypertensive left ventricles (108 +/- 10 fmol/mg, n = 7; p less than 0.01) as compared with that found in normal left ventricles (68.6 +/- 5.2 fmol/mg, n = 15), while beta-adrenergic receptor affinity decreased in the hypertensive left ventricles (10.4 +/- 1.2 nM) compared with that found in the normal left ventricles (5.0 +/- 0.7 nM). Plasma norepinephrine levels were similar in the two groups, but myocardial norepinephrine levels were depressed (p less than 0.05) in dogs with hypertension. Moderate left ventricular hypertrophy induced by long-term aortic banding in dogs resulted in elevations in beta-adrenergic receptor density (115 +/- 14 fmol/mg) and decreases in affinity (10.4 +/- 2.2 nM) similar to those observed in the dogs with left ventricular hypertrophy induced by hypertension. Thus, these results suggest that perinephritic hypertension in the dog induces divergent effects on cholinergic and beta-adrenergic receptor density. The increased beta-adrenergic receptor density and decreased affinity may be a characteristic of left ventricular hypertrophy rather than hypertension

  12. Characterization of α2-adrenergic receptors in rat cerebral cortex

    International Nuclear Information System (INIS)

    Nasseri, A.

    1987-01-01

    The properties of 3 H-RX 781094 binding sites and the receptors inhibiting norepinephrine (NE) release and cyclic AMP accumulation in rat cerebral cortex were compared. 3 H-RX 781094, a new α 2 -adrenergic receptor antagonist radioligand, labelled a homogeneous population of binding sites at 37 0 C with the pharmacological specificity expected of α 2 -adrenergic receptors. Gpp(NH)p and NaCl decreased the potencies of agonists at 3 H-RX 781094 binding sites 3-22 fold. Antagonists blocked the inhibition of potassium-evoked tritium release from cortical slices preloaded with 3 H-NE by exogenous NE with potencies similar to those observed in competition for specific 3 H-RX 781094 binding sites. EEDQ, an irreversible α 2 -adrenergic receptors and determine whether there was a receptor reserve for the inhibition of tritium release

  13. Cloning and expression of a rat brain α2B-adrenergic receptor

    International Nuclear Information System (INIS)

    Flordellis, C.S.; Handy, D.E.; Bresnahan, M.R.; Zannis, V.I.; Gavras, H.

    1991-01-01

    The authors isolated a cDNA clone (RBα 2B ) and its homologous gene (GRα 2B ) encoding an α 2B -adrenergic receptor subtype by screening a rat brain cDNA and a rat genomic library. Nucleotide sequence analysis showed that both clones code for a protein of 458 amino acids, which is 87% homologous to the human kidney glycosylated adrenergic receptor (α 2 -C4) and divergent from the rat kidney nonglycosylated α 2B subtype (RNGα 2 ). Transient expression of RBα 2B in COS-7 cells resulted in high-affinity saturable binding for [ 3 H]rauwolscine and a high receptor number in the membranes of transfected COS-7 cells. Pharmacological analysis demonstrated that the expressed receptor bound adrenergic ligands with the following order of potency: rauwolscine > yohimbine > prazosin > oxymetazoline, with a prazosin-to-oxymetazoline K i ratio of 0.34. This profile is characteristic of the α 2B -adrenergic receptor subtype. Blotting analysis of rat brain mRNA gave one major and two minor mRNA species, and hybridization with strand-specific probes showed that both DNA strands of GRα 2B may be transcriptionally active. These findings show that rat brain expresses an α 2B -adrenergic receptor subtype that is structurally different from the rat kidney nonglycosylated α 2B subtype. Thus the rat expresses at least two divergent α 2B -adrenergic receptors

  14. ''Spare'' alpha 1-adrenergic receptors and the potency of agonists in rat vas deferens

    International Nuclear Information System (INIS)

    Minneman, K.P.; Abel, P.W.

    1984-01-01

    The existence of ''spare'' alpha 1-adrenergic receptors in rat vas deferens was examined directly using radioligand binding assays and contractility measurements. Alpha 1-adrenergic receptors in homogenates of rat vas deferens were labeled with [ 125 I]BE 2254 ( 125 IBE). Norepinephrine and other full alpha 1-adrenergic receptor agonists were much less potent in inhibiting 125 IBE binding than in contracting the vas deferens in vitro. Treatment with 300 nM phenoxybenzamine for 10 min to irreversibly inactivate alpha 1-adrenergic receptors caused a large decrease in the potency of full agonists in causing contraction of this tissue and a 23-48% decrease in the maximal contraction observed. Using those data, equilibrium constants for activation (Kact values) of the receptors by agonists were calculated. These Kact values agreed well with the equilibrium binding constants (KD values) determined from displacement of 125 IBE binding. The reduction in alpha 1-adrenergic receptor density following phenoxybenzamine treatment was determined by Scatchard analysis of specific 125 IBE binding sites and compared with the expected reduction (q values) calculated from the agonist dose-response curves before and after phenoxybenzamine treatment. This suggests that phenoxybenzamine functionally inactivates alpha 1-adrenergic receptors at or near the receptor binding site. These experiments suggest that the potencies of agonists in activating alpha 1-adrenergic receptors in rat vas deferens agree well with their potencies in binding to the receptors. The greater potency of agonists in causing contraction may be due to spare receptors in this tissue. The data also demonstrate that phenoxybenzamine irreversibly inactivates alpha 1-adrenergic receptors in rat vas deferens, but that the decrease in receptor density is much smaller than that predicted from receptor theory

  15. Prostaglandin (PG) E3 synthesis elicted by adrenergic stimuli in guinea-pig trachea (GPT) is mediated primarily by B2 adrenergic receptors

    International Nuclear Information System (INIS)

    Nadel, G.L.; Malik, K.U.; Lew, D.B.

    1990-01-01

    The purpose of this study was to examine arachidonic acid (AA) metabolism and to characterize the type of adrenergic receptor (AR) involved in the production of the major metabolite of this fatty acid. [ 14 C]AA was incubated with GPT-rings and the radiolabelled products were extracted and separated by TLC method. The medium was also assayed for radiolabelled immunoreactive PG's (iPG's) and leukotrienes (LT) B4 and C4 by RIA or Enzyme immunoassay (EIA) after exposure to various AR agonists. [ 14 C]AA was incorporated into GPT-rings and metabolized mainly into iPGE2 and smaller amounts into PGF2α. Trace amounts of PGD2 and 6-keto-PGF1α but not LTB4 or LTC4 were detected by RIA and/or EIA. Incubation of GPT rings for 15 minutes with isoproterenol and salbutamol resulted in a significant increase of PGE2 synthesis (optimum conc: 10 -7 , 10 -7 M respectively). In contrast, dobutamine, norepinephrine, phenylnephrine and xylazine (up to 10 -6 M) did not significantly increase PGE2 production. Isoproterenol-induced iPGE2 production was inhibited by a selective β2 antagonist, butoxamine (70%: 10 -7 M, 91%: 10 -6 M) and somewhat reduced by β1 antagonists practolol and metoprolol (30-64%:10 -6 M). These data suggest that isoproterenol induced iPGE2 synthesis is primarily mediated via activation of β2 adrenergic receptor

  16. Mood states, sympathetic activity, and in vivo beta-adrenergic receptor function in a normal population.

    Science.gov (United States)

    Yu, Bum-Hee; Kang, Eun-Ho; Ziegler, Michael G; Mills, Paul J; Dimsdale, Joel E

    2008-01-01

    The purpose of this study was to examine the relationship between mood states and beta-adrenergic receptor function in a normal population. We also examined if sympathetic nervous system activity is related to mood states or beta-adrenergic receptor function. Sixty-two participants aged 25-50 years were enrolled in this study. Mood states were assessed using the Profile of Mood States (POMS). Beta-adrenergic receptor function was determined using the chronotropic 25 dose isoproterenol infusion test. Level of sympathetic nervous system activity was estimated from 24-hr urine norepinephrine excretion. Higher tension-anxiety, depression-dejection, and anger-hostility were related to decreased beta-adrenergic receptor sensitivity (i.e., higher chronotropic 25 dose values), but tension-anxiety was the only remaining independent predictor of beta-adrenergic receptor function after controlling for age, gender, ethnicity, and body mass index (BMI). Urinary norepinephrine excretion was unrelated to either mood states or beta-adrenergic receptor function. These findings replicate previous reports that anxiety is related to decreased (i.e., desensitized) beta-adrenergic receptor sensitivity, even after controlling for age, gender, ethnicity, and body mass index.

  17. β-adrenergic receptor responsiveness in aging heart and clinical implications

    Science.gov (United States)

    Ferrara, Nicola; Komici, Klara; Corbi, Graziamaria; Pagano, Gennaro; Furgi, Giuseppe; Rengo, Carlo; Femminella, Grazia D.; Leosco, Dario; Bonaduce, Domenico

    2014-01-01

    Elderly healthy individuals have a reduced exercise tolerance and a decreased left ventricle inotropic reserve related to increased vascular afterload, arterial-ventricular load mismatching, physical deconditioning and impaired autonomic regulation (the so called “β-adrenergic desensitization”). Adrenergic responsiveness is altered with aging and the age-related changes are limited to the β-adrenergic receptor density reduction and to the β-adrenoceptor-G-protein(s)-adenylyl cyclase system abnormalities, while the type and level of abnormalities change with species and tissues. Epidemiological studies have shown an high incidence and prevalence of heart failure in the elderly and a great body of evidence correlate the changes of β-adrenergic system with heart failure pathogenesis. In particular it is well known that: (a) levels of cathecolamines are directly correlated with mortality and functional status in heart failure, (b) β1-adrenergic receptor subtype is down-regulated in heart failure, (c) heart failure-dependent cardiac adrenergic responsiveness reduction is related to changes in G proteins activity. In this review we focus on the cardiovascular β-adrenergic changes involvement in the aging process and on similarities and differences between aging heart and heart failure. PMID:24409150

  18. β-adrenergic receptor binding characteristics and responsiveness in cultured Wistar-Kyoto rat arterial smooth muscle cells

    International Nuclear Information System (INIS)

    Jazayeri, A.; Meyer, W.J. III

    1988-01-01

    The tone of arterial blood vessels is regulated by the catecholamines through their receptors on arterial smooth muscle cells (ASMC). β- 2 -adrenergic receptors of ASMC mediate vasodilation through agonist mediated c-AMP production. Previous reports have described these receptors on freshly isolated blood vessels. This study demonstrates the presence of β 2 -adrenergic receptors on cultured rat ASMC and that these receptors are functional. β-adrenergic receptor binding was measured using [ 3 H]-dihydroalprenolol (DHA) binding to the membrane of cultured ASMC from normotensive Wistar-Kyoto rats. The ASMC β-adrenergic receptors have a Kd of 0.56 +/- 0.16 nM and a Bmax of 57.2 +/- 21.7 fmol/mg protein. Competition binding studies revealed a much greater affinity of these receptors for epinephrine than norepinephrine, indicating the preponderance of a β 2 -adrenergic receptor subtype. Isoproterenol stimulation of cultured ASMC resulted in a 14 +/- 7 fold increase in intracellular c-AMP content of these cells indicating these receptors are functional. β-adrenergic receptors of cultured ASMC provide an excellent system in which the association between hypertension and observed β-adrenergic receptor differences can be further explored

  19. Molecular characterization of a rat α2B-adrenergic receptor

    International Nuclear Information System (INIS)

    Zeng, D.; Harrison, J.K.; D'Angelo, D.D.; Barber, C.M.; Tucker, A.L.; Lu, Z.; Lynch, K.R.

    1990-01-01

    α 2 -Adrenergic receptors comprise a heterogeneous population based on pharmacologic and molecular evidence. The authors have isolated a cDNA clone (pRNGα 2 ) encoding a rat α 2 -adrenergic receptor. A rat kidney cDNA library was screened with an oligonucleotide complementary to a highly conserved region found in all biogenic amine receptors described to date. The deduced amino acid sequence displays many features of guanyl nucleotide-binding protein-coupled receptors except it does not have a consensus N-linked glycosylation site near the amino terminus. Membranes prepared from COS cells transfected with pRNGα 2 DNA display high affinity an saturable binding to [ 3 H]rauwolscine. Competition curve data analysis shows that RNGα 2 protein binds to a variety of adrenergic drugs with the following rank order of potency: yohimbine ≥ chlorpromazine > prazosin ≥ clonidine > norepinephrine ≥ oxymetazoline. RNGα 2 RNA accumulates in both rat kidney and neonatal rat lung. When a cysteine residue (Cys-169) that is conserved among all members of the seven-transmembrane-region superfamily is changed to phenylalanine, the RNGα 2 protein fails to bind [ 3 H]rauwolscine after expression in COS cells. They conclude that pRNGα 2 likely represents a cDNA for a rat α 2B -adrenergic receptor

  20. Characterization of beta-adrenergic receptors through the replicative life span of IMR-90 cells

    International Nuclear Information System (INIS)

    Scarpace, P.J.

    1987-01-01

    Beta-adrenergic receptor number and receptor affinity for isoproterenol were assessed at various in vitro ages of the human diploid fibroblast cell line IMR-90. From population doubling level (PDL) 33 to 44, there was a positive correlation between beta-adrenergic receptor density and PDL. Beta-adrenergic receptors, assessed by Scatchard analysis of [ 125 I]-iodocyanopindolol (ICYP) binding, increased from 15 fmol/mg protein at PDL 33 to 36 fmol/mg protein at PDL 44. In contrast, from PDL 44 to 59, there was a negative correlation between beta-adrenergic receptor density and PDL. Receptor density declined to 12 fmol/mg protein at PDL 59. When the density of beta-adrenergic receptors was expressed as receptor per cell, the findings were similar. Receptor agonist affinity for isoproterenol was determined from Hill plots of [ 125 I]-ICYP competition with isoproterenol. There was no change in the dissociation constant for isoproterenol with in vitro age. In humans, serum norepinephrine concentrations increase with age. This increase in serum norepinephrine may be partially responsible for the decreased beta-adrenergic receptor-agonist affinity observed with age in human lymphocytes and rat heart and lung. The present findings are consistent with the hypothesis that the decreases in receptor agonist affinity in rat and man with age are secondary to increases in catecholamine concentrations

  1. Beta 2-adrenergic receptors are colocalized and coregulated with whisker barrels in rat somatosensory cortex

    International Nuclear Information System (INIS)

    Vos, P.; Kaufmann, D.; Hand, P.J.; Wolfe, B.B.

    1990-01-01

    Autoradiography has been used to visualize independently the subtypes of beta-adrenergic receptors in rat somatosensory cortex. Beta 2-adrenergic receptors, but not beta 1-adrenergic receptors colocalize with whisker barrels in this tissue. Thus, each whisker sends a specific multisynaptic pathway to the somatosensory cortex that can be histochemically visualized and only one subtype of beta-adrenergic receptor is specifically associated with this cortical representation. Additionally, neonatal lesion of any or all of the whisker follicles results in loss of the corresponding barrel(s) as shown by histochemical markers. This loss is paralleled by a similar loss in the organization of beta 2-adrenergic receptors in the somatosensory cortex. Other results indicate that these beta 2-adrenergic receptors are not involved in moment-to-moment signal transmission in this pathway and, additionally, are not involved in a gross way in the development of whisker-barrel array

  2. Age-dependent changes in expression of alpha1-adrenergic receptors in rat myocardium

    International Nuclear Information System (INIS)

    Schaffer, W.; Williams, R.S.

    1986-01-01

    The expression of alpha 1 -adrenergic receptors within ventricular myocardium of rats ranging in age from 21 days of fetal life to 24 months after birth was measured from [ 125 I] 2-(β hydroxy phenyl) ethylaminomethyl tetralone binding isotherms. No difference was observed in binding affinity between any of the age groups studied. The number of alpha 1 -adrenergic receptors was found to be 60-120% higher in membranes from fetal or immature rats up to 25 days of age when compared with adult animals. The increased expression of alpha 1 -adrenergic receptors in the developing heart relative to that observed in adult heart is consistent with the hypothesis that alpha 1 -adrenergic receptor stimulation may modulate protein synthesis and growth in mammalian myocardium

  3. Monovalent cation and amiloride analog modulation of adrenergic ligand binding to the unglycosylated alpha 2B-adrenergic receptor subtype

    International Nuclear Information System (INIS)

    Wilson, A.L.; Seibert, K.; Brandon, S.; Cragoe, E.J. Jr.; Limbird, L.E.

    1991-01-01

    The unglycosylated alpha 2B subtype of the alpha 2-adrenergic receptor found in NG-108-15 cells possesses allosteric regulation of adrenergic ligand binding by monovalent cations and 5-amino-substituted amiloride analogs. These findings demonstrate that allosteric modulation of adrenergic ligand binding is not a property unique to the alpha 2A subtype. The observation that amiloride analogs as well as monovalent cations can modulate adrenergic ligand binding to the nonglycosylated alpha 2B subtype indicates that charge shielding due to carbohydrate moieties does not play a role in this allosteric modulation but, rather, these regulatory effects result from interactions of cations and amiloride analogs with the protein moiety of the receptor. Furthermore, the observation that both alpha 2A and alpha 2B receptor subtypes are modulated by amiloride analogs suggests that structural domains that are conserved between the two are likely to be involved in this allosteric modulation

  4. Pet measurements of postsynaptic muscarinic and beta adrenergic receptors in the heart

    International Nuclear Information System (INIS)

    Syrota, A.

    1991-01-01

    There is ample evidence from both experimental and clinical studies that changes in β-adrenergic and muscarinic receptor density can be associated with such cardiac diseases as congestive heart failure, myocardial ischemia and infarction, cardiomyopathy, diabetes, or thyroid-induced muscle disease. Changes in B-adrenergic density also have been shown in the denervated transplanted heart. These alterations of cardiac receptors have been demonstrated in vitro on homogenates from samples collected mainly during surgery or post mortem. Recent developments of Positron Emission Tomography (PET) techniques and of radioligands suitable for cardiac receptor binding studies in vivo have made possible both the imaging and the measurement of receptor density. From these studies, important information is now available concerning physiologic and pathologic conditions, as well as alterations induced by treatment. For the investigation of myocardial B-adrenergic receptors we have used [ 11 C] CGP 12177, a potent hydrophilic antagonist of the 3-adrenergic receptor. The quantification of myocardial muscarinic receptors in vivo has been obtained with [ 11 C] MQNB, a nonmetabolized hydrophilic antagonist of the muscarinic receptor. Receptor density and affinity have been measured by a kinetic, nonequilibrium approach in an experimental protocol that provides sufficient data to determine values for all parameters from a single experiment

  5. [H-3]dihydroalprenolol binding to beta adrenergic receptors in multiple sclerosis brain

    NARCIS (Netherlands)

    Zeinstra, E; Wilczak, N; De Keyser, J

    2000-01-01

    By using immunocytochemistry we previously reported the absence of beta(2) adrenergic receptors on astrocytes in multiple sclerosis (MS) white matter. Here, we measured beta(1) and beta(2) adrenergic receptor concentrations in postmortem brain sections of six MS patients and six controls by using

  6. On the role of renal alpha-adrenergic receptors in spontaneously hypertensive rats

    NARCIS (Netherlands)

    Michel, M. C.; Jäger, S.; Casto, R.; Rettig, R.; Graf, C.; Printz, M.; Insel, P. A.; Philipp, T.; Brodde, O. E.

    1992-01-01

    We tested the hypothesis that a genetically determined increase in renal alpha-adrenergic receptor density might be a pathophysiologically important factor in the spontaneously hypertensive rat model of genetic hypertension. In a first study, we compared renal alpha 1 and alpha 2-adrenergic receptor

  7. Prostaglandin (PG) E3 synthesis elicted by adrenergic stimuli in guinea-pig trachea (GPT) is mediated primarily by B2 adrenergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Nadel, G.L.; Malik, K.U.; Lew, D.B. (Univ. of Tennessee, Memphis (United States))

    1990-02-26

    The purpose of this study was to examine arachidonic acid (AA) metabolism and to characterize the type of adrenergic receptor (AR) involved in the production of the major metabolite of this fatty acid. ({sup 14}C)AA was incubated with GPT-rings and the radiolabelled products were extracted and separated by TLC method. The medium was also assayed for radiolabelled immunoreactive PG's (iPG's) and leukotrienes (LT) B4 and C4 by RIA or Enzyme immunoassay (EIA) after exposure to various AR agonists. ({sup 14}C)AA was incorporated into GPT-rings and metabolized mainly into iPGE2 and smaller amounts into PGF2{alpha}. Trace amounts of PGD2 and 6-keto-PGF1{alpha} but not LTB4 or LTC4 were detected by RIA and/or EIA. Incubation of GPT rings for 15 minutes with isoproterenol and salbutamol resulted in a significant increase of PGE2 synthesis (optimum conc: 10{sup {minus}7}, 10{sup {minus}7}M respectively). In contrast, dobutamine, norepinephrine, phenylnephrine and xylazine (up to 10{sup {minus}6}M) did not significantly increase PGE2 production. Isoproterenol-induced iPGE2 production was inhibited by a selective {beta}2 antagonist, butoxamine (70%: 10{sup {minus}7}M, 91%: 10{sup {minus}6}M) and somewhat reduced by {beta}1 antagonists practolol and metoprolol (30-64%:10{sup {minus}6}M). These data suggest that isoproterenol induced iPGE2 synthesis is primarily mediated via activation of {beta}2 adrenergic receptor.

  8. The Role of Beta-Adrenergic Receptors in the Regulation of Circadian Intraocular Pressure Rhythm in Mice.

    Science.gov (United States)

    Tsuchiya, Shunsuke; Higashide, Tomomi; Toida, Kazunori; Sugiyama, Kazuhisa

    2017-07-01

    To investigate whether the elimination of β1- and β2-adrenergic receptors alters the diurnal intraocular pressure (IOP) rhythm in mice. β1-/β2-adrenergic receptor double-knockout and C57BL/6J mice were anesthetized intraperitoneally, with their IOPs measured via microneedle method. After entrainment to a 12-h light-dark (LD) cycle (light phase 6:00-18:00), IOPs were measured every 3 h from 9:00 to 24:00 (group 1, β1-/β2-adrenergic receptor double-knockout mice, n = 11; C57BL/6J, n = 15). The IOP measurements at 15:00 and 24:00 under a 12-h LD cycle and in the constant darkness (1 day and 8 days after exposure to darkness, respectively) were performed in another group of β1-/β2-adrenergic receptor double-knockout mice (group 2, n = 12). IOP variance throughout the day and mean IOP differences among time points were evaluated using a linear mixed model. β1-/β2-adrenergic receptor double-knockout and C57BL/6J mice showed biphasic IOP curves, low during the light phase and high during the dark phase; the fluctuation was significant (P adrenergic receptor double-knockout mice group. IOP curves of β1-/β2-adrenergic receptor double-knockout and C57BL/6J were nearly parallel, and the IOPs of β1-/β2-adrenergic receptor double-knockout mice were significantly higher than those of C57BL/6J mice (P adrenergic receptors did not disturb the biphasic diurnal IOP rhythm in mice.

  9. Competitive receptor binding radioassay for β-1 and β-2 adrenergic agents

    International Nuclear Information System (INIS)

    Hussain, M.N.; Culbreth, W.; Dalrymple, R.; Fung, C.; Ricks, C.

    1987-01-01

    A rapid and sensitive competitive receptor bonding assay for β-1 and β-2 adrenergic binding for adrenergic agents has been developed. The steps that are critical for the success of the assay are given in detail so that the assay can be set up in any routine laboratory with relative ease. The rationale behind the use of specific reagents is discussed. The assay requires microgram quantities of test compound, a radiolabeled specific β adrenergic antagonist [ 3 H]dihydroalprenolol (DHA), and turkey erythrocyte β-1 and rat erythrocyte β-2 receptor membranes. Serial dilutions of sample are incubated with appropriate receptor membranes and DHA for 1 hr at room temperature. After equilibrium is attained, the bound radioligand is separated by rapid filtration under vacuum through Whatman GF/B filters. The amount of bound DHA trapped on the filter is inversely proportional to the degree of β-1 and β-2 adrenergic binding of the sample. Separation of bound from free radioligand by filtration permits rapid determination of a large number of samples. This assay quantitates and differentiates β-1 and β-2 adrenergic binding of synthetic adrenergic agents

  10. Effect of age on upregulation of the cardiac adrenergic beta receptors

    International Nuclear Information System (INIS)

    Tumer, N.; Houck, W.T.; Roberts, J.

    1990-01-01

    Radioligand binding studies were performed to determine whether upregulation of postjunctional beta receptors occurs in sympathectomized hearts of aged animals. Fischer 344 rats 6, 12, and 24 months of age (n = 10) were used in these experiments. To produce sympathectomy, rats were injected with 6-hydroxydopamine hydrobromide (6-OHDA; 2 x 50 mg/kg iv) on days 1 and 8; the animals were decapitated on day 15. The depletion of norepinephrine in the heart was about 86% in each age group. 125I-Iodopindolol (IPIN), a beta adrenergic receptor antagonist, was employed to determine the affinity and total number of beta adrenergic receptors in the ventricles of the rat heart. The maximal number of binding sites (Bmax) was significantly elevated by 37%, 48%, and 50% in hearts from sympathectomized 6-, 12-, and 24-month-old rats, respectively. These results indicate that beta receptor mechanisms in older hearts can respond to procedures that cause upregulation of the beta adrenergic receptors

  11. Mammalian β1- and β2-adrenergic receptors: immunological and structural comparison

    International Nuclear Information System (INIS)

    Moxham, C.P.; George, S.T.; Graziano, M.P.; Brandwein, H.J.; Malbon, C.C.

    1986-01-01

    β 1 - and β 2 -adrenergic receptors, pharmacologically distinct proteins, have been reported to be structurally dissimilar. In the present study three techniques were employed to compare the nature of mammalian β 1 - and β 2 -adrenergic receptors. Antibodies against each of the receptor subtypes were raised separately. Polyclonal antisera against β 1 -receptors of rat fat cells were raised in mice, and antisera against β 2 -receptors of guinea pig lung were raised in rabbits. Receptors purified from rat fat cells (β 1 -), S49 mouse lymphoma cells (β 2 -), and rat liver (β 2 -) were probed with these antisera. Each anti-receptor antisera demonstrated the ability to immunoprecipitate purified receptors of both β 1 - and β 2 -subtypes. The mobility of β-receptors subjected to polyacrylamide gel electrophoresis was probed using antireceptor antibodies and nitrocellulose blots of the gels. Fat cell β 1 -adrenergic receptors display M/sub r/ = 67,000 under reducing conditions and M/sub r/ = 54,000 under nonreducing conditions, as previously reported. Both β 1 - and β 2 -receptors displayed this same shift in electrophoretic mobility observed in the presence as compared to the absence of disulfide bridge-reducing agents, as detected both by autoradiography of the radiolabeled receptors and by immunoblotting of native receptors. Finally, isoelectric focusing of purified radioiodinated β 1 - and β 2 -adrenergic receptors revealed identical isoelectric points. These data are the first to provide analyses of immunological, structural, and biochemical features of β 1 - and β 2 -subtypes in tandem and underscore the structural similarities that exist between these pharmacologically distinct receptors

  12. Alpha-adrenergic receptors in rat skeletal muscle

    DEFF Research Database (Denmark)

    Rattigan, S; Appleby, G J; Edwards, S J

    1986-01-01

    Sarcolemma-enriched preparations from muscles rich in slow oxidative red fibres contained specific binding sites for the alpha 1 antagonist, prazosin (e.g. soleus Kd 0.13 nM, Bmax 29 fmol/mg protein). Binding sites for prazosin were almost absent from white muscle. Displacement of prazosin bindin...... adrenergic receptors are present on the sarcolemma of slow oxidative red fibres of rat skeletal muscle. The presence provides the mechanistic basis for apparent alpha-adrenergic effects to increase glucose and oxygen uptake in perfused rat hindquarter....

  13. β adrenergic receptor modulation of neurotransmission to cardiac vagal neurons in the nucleus ambiguus.

    Science.gov (United States)

    Bateman, R J; Boychuk, C R; Philbin, K E; Mendelowitz, D

    2012-05-17

    β-adrenergic receptors are a class of G protein-coupled receptors that have essential roles in regulating heart rate, blood pressure, and other cardiorespiratory functions. Although the role of β adrenergic receptors in the peripheral nervous system is well characterized, very little is known about their role in the central nervous system despite being localized in many brain regions involved in autonomic activity and regulation. Since parasympathetic activity to the heart is dominated by cardiac vagal neurons (CVNs) originating in the nucleus ambiguus (NA), β adrenergic receptors localized in the NA represent a potential target for modulating cardiac vagal activity and heart rate. This study tests the hypothesis that activation of β adrenergic receptors alters the membrane properties and synaptic neurotransmission to CVNs. CVNs were identified in brainstem slices, and membrane properties and synaptic events were recorded using the whole-cell voltage-clamp technique. The nonselective β agonist isoproterenol significantly decreased inhibitory GABAergic and glycinergic as well as excitatory glutamatergic neurotransmission to CVNs. In addition, the β(1)-selective receptor agonist dobutamine, but not β(2) or β(3) receptor agonists, significantly decreased inhibitory GABAergic and glycinergic and excitatory glutamatergic neurotransmission to CVNs. These decreases in neurotransmission to CVNs persisted in the presence of tetrodotoxin (TTX). These results provide a mechanism by which activation of adrenergic receptors in the brainstem can alter parasympathetic activity to the heart. Likely physiological roles for this adrenergic receptor activation are coordination of parasympathetic-sympathetic activity and β receptor-mediated increases in heart rate upon arousal. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. Ischemia- and agonist-induced changes in α- and β-adrenergic receptor traffic in guinea pig hearts

    International Nuclear Information System (INIS)

    Maisel, A.S.; Motulsky, H.J.; Ziegler, M.G.; Insel, P.A.

    1987-01-01

    The authors have used radioligand binding techniques and subcellular fraction to assess whether changes in expression of myocardial α 1 - and β-adrenergic receptors are mediated by a redistribution of receptors between various membrane fractions. Three fractions were prepared from the left ventricles of guinea pigs that underwent either 1 h of ischemia or injection of epinephrine a crude membrane, a purified sarcolemma, and a light vesicle fraction. In control animals α 1 -adrenergic receptors ([ 3 H]prazosin binding) in light vesicles was only 25% of the total α 1 -receptor density found in sarcolemmal and light vesicle fractions as compared with 50% for β-adrenergic receptors ([ 125 I]iodocyanopindolol binding sites). Although ischemia was associated with a 53% decrease in the number of light vesicle β-adrenergic receptors and a 42% increase in the number of sarcolemma β-receptors there was no change in the number of light vesicle α 1 -receptors, even though the number of sarcolemmal α 1 -receptors increased 34%. Epinephrine treatment promoted internalization of β-adrenergic receptors. These results indicate that α 1 and β 1 -adrenergic receptors may undergo a different cellular itinerary in guinea pig myocardium. Agonist and ischemia-induced changes in surface β-receptors, but not α 1 -receptors, appear to result from entry and exit of receptors from an intracellular pool that can be isolated in a light vesicle fraction. Changes in expression of α 1 -adrenergic receptors may represent changes in the properties of receptors found in the sarcolemma or in a membrane fraction other than the light vesicle fraction that they have isolated

  15. Identification and characterization of alpha 1 adrenergic receptors in the canine prostate using [125I]-Heat

    International Nuclear Information System (INIS)

    Lepor, H.; Baumann, M.; Shapiro, E.

    1987-01-01

    We have recently utilized radioligand receptor binding methods to characterize muscarinic cholinergic and alpha adrenergic receptors in human prostate adenomas. The primary advantages of radioligand receptor binding methods are that neurotransmitter receptor density is quantitated, the affinity of unlabelled drugs for receptor sites is determined, and receptors can be localized using autoradiography on slide-mounted tissue sections. Recently, [ 125 I]-Heat, a selective and high affinity ligand with high specific activity (2200 Ci/mmole) has been used to characterize alpha 1 adrenergic receptors in the brain. In this study alpha 1 adrenergic receptors in the dog prostate were characterized using [ 125 I]-Heat. The Scatchard plots were linear indicating homogeneity of [ 125 I]-Heat binding sites. The mean alpha 1 adrenergic receptor density determined from these Scatchard plots was 0.61 +/- 0.07 fmol/mg. wet wt. +/- S.E.M. The binding of [ 125 I]-Heat to canine prostate alpha 1 adrenergic binding sites was of high affinity (Kd = 86 +/- 19 pM). Steady state conditions were reached following an incubation interval of 30 minutes and specific binding and tissue concentration were linear within the range of tissue concentrations assayed. The specificity of [ 125 I]-Heat for alpha 1 adrenergic binding sites was confirmed by competitive displacement assays using unlabelled clonidine and prazosin. Retrospective analysis of the saturation experiments demonstrated that Bmax can be accurately calculated by determining specific [ 125 I]-Heat binding at a single ligand concentration. [ 125 I]-Heat is an ideal ligand for studying alpha 1 adrenergic receptors in the prostate and its favorable properties should facilitate the autoradiographic localization of alpha 1 adrenergic receptors in the prostate

  16. Platelet alpha-2 adrenergic receptor-mediated phosphoinositide responses in endogenous depression

    International Nuclear Information System (INIS)

    Mori, Hideki; Koyama, Tsukasa; Yamashita, Itaru

    1991-01-01

    We have previously indicated that epinephrine stimulates phosphoinositide (PI) hydrolysis by activating alpha-2 adrenergic receptors in human platelets. This method involves the measurement of the accumulation of [ 3 H]-inositol-1-phosphate (IP-1) as an index of Pl hydrolysis; lithium is added to inhibit the metabolism of IP-1, thus giving an enhanced signal. In the present study, we assessed the platelet alpha-2 adrenergic receptor-mediated PI responses in samples from 15 unmedicated patients with endogenous depression and 15 age- and sex-matched control subjects. The responses to epinephrine in the depressed patients were significantly higher than those of the controls, whereas the basal values did not differ significantly. These results support the hypothesis that platelet alpha-2 adrenergic receptors may be supersensitive in patients with endogenous depression

  17. Species differences in the localization and number of CNS beta adrenergic receptors: Rat versus guinea pig

    International Nuclear Information System (INIS)

    Booze, R.M.; Crisostomo, E.A.; Davis, J.N.

    1989-01-01

    The localization and number of beta adrenergic receptors were directly compared in the brains of rats and guinea pigs. The time course of association and saturability of [125I]cyanopindolol (CYP) binding to slide-mounted tissue sections was similar in rats (Kd = 17 pM) and guinea pigs (Kd = 20 pM). The beta-1 and beta-2 receptor subtypes were examined through the use of highly selective unlabeled receptor antagonists, ICI 118,551 (50 nM) and ICI 89,406 (70 nM). Dramatic species differences between rats and guinea pigs were observed in the neuroanatomical regional localization of the beta adrenergic receptor subtypes. For example, in the thalamus prominent beta-1 and beta-2 receptor populations were identified in the rat; however, the entire thalamus of the guinea pig had few, if any, beta adrenergic receptors of either subtype. Hippocampal area CA1 had high levels of beta-2 adrenergic receptors in both rats and guinea pigs but was accompanied by a widespread distribution of beta-2 adrenergic receptors only in rats. Quantitative autoradiographic analyses of 25 selected neuroanatomical regions (1) confirmed the qualitative differences in CNS beta adrenergic receptor localization, (2) determined that guinea pigs had significantly lower levels of beta adrenergic receptors than rats and (3) indicated a differential pattern of receptor subtypes between the two species. Knowledge of species differences in receptor patterns may be useful in designing effective experiments as well as in exploring the relationships between receptor and innervation patterns. Collectively, these data suggest caution be used in extrapolation of the relationships of neurotransmitters and receptors from studies of a single species

  18. Blocking beta 2-adrenergic receptor inhibits dendrite ramification in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Wu, Qin; Sun, Jin-Xia; Song, Xiang-He; Wang, Jing; Xiong, Cun-Quan; Teng, Fei-Xiang; Gao, Cui-Xiang

    2017-09-01

    Dendrite ramification affects synaptic strength and plays a crucial role in memory. Previous studies revealed a correlation between beta 2-adrenergic receptor dysfunction and Alzheimer's disease (AD), although the mechanism involved is still poorly understood. The current study investigated the potential effect of the selective β 2 -adrenergic receptor antagonist, ICI 118551 (ICI), on Aβ deposits and AD-related cognitive impairment. Morris water maze test results demonstrated that the performance of AD-transgenic (TG) mice treated with ICI (AD-TG/ICI) was significantly poorer compared with NaCl-treated AD-TG mice (AD-TG/NaCl), suggesting that β 2 -adrenergic receptor blockage by ICI might reduce the learning and memory abilities of mice. Golgi staining and immunohistochemical staining revealed that blockage of the β 2 -adrenergic receptor by ICI treatment decreased the number of dendritic branches, and ICI treatment in AD-TG mice decreased the expression of hippocampal synaptophysin and synapsin 1. Western blot assay results showed that the blockage of β 2 -adrenergic receptor increased amyloid-β accumulation by downregulating hippocampal α-secretase activity and increasing the phosphorylation of amyloid precursor protein. These findings suggest that blocking the β 2 -adrenergic receptor inhibits dendrite ramification of hippocampal neurons in a mouse model of AD.

  19. Neurohumoral activation in heart failure: the role of adrenergic receptors

    Directory of Open Access Journals (Sweden)

    Patricia C. Brum

    2006-09-01

    Full Text Available Heart failure (HF is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.A insuficiência cardíaca (IC é a via final comum da maioria das doenças cardiovasculares e uma das maiores causas de morbi-mortalidade. O desenvolvimento do estágio final da IC freqüentemente envolve um insulto inicial do miocárdio, reduzindo o débito cardíaco e levando ao aumento compensatório da atividade do sistema nervoso simpático (SNS. Existem evidências de que apesar da exposição aguda ser benéfica, exposições crônicas a elevadas concentra

  20. Characterization of beta-adrenergic receptors in synaptic membranes from rat cerebral cortex and cerebellum

    International Nuclear Information System (INIS)

    Lautens, L.

    1986-01-01

    Beta-adrenergic receptor ligand binding sites have been characterized in synaptic membranes from rat cerebral cortex and cerebellum using radioligand binding techniques. The equilibrium and kinetic properties of binding were assessed. The binding sites were non-interacting and exhibited two states of agonist binding which were sensitive to guanyl nucleotide. Synaptic membranes from cerebral cortex contained an equal number of beta 1 - and beta 2 -receptors; membranes from cerebellum possessed more beta 2 -than beta 1 -receptors. Photoaffinity labeling experiments revealed two different beta-adrenergic receptor polypeptides, R 1 and R 2 (and possibly a third, R 3 ) in synaptic membranes. The ratios of incorporation of photoaffinity label into R 1 : 2 were approximately 1:1 (cerebral cortex) and 5:1 (cerebellum). Photoaffinity labeling of R 1 and R 2 was inhibited equally well by both agonist and antagonist in synaptic membranes from cerebellum; whereas agonist was a less potent inhibitor in membranes from cerebral cortex. Both subtypes of beta-adrenergic receptors exhibited the same apparent molecular weight in synaptic membranes from cerebral cortex. The beta-adrenergic receptors in synaptic membranes from cerebral cortex and cerebellum were glycoproteins which exhibited the same apparent molecular weight after exposure to endoglycosidase F. The partial proteolytic digest maps of photoaffinity labeled beta-adrenergic receptors from rat cerebral cortex, cerebellum, lung and heart were compared

  1. Photoaffinity cross-linking of a radioiodinated probe, 125I-A55453, into alpha 1-adrenergic receptors

    International Nuclear Information System (INIS)

    Dickinson, K.E.; Leeb-Lundberg, L.M.; Heald, S.L.; Wikberg, J.E.; DeBernardis, J.F.; Caron, M.G.; Lefkowitz, R.J.

    1984-01-01

    We have synthesized and characterized a high-affinity alpha 1-adrenergic receptor probe, 4-amino-6,7-dimethoxy-2[4'- [5''(3'''- 125 I-iodo-4'''-aminophenyl)pentanoyl]-1'-piperazinyl] quinazoline ( 125 I-A55453). This ligand binds reversibly to rat hepatic plasma membranes with high affinity (KD . 77 +/- 6 pM), and it labels the same number of specific prazosin-competable sites as the alpha 1-adrenergic receptor-selective radioligand [ 125 I] iodo-2-[beta-(4-hydroxyphenyl)-ethylaminomethyl]tetralone. Specific binding is stereoselective and competed for by alpha-adrenergic agents with an alpha 1-adrenergic receptor specificity. 125 I-A55453 can be covalently photoincorporated into peptides of rat hepatic and splenic membranes using the bifunctional photoactive cross-linker, N-succinimidyl-6- (4'-azido-2'-nitrophenylamino)hexanoate. Following photolysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of labeled hepatic membranes reveals a major specifically labeled peptide of Mr . 82,000 (+/- 1,000) with minor peptides at Mr . 50,000 (+/- 500), and 40,000 (+/- 300). Covalent incorporation of 125 I-A55453 into the Mr . 82,000 peptide is inhibited by adrenergic drugs with an alpha 1-adrenergic receptor specificity. Labeled splenic membranes demonstrate a broad band of photoincorporated radioactivity centered at Mr . 82,000, and covalent incorporation into this peptide is also attenuated with an alpha 1-adrenergic receptor specificity. This new high-affinity radioiodinated probe has features which should make it useful for the molecular characterization of alpha 1-adrenergic receptors in tissues

  2. Alpha adrenergic receptors in dog coronary arteries as detected with autoradiography

    International Nuclear Information System (INIS)

    Muntz, K.; Calianos, T.; Buja, L.M.

    1986-01-01

    The authors used previously established methods to determine the presence of alpha adrenergic receptors in different sizes of dog coronary arteries using autoradiography of 3 H-prazosin (PRAZ) and 125 I-BE 2254 (HEAT) to label alpha 1 adrenergic receptors and 3 H-rauwolscine (RAUW) to label alpha 2 adrenergic receptors. Frozen sections of the left main coronary artery (LMA), the left anterior descending artery (LAD) and myocardium were incubated in 3 concentrations of PRAZ (0.1, 0.5 and 1.0 nM) (n=5 dogs), 3 concentrations of RAUW (1, 3 and 5 nM) (n=5) and one concentration of HEAT (50 pM) (n=3). All incubations were done in the absence of (total binding) or presence of (nonspecific binding) 10 -5 M phentolamine or yohimbine. The sections were processed for autoradiography and silver grains quantitated using an image analyzer. Analysis of variance determined that there was a significant difference between total and nonspecific binding in the LMA incubated with PRAZ (p 1 receptors decreases as vessel size decreases, while the number of alpha 2 receptors increases as vessel size decreases

  3. β2-adrenergic receptor Thr164Ile polymorphism, obesity, and diabetes

    DEFF Research Database (Denmark)

    Thomsen, Mette; Dahl, Morten; Tybjærg-Hansen, Anne

    2012-01-01

    The β(2)-adrenergic receptor (ADRB2) influences regulation of energy balance by stimulating catecholamine-induced lipolysis in adipose tissue. The rare functional ADRB2rs1800888(Thr164Ile) polymorphism could therefore influence risk of obesity and subsequently diabetes.......The β(2)-adrenergic receptor (ADRB2) influences regulation of energy balance by stimulating catecholamine-induced lipolysis in adipose tissue. The rare functional ADRB2rs1800888(Thr164Ile) polymorphism could therefore influence risk of obesity and subsequently diabetes....

  4. Antagonism of Lateral Amygdala Alpha1-Adrenergic Receptors Facilitates Fear Conditioning and Long-Term Potentiation

    Science.gov (United States)

    Lazzaro, Stephanie C.; Hou, Mian; Cunha, Catarina; LeDoux, Joseph E.; Cain, Christopher K.

    2010-01-01

    Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala…

  5. Modeling the Effects of β1-Adrenergic Receptor Blockers and Polymorphisms on Cardiac Myocyte Ca2+ Handling

    Science.gov (United States)

    Amanfu, Robert K.

    2014-01-01

    β-Adrenergic receptor blockers (β-blockers) are commonly used to treat heart failure, but the biologic mechanisms governing their efficacy are still poorly understood. The complexity of β-adrenergic signaling coupled with the influence of receptor polymorphisms makes it difficult to intuit the effect of β-blockers on cardiac physiology. While some studies indicate that β-blockers are efficacious by inhibiting β-adrenergic signaling, other studies suggest that they work by maintaining β-adrenergic responsiveness. Here, we use a systems pharmacology approach to test the hypothesis that in ventricular myocytes, these two apparently conflicting mechanisms for β-blocker efficacy can occur concurrently. We extended a computational model of the β1-adrenergic pathway and excitation-contraction coupling to include detailed receptor interactions for 19 ligands. Model predictions, validated with Ca2+ and Förster resonance energy transfer imaging of adult rat ventricular myocytes, surprisingly suggest that β-blockers can both inhibit and maintain signaling depending on the magnitude of receptor stimulation. The balance of inhibition and maintenance of β1-adrenergic signaling is predicted to depend on the specific β-blocker (with greater responsiveness for metoprolol than carvedilol) and β1-adrenergic receptor Arg389Gly polymorphisms. PMID:24867460

  6. Developmental changes of beta-adrenergic receptor-linked adenylate cyclase of rat liver

    International Nuclear Information System (INIS)

    Katz, M.S.; Boland, S.R.; Schmidt, S.J.

    1985-01-01

    beta-Adrenergic agonist-sensitive adenylate cyclase activity and binding of the beta-adrenergic antagonist(-)-[ 125 I]iodopindolol were studied in rat liver during development of male Fischer 344 rats ages 6-60 days. In liver homogenates maximum adenylate cyclase response to beta-adrenergic agonist (10(-5) M isoproterenol or epinephrine) decreased by 73% (P less than 0.01) between 6 and 60 days, with most of the decrease (56%; P less than 0.01) occurring by 20 days. beta-adrenergic receptor density (Bmax) showed a corresponding decrease of 66% (P less than 0.01) by 20 days without subsequent change. Binding characteristics of stereospecificity, pharmacological specificity, saturability with time, and reversibility were unchanged with age. GTP-, fluoride-, forskolin-, and Mn2+-stimulated adenylate cyclase activities also decreased during development, suggesting a decrease of activity of the catalytic component and/or guanine nucleotide regulatory component of adenylate cyclase. These results indicate that the developmental decrease of beta-adrenergic agonist-sensitive adenylate cyclase activity may result from decreased numbers of beta-adrenergic receptors. Developmental alterations of nonreceptor components of the enzyme may also contribute to changes of catecholamine-sensitive adenylate cyclase

  7. Decreased α1-adrenergic receptor-mediated inositide hydrolysis in neurons from hypertensive rat brain

    International Nuclear Information System (INIS)

    Feldstein, J.B.; Gonzales, R.A.; Baker, S.P.; Sumners, C.; Crews, F.T.; Raizada, M.K.

    1986-01-01

    The expression of α 1 -adrenergic receptors and norepinephrine (NE)-stimulated hydrolysis of inositol phospholipid has been studied in neuronal cultures from the brains of normotensive (Wistar-Kyoto, WKY) and spontaneously hypertensive (SH) rats. Binding of 125 I-1-[β-(4-hydroxyphenyl)-ethyl-aminomethyl] tetralone (HEAT) to neuronal membranes was 68-85% specific and was rapid. Competition-inhibition experiments with various agonists and antagonists suggested that 125 I-HEAT bound selectively to α 1 -adrenergic receptors. Specific binding of 125 I-HEAT to neuronal membranes from SH rat brain cultures was 30-45% higher compared with binding in WKY normotensive controls. This increase was attributed to an increase in the number of α 1 -adrenergic receptors on SH rat brain neurons. Incubation of neuronal cultures of rat brain from both strains with NE resulted in a concentration-dependent stimulation of release of inositol phosphates, although neurons from SH rat brains were 40% less responsive compared with WKY controls. The decrease in responsiveness of SH rat brain neurons to NE, even though the α 1 -adrenergic receptors are increased, does not appear to be due to a general defect in membrane receptors and postreceptor signal transduction mechanisms. This is because neither the number of muscarinic-cholinergic receptors nor the carbachol-stimulated release of inositol phosphates is different in neuronal cultures from the brains of SH rats compared with neuronal cultures from the brains of WKY rats. These observations suggest that the increased expression of α 1 -adrenergic receptors does not parallel the receptor-mediated inositol phosphate hydrolysis in neuronal cultures from SH rat brain

  8. Imaging the β-adrenergic receptor. II: [F-18]-fluoroalkyl derivatives of carazolol

    International Nuclear Information System (INIS)

    Kinsey, B.M.; Tewson, T.J.

    1990-01-01

    Carazolol is a ligand with one of the highest association constants known for the β-adrenergic receptor and presumably has one of the slowest rates of dissociation from the receptor. The authors have prepared a [F-18]-fluoroalkyl derivative of carazolol which the authors believe will be useful in the in vivo detection and measurement of the β-adrenergic receptor. The synthesis is based upon the formation of a hydrazole from cyclohexanedione and para-[2-hydroxyethyl]phenylhydrazine followed by Fischer indole synthesis, dehydrogenation and side chain addition to give the protected hydroxyethylcarazolol derivative 1

  9. α(1) adrenergic receptor agonist, phenylephrine, actively contracts early rat rib fracture callus ex vivo.

    Science.gov (United States)

    McDonald, Stuart J; Dooley, Philip C; McDonald, Aaron C; Djouma, Elvan; Schuijers, Johannes A; Ward, Alex R; Grills, Brian L

    2011-05-01

    Early, soft fracture callus that links fracture ends together is smooth muscle-like in nature. We aimed to determine if early fracture callus could be induced to contract and relax ex vivo by similar pathways to smooth muscle, that is, contraction via α(1) adrenergic receptor (α(1) AR) activation with phenylephrine (PE) and relaxation via β(2) adrenergic receptor (β(2) AR) stimulation with terbutaline. A sensitive force transducer quantified 7 day rat rib fracture callus responses in modified Krebs-Henseliet (KH) solutions. Unfractured ribs along with 7, 14, and 21 day fracture calluses were analyzed for both α(1) AR and β(2) AR gene expression using qPCR, whilst 7 day fracture callus was examined via immunohistochemistry for both α(1) AR and β(2) AR- immunoreactivity. In 7 day callus, PE (10(-6)  M) significantly induced an increase in force that was greater than passive force generated in calcium-free KH (n = 8, mean 51% increase, 95% CI: 26-76%). PE-induced contractions in calluses were attenuated by the α(1) AR antagonist, prazosin (10(-6)  M; n = 7, mean 5% increase, 95% CI: 2-11%). Terbutaline did not relax callus. Gene expression of α(1) ARs was constant throughout fracture healing; however, β(2) AR expression was down-regulated at 7 days compared to unfractured rib (p contract. We propose that increased concentrations of α(1) AR agonists such as noradrenaline may tonically contract callus in vivo to promote osteogenesis. Copyright © 2010 Orthopaedic Research Society.

  10. Hypoxia increases exercise heart rate despite combined inhibition of β-adrenergic and muscarinic receptors

    DEFF Research Database (Denmark)

    Siebenmann, Christoph; Rasmussen, Peter; Sørensen, Henrik

    2015-01-01

    Hypoxia increases the heart rate (HR) response to exercise but the mechanism(s) remain unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate but not combined inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exercise...... combined β-adrenergic and muscarinic receptor inhibition....

  11. Concanavalin a increases beta-adrenergic and glucocorticoid receptors in porcine splenocytes

    International Nuclear Information System (INIS)

    Kelley, K.N.; Westly, H.J.

    1986-01-01

    We identified specific glucocorticoid and beta-adrenergic receptors on porcine splenocytes. There are 2000 to 4000 glucocorticoid receptors per cell with a K /SUB D/ of 2 to 4 nM and 1000 beta-adrenergic receptors with a K /SUB D/ of 0.3 to 0.6 nM. When splenocytes were incubated with concanavalin A (Con A), there was an approximate 2-fold increase in both gluococorticoid and beta-adrenergic receptors with no change in binding affinity. Incubation of splenocytes with cortisol as low as 40 nM (13 ng/ml) inhibited proliferation in response to Con A. This inhibitory effect of cortisol was not due to cytotoxic effects of glucocorticoids. At maximal physiologic concentrations (400 nM; 135 ng/ml), cortisol caused reductions in Con A activation of thymocytes and peripheral blood mononuclear cells. When eight wk old pigs were restrained, there was an increase in plasma cortisol, atrophy of thymus and reduction in skin test responses to phytohemagglutinin. On the basis of the data, we suggest that physiologic concentrations of stress asociated hormones affect functional activities of porcine lymphoid cells. Since activated splenocytes display increased numbers of receptors for these hormones, perhaps glucocorticoids or catecholamines normally function in vivo to suppress clonal expansion of antigen activated and autoreactive T lymphocytes

  12. The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat

    DEFF Research Database (Denmark)

    Abelson, Klas S P; Höglund, A Urban

    2004-01-01

    Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinal acetylcholine. The cholinergic receptor system interacts with several other receptor types, such as alpha2-adrenergic receptors. To fully understand these interactions, the effects...... of various receptor ligands on the cholinergic system must be investigated in detail. This study was initiated to investigate the effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine and the alpha2-adrenergic receptor antagonists yohimbine and efaroxan on spinal cholinergic receptors......, all ligands possessed affinity for nicotinic receptors. Clonidine and yohimbine binding was best fit to a one site binding curve and rilmenidine and efaroxan to a two site binding curve. The present study demonstrates that the tested alpha2-adrenergic receptor ligands affect intraspinal acetylcholine...

  13. Brain α1-adrenergic receptors: suitability of [125I]HEAT as a radioligand for in vitro autoradiography

    International Nuclear Information System (INIS)

    Jones, L.S.; Gauger, L.L.; Davis, J.N.

    1983-01-01

    [2-(β-4-Hydroxyphenyl)-ethylaminomethyl)-tetralone] (BE 2254, HEAT) is a new potent α 1 -adrenergic receptor blocker. The iodinated radioligand, [ 125 I]HEAT appears to be even more potent than HEAT (Engel and Hoyer, 1981; Glossman et al., 1981) and has proved useful for the studying of α 1 -adrenergic receptors in membrane preparations of rat brain. The authors report the suitability of [ 125 I]HEAT for α 1 -adrenergic binding site autoradiography and a degree of localization of α 1 -adrenergic receptor binding sites that has not been possible with [ 3 H]WB 4101 and [ 3 H]prazosin autoradiography. (Auth.)

  14. Beta-Adrenergic Receptors and Mechanisms in Asthma: The New Long-Acting Beta-Agonists

    Directory of Open Access Journals (Sweden)

    Robert G Townley

    1996-01-01

    Full Text Available The objective is to review β-adrenergic receptors and mechanisms in the immediate and late bronchial reaction in asthma and the new long-acting β-agonist. This will be discussed in light of the controversy of the potential adverse effect of regular use of long-acting β-agonists. We studied the effect of formoterol on the late asthmatic response (LAR and airway inflammation in guinea-pigs. Formoterol suppressed the LAR, antigen-induced airway inflammation and hyperresponsiveness, although isoproterenol failed to inhibit these parameters. β-Adrenergic hyporesponsiveness, and cholinergic and a- adrenergic hyperresponsiveness have been implicated in the pathogenesis of asthma. A decrease in β-adrenoreceptor function can result either from exogenously administered β-agonist or from exposure to allergens resulting in a late bronchial reaction. There is increasing evidence that eosinophils, macrophages, and lymphocytes which are of primary importance in the late bronchial reaction are also modulated by β2- adrenoreceptors. In functional studies of guinea-pig or human isolated trachea and lung parenchyma, PAF and certain cytokines significantly reduced the potency of isoproterenol to reverse methacholine- or histamine-induced contraction. The effect of glucocorticoids on pulmonary β-adrenergic receptors and responses suggests an important role for glucocorticoids to increase β-adrenergic receptors and responsiveness.

  15. Astrocytic β2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice.

    Directory of Open Access Journals (Sweden)

    Cathy Joanna Jensen

    Full Text Available In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the β2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific β2-adrenergic receptor knock-out mice were generated by crossing homozygous β2-adrenergic receptor floxed mice (Adrb2flox and mice with heterozygous tamoxifen-inducible Cre recombinase-expression driven by the astrocyte specific L-glutamate/L-aspartate transporter promoter (GLAST-CreERT2. Assessments using the modified SHIRPA (SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment test battery, swimming ability test, and accelerating rotarod test, performed at 1, 2 and 4 weeks, 6 and 12 months after tamoxifen (or vehicle administration did not reveal any differences in physical health or motor functions between the knock-out mice and controls. However deficits were found in the cognitive ability of aged, but not young adult mice, reflected in impaired learning in the Morris Water Maze. Similarly, long-term potentiation (LTP was impaired in hippocampal brain slices of aged knock-out mice maintained in low glucose media. Using microdialysis in cerebellar white matter we found no significant differences in extracellular lactate or glucose between the young adult knock-out mice and controls, although trends were detected. Our results suggest that β2-adrenergic receptor expression on astrocytes in mice may be important for maintaining cognitive health at advanced age, but is dispensable for motor function.

  16. Monoclonal antibody to the rat glucocorticoid receptor. Relationship between the immunoreactive and DNA-binding domain

    International Nuclear Information System (INIS)

    Eisen, L.P.; Reichman, M.E.; Thompson, E.B.; Gametchu, B.; Harrison, R.W.; Eisen, H.J.

    1985-01-01

    The region of the glucocorticoid receptor that reacted with a monoclonal antibody (BUGR-1) was identified. In order to identify the immunoreactive region, the rat liver glucocorticoid receptor was subjected to limited proteolysis; immunoreactive fragments were identified by Western blotting. The monoclonal antibody reacted with both the undigested Mr approximately 97,000 receptor subunit and a Mr approximately 45,000 fragment containing the steroid-binding and DNA-binding domains. Digestion by trypsin also produced two steroid-binding fragments of Mr approximately 27,000 and 31,000 which did not react with the antibody and an immunoreactive Mr approximately 16,000 fragment. This Mr approximately 16,000 fragment was shown to bind to DNA-cellulose, indicating that it contained a DNA-binding domain of the receptor. The undigested receptor must have steroid associated with it to undergo activation to a DNA-binding form. However, the Mr approximately 16,000 immunoreactive fragment binds to DNA-cellulose even if it is obtained by digestion of the steroid-free holoreceptor which does not itself bind to DNA

  17. Stimulation of postsynapse adrenergic α2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder.

    Science.gov (United States)

    Kawaura, Kazuaki; Karasawa, Jun-ichi; Chaki, Shigeyuki; Hikichi, Hirohiko

    2014-08-15

    A 5-trial inhibitory avoidance test using spontaneously hypertensive rat (SHR) pups has been used as an animal model of attention deficit hyperactivity disorder (ADHD). However, the roles of noradrenergic systems, which are involved in the pathophysiology of ADHD, have not been investigated in this model. In the present study, the effects of adrenergic α2 receptor stimulation, which has been an effective treatment for ADHD, on attention/cognition performance were investigated in this model. Moreover, neuronal mechanisms mediated through adrenergic α2 receptors were investigated. We evaluated the effects of both clonidine, a non-selective adrenergic α2 receptor agonist, and guanfacine, a selective adrenergic α2A receptor agonist, using a 5-trial inhibitory avoidance test with SHR pups. Juvenile SHR exhibited a shorter transfer latency, compared with juvenile Wistar Kyoto (WKY) rats. Both clonidine and guanfacine significantly prolonged the transfer latency of juvenile SHR. The effects of clonidine and guanfacine were significantly blocked by pretreatment with an adrenergic α2A receptor antagonist. In contrast, the effect of clonidine was not attenuated by pretreatment with an adrenergic α2B receptor antagonist, or an adrenergic α2C receptor antagonist, while it was attenuated by a non-selective adrenergic α2 receptor antagonist. Furthermore, the effects of neither clonidine nor guanfacine were blocked by pretreatment with a selective noradrenergic neurotoxin. These results suggest that the stimulation of the adrenergic α2A receptor improves the attention/cognition performance of juvenile SHR in the 5-trial inhibitory avoidance test and that postsynaptic, rather than presynaptic, adrenergic α2A receptor is involved in this effect. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Guanine nucleotide regulation of α1-adrenergic receptors of muscle and kidney eptihelial cells

    International Nuclear Information System (INIS)

    Terman, B.I.; Hughes, R.J.; Slivka, S.R.; Insel, P.A.

    1986-01-01

    The authors have examined the effect of guanine nucleotides on the interaction of adrenergic agents with α 1 -adrenergic receptors of two cell lines, the Madin-Darby Canine Kidney (MDCK) and BC3H-1 muscle cells. While gaunylylimidodiphosphoate (Gpp(NH)p) had no effect on the affinity or the total number of [ -3 H]prazosin binding sites in membranes prepared from these cells, the nucleotide decreased the apparent affinity of the agonist epinephrine in competing for [ 3 H]prazosin binding sites in both cell types. The EC 50 of Gpp(NH)p was ∼100 μM, and a maximal effect was seen at 500 μM. In contrast, 100 μM Gpp(NH)p yielding maximal shifts in binding of epinephrine to β-adrenergic receptors in BC3H-1 cell membranes. Guanine nucleotides were significantly more effective than adenine nucleotides in shifting agonist affinity for the α 1 -receptor and Mg ++ was required to observe a maximal effect. α 1 -receptor agonists activated phosphatidylinositol (PI) hydrolysis in both cell types, but have no direct effect on membrane adenylate cyclase activity. In intact BC3H-1 cells, α 1 -agonists inhibited β-adrenergic cAMP production, an effect which appears in preliminary studies not to result from enhanced phosphodieterase activity. These results show that agonist binding to α 1 -adrenergic receptors in mammalian kidney and muscle cells is regulated by guanine nucleotides. This regulation and inturn transmembrane signalling (PI hydrolysis) by these receptors appear to involve a guanine nucleotide binding (G) protein, which may be different than G/sub s/ and G/sub i/

  19. Adverse Effects on β-Adrenergic Receptor Coupling: Ischemic Postconditioning Failed to Preserve Long-Term Cardiac Function.

    Science.gov (United States)

    Schreckenberg, Rolf; Bencsik, Péter; Weber, Martin; Abdallah, Yaser; Csonka, Csaba; Gömöri, Kamilla; Kiss, Krisztina; Pálóczi, János; Pipis, Judit; Sárközy, Márta; Ferdinandy, Péter; Schulz, Rainer; Schlüter, Klaus-Dieter

    2017-12-22

    Ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) are currently among the most efficient strategies protecting the heart against ischemia/reperfusion injury. However, the effect of IPC and IPoC on functional recovery following ischemia/reperfusion is less clear, particularly with regard to the specific receptor-mediated signaling of the postischemic heart. The current article examines the effect of IPC or IPoC on the regulation and coupling of β-adrenergic receptors and their effects on postischemic left ventricular function. The β-adrenergic signal transduction was analyzed in 3-month-old Wistar rats for each of the intervention strategies (Sham, ischemia/reperfusion, IPC, IPoC) immediately and 7 days after myocardial infarction. Directly after the infarction a cardioprotective potential was demonstrated for both IPC and IPoC: the infarct size was reduced, apoptosis and production of reactive oxygen species were lowered, and the myocardial tissue was preserved. Seven days after myocardial ischemia, only IPC hearts showed significant functional improvement. Along with a deterioration in fractional shortening, IPoC hearts no longer responded adequately to β-adrenergic stimulation. The stabilization of β-adrenergic receptor kinase-2 via increased phosphorylation of Mdm2 (an E3-ubiquitin ligase) was responsible for desensitization of β-adrenergic receptors and identified as a characteristic specific to IPoC hearts. Immediately after myocardial infarction, rapid and transient activation of β-adrenergic receptor kinase-2 may be an appropriate means to protect the injured heart from excessive stress. In the long term, however, induction and stabilization of β-adrenergic receptor kinase-2, with the resultant loss of positive inotropic function, leads to the functional picture of heart failure. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  20. Adrenergic receptors in frontal cortex in human brain.

    Science.gov (United States)

    Cash, R; Raisman, R; Ruberg, M; Agid, Y

    1985-02-05

    The binding of three adrenergic ligands ([3H]prazosin, [3H]clonidine, [3H]dihydroalprenolol) was studied in the frontal cortex of human brain. alpha 1-Receptors, labeled by [3H]prazosin, predominated. [3H]Clonidine bound to two classes of sites, one of high affinity and one of low affinity. Guanosine triphosphate appeared to lower the affinity of [3H]clonidine for its receptor. [3H]Dihydroalprenolol bound to three classes of sites: the beta 1-receptor, the beta 2-receptor and a receptor with low affinity which represented about 40% of the total binding, but which was probably a non-specific site; the beta 1/beta 2 ratio was 1/2.

  1. Impact of the Tamsulosin in Alpha Adrenergic Receptor of Airways at Patients with Increased Bronchial Reactibility.

    Science.gov (United States)

    Mustafa, Lirim; Ilazi, Ali; Dauti, Arta; Islami, Pellumb; Kastrati, Bashkim; Islami, Hilmi

    2015-08-01

    In this work, effect of tamsulosin as antagonist of alpha1A and alpha1B adrenergic receptor and effect of agonists of beta2 adrenergic receptor-salbutamol in patients with increased bronchial reactibility was studied. Parameters of the lung function are determined with Body plethysmography six (6) hours after administration of tamsulosin. Raw and ITGV were registered and specific resistance (SRaw) was calculated as well. Tamsulosin was administered in per os manner as a preparation in the shape of the capsules with a brand name of "Prolosin", produced by Niche Generics Limited, Hitchin, Herts. After six (6) hours of administration of tamsulosin, results gained indicate that blockage of alpha1A and alpha1B-adrenergic receptor (0.8 mg per os) has not changed significantly (p > 0.1) the bronchomotor tonus of tracheobronchial tree in comparison to the check-up that has inhaled salbutamol agonist of adrenergic beta2 receptor (2 inh. x 0.2 mg), (p tamsulosin. This suggests that even after six hours of administration of tamsulosin, and determining of lung function parameters, the activity of alpha1A and alpha1B-adrenergic receptor in the smooth bronchial musculature has not changed in patients with increased bronchial reactibility.

  2. Platelet alpha 2-adrenergic receptors in major depressive disorder. Binding of tritiated clonidine before and after tricyclic antidepressant drug treatment

    International Nuclear Information System (INIS)

    Garcia-Sevilla, J.A.; Zis, A.P.; Hollingsworth, P.J.; Greden, J.F.; Smith, C.B.

    1981-01-01

    The specific binding of tritiated (3H)-clonidine, an alpha 2-adrenergic receptor agonist, to platelet membranes was measured in normal subjects and in patients with major depressive disorder. The number of platelet alpha 2-adrenergic receptors from the depressed group was significantly higher than that found in platelets obtained from the control population. Treatment with tricyclic antidepressant drugs led to significant decreases in the number of platelet alpha 2-adrenergic receptors. These results support the hypothesis that the depressive syndrome is related to an alpha 2-adrenergic receptor supersensitivity and that the clinical effectiveness of tricyclic antidepressant drugs is associated with a decrease in the number of these receptors

  3. α1B-Adrenergic Receptors Differentially Associate with Rab Proteins during Homologous and Heterologous Desensitization

    Science.gov (United States)

    Castillo-Badillo, Jean A.; Sánchez-Reyes, Omar B.; Alfonzo-Méndez, Marco A.; Romero-Ávila, M. Teresa; Reyes-Cruz, Guadalupe; García-Sáinz, J. Adolfo

    2015-01-01

    Internalization of G protein-coupled receptors can be triggered by agonists or by other stimuli. The process begins within seconds of cell activation and contributes to receptor desensitization. The Rab GTPase family controls endocytosis, vesicular trafficking, and endosomal fusion. Among their remarkable properties is the differential distribution of its members on the surface of various organelles. In the endocytic pathway, Rab 5 controls traffic from the plasma membrane to early endosomes, whereas Rab 4 and Rab 11 regulate rapid and slow recycling from early endosomes to the plasma membrane, respectively. Moreover, Rab 7 and Rab 9 regulate the traffic from late endosomes to lysosomes and recycling to the trans-Golgi. We explore the possibility that α1B-adrenergic receptor internalization induced by agonists (homologous) and by unrelated stimuli (heterologous) could involve different Rab proteins. This possibility was explored by Fluorescence Resonance Energy Transfer (FRET) using cells coexpressing α1B-adrenergic receptors tagged with the red fluorescent protein, DsRed, and different Rab proteins tagged with the green fluorescent protein. It was observed that when α1B-adrenergic receptors were stimulated with noradrenaline, the receptors interacted with proteins present in early endosomes, such as the early endosomes antigen 1, Rab 5, Rab 4, and Rab 11 but not with late endosome markers, such as Rab 9 and Rab 7. In contrast, sphingosine 1-phosphate stimulation induced rapid and transient α1B-adrenergic receptor interaction of relatively small magnitude with Rab 5 and a more pronounced and sustained one with Rab 9; interaction was also observed with Rab 7. Moreover, the GTPase activity of the Rab proteins appears to be required because no FRET was observed when dominant-negative Rab mutants were employed. These data indicate that α1B-adrenergic receptors are directed to different endocytic vesicles depending on the desensitization type (homologous vs

  4. Demonstration of β-adrenergic receptors and catecholamine-mediated effects on cell proliferation in embryonic palatal tissue

    International Nuclear Information System (INIS)

    Pisano, M.M.

    1986-01-01

    The ability of catecholamines to modulate cell proliferation, differentiation and morphogenesis in other systems, and modulate adenylate cyclase activity in the developing palate during the period of cellular differentiation, made it of interest to determine their involvement in palatal ontogenesis. Catecholamines exert their physiologic effects via interaction with distinct membrane-bound receptors, one class being the B-adrenergic receptors which are coupled to stimulation of adenylate cyclase and the generation of cAMP. A direct radioligand binding technique utilizing the B-adrenergic antagonist [ 3 H]-dihydroalprenolol ([ 3 H]-DHA) was employed in the identification of B-adrenergic receptors in the developing murine secondary palate. Specific binding of [ 3 H]-DHA in embryonic (day 13) palatal tissue homogenates was saturable and of high affinity. The functionality of B-adrenergic receptor binding sites was assessed from the ability of embryonic palate mesenchmyal cells in vitro to respond to catecholamines with elevations of cAMP. Embryonic palate mesenchymal cells responded to various B-adrenergic catecholamine agonists with significant, dose-dependent accumulations of intracellular cAMP. Embryonic (day 13) maxillary tissue homogenates were analyzed for the presence of catecholamines by high performance liquid chromatography and radioenzymatic assay. Since normal palatal and craniofacial morphogenesis depends on proper temporal and spatial patterns of growth, the effect of B-adrenergic catecholamines on embryonic palate mesenchymal cell proliferation was investigated

  5. Quantitation of alpha 1-adrenergic receptors in porcine uterine and mesenteric arteries

    International Nuclear Information System (INIS)

    Farley, D.B.; Ford, S.P.; Reynolds, L.P.; Bhatnagar, R.K.; Van Orden, D.E.

    1984-01-01

    The activation of vascular alpha-adrenergic receptors may be involved in the control of uterine blood flow. A radioligand binding assay with the use of the alpha 1-adrenergic antagonist 3 H-WB-4101 was established to characterize the alpha-adrenergic receptors in uterine and mesenteric arterial membranes obtained from nonpregnant pigs. Specific binding of 3 H-WB-4101 was rapid, saturable, and exhibited the alpha-adrenergic agonist potency order of (-)-epinephrine inhibition constant [Ki] . 0.6 mumol/L greater than (-)-norepinephrine (Ki . 1.5 mumol/L) much greater than (-)-isoproterenol (Ki . 120 mumol/L). The alpha-adrenergic antagonist phentolamine (Ki . 6.0 nmol/L) was 200 times more potent than the beta-adrenergic antagonist (+/-)-propranolol (Ki . 1,200 nmol/L); the alpha 1-selective antagonist prazosin (Ki . 1.2 nmol/L) was 130 times more potent than the alpha 2-selective antagonist yohimbine (Ki . 160 nmol/L). Scatchard analysis, as well as iterative curve-fitting analysis, demonstrated that 3 H-WB-4101 binding by arterial membranes was to a single class of binding sites. Uterine arteries exhibited greater maximal binding capacity (BMax) than that of mesenteric arteries (47.5 +/- 3.2 versus 30.9 +/- 3.6 fmol per milligram of protein, p less than 0.01), but the uterine artery dissociation constant (Kd) was higher, thus indicating a lower affinity, when compared with mesenteric artery (0.43 +/- 0.04 versus 0.33 +/- 0.04 nmol/L, p less than 0.05)

  6. Adrenergic receptors and gastric secretion in dogs. Is a "tonic balance" relationship between vagal and beta 2-adrenergic activity a possibility?

    DEFF Research Database (Denmark)

    Gottrup, F; Hovendal, C; Bech, K

    1984-01-01

    The relative influence of adrenergic receptors on gastric acid secretion in the dog stomach with different vagal activity or "tone" is almost unknown. beta-adrenoceptors seem to be most important for the direct effect of adrenergic stimulation on acid secretion. In this study the effects...... acid secretion was not influenced significantly by beta-blockade. Similar dose-response curves were found for non-vagotomized dogs with high beta 2-adrenergic tone and dogs with low vagal tone (vagotomy) after pentagastrin and histamine stimulated acid secretion. This study indicates...... that a counterbalance between beta 2-adrenergic and cholinergic vagal tone exists. A "tonic balance theory" is suggested and is probably involved in the resulting acid secretion after vagotomy....

  7. Synthesis and characterization of arylamine derivatives of rauwolscine as molecular probes for alpha 2-adrenergic receptors

    International Nuclear Information System (INIS)

    Lanier, S.M.; Graham, R.M.; Hess, H.J.; Grodski, A.; Repaske, M.G.; Nunnari, J.M.; Limbird, L.E.; Homcy, C.J.

    1987-01-01

    The selective alpha 2-adrenergic receptor antagonist rauwolscine was structurally modified to yield a series of arylamine carboxamide derivatives, which were investigated as potential molecular probes for the localization and structural characterization of alpha 2-adrenergic receptors. The arylamine carboxamides differ in the number of carbon atoms separating the reactive phenyl moiety from the fused ring structure of the parent compound, rauwolscine carboxylate. Competitive inhibition studies with [ 3 H]rauwolscine in rat kidney membranes indicate that the affinity for the carboxamide derivatives is inversely related to the length of the carbon spacer arm with rauwolscine 4-aminophenyl carboxamide exhibiting the highest affinity (Kd = 2.3 +/- 0.2 nM). Radioiodination of rau-AMPC yields a ligand, 125 I-rau-AMPC, which binds to rat kidney alpha 2-adrenergic receptors with high affinity, as determined by both kinetic analysis (Kd = k2/k1 = 0.016 min-1/2.1 X 10(7) M-1 min-1 = 0.76 nM) and equilibrium binding studies (Kd = 0.78 +/- 0.16 nM). 125 I-rau-AMPC was quantitatively converted to the photolabile arylazide derivative 17 alpha-hydroxy-20 alpha-yohimban-16 beta-(N-4-azido-3-[ 125 I]iodophenyl) carboxamide ( 125 I-rau-AZPC). In a partially purified receptor preparation from porcine brain, this compound photolabels a major (Mr = 62,000) peptide. The labeling of this peptide is inhibited by adrenergic agonists and antagonists with a rank order of potency consistent with an alpha 2-adrenergic receptor binding site. Both 125 I-rau-AMPC and the photolabile arylazide derivative, 125 I-rau-AZPC, should prove useful as molecular probes for the structural and biochemical characterization of alpha 2-adrenergic receptors

  8. Stress-induced decrease of uterine blood flow in sheep is mediated by alpha 1-adrenergic receptors.

    Science.gov (United States)

    Dreiling, Michelle; Bischoff, Sabine; Schiffner, Rene; Rupprecht, Sven; Kiehntopf, Michael; Schubert, Harald; Witte, Otto W; Nathanielsz, Peter W; Schwab, Matthias; Rakers, Florian

    2016-09-01

    Prenatal maternal stress can be transferred to the fetus via a catecholamine-dependent decrease of uterine blood flow (UBF). However, it is unclear which group of adrenergic receptors mediates this mechanism of maternal-fetal stress transfer. We hypothesized that in sheep, alpha 1-adrenergic receptors may play a key role in catecholamine mediated UBF decrease, as these receptors are mainly involved in peripheral vasoconstriction and are present in significant number in the uterine vasculature. After chronic instrumentation at 125 ± 1 days of gestation (dGA; term 150 dGA), nine pregnant sheep were exposed at 130 ± 1 dGA to acute isolation stress for one hour without visual, tactile, or auditory contact with their flockmates. UBF, blood pressure (BP), heart rate (HR), stress hormones, and blood gases were determined before and during this isolation challenge. Twenty-four hours later, experiments were repeated during alpha 1-adrenergic receptor blockage induced by a continuous intravenous infusion of urapidil. In both experiments, ewes reacted to isolation with an increase in serum norepinephrine, cortisol, BP, and HR as typical signs of activation of sympatho-adrenal and the hypothalamic-pituitary-adrenal axis. Stress-induced UBF decrease was prevented by alpha 1-adrenergic receptor blockage. We conclude that UBF decrease induced by maternal stress in sheep is mediated by alpha 1-adrenergic receptors. Future studies investigating prevention strategies of impact of prenatal maternal stress on fetal health should consider selective blockage of alpha 1-receptors to interrupt maternal-fetal stress transfer mediated by utero-placental malperfusion.

  9. Interaction between Ca++-channel antagonists and α2-adrenergic receptors in rabbit ileal cell membrane

    International Nuclear Information System (INIS)

    Homeidan, F.R.; Wicks, J.; Cusolito, S.; El-Sabban, M.E.; Sharp, G.W.G.; Donowitz, M.

    1986-01-01

    An interaction between Ca ++ -channel antagonists and the α 2 -adrenergic receptor on active electrolyte transport was demonstrated in rabbit ileum. Clonidine, an α 2 -agonist, stimulated NaCl absorption apparently by Ca ++ -channel antagonism since it inhibited 45 Ca ++ uptake across the basolateral membrane and decreased total ileal calcium content. This stimulation was inhibited by the Ca ++ -channel antagonists dl- and l-verapamil and cadmium but not by nifedipine. The binding of 3 H-yohimbine, a specific α 2 -adrenergic antagonist, was studied on purified ileal cell membranes using a rapid filtration technique. dl-Verapamil and Cd ++ inhibited the specific binding of 3 H-yohimbine over the same concentration range in which they affected transport. In contrast, nifedipine had no effect on binding, just as it had no effect on clonidine-stimulated NaCl absorption. These data demonstrate that there is an interaction between Ca ++ -channels and α 2 -adrenergic receptors in ileal basolateral membranes. Some Ca ++ -channel antagonists alter α 2 -adrenergic binding to the receptor and α 2 -agonist binding leads to changes in Ca ++ entry. A close spatial relationship between the Ca ++ -channel and the α 2 -receptor could explain the data

  10. Opposing Effects of α2- and β-Adrenergic Receptor Stimulation on Quiescent Neural Precursor Cell Activity and Adult Hippocampal Neurogenesis

    Science.gov (United States)

    Prosper, Boris W.; Marathe, Swanand; Husain, Basma F. A.; Kernie, Steven G.; Bartlett, Perry F.; Vaidya, Vidita A.

    2014-01-01

    Norepinephrine regulates latent neural stem cell activity and adult hippocampal neurogenesis, and has an important role in modulating hippocampal functions such as learning, memory and mood. Adult hippocampal neurogenesis is a multi-stage process, spanning from the activation and proliferation of hippocampal stem cells, to their differentiation into neurons. However, the stage-specific effects of noradrenergic receptors in regulating adult hippocampal neurogenesis remain poorly understood. In this study, we used transgenic Nestin-GFP mice and neurosphere assays to show that modulation of α2- and β-adrenergic receptor activity directly affects Nestin-GFP/GFAP-positive precursor cell population albeit in an opposing fashion. While selective stimulation of α2-adrenergic receptors decreases precursor cell activation, proliferation and immature neuron number, stimulation of β-adrenergic receptors activates the quiescent precursor pool and enhances their proliferation in the adult hippocampus. Furthermore, our data indicate no major role for α1-adrenergic receptors, as we did not observe any change in either the activation and proliferation of hippocampal precursors following selective stimulation or blockade of α1-adrenergic receptors. Taken together, our data suggest that under physiological as well as under conditions that lead to enhanced norepinephrine release, the balance between α2- and β-adrenergic receptor activity regulates precursor cell activity and hippocampal neurogenesis. PMID:24922313

  11. Crystal structure of the β2 adrenergic receptor-Gs protein complex

    DEFF Research Database (Denmark)

    Rasmussen, Søren Gøgsig Faarup; DeVree, Brian T; Zou, Yaozhong

    2011-01-01

    -occupied receptor. The β(2) adrenergic receptor (β(2)AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric β(2)AR and nucleotide-free Gs...

  12. Catecholamine-induced desensitization of adenylate cyclase coupled β-adrenergic receptors in turkey erythrocytes: evidence for a two-step mechanism

    International Nuclear Information System (INIS)

    Stadel, J.M.; Rebar, R.; Crooke, S.T.

    1987-01-01

    Preincubation of turkey erythrocytes with isoproterenol is associated with (1) 50-60% attenuation of agonist-stimulated adenylate cyclase activity, (2) altered mobility of the β-adrenergic receptor on sodium dodecyl sulfate-polyacrylamide gels, and (3) increased phosphorylation of the β-adrenergic receptor. Using a low-cross-linked polyacrylamide gel, the β-adrenergic receptor protein from isoproterenol-desensitized cells, labeled with 32 P or with the photoaffinity label 125 I-(p-azidobenzyl)carazolol, can be resolved into a doublet (M/sub r/ similarly ordered 37,000 and M/sub r/ similarly ordered 41,000) as compared to a single M/sub r/ similarly ordered 37,000 β-adrenergic receptor protein from control erythrocytes. The appearance of the doublet was dependent on the concentration of agonist used to desensitize the cells. Incubation of erythrocytes with dibutyryl-cAMP did not promote formation of the doublet but decreased agonist-stimulated adenylate cyclase activity 40-50%. Limited-digestion peptide maps of 32 P-labeled β-adrenergic receptors using papain revealed a unique phosphopeptide in the larger molecular weight band (M/sub r/ similarly ordered 41,000) of the doublet from the agonist-desensitized preparation that was absent in the peptide maps of the smaller band (M/sub r/ similarly ordered 37,000), as well as control or dibutyryl-cAMP-desensitized receptor. These data provide evidence that maximal agonist-induced desensitization of adenylate cyclase coupled β-adrenergic receptors in turkey erythrocytes occurs by a two-step mechanism

  13. Structural derivatives of pindolol: relationship between in vivo and in vitro potencies for their interaction with central beta-adrenergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Tejani-Butt, S.M.; Brunswick, D.J.

    1987-08-24

    Although (-)-/sup 125/I-iodopindolol (IPIN) can be used to label beta-adrenergic receptors in the central nervous system (CNS) in vivo, use of this ligand for receptor imaging studies in humans may be limited due to its relatively poor penetration into the CNS. A series of derivatives related to pindolol was therefore studied in an effort to determine the factors that might influence the penetration and interaction of these compounds with central beta-adrenergic receptors in vivo. Evaluation of the ability of these derivatives to displace the binding of IPIN in the brain upon systemic administration provides an assessment of whether the derivatives penetrate and interact with central beta-adrenergic receptors in vivo. Multiple regression analyses showed that the most important factor which influences the ability of the pindolol derivatives to penetrate into the brain and interact with beta-adrenergic receptors in vivo is the affinity of the derivatives for binding to beta-adrenergic receptors in vitro. Both lipophilicity and the molecular weights of the derivatives are important secondary factors which influence their in vivo potency. 15 references, 4 figures, 1 table.

  14. Structural derivatives of pindolol: relationship between in vivo and in vitro potencies for their interaction with central beta-adrenergic receptors

    International Nuclear Information System (INIS)

    Tejani-Butt, S.M.; Brunswick, D.J.

    1987-01-01

    Although (-)- 125 I-iodopindolol (IPIN) can be used to label beta-adrenergic receptors in the central nervous system (CNS) in vivo, use of this ligand for receptor imaging studies in humans may be limited due to its relatively poor penetration into the CNS. A series of derivatives related to pindolol was therefore studied in an effort to determine the factors that might influence the penetration and interaction of these compounds with central beta-adrenergic receptors in vivo. Evaluation of the ability of these derivatives to displace the binding of IPIN in the brain upon systemic administration provides an assessment of whether the derivatives penetrate and interact with central beta-adrenergic receptors in vivo. Multiple regression analyses showed that the most important factor which influences the ability of the pindolol derivatives to penetrate into the brain and interact with beta-adrenergic receptors in vivo is the affinity of the derivatives for binding to beta-adrenergic receptors in vitro. Both lipophilicity and the molecular weights of the derivatives are important secondary factors which influence their in vivo potency. 15 references, 4 figures, 1 table

  15. {beta}-adrenergic receptor density and adenylate cyclase activity in lead-exposed rat brain after cessation of lead exposure

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Huoy-Rou [I-Shou University, Department of Biomedical Engineering, Dashu Shiang, Kaohsiung County (Taiwan); Tsao, Der-An [Fooyin University of Technology, Department of Medical Technology (Taiwan); Yu, Hsin-Su [Taiwan University, Department of Dermatology, College of Medicine (Taiwan); Ho, Chi-Kung [Kaohsiung Medical University, Occupational Medicine (Taiwan); Kaohsiung Medical University, Graduate Institute of Medicine, Research Center for Occupational Disease (Taiwan)

    2005-01-01

    To understanding the reversible or irreversible harm to the {beta}-adrenergic system in the brain of lead-exposed rats, this study sets up an animal model to estimate the change in the sympathetic nervous system of brain after lead exposure was withdrawn. We address the following topics in this study: (a) the relationship between withdrawal time of lead exposure and brain {beta}-adrenergic receptor, blood lead level, and brain lead level in lead-exposed rats after lead exposure was stopped; and (b) the relationship between lead level and {beta}-adrenergic receptor and cyclic AMP (c-AMP) in brain. Wistar rats were chronically fed with 2% lead acetate and water for 2 months. Radioligand binding was assayed by a method that fulfilled strict criteria of {beta}-adrenergic receptor using the ligand [{sup 125}I]iodocyanopindolol. The levels of lead were determined by electrothermal atomic absorption spectrometry. The c-AMP level was determined by radioimmunoassay. The results showed a close relationship between decreasing lead levels and increasing numbers of brain {beta}-adrenergic receptors and brain adenylate cyclase activity after lead exposure was withdrawn. The effect of lead exposure on the {beta}-adrenergic system of the brain is a partly reversible condition. (orig.)

  16. Vascular adrenergic receptor responses in skeletal muscle in myotonic dystrophy

    International Nuclear Information System (INIS)

    Mechler, F.; Mastaglia, F.L.

    1981-01-01

    The pharmacological responses of vascular adrenergic receptors to intravenously administered epinephrine, phentolamine, and propranolol were assessed by measuring muscle blood flow (MBF) changes in the tibialis anterior muscle using the xenon 133 clearance technique and were compared in 8 normal subjects and 11 patients with myotonic dystrophy. In cases with advanced involvement of the muscle, the resting MBF was reduced and was not significantly altered by epinephrine before or after alpha- or beta-receptor blockade. In patients in whom the tibialis anterior muscle was normal or only minimally affected clinically, a paradoxical reduction in the epinephrine-induced increase in MBF was found after alpha blockade by phentolamine, and the epinephrine-induced MBF increase was not completely blocked by propranolol as in the normal subjects. These findings point to functional alteration in the properties of vascular adrenergic receptors in muscle in myotonic dystrophy. While this may be another manifestation of a widespread cell membrane defect in the disease, the possibility that the changes are secondary to the myotonic state cannot be excluded

  17. Modulation of β-adrenergic receptors in the pituitary gland following adrenalectomy in rats

    International Nuclear Information System (INIS)

    Souza, E.B. de

    1987-01-01

    The effects of adrenalectomy on β-adrenergic receptors in the rat pituitary were examined using quantitative in vitro autoradiography with 125 I-iodocyanopindolol( 125 ICYP). 125 ICYP binding in the anterior, intermediate and posterior lobes of the pituitary gland was significantly increased in chronically adrenalectomized rats. The increase in 125 ICYP binding sites in the rat pituitary following adrenalectomy was not reversed by glucocorticoid replacement with dexamethasone. These data indicate that catecholamines of adrenomedullary origin are capable of modulating β-adrenergic receptors in the pituitary gland and suggest that peripheral epinephrine may be important in regulating pituitary hormone secretion. (author)

  18. Covalent labeling of the beta-adrenergic ligand-binding site with para-(bromoacetamidyl)benzylcarazolol. A highly potent beta-adrenergic affinity label

    International Nuclear Information System (INIS)

    Dickinson, K.E.; Heald, S.L.; Jeffs, P.W.; Lefkowitz, R.J.; Caron, M.G.

    1985-01-01

    Para-(Bromoacetamidyl)benzylcarazolol (pBABC) was synthesized and found to be an extremely potent affinity label for beta-adrenergic receptors. Its interaction with mammalian (rabbit and hamster lung) and nonmammalian (turkey and frog erythrocyte) beta-adrenergic receptors was similar, displaying EC 50 values of 400-900 pM for inhibiting 125 I-cyanopindolol binding to these receptors. pBABC reduced the number of beta-adrenergic receptors in frog erythrocyte membranes, without any change in the affinity of the remaining sites for [ 125 I]iodocyanopindolol. pBABC has been radioiodinated. As assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, this affinity probe specifically labeled the beta-adrenergic peptide of a purified preparation of hamster lung, with high efficiency (approximately 40%) and with a pharmacological specificity characteristic of an interaction at the beta 2-adrenergic receptor ligand-binding site. Comparison of the proteolyzed products derived from purified receptor labeled with [ 125 I]pBABC and with the photoaffinity agent [ 125 I]p-azidobenzylcarazolol suggested that covalent labeling of the beta-adrenergic receptor by these probes occurs at similar domains of the beta-adrenergic receptor

  19. Development of serotonergic and adrenergic receptors in the rat spinal cord: effects of neonatal chemical lesions and hyperthyroidism.

    Science.gov (United States)

    Lau, C; Pylypiw, A; Ross, L L

    1985-03-01

    The sympathetic preganglionic neurons in the spinal cord receive dense serotonergic (5-HT) and catecholaminergic (CA) afferent inputs from the descending supraspinal pathways. In the rat spinal cord, the levels of these biogenic amines and their receptors are low at birth, but undergo rapid ontogenetic increases in the ensuing 2-3 postnatal weeks until the adult levels are reached. In many systems it has been shown that denervation of presynaptic neurons leads to an up-regulation of the number of postsynaptic receptors. To determine whether the 5-HT and CA receptors in the developing spinal cord are also subject to such transsynaptic regulation, we examined the ontogeny of serotonergic receptors and alpha- and beta-adrenergic receptors in thoracolumbar spinal cord of rats given neurotoxins which destroy serotonergic (5,7-dihydroxytryptamine (5,7-DHT)) or noradrenergic (6-hydroxydopamine (6-OHDA)) nerve terminals. Intracisternal administration of 5,7-DHT or 6-OHDA at 1 and 6 days of age prevented, respectively, the development of 5-HT and CA levels in the spinal cord. Rats lesioned with 5,7-DHT displayed a marked elevation of 5-HT receptors with a binding of 50% greater than controls at 1 week and a continuing increase to twice normal by 4 weeks. A similar pattern of up-regulation was also detected with the alpha-adrenergic receptor, as rats lesioned with 6-OHDA exhibited persistent increases in receptor concentration. However, in these same animals ontogeny of the beta-adrenergic receptor in the spinal cord remained virtually unaffected by the chemical lesion. In several other parts of the nervous system, it has been demonstrated that the beta-adrenergic sensitivity can be modulated by hormonal signals, particularly that of the thyroid hormones. This phenomenon was examined in the spinal cord and in confirmation with previous studies neonatal treatment of triiodothyronine (0.1 mg/kg, s.c. daily) was capable of evoking persistent increases in beta-adrenergic

  20. Molecular Mechanisms of β2-Adrenergic Receptor Function and Regulation

    OpenAIRE

    McGraw, Dennis W.; Liggett, Stephen B.

    2005-01-01

    It is now clear that the β2-adrenergic receptor continuously oscillates between various conformations in the basal state, and that agonists act to stabilize one or more conformations. It is conceivable that synthetic agonists might be engineered to preferentially confine the receptor to certain conformations deemed clinically important while having a less stabilizing effect on unwanted conformations. In addition, studies of genetically engineered mice have revealed previously unrecognized cro...

  1. Significance of adrenergic receptors for the development of nevus flammeus and nevus anemicus

    Energy Technology Data Exchange (ETDEWEB)

    Raff, M [Vienna Univ. (Austria). 2. Hautklinik

    1981-01-01

    Examination of patients with nevus flammeus or nevus anemicus showed disturbed sensibility in the area of the nevus in the majority of cases. Histologically and with special technique of histochemistry and fluorescence microscopy there was no evidence for neurogenic lesions. However, signs of vegetative disfunction were present: hyperhidrosis and absent reactivity of vasculature in the nevus area to vasoconstrictive and vasodilatatory stimuli. Based on these findings a disturbed regulation of vascular intramural adrenergic receptors seemed possible and really could be demonstrated by means of autoradiography. In both types of nevi only one of the adrenergic receptors could be marked with specific antagonists. Therefore, the persistent vascular dilatation and constriction can be accounted for by the absence of one of these receptors. This abnormal distribution of receptors could be due to a developmental defect influenced by the ''nerve growth factor''.

  2. (-)[125I]-iodopindolol, a new highly selective radioiodinated beta-adrenergic receptor antagonist: measurement of beta-receptors on intact rat astrocytoma cells

    International Nuclear Information System (INIS)

    Barovsky, K.; Brooker, G.

    1980-01-01

    (-)-Pindolol, one of the most potent beta-adrenergic receptor antagonists, was radioiodinated using chloramine-T oxidation of carrier-free Na 125I and separated from unreacted pindolol to yield 2200 Ci/mmole (-)-[125I]-iodopindolol ((-)-[125I]-IPin). Mass and ultraviolet spectra confirmed that the iodination occurred on the indole ring, presumably at the 3 position. The binding of radiolabeled (-)-[125I]-IPin to beta-adrenergic receptors has been studied using intact C6 rat astrocytoma cells (2B subclone) grown in monolayer cultures. Binding of (-)[125IPin was saturable with time and concentration. Using 13 pM (-)-[125I]IPin, binding equilibrium was reached in 90 min at 21-22 degrees C. The reverse rate constant was 0.026 min-1 at 21 0 C. Specific binding (expressed as 1 microM(-)-propranolol displaceable counts) of (-)-[125I]-IPin was 95% of total binding. Scatchard analysis of (-)-[125I]-I]Pin binding revealed approximately 4300 receptors/cell and a dissociation constant of 30 pM. This was in excellent agreement with the kinetically determined dissociation constant of 35 pM. Displacement by propranolol and isoproterenol showed that (-)-[125I]-IPin binding sites were pharmacologically and stereospecifically selective. These results indicate that (-)-[125I]-IPin, a pure (-)-stereoisomer, high specific activity radioligand, selectively binds to beta-adrenergic receptors in whole cells with a high percentage of specific binding and should therefore be useful in the study and measurement of cellular beta-adrenergic receptors

  3. [Density of beta-adrenergic receptors and left ventricular mass in patients with primary essential hypertension].

    Science.gov (United States)

    Gajek, J; Zyśko, D; Spring, A

    2000-08-01

    Left ventricular hypertrophy (LVH) is one of the more important risk factors for sudden death. There are multiple factors for development of LVH in patients with hypertension. Sympathetic nervous system may play a key role causing afterload increase and neurohumoral mechanisms activation. The aim of the study was to determine beta-adrenergic receptors density and its relations to left ventricular mass in hypertensive subjects. The study was carried out in 63 patients (23 women and 40 men), mean age 43.3 +/- 11.6 yrs with primary hypertension: stage I--42 pts and stage II--21 pts. The control group consisted of 26 healthy persons matched for age and sex. We evaluated the density of beta-adrenergic receptors using 125I-cyanopindolol radioligand labeling method. Left ventricular dimensions were assessed by echocardiography (Hewlett-Packard 77010 CF) and left ventricular mass index (LVMI) was calculated. Systolic and diastolic blood pressure and LVMI was significantly higher in hypertension group 156.7 +/- 12.5 vs. 119.8 +/- 8.8 mmHg, p < 0.0001, 95.9/5.5 vs. 78.8 +/- 6.5 mmHg, p < 0.0001, 126.5 +/- 41.9 vs. 93.1 +/- 19.9 g/m2, p < 0.001 respectively. Beta-adrenergic receptors density was 40.7 +/- 29.9 fmol/ml in the hypertensive vs. 37.2 +/- 17.8 fmol/ml in control group (p = NS). There was no correlation between beta-adrenergic receptors density and LVMI. There was a statistically significant positive correlation between LVMI and systolic and diastolic blood pressure (r = 0.44, p < 0.05; r = 0.60, p < 0.01 respectively). 1. Beta-adrenergic receptors density was unchanged in patients with hypertension and did not correlate with LVMI. 2. A high positive correlation between blood pressure values and LVMI, but only in stage II hypertension was revealed.

  4. Involvement of Cholinergic and Adrenergic Receptors in Pathogenesis and Inflammatory Response Induced by Alpha-Neurotoxin Bot III of Scorpion Venom.

    Science.gov (United States)

    Nakib, Imene; Martin-Eauclaire, Marie-France; Laraba-Djebari, Fatima

    2016-10-01

    Bot III neurotoxin is the most lethal α neurotoxin purified from Buthus occitanus tunetanus scorpion venom. This toxin binds to the voltage-gated sodium channel of excitable cells and blocks its inactivation, inducing an increased release of neurotransmitters (acetylcholine and catecholamines). This study aims to elucidate the involvement of cholinergic and adrenergic receptors in pathogenesis and inflammatory response triggered by this toxin. Injection of Bot III to animals induces an increase of peroxidase activities, an imbalance of oxidative status, tissue damages in lung parenchyma, and myocardium correlated with metabolic disorders. The pretreatment with nicotine (nicotinic receptor agonist) or atropine (muscarinic receptor antagonist) protected the animals from almost all disorders caused by Bot III toxin, especially the immunological alterations. Bisoprolol administration (selective β1 adrenergic receptor antagonist) was also efficient in the protection of animals, mainly on tissue damage. Propranolol (non-selective adrenergic receptor antagonist) showed less effect. These results suggest that both cholinergic and adrenergic receptors are activated in the cardiopulmonary manifestations induced by Bot III. Indeed, the muscarinic receptor appears to be more involved than the nicotinic one, and the β1 adrenergic receptor seems to dominate the β2 receptor. These results showed also that the activation of nicotinic receptor leads to a significant protection of animals against Bot III toxin effect. These findings supply a supplementary data leading to better understanding of the mechanism triggered by scorpionic neurotoxins and suggest the use of drugs targeting these receptors, especially the nicotinic one in order to counteract the inflammatory response observed in scorpion envenomation.

  5. Maternal separation diminishes α-adrenergic receptor density and function in renal vasculature from male Wistar-Kyoto rats.

    Science.gov (United States)

    Loria, Analia S; Osborn, Jeffrey L

    2017-07-01

    Adult rats exposed to maternal separation (MatSep) are normotensive but display lower glomerular filtration rate and increased renal neuroadrenergic drive. The aim of this study was to determine the renal α-adrenergic receptor density and the renal vascular responsiveness to adrenergic stimulation in male rats exposed to MatSep. In addition, baroreflex sensitivity was assessed to determine a component of neural control of the vasculature. Using tissue collected from 4-mo-old MatSep and control rats, α 1 -adrenergic receptors (α 1 -ARs) were measured in renal cortex and isolated renal vasculature using receptor binding assay, and the α-AR subtype gene expression was determined by RT-PCR. Renal cortical α 1 -AR density was similar between MatSep and control tissues (B max = 44 ± 1 vs. 42 ± 2 fmol/mg protein, respectively); however, MatSep reduced α 1 -AR density in renal vasculature (B max = 47 ± 4 vs. 62 ± 4 fmol/mg protein, P adrenergic receptor expression and function in the renal vasculature could develop secondary to MatSep-induced overactivation of the renal neuroadrenergic tone. Copyright © 2017 the American Physiological Society.

  6. Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists.

    Directory of Open Access Journals (Sweden)

    Gunnar Kleinau

    Full Text Available Trace amine-associated receptors (TAAR are rhodopsin-like G-protein-coupled receptors (GPCR. TAAR are involved in modulation of neuronal, cardiac and vascular functions and they are potentially linked with neurological disorders like schizophrenia and Parkinson's disease. Subtype TAAR1, the best characterized TAAR so far, is promiscuous for a wide set of ligands and is activated by trace amines tyramine (TYR, phenylethylamine (PEA, octopamine (OA, but also by thyronamines, dopamine, and psycho-active drugs. Unfortunately, effects of trace amines on signaling of the two homologous β-adrenergic receptors 1 (ADRB1 and 2 (ADRB2 have not been clarified yet in detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular reasons for TAAR1 ligand promiscuity and for observed differences in signaling effects on particular aminergic receptors we compared TAAR, tyramine (TAR octopamine (OAR, ADRB1/2 and dopamine receptors at the structural level. We found especially for TAAR1 that the remarkable ligand promiscuity is likely based on high amino acid similarity in the ligand-binding region compared with further aminergic receptors. On the other hand few TAAR specific properties in the ligand-binding site might determine differences in ligand-induced effects compared to ADRB1/2. Taken together, this study points to molecular details of TAAR1-ligand promiscuity and identified specific trace amines as allosteric or orthosteric ligands of particular β-adrenergic receptor subtypes.

  7. GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function

    DEFF Research Database (Denmark)

    Rosenbaum, Daniel M; Cherezov, Vadim; Hanson, Michael A

    2007-01-01

    The beta2-adrenergic receptor (beta2AR) is a well-studied prototype for heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) that respond to diffusible hormones and neurotransmitters. To overcome the structural flexibility of the beta2AR and to facilitate its cr...

  8. Laminar pattern of cholinergic and adrenergic receptors in rat visual cortex using quantitative receptor autoradiography

    International Nuclear Information System (INIS)

    Schliebs, R.; Walch, C.

    1989-01-01

    The laminar distribution of muscarinic acetylcholine receptors, including the M1-receptor subtype, of beta-adrenergic receptors, and noradrenaline uptake sites, was studied in the adult rat visual, frontal, somatosensory and motor cortex, using quantitative receptor autoradiography. In the visual cortex, the highest density of muscarinic acetylcholine receptors was found in layer I. From layer II/III to layer V binding decreases continueously reaching a constant binding level in layers V and VI. This laminar pattern of muscarinic receptor density differs somewhat from that observed in the non-visual cortical regions examined: layer II/III contained the highest receptor density followed by layer I and IV: lowest density was found in layer V and VI. The binding profile of the muscarinic cholinergic M1-subtype through the visual cortex shows a peak in cortical layer II and in the upper part of layer VI, whereas in the non-visual cortical regions cited the binding level was high in layer II/III, moderate in layer I and IV, and low in layer VI. Layers I to IV of the visual cortex contained the highest beta-adrenergic receptor densities, whereas only low binding levels were observed in the deeper layers. A similar laminar distribution was found also in the frontal, somatosensory and motor cortex. The density of noradrenaline uptake sites was high in all layers of the cortical regions studied, but with noradrenaline uptake sites somewhat more concentrated in the superficial layers than in deeper ones. The distinct laminar pattern of cholinergic and noradrenergic receptor sites indicates a different role for acetylcholine and noradrenaline in the functional anatomy of the cerebral cortex, and in particular, the visual cortex. (author)

  9. Laminar pattern of cholinergic and adrenergic receptors in rat visual cortex using quantitative receptor autoradiography

    Energy Technology Data Exchange (ETDEWEB)

    Schliebs, R; Walch, C [Leipzig Univ. (German Democratic Republic). Bereich Medizin; Stewart, M G [Open Univ., Milton Keynes (UK)

    1989-01-01

    The laminar distribution of muscarinic acetylcholine receptors, including the M1-receptor subtype, of beta-adrenergic receptors, and noradrenaline uptake sites, was studied in the adult rat visual, frontal, somatosensory and motor cortex, using quantitative receptor autoradiography. In the visual cortex, the highest density of muscarinic acetylcholine receptors was found in layer I. From layer II/III to layer V binding decreases continueously reaching a constant binding level in layers V and VI. This laminar pattern of muscarinic receptor density differs somewhat from that observed in the non-visual cortical regions examined: layer II/III contained the highest receptor density followed by layer I and IV: lowest density was found in layer V and VI. The binding profile of the muscarinic cholinergic M1-subtype through the visual cortex shows a peak in cortical layer II and in the upper part of layer VI, whereas in the non-visual cortical regions cited the binding level was high in layer II/III, moderate in layer I and IV, and low in layer VI. Layers I to IV of the visual cortex contained the highest beta-adrenergic receptor densities, whereas only low binding levels were observed in the deeper layers. A similar laminar distribution was found also in the frontal, somatosensory and motor cortex. The density of noradrenaline uptake sites was high in all layers of the cortical regions studied, but with noradrenaline uptake sites somewhat more concentrated in the superficial layers than in deeper ones. The distinct laminar pattern of cholinergic and noradrenergic receptor sites indicates a different role for acetylcholine and noradrenaline in the functional anatomy of the cerebral cortex, and in particular, the visual cortex. (author).

  10. The significance of adrenergic receptors for the development of nevus flammeus and nevus anemicus

    International Nuclear Information System (INIS)

    Raff, M.

    1981-01-01

    Examination of patients with nevus flammeus or nevus anemicus showed disturbed sensibility in the area of the nevus in the majority of cases. Histologically and with special technique of histochemistry and fluorescencemicroscopy there was no evidence for neurogenic lesions. However, signs of vegetative disfunction were present: hyperhidrosis and absent reactivity of vasculature in the nevus area to vasoconstrictive and vasodilatatory stimuli. Based on these findings a disturbed regulation of vascular intramural adrenergic receptors seemed possible and really could be demonstrated by means of autoradiography. In both types of nevi only one of the adrenergic receptors could be marked with specific antagonists. Therefore, the persistent vascular dilatation and constriction can be accounted for by the absence of one of these receptors. This abnormal distribution of receptors could be due to a developmental defect influenced by the ''nerve growth factor''. (author)

  11. Role of adrenergic receptors in the caffeine-induced increase in ...

    African Journals Online (AJOL)

    The present study was designed to investigate the effects of alpha and beta adrenergic receptor blockers on caffeine-induced increase in canine hindlimb glucose uptake. The study was carried out on fasted male anaesthetized dogs divided into five groups (5dogs per group). Each dog was given a bolus injection of normal ...

  12. Differential expression and role of hyperglycemia induced oxidative stress in epigenetic regulation of β1, β2 and β3-adrenergic receptors in retinal endothelial cells

    Science.gov (United States)

    2014-01-01

    Background Aberrant epigenetic profiles are concomitant with a spectrum of developmental defects and diseases. Role of methylation is an increasingly accepted factor in the pathophysiology of diabetes and its associated complications. This study aims to examine the correlation between oxidative stress and methylation of β1, β2 and β3-adrenergic receptors and to analyze the differential variability in the expression of these genes under hyperglycemic conditions. Methods Human retinal endothelial cells were cultured in CSC complete medium in normal (5 mM) or high (25 mM) glucose to mimic a diabetic condition. Reverse transcription PCR and Western Blotting were performed to examine the expression of β1, β2 and β3-adrenergic receptors. For detections, immunocytochemistry was used. Bisulfite sequencing method was used for promoter methylation analysis. Apoptosis was determined by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Dichlorodihydrofluorescein diacetate (DCFH-DA) assay was used to measure reactive oxygen species (ROS) production in the cells. Results β1 and β3-adrenergic receptors were expressed in retinal endothelial cells while β2-adrenergic receptor was not detectable both at protein and mRNA levels. Hyperglycemia had no significant effect on β1 and β2-adrenergic receptors methylation and expression however β3-adrenergic receptors showed a significantly higher expression (p adrenergic receptors methylation with no significant effect on β1 and β2-adrenergic receptors. β2-adrenergic receptor was hypermethylated with halted expression. Conclusion Our study demonstrates that β1 and β3-adrenergic receptors expressed in human retinal endothelial cells. Oxidative stress and apoptosis are inversely proportional to the extent of promoter methylation, suggesting that methylation loss might be due to oxidative stress-induced DNA damage. PMID:24885710

  13. Conversion of agonist site to metal-ion chelator site in the beta(2)-adrenergic receptor

    DEFF Research Database (Denmark)

    Elling, C E; Thirstrup, K; Holst, Birgitte

    1999-01-01

    Previously metal-ion sites have been used as structural and functional probes in seven transmembrane receptors (7TM), but as yet all the engineered sites have been inactivating. Based on presumed agonist interaction points in transmembrane III (TM-III) and -VII of the beta(2)-adrenergic receptor,...... as generic, pharmacologic tools to switch 7TM receptors with engineered metal-ion sites on or off at will.......Previously metal-ion sites have been used as structural and functional probes in seven transmembrane receptors (7TM), but as yet all the engineered sites have been inactivating. Based on presumed agonist interaction points in transmembrane III (TM-III) and -VII of the beta(2)-adrenergic receptor......, in this paper we construct an activating metal-ion site between the amine-binding Asp-113 in TM-III-or a His residue introduced at this position-and a Cys residue substituted for Asn-312 in TM-VII. No increase in constitutive activity was observed in the mutant receptors. Signal transduction was activated...

  14. Analysis of hydrophobic interactions of antagonists with the beta2-adrenergic receptor.

    Science.gov (United States)

    Novoseletsky, V N; Pyrkov, T V; Efremov, R G

    2010-01-01

    The adrenergic receptors mediate a wide variety of physiological responses, including vasodilatation and vasoconstriction, heart rate modulation, and others. Beta-adrenergic antagonists ('beta-blockers') thus constitute a widely used class of drugs in cardiovascular medicine as well as in management of anxiety, migraine, and glaucoma. The importance of the hydrophobic effect has been evidenced for a wide range of beta-blocker properties. To better understand the role of the hydrophobic effect in recognition of beta-blockers by their receptor, we carried out a molecular docking study combined with an original approach to estimate receptor-ligand hydrophobic interactions. The proposed method is based on automatic detection of molecular fragments in ligands and the analysis of their interactions with receptors separately. A series of beta-blockers, based on phenylethanolamines and phenoxypropanolamines, were docked to the beta2-adrenoceptor binding site in the crystal structure. Hydrophobic complementarity between the ligand and the receptor was calculated using the PLATINUM web-server (http://model.nmr.ru/platinum). Based on the analysis of the hydrophobic match for molecular fragments of beta-blockers, we have developed a new scoring function which efficiently predicts dissociation constant (pKd) with strong correlations (r(2) approximately 0.8) with experimental data.

  15. Astrocytic β2-adrenergic receptors mediate hippocampal long-term memory consolidation

    KAUST Repository

    Gao, Virginia; Suzuki, Akinobu; Magistretti, Pierre J.; Lengacher, Sylvain; Pollonini, Gabriella; Steinman, Michael Q.; Alberini, Cristina M.

    2016-01-01

    Emotionally relevant experiences form strong and long-lasting memories by critically engaging the stress hormone/neurotransmitter noradrenaline, which mediates and modulates the consolidation of these memories. Noradrenaline acts through adrenergic receptors (ARs), of which β2- Adrenergic receptors (βARs) are of particular importance. The differential anatomical and cellular distribution of βAR subtypes in the brain suggests that they play distinct roles in memory processing, although much about their specific contributions and mechanisms of action remains to be understood. Here we show that astrocytic rather than neuronal β2ARs in the hippocampus play a key role in the consolidation of a fear-based contextual memory. These hippocampal β2ARs, but not β1ARs, are coupled to the training-dependent release of lactate from astrocytes, which is necessary for long- Term memory formation and for underlying molecular changes. This key metabolic role of astrocytic β2ARs may represent a novel target mechanism for stress-related psychopathologies and neurodegeneration.

  16. Astrocytic β2-adrenergic receptors mediate hippocampal long-term memory consolidation

    KAUST Repository

    Gao, Virginia

    2016-07-12

    Emotionally relevant experiences form strong and long-lasting memories by critically engaging the stress hormone/neurotransmitter noradrenaline, which mediates and modulates the consolidation of these memories. Noradrenaline acts through adrenergic receptors (ARs), of which β2- Adrenergic receptors (βARs) are of particular importance. The differential anatomical and cellular distribution of βAR subtypes in the brain suggests that they play distinct roles in memory processing, although much about their specific contributions and mechanisms of action remains to be understood. Here we show that astrocytic rather than neuronal β2ARs in the hippocampus play a key role in the consolidation of a fear-based contextual memory. These hippocampal β2ARs, but not β1ARs, are coupled to the training-dependent release of lactate from astrocytes, which is necessary for long- Term memory formation and for underlying molecular changes. This key metabolic role of astrocytic β2ARs may represent a novel target mechanism for stress-related psychopathologies and neurodegeneration.

  17. THE EFFECTS OF ACUTE AND CHRONIC STRESS ON ERYTHROCYTE DYNAMIC IN COMBINATION WITH ß–ADRENERGIC RECEPTORS BLOCKADE IN RATS

    Directory of Open Access Journals (Sweden)

    Lucian Hritcu

    2005-08-01

    Full Text Available : 3 consecutive days propranolol hydrochloride administration (5 mg/kg b.w., subcutaneous injections under acute and chronic stress conditions causes changes of peripheral erythrocyte distribution in rats. The effects of acute stress and its combination with ȕ-adrenergic receptor blockade on erythrocyte dynamic were more pregnant beside the effects of chronic stress and its combination with ȕ-adrenergic receptor blockade, respectively. ȕ-adrenergic mechanisms were shown to be involved in regulation of erythrocyte dynamic in acute and chronic stress response.

  18. Suppressive Effects of Bee Venom Acupuncture on Paclitaxel-Induced Neuropathic Pain in Rats: Mediation by Spinal α2-Adrenergic Receptor

    Directory of Open Access Journals (Sweden)

    Jiho Choi

    2017-10-01

    Full Text Available Paclitaxel, a chemotherapy drug for solid tumors, induces peripheral painful neuropathy. Bee venom acupuncture (BVA has been reported to have potent analgesic effects, which are known to be mediated by activation of spinal α-adrenergic receptor. Here, we investigated the effect of BVA on mechanical hyperalgesia and spinal neuronal hyperexcitation induced by paclitaxel. The role of spinal α-adrenergic receptor subtypes in the analgesic effect of BVA was also observed. Administration of paclitaxel (total 8 mg/kg, intraperitoneal on four alternate days (days 0, 2, 4, and 6 induced significant mechanical hyperalgesic signs, measured using a von Frey filament. BVA (1 mg/kg, ST36 relieved this mechanical hyperalgesia for at least two hours, and suppressed the hyperexcitation in spinal wide dynamic range neurons evoked by press or pinch stimulation. Both melittin (0.5 mg/kg, ST36 and phospholipase A2 (0.12 mg/kg, ST36 were shown to play an important part in this analgesic effect of the BVA, as they significantly attenuated the pain. Intrathecal pretreatment with the α2-adrenergic receptor antagonist (idazoxan, 50 µg, but not α1-adrenergic receptor antagonist (prazosin, 30 µg, blocked the analgesic effect of BVA. These results suggest that BVA has potent suppressive effects against paclitaxel-induced neuropathic pain, which were mediated by spinal α2-adrenergic receptor.

  19. Suppressive Effects of Bee Venom Acupuncture on Paclitaxel-Induced Neuropathic Pain in Rats: Mediation by Spinal α₂-Adrenergic Receptor.

    Science.gov (United States)

    Choi, Jiho; Jeon, Changhoon; Lee, Ji Hwan; Jang, Jo Ung; Quan, Fu Shi; Lee, Kyungjin; Kim, Woojin; Kim, Sun Kwang

    2017-10-31

    Paclitaxel, a chemotherapy drug for solid tumors, induces peripheral painful neuropathy. Bee venom acupuncture (BVA) has been reported to have potent analgesic effects, which are known to be mediated by activation of spinal α-adrenergic receptor. Here, we investigated the effect of BVA on mechanical hyperalgesia and spinal neuronal hyperexcitation induced by paclitaxel. The role of spinal α-adrenergic receptor subtypes in the analgesic effect of BVA was also observed. Administration of paclitaxel (total 8 mg/kg, intraperitoneal) on four alternate days (days 0, 2, 4, and 6) induced significant mechanical hyperalgesic signs, measured using a von Frey filament. BVA (1 mg/kg, ST36) relieved this mechanical hyperalgesia for at least two hours, and suppressed the hyperexcitation in spinal wide dynamic range neurons evoked by press or pinch stimulation. Both melittin (0.5 mg/kg, ST36) and phospholipase A2 (0.12 mg/kg, ST36) were shown to play an important part in this analgesic effect of the BVA, as they significantly attenuated the pain. Intrathecal pretreatment with the α₂-adrenergic receptor antagonist (idazoxan, 50 µg), but not α₁-adrenergic receptor antagonist (prazosin, 30 µg), blocked the analgesic effect of BVA. These results suggest that BVA has potent suppressive effects against paclitaxel-induced neuropathic pain, which were mediated by spinal α₂-adrenergic receptor.

  20. α2-Adrenergic modulation of the glutamate receptor and transporter function in a chronic ocular hypertension model.

    Science.gov (United States)

    Jung, Kyoung In; Kim, Jie Hyun; Park, Chan Kee

    2015-10-15

    Excitotoxicity, glutamate-induced toxic effects to retinal ganglion cells (RGCs), is one of several mechanisms of RGC loss suggested in glaucoma. In this study, we focused on the role of glutamate transporter of glial cells as well as N-methyl-d-aspartate (NMDA) receptor with regard to glutamate toxicity in glaucoma. We also investigated whether α2-adrenoceptor activation could modulate glutamate transporters and NMDA receptors in a chronic ocular hypertension model. Brimonidine 0.15% was administered topically to the eyes of experimental glaucoma and control animals twice daily. After 8 weeks of intraocular pressure (IOP) elevation, staining with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) revealed an increase in the ganglion cell layer, and the number of TUNEL-positive cells was reduced by brimonidine treatment (P<0.05). Animals with experimentally induced glaucoma exhibited an increase in retinal stress marker glial fibrillary acidic protein (GFAP) immunoreactivity; brimonidine treatment reduced GFAP. Excitatory amino acid transporter 1(EAAT1) expression remained stable throughout the period of chronic ocular hypertension. α2-Adrenergic treatment upregulated EAAT1 protein levels (P<0.05). NMDA receptor (GluN1) expression was stimulated by chronic elevation of IOP, and GluN1-positive cells in ganglion cell layer were co-localized with TUNEL staining. Brimonidine administration suppressed GluN1 levels (P<0.05). These results indicate that brimonidine decreased RGC apoptosis, upregulating EAAT1 and downregulating NMDA receptors. We suggest that topical brimonidine treatment may decrease the glutamate excitotoxicity through modulation of glutamate transporter and NMDA receptor in glaucoma. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Optodynamic simulation of β-adrenergic receptor signalling.

    Science.gov (United States)

    Siuda, Edward R; McCall, Jordan G; Al-Hasani, Ream; Shin, Gunchul; Il Park, Sung; Schmidt, Martin J; Anderson, Sonya L; Planer, William J; Rogers, John A; Bruchas, Michael R

    2015-09-28

    Optogenetics has provided a revolutionary approach to dissecting biological phenomena. However, the generation and use of optically active GPCRs in these contexts is limited and it is unclear how well an opsin-chimera GPCR might mimic endogenous receptor activity. Here we show that a chimeric rhodopsin/β2 adrenergic receptor (opto-β2AR) is similar in dynamics to endogenous β2AR in terms of: cAMP generation, MAP kinase activation and receptor internalization. In addition, we develop and characterize a novel toolset of optically active, functionally selective GPCRs that can bias intracellular signalling cascades towards either G-protein or arrestin-mediated cAMP and MAP kinase pathways. Finally, we show how photoactivation of opto-β2AR in vivo modulates neuronal activity and induces anxiety-like behavioural states in both fiber-tethered and wireless, freely moving animals when expressed in brain regions known to contain β2ARs. These new GPCR approaches enhance the utility of optogenetics and allow for discrete spatiotemporal control of GPCR signalling in vitro and in vivo.

  2. Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the α1-adrenergic receptor.

    Science.gov (United States)

    Pügge, Carolin; Mediratta, Jai; Marcus, Noah J; Schultz, Harold D; Schiller, Alicia M; Zucker, Irving H

    2016-02-01

    Recent data suggest that exercise training (ExT) is beneficial in chronic heart failure (CHF) because it improves autonomic and peripheral vascular function. In this study, we hypothesized that ExT in the CHF state ameliorates the renal vasoconstrictor responses to hypoxia and that this beneficial effect is mediated by changes in α1-adrenergic receptor activation. CHF was induced in rabbits. Renal blood flow (RBF) and renal vascular conductance (RVC) responses to 6 min of 5% isocapnic hypoxia were assessed in the conscious state in sedentary (SED) and ExT rabbits with CHF with and without α1-adrenergic blockade. α1-adrenergic receptor expression in the kidney cortex was also evaluated. A significant decline in baseline RBF and RVC and an exaggerated renal vasoconstriction during acute hypoxia occurred in CHF-SED rabbits compared with the prepaced state (P renal denervation (DnX) blocked the hypoxia-induced renal vasoconstriction in CHF-SED rabbits. α1-adrenergic protein in the renal cortex of animals with CHF was increased in SED animals and normalized after ExT. These data provide evidence that the acute decline in RBF during hypoxia is caused entirely by the renal nerves but is only partially mediated by α1-adrenergic receptors. Nonetheless, α1-adrenergic receptors play an important role in the beneficial effects of ExT in the kidney. Copyright © 2016 the American Physiological Society.

  3. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor

    DEFF Research Database (Denmark)

    Cherezov, Vadim; Rosenbaum, Daniel M; Hanson, Michael A

    2007-01-01

    Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human beta2-adrenergic receptor-T4 lysozyme fusion protein bound to t...

  4. Adrenergic receptor-mediated modulation of striatal firing patterns.

    Science.gov (United States)

    Ohta, Hiroyuki; Kohno, Yu; Arake, Masashi; Tamura, Risa; Yukawa, Suguru; Sato, Yoshiaki; Morimoto, Yuji; Nishida, Yasuhiro; Yawo, Hiromu

    2016-11-01

    Although noradrenaline and adrenaline are some of the most important neurotransmitters in the central nervous system, the effects of noradrenergic/adrenergic modulation on the striatum have not been determined. In order to explore the effects of adrenergic receptor (AR) agonists on the striatal firing patterns, we used optogenetic methods which can induce continuous firings. We employed transgenic rats expressing channelrhodopsin-2 (ChR2) in neurons. The medium spiny neuron showed a slow rising depolarization during the 1-s long optogenetic striatal photostimulation and a residual potential with 8.6-s half-life decay after the photostimulation. As a result of the residual potential, five repetitive 1-sec long photostimulations with 20-s onset intervals cumulatively increased the number of spikes. This 'firing increment', possibly relating to the timing control function of the striatum, was used to evaluate the AR modulation. The β-AR agonist isoproterenol decreased the firing increment between the 1st and 5th stimulation cycles, while the α 1 -AR agonist phenylephrine enhanced the firing increment. Isoproterenol and adrenaline increased the early phase (0-0.5s of the photostimulation) firing response. This adrenergic modulation was inhibited by the β-antagonist propranolol. Conversely, phenylephrine and noradrenaline reduced the early phase response. β-ARs and α 1 -ARs work in opposition controlling the striatal firing initiation and the firing increment. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  5. Muscarinic and alpha 1-adrenergic receptor binding characteristics of saw palmetto extract in rat lower urinary tract.

    Science.gov (United States)

    Suzuki, Mayumi; Oki, Tomomi; Sugiyama, Tomomi; Umegaki, Keizo; Uchida, Shinya; Yamada, Shizuo

    2007-06-01

    To elucidate the in vitro and ex vivo effects of saw palmetto extract (SPE) on autonomic receptors in the rat lower urinary tract. The in vitro binding affinities for alpha 1-adrenergic, muscarinic, and purinergic receptors in the rat prostate and bladder were measured by radioligand binding assays. Rats received vehicle or SPE (0.6 to 60 mg/kg/day) orally for 4 weeks, and alpha 1-adrenergic and muscarinic receptor binding in tissues of these rats were measured. Saw palmetto extract inhibited specific binding of [3H]prazosin and [N-methyl-3H]scopolamine methyl chloride (NMS) but not alpha, beta-methylene adenosine triphosphate [2,8-(3)H]tetrasodium salt in the rat prostate and bladder. The binding activity of SPE for muscarinic receptors was four times greater than that for alpha 1-adrenergic receptors. Scatchard analysis revealed that SPE significantly reduced the maximal number of binding sites (Bmax) for each radioligand in the prostate and bladder under in vitro condition. Repeated oral administration of SPE to rats brought about significant alteration in Bmax for prostatic [3H]prazosin binding and for bladder [3H]NMS binding. Such alteration by SPE was selective to the receptors in the lower urinary tract. Saw palmetto extract exerts significant binding activity on autonomic receptors in the lower urinary tract under in vitro and in vivo conditions.

  6. Dopamine D1 and D2 receptor immunoreactivities in the arcuate-median eminence complex and their link to the tubero-infundibular dopamine neurons

    Directory of Open Access Journals (Sweden)

    W. Romero-Fernandez

    2014-07-01

    Full Text Available Dopamine D1 and D2 receptor immunohistochemistry and Golgi techniques were used to study the structure of the adult rat arcuate-median eminence complex, and determine the distribution of the dopamine D1 and D2 receptor immunoreactivities therein, particularly in relation to the tubero-infundibular dopamine neurons. Punctate dopamine D1 and D2 receptor immunoreactivities, likely located on nerve terminals, were enriched in the lateral palisade zone built up of nerve terminals, while the densities were low to modest in the medial palisade zone. A codistribution of dopamine D1 receptor or dopamine D2 receptor immunoreactive puncta with tyrosine hydroxylase immunoreactive nerve terminals was demonstrated in the external layer. Dopamine D1 receptor but not dopamine D2 receptor immnunoreactivites nerve cell bodies were found in the ventromedial part of the arcuate nucleus and in the lateral part of the internal layer of the median eminence forming a continuous cell mass presumably representing neuropeptide Y immunoreactive nerve cell bodies. The major arcuate dopamine/ tyrosine hydroxylase nerve cell group was found in the dorsomedial part. A large number of tyrosine hydroxylase immunoreactive nerve cell bodies in this region demonstrated punctate dopamine D1 receptor immunoreactivity but only a few presented dopamine D2 receptor immunoreactivity which were mainly found in a substantial number of tyrosine hydroxylase cell bodies of the ventral periventricular hypothalamic nucleus, also belonging to the tubero-infundibular dopamine neurons. Structural evidence for projections of the arcuate nerve cells into the median eminence was also obtained. Distal axons formed horizontal axons in the internal layer issuing a variable number of collaterals classified into single or multiple strands located in the external layer increasing our understanding of the dopamine nerve terminal networks in this region.  Dopamine D1 and D2 receptors may therefore directly

  7. Functional response of white rats isolated heart to the stimulation of adrenergic receptors after gamma-irradiation in low doses

    International Nuclear Information System (INIS)

    Antonenko, A.N.; Lobanok, L.M.

    1999-01-01

    It was investigated the effects of acute gamma-irradiation on bio mechanical activity of rats heart isolated by Langendorf's method in early and delayed terms after exposure to gamma-rays. Intra ventricle pressure and the rate of its growth, volumetric rate of coronal flow, frequency of heart contraction were registered. Stimulation of alpha-adrenergic receptors was conducted by means of specific agonist mesatone and stimulation of beta-adrenergic receptors was made by means of isoprenaline. The study has shown that acute irradiation of rats caused the decrease of both contractile ability and relaxation of myocardium in a 10 days after exposure. In delayed period bio mechanical activity of isolated heart was restored. Functional response of heart to the stimulation of alpha- and beta-adrenergic receptors was decreased in all terms of investigation

  8. Probenecid inhibits α-adrenergic receptor-mediated vasoconstriction in the human leg vasculature

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Piil, Peter Bergmann; Kiehn, Oliver Thistrup

    2018-01-01

    to α1- and α2-adrenergic receptor stimulation in the human forearm and leg vasculature of young healthy male subjects (23±3 years). By use of immunolabeling and confocal microscopy, Panx1 channels were found to be expressed in vascular smooth muscle cells of arterioles in human leg skeletal muscle....... Probenecid treatment increased (Padrenergic receptor stimulation) by ≈15%, whereas the response to the α1-agonist phenylephrine was unchanged. Inhibition...

  9. Effects of local alpha2-adrenergic receptor blockade on adipose tissue lipolysis during prolonged systemic adrenaline infusion in normal man

    DEFF Research Database (Denmark)

    Simonsen, Lene; Enevoldsen, Lotte H; Stallknecht, Bente

    2008-01-01

    During prolonged adrenaline infusion, lipolysis peaks within 30 min and thereafter tends to decline, and we hypothesized that the stimulation of local adipose tissue alpha2-adrenergic receptors accounts for this decline. The lipolytic effect of a prolonged intravenous adrenaline infusion combined....... Regional adipose tissue blood flow was measured by the (133)Xe clearance technique. Regional glycerol output (lipolytic rate) was calculated from these measurements and simultaneous measurements of arterial glycerol concentrations. Adrenaline infusion increased lipolysis in all three depots (data...... circulating adrenaline concentrations, and the decrease in lipolysis in subcutaneous adipose tissue under prolonged adrenaline stimulation is thus not attributed to alpha2-adrenergic receptor inhibition of lipolysis. However, in the preperitoneal adipose tissue depot, alpha2-adrenergic receptor tone plays...

  10. Determination of beta-adrenergic receptor blocking pharmaceuticals in united states wastewater effluent

    Energy Technology Data Exchange (ETDEWEB)

    Huggett, D.B.; Khan, I.A.; Foran, C.M.; Schlenk, D

    2003-02-01

    This is the first report of beta-adrenergic receptor antagonist pharmaceuticals in United States wastewater effluent. - Beta adrenergic receptor antagonists ({beta}-Blockers) are frequently prescribed medications in the United States and have been identified in European municipal wastewater effluent, however no studies to date have investigated these compounds in United States wastewater effluent. Municipal wastewater effluent was collected from treatment facilities in Mississippi, Texas, and New York to investigate the occurrence of metoprolol, nadolol, and propranolol. Propranolol was identified in all wastewater samples analyzed (n=34) at concentrations {<=}1.9 {mu}g/l. Metoprolol and nadolol were identified in {>=}71% of the samples with concentrations of metoprolol {<=}1.2 {mu}g/l and nadolol {<=}0.36 {mu}g/l. Time course studies at both Mississippi plants and the Texas plant indicate that concentrations of propranolol, metoprolol, and nadolol remain relatively constant at each sampling period. This study indicates that {beta}-Blockers are present in United States wastewater effluent in the ng/l to {mu}g/l range.

  11. Time dependent changes in myocardial norepinephrine concentration and adrenergic receptor density following X-irradiation of the rat heart

    NARCIS (Netherlands)

    Franken, N. A.; van der Laarse, A.; Bosker, F. J.; Reynart, I. W.; van Ravels, F. J.; Strootman, E.; Wondergem, J.

    1992-01-01

    The hearts of 9 to 12-weeks-old Sprague-Dawley rats were locally irradiated with a single dose of 20 Gy. The effects on myocardial norepinephrine concentrations and on alpha-adrenergic and beta-adrenergic receptor densities was examined up to 16 months post-treatment. Myocardial norepinephrine

  12. Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats.

    Science.gov (United States)

    Rudoy, C A; Van Bockstaele, E J

    2007-06-30

    Anxiety has been indicated as one of the main symptoms of the cocaine withdrawal syndrome in human addicts and severe anxiety during withdrawal may potentially contribute to relapse. As alterations in noradrenergic transmission in limbic areas underlie withdrawal symptomatology for many drugs of abuse, the present study sought to determine the effect of cocaine withdrawal on beta-adrenergic receptor (beta(1) and beta(2)) expression in the amygdala. Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that beta(1)-adrenergic receptor, but not beta(2)-adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with betaxolol, a highly selective beta(1)-adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 h following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 h following the last betaxolol injection. Following behavioral testing, betaxolol effects on beta(1)-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal. Animals treated with betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline. Furthermore

  13. Cannabinoid receptor-2 immunoreactivity is associated with survival in squamous cell carcinoma of the head and neck.

    Science.gov (United States)

    Klein Nulent, Thomas J W; Van Diest, Paul J; van der Groep, Petra; Leusink, Frank K J; Kruitwagen, Cas L J J; Koole, Ronald; Van Cann, Ellen M

    2013-10-01

    The prediction of progression of individual tumours, prognosis, and survival in squamous cell carcinoma (SCC) of the head and neck is difficult. Cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptor expression is related to survival in several types of cancer, and the aim of this study was to find out whether the expression of CB1 and CB2 receptors is associated with survival in primary SCC of the head and neck. We made immunohistochemical analyses of the cannabinoid receptors on tissue arrays from 240 patients with the disease. Receptor immunoreactivity was classified as none, weak, moderate, or strong staining. Overall survival and disease-specific survival were plotted using Kaplan-Meier survival curves. A multivariate Cox proportional hazard model was created with all the relevant clinical and pathological features. Strong immunoreactivity of the CB2 receptor was significantly associated with reduced disease-specific survival (p=0.007). Cox-proportional hazard ratio (HR) showed that CB2 receptor immunoreactivity contributed to the prediction of survival (HR 3.6, 95% CI 1.5-8.7, p=0.004). Depth of invasion (HR 2.2, 95% CI 1.2-4.2, p=0.01) and vascular invasion (HR 2.5, 95% CI 1.4-4.5, p=0.001) were also associated with survival. Copyright © 2013 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

  14. Muscarinic cholinergic and alpha 2-adrenergic receptors in the epithelium and muscularis of the human ileum

    International Nuclear Information System (INIS)

    Lepor, H.; Rigaud, G.; Shapiro, E.; Baumann, M.; Kodner, I.J.; Fleshman, J.W.

    1990-01-01

    The aim of this study was to characterize the binding and functional properties of muscarinic cholinergic (MCh) and alpha 2-adrenergic receptors in the human ileum to provide insight into pharmacologic strategies for managing urinary and fecal incontinence after bladder and rectal replacement with intestinal segments. MCh and alpha 2-adrenergic binding sites were characterized in the epithelium and muscularis of eight human ileal segments with 3H-N-methylscopolamine and 3H-rauwolscine, respectively. The dissociation constant for 3H-N-methylscopolamine in the epithelium and muscularis was 0.32 +/- 0.07 nmol/L and 0.45 +/- 0.10 nmol/L, respectively (p = 0.32). The MCh receptor content was approximately eightfold greater in the muscularis compared with the epithelium (p = 0.008). The dissociation constant for 3H-rauwolscine in the muscularis and epithelium was 2.55 +/- 0.42 nmol/L and 2.03 +/- 0.19 nmol/L, respectively (p = 0.29). The alpha 2-adrenoceptor density was twofold greater in the epithelium compared with the muscularis (p = 0.05). Noncumulative concentration-response experiments were performed with carbachol, an MCh agonist, and UK-14304, a selective alpha 2-adrenergic agonist. The epithelium did not contract in the presence of high concentrations of carbachol and UK-14304. The muscularis preparations were responsive only to carbachol. The muscularis contains primarily MCh receptors mediating smooth muscle contraction. The alpha 2-adrenoceptors are localized primarily to the epithelium and may regulate water secretion in the intestine. The distribution and functional properties of ileal MCh and alpha 2-adrenergic receptors provide a theoretic basis for the treatment of incontinence after bladder and rectal replacement with intestinal segments

  15. Norepinephrine-induced alteration in the coupling of α1-adrenergic receptor occupancy to calcium efflux in rabbit aortic smooth muscle cells

    International Nuclear Information System (INIS)

    Colucci, W.S.; Alexander, R.W.

    1986-01-01

    To determine whether α-adrenergic desensitization of vascular smooth muscle is due to an alteration in α 1 -adrenergic receptor coupling, the authors determined the relationship between receptor occupancy and maximal receptor-coupled Ca 2+ efflux in cultured rabbit aortic smooth muscle cells (i) under basal conditions as defined by receptor inactivation with phenoxybenzamine and (ii) after 48 hr of exposure to several concentrations of 1-norepinephrine (NE). Neither phenoxybenzamine nor NE exposure caused a change in binding affinity for [ 3 H]prazosin or NE. Maximal [ 3 H]prazosin binding capacity and maximal NE-stimulated 45 Ca 2+ efflux decreased progressively with exposure of incubated cells to increasing concentrations of phenoxybenzamine or NE. An approximately 80% decrease in maximal [ 3 H]prazosin binding capacity caused by either phenoxybenzamine or NE resulted in complete loss of NE-stimulated 45 Ca 2+ efflux, indicating that under these conditions approximately 20% of α 1 -adrenergic receptors are not coupled to the Ca 2+ efflux. Under basal conditions, the relationship between maximal [ 3 H]prazosin binding capacity and maximal NE-stimulated 45 Ca 2+ efflux was markedly nonlinear, so that a near maximal response could be elicited by occupancy of only approximately 40% of the receptors. Thus, an alteration in occupancy-response coupling at a step proximal to Ca 2+ mobilization and/or influx, rather than a reduction in receptor number, is of primary importance in the process of agonist-induced α-adrenergic receptor desensitization of vascular smooth muscle cells

  16. Synthesis and biological evaluation of [11C]MK-912 as an α2-adrenergic receptor radioligand for PET studies

    International Nuclear Information System (INIS)

    Shiue Chyngyann; Pleus, Richard C.; Shiue, Grace G.; Rysavy, Joseph A.; Sunderland, John J.; Cornish, Kurtis G.; Young, Steven D.; Bylund, David B.

    1998-01-01

    ABSTRACT. In vitro studies showed that MK-912 ((2S, 12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octahydro-2H-benzo[b]furo [2,3-a]quinolizine)-2,4'-pyrimidin-2'-one) is a potent α 2 -adrenergic receptor antagonist with high affinity (K i = 0.42, 0.26 and 0.03 nM to α 2A , α 2B and α 2C , respectively) and high selectivity (α 2A /α 1A = 240; α 2A /D-1 = 3600; α 2A /D-2 3500; α 2A /5-HT 1 = 700; α 2A /5-HT 2 = 4100). The compound was labeled with 11 C and evaluated in rodents and monkey as a specific radioligand for studying α 2 -adrenergic receptors using PET. [ 11 C]MK-912 was synthesized by methylation of its desmethyl precursor, L-668,929, with [ 11 C]CH 3 I in (Bu 3 O)P=O at 85 deg. C for 8 min followed by purification with HPLC in 18% yield in a synthesis time of 45 min from end of bombardment (EOB). The specific activity was 0.83-0.93 Ci/μmol and the radiochemical purity was 97%. The initial uptake of [ 11 C]MK-912 in mouse brain, heart, lung, liver and kidney was high (5%, 4%, 5%, 17% and 8% per gram of organ, respectively, at 5 min postinjection) and the activities were then slowly cleared from these organs. The uptake of [ 11 C]MK-912 in rat olfactory tubercle, a brain region with high density of α 2 -adrenergic receptors, was reduced by 30%, and the ratio of radioactivity in olfactory tubercle/cerebellum was reduced from 2:1 to 1:1 by coinjection of [ 11 C]MK-912 with a potent α 2 -adrenergic receptor antagonist, atipamezole (3 mg/kg), indicating that compound 2 binds to α 2 -adrenergic receptors. However, a PET study in a rhesus monkey revealed that the initial influx of [ 11 C]MK-912 into various brain regions (cerebellum, cortex, olfactory tubercle and striatum) was high (0.02%/cc), and the radioactivity was then washed out slowly and without significantly differential retention in these brain regions. This, coupled with the fact that none of the high-density α 2 -adrenergic receptor brain regions exceeds a few millimeters in diameter

  17. Noradrenaline, oxymetazoline and phorbol myristate acetate induce distinct functional actions and phosphorylation patterns of α1A-adrenergic receptors.

    Science.gov (United States)

    Alcántara-Hernández, Rocío; Hernández-Méndez, Aurelio; Romero-Ávila, M Teresa; Alfonzo-Méndez, Marco A; Pupo, André S; García-Sáinz, J Adolfo

    2017-12-01

    In LNCaP cells that stably express α 1A -adrenergic receptors, oxymetazoline increased intracellular calcium and receptor phosphorylation, however, this agonist was a weak partial agonist, as compared to noradrenaline, for calcium signaling. Interestingly, oxymetazoline-induced receptor internalization and desensitization displayed greater effects than those induced by noradrenaline. Phorbol myristate acetate induced modest receptor internalization and minimal desensitization. α 1A -Adrenergic receptor interaction with β-arrestins (colocalization/coimmunoprecipitation) was induced by noradrenaline and oxymetazoline and, to a lesser extent, by phorbol myristate acetate. Oxymetazoline was more potent and effective than noradrenaline in inducing ERK 1/2 phosphorylation. Mass spectrometric analysis of immunopurified α 1A -adrenergic receptors from cells treated with adrenergic agonists and the phorbol ester clearly showed that phosphorylated residues were present both at the third intracellular loop and at the carboxyl tail. Distinct phosphorylation patterns were observed under the different conditions. The phosphorylated residues were: a) Baseline and all treatments: T233; b) noradrenaline: S220, S227, S229, S246, S250, S389; c) oxymetazoline: S227, S246, S381, T384, S389; and d) phorbol myristate acetate: S246, S250, S258, S351, S352, S401, S402, S407, T411, S413, T451. Our novel data, describing the α 1A -AR phosphorylation sites, suggest that the observed different phosphorylation patterns may participate in defining adrenoceptor localization and action, under the different conditions examined. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Activation of vascular cholinergic and adrenergic receptors induced by gamma rays

    International Nuclear Information System (INIS)

    Alya, G.

    1999-10-01

    Activation of vascular cholinergic receptors and adrenoceptors plays an important role in vasomotoricity and peripheric vascular resistance. These factors are essential in maintaining a stable blood pressure. The aim of this study is to investigate the radiosensitivity differences between vascular cholinergic receptors and adrenoceptors, and consequently to determinate the effects of ionizing radiation (whole body irradiation) on contractile response regulation of vascular smooth muscle fibers VSMF isolated from rat portal vein. Our results show that Clonidine, (non-specific adrenergic agonist), and phenylephrine which is more specific α1-adrenoceptor agonist, increase the VSMF contractions. The maximum effect is obtained at 10 -5 - 3.10 -5 M. On irradiated rats (1-3-5 Gy), there is an important shift thus, the maximal response (E m ax) can be obtained in lower concentrations of clonidine and phenylephrine. Irradiation deceases the contractile responses of VSMF mediated by cholinergic stimulation, in a dose dependant manner. With E m ax 1 Gy>E m ax 3 Gy>E m ax 5 Gy. Irradiated muscular fibers became less sensitive to acetylcholine, thus 3.10 -8 M. A. ch induced more than 50% of contraction force increase in normal conditions. This concentration induce generally a negligible effect after irradiation. The results reveal the existence of radiosensitivity differences between vascular cholinergic and adrenergic receptors. (author)

  19. β(2) -adrenergic receptor Thr164IIe polymorphism, blood pressure and ischaemic heart disease in 66 750 individuals

    DEFF Research Database (Denmark)

    Thomsen, M; Dahl, Morten; Tybjærg-Hansen, Anne

    2012-01-01

    Abstract. Thomsen M, Dahl M, Tybjaerg-Hansen A, Nordestgaard BG (Copenhagen University Hospital, Copenhagen; University of Copenhagen, Copenhagen, Denmark). ß(2) -adrenergic receptor Thr164IIe polymorphism, blood pressure and ischaemic heart disease in 66 750 individuals. J Intern Med 2011; doi: 10.......1111/j.1365-2796.2011.02447.x Objectives. The ß(2) -adrenergic receptor (ADRB2) is located on smooth muscle cells and is an important regulator of smooth muscle tone. The Thr164Ile polymorphism (rs1800888) in the ADRB2 gene is rare but has profound functional consequences on receptor function and could...

  20. Chromosomal organization of adrenergic receptor genes

    International Nuclear Information System (INIS)

    Yang-Feng, T.L.; Xue, Feiyu; Zhong, Wuwei; Cotecchia, S.; Frielle, T.; Caron, M.G.; Lefkowitz, R.J.; Francke, U.

    1990-01-01

    The adrenergic receptors (ARs) (subtypes α 1 , α 2 , β 1 , and β 2 ) are a prototypic family of guanine nucleotide binding regulatory protein-coupled receptors that mediate the physiological effects of the hormone epinephrine and the neurotransmitter norepinephrine. The authors have previously assigned the genes for β 2 -and α 2 -AR to human chromosomes 5 and 10, respectively. By Southern analysis of somatic cell hybrids and in situ chromosomal hybridization, they have now mapped the α 1 -AR gene to chromosome 5q32→q34, the same position as β 2 -AR, and the β 1 -AR gene to chromosome 10q24→q26, the region where α 2 -AR, is located. In mouse, both α 2 -and β 1 -AR genes were assigned to chromosome 19, and the α 1 -AR locus was localized to chromosome 11. Pulsed field gel electrophoresis has shown that the α 1 -and β 2 -AR genes in humans are within 300 kilobases (kb) and the distance between the α 2 - and β 1 -AR genes is <225 kb. The proximity of these two pairs of AR genes and the sequence similarity that exists among all the ARs strongly suggest that they are evolutionarily related. Moreover, they likely arose from a common ancestral receptor gene and subsequently diverged through gene duplication and chromosomal duplication to perform their distinctive roles in mediation the physiological effects of catecholamines. The AR genes thus provide a paradigm for understanding the evolution of such structurally conserved yet functionally divergent families off receptor molecules

  1. Topical administration of adrenergic receptor pharmaceutics and nerve growth factor

    OpenAIRE

    Steinle, Jena

    2010-01-01

    Jena J SteinleDepartments of Ophthalmology and Anatomy and Neurobiology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USAAbstract: Topical application of nerve growth factor (NGF) and adrenergic receptor pharmaceutics are currently in use for corneal ulcers and glaucoma. A recent interest in the neuroprotective abilities of NGF has led to a renewed interest in NGF as a therapeutic for retinal and choroidal diseases. NGF can promote cell proliferati...

  2. 164Ile allele in the beta2-Adrenergic receptor gene is associated with risk of elevated blood pressure in women. The Copenhagen City Heart Study

    DEFF Research Database (Denmark)

    Sethi, AA; Tybjærg-Hansen, A; Jensen, Gorm Boje

    2005-01-01

    Since beta2-adrenergic receptors are important regulators of blood pressure, genetic variation in this receptor could explain risk of elevated blood pressure in selected individuals. We tested the hypothesis that Gly16Arg, Gln27Glu, and Thr164Ile in the beta2-adrenergic receptor gene associated w...

  3. In Vivo Phosphoproteomics Analysis Reveals the Cardiac Targets of β-Adrenergic Receptor Signaling

    DEFF Research Database (Denmark)

    Lundby, Alicia; Andersen, Martin N; Steffensen, Annette B

    2013-01-01

    β-Blockers are widely used to prevent cardiac arrhythmias and to treat hypertension by inhibiting β-adrenergic receptors (βARs) and thus decreasing contractility and heart rate. βARs initiate phosphorylation-dependent signaling cascades, but only a small number of the target proteins are known. We...

  4. Determination of beta-adrenergic receptor blocking pharmaceuticals in united states wastewater effluent

    International Nuclear Information System (INIS)

    Huggett, D.B.; Khan, I.A.; Foran, C.M.; Schlenk, D.

    2003-01-01

    This is the first report of beta-adrenergic receptor antagonist pharmaceuticals in United States wastewater effluent. - Beta adrenergic receptor antagonists (β-Blockers) are frequently prescribed medications in the United States and have been identified in European municipal wastewater effluent, however no studies to date have investigated these compounds in United States wastewater effluent. Municipal wastewater effluent was collected from treatment facilities in Mississippi, Texas, and New York to investigate the occurrence of metoprolol, nadolol, and propranolol. Propranolol was identified in all wastewater samples analyzed (n=34) at concentrations ≤1.9 μg/l. Metoprolol and nadolol were identified in ≥71% of the samples with concentrations of metoprolol ≤1.2 μg/l and nadolol ≤0.36 μg/l. Time course studies at both Mississippi plants and the Texas plant indicate that concentrations of propranolol, metoprolol, and nadolol remain relatively constant at each sampling period. This study indicates that β-Blockers are present in United States wastewater effluent in the ng/l to μg/l range

  5. Involvement of norepinephrine activity in the regulation of α1 adrenergic receptors in the medial preoptic nucleus of estradiol-treated rats

    International Nuclear Information System (INIS)

    Sortino, M.A.; Weiland, N.G.; Wise, P.M.

    1989-01-01

    To establish whether the diurnal decrease in the density of α1 receptors observed in the medial preoptic nucleus (MPN) of estrogen (E 2 )-treated rats is related to the concomitant diurnal increase in norepinephrine (NE) turnover rates, we quantitiated the density of [ 3 H]-Prazosin binding to α1 receptors after blockade of NE turnover with alpha-methyl-paratyrosine (αMPT). A series of preliminary studies was performed to rule out an interference of this drug with [ 3 H]-Prazosin binding to α1 adrenergic receptors in vitro and in vivo. Incubation of brain slices with αMPT produced a dose-dependent inhibition of [ 3 H]-Prazosin binding to α1 adrenergic receptors with an IC 50 of approximately 6 mM. Scatchard analysis demonstrated that αMPT exhibited a simple competitive interaction with [ 3 H]-Prazosin binding sites as shown by an increase in the apparent dissociation constant (Kd) of the ligand and no change in the number of α1 receptors (B/sub max/). In contrast, preincubation of brain slices with αMPT and prior in vivo administration of αMPT did not affect [ 3 H]-Prazosin binding to α1 adrenergic receptors. The density of α1 adrenergic receptors in MPN was quantitated autoradiographically. Blockade of NE turnover with αMPT only partially prevented the reduction in α1 receptor density observed in the E 2 -treated rats, suggesting that the decrease in the level of [ 3 H]-Prazosin binding sites cannot be completely ascribed to increased NE turnover rates

  6. Betaxolol, a selective β1-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats

    Science.gov (United States)

    Rudoy, C.A.; Van Bockstaele, E.J.

    2007-01-01

    Background Anxiety has been indicated as one of the main symptoms of the cocaine withdrawal syndrome in human addicts and severe anxiety during withdrawal may potentially contribute to relapse. As alterations in noradrenergic transmission in limbic areas underlie withdrawal symptomatology for many drugs of abuse, the present study sought to determine the effect of cocaine withdrawal on β-adrenergic receptor (β1 and β2) expression in the amygdala. Methods Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that β1–adrenergic receptor, but not β2–adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with betaxolol, a highly selective β1–adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 hours following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 hours following the last betaxolol injection. Following behavioral testing, betaxolol effects on β1-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal. Results Animals treated with betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline

  7. β3-Adrenergic receptors, adipokines and neuroendocrine activation during stress induced by repeated immune challenge in male and female rats.

    Science.gov (United States)

    Csanova, Agnesa; Hlavacova, Natasa; Hasiec, Malgorzata; Pokusa, Michal; Prokopova, Barbora; Jezova, Daniela

    2017-05-01

    The main hypothesis of the study is that stress associated with repeated immune challenge has an impact on β 3 -adrenergic receptor gene expression in the brain. Sprague-Dawley rats were intraperitoneally injected with increasing doses of lipopolysaccharide (LPS) for five consecutive days. LPS treatment was associated with body weight loss and increased anxiety-like behavior. In LPS-treated animals of both sexes, β 3 -receptor gene expression was increased in the prefrontal cortex but not the hippocampus. LPS treatment decreased β 3 -receptor gene expression in white adipose tissue with higher values in males compared to females. In the adipose tissue, LPS reduced peroxisome proliferator-activated receptor-gamma, leptin and adiponectin gene expression, but increased interleukin-6 expression, irrespective of sex. Repeated immune challenge resulted in increased concentrations of plasma aldosterone and corticosterone with higher values of corticosterone in females compared to males. Concentrations of dehydroepiandrosterone (DHEA) in plasma were unaffected by LPS, while DHEA levels in the frontal cortex were lower in the LPS-treated animals compared to the controls. Thus, changes of DHEA levels in the brain take place irrespective of the changes of this neurosteroid in plasma. We have provided the first evidence on stress-induced increase in β 3 -adrenergic receptor gene expression in the brain. Greater reduction of β 3 -adrenergic receptor expression in the adipose tissue and of the body weight gain by repeated immune challenge in male than in female rats suggests sex differences in the role of β 3 -adrenergic receptors in the metabolic functions. LPS-induced changes in adipose tissue regulatory factors and hormone concentrations might be important for coping with chronic infections.

  8. Norepinephrine signaling through β-adrenergic receptors is critical for expression of cocaine-induced anxiety

    Science.gov (United States)

    Schank, Jesse R.; Liles, L. Cameron; Weinshenker, David

    2008-01-01

    Background Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine’s rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. Methods In this study we evaluated the performance of dopamine β-hydroxylase knockout (Dbh −/−) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. Results We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/−) mice, as measured by a decrease in open arm exploration. Dbh −/− mice had normal baseline performance in the EPM, but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/− mice following administration of disulfiram, a DBH inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the β-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/− and wild-type C57BL6/J mice, while the α1 antagonist prazosin and the α2 antagonist yohimbine had no effect. Conclusions These results indicate that noradrenergic signaling via β-adrenergic receptors is required for cocaine-induced anxiety in mice. PMID:18083142

  9. Norepinephrine signaling through beta-adrenergic receptors is critical for expression of cocaine-induced anxiety.

    Science.gov (United States)

    Schank, Jesse R; Liles, L Cameron; Weinshenker, David

    2008-06-01

    Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/-) mice, as measured by a decrease in open arm exploration. The Dbh -/- mice had normal baseline performance in the EPM but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/- mice following administration of disulfiram, a dopamine beta-hydroxylase (DBH) inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the beta-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/- and wild-type C57BL6/J mice, while the alpha(1) antagonist prazosin and the alpha(2) antagonist yohimbine had no effect. These results indicate that noradrenergic signaling via beta-adrenergic receptors is required for cocaine-induced anxiety in mice.

  10. An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity

    Directory of Open Access Journals (Sweden)

    Ju Youn Beak, PhD

    2017-02-01

    Full Text Available Summary: Alpha-1 adrenergic receptors (α1-ARs play adaptive and protective roles in the heart. Dabuzalgron is an oral selective α1A-AR agonist that was well tolerated in multiple clinical trials of treatment for urinary incontinence, but has never been used to treat heart disease in humans or animal models. In this study, the authors administered dabuzalgron to mice treated with doxorubicin (DOX, a widely used chemotherapeutic agent with dose-limiting cardiotoxicity that can lead to heart failure (HF. Dabuzalgron protected against DOX-induced cardiotoxicity, likely by preserving mitochondrial function. These results suggest that activating cardiac α1A-ARs with dabuzalgron, a well-tolerated oral agent, might represent a novel approach to treating HF. Key Words: alpha adrenergic receptors, anthracyclines, cardioprotection, catecholamines, heart failure

  11. The change of β-adrenergic system after cessation of lead exposure

    International Nuclear Information System (INIS)

    Chang, H.-R.; Tsao, D.-A.; Yu, H.-S.; Ho, C.-K.

    2005-01-01

    For understanding a reversible or irreversible harm of β-adrenergic system in lead induced cardiovascular disease (hypertension), We set up animal model to estimate the change of blood pressure and sympathetic nervous system after lead exposure withdrawn in the study. We address three topics in this study: (a) the relationship between withdrawal time of lead exposure and β-adrenergic receptor, plasma catecholamine level, blood pressure, and lead level in heart, aorta, and kidney in lead-induced hypertensive rats after lead exposure stopped; (b) the relationship between blood pressure and β-adrenergic receptor in heart, aorta, and kidney; (c) the estimation of relationship between lead withdrawn and the variation of β-adrenergic system. Wistar rats were chronically fed with 2% lead acetate (experimental group) and water (control group) for 2 months. The rats were divided into 8 groups by withdrawal time of lead exposure stopped. Plasma catecholamine level was measured by high-performance liquid chromatography. Radioligand binding assay was measured by a method that fulfilled strict criteria of β-adrenergic receptor using the ligand [ 125 I]iodocyanopindolol. The levels of lead were determined by electrothermal atomic absorption spectrometry. The results showed that a close relation between reduced lead level and the plasma catecholamine level decreased, aorta β-adrenergic receptor increased, kidney β-adrenergic receptor diminished, heart β-adrenergic receptor increased, and blood pressure dropped after lead exposure withdrawn. The study on the regulation of β-adrenergic system in lead-induced hypertension after lead withdrawn might also provide insight about the nature of this disease state

  12. Circulating sex hormones and gene expression of subcutaneous adipose tissue oestrogen and alpha-adrenergic receptors in HIV-lipodystrophy: implications for fat distribution

    DEFF Research Database (Denmark)

    Andersen, Ove; Pedersen, Steen B; Svenstrup, Birgit

    2007-01-01

    of alpha2A-adrenergic-receptor correlated positively with expression of oestrogen-receptor-alpha. CONCLUSIONS: The results fit the hypothesis that sex hormones play a role in altered fat distribution and insulin sensitivity of male patients with HIV-lipodystrophy. The effect of oestradiol...... patients, correlated positively with both plasma oestradiol and testosterone (n = 31). Glycerol concentration during clamp (a marker of lipolysis) correlated inversely with expression of alpha2A-adrenergic-receptor, ratio of subcutaneous to total abdominal fat mass, and limb fat, respectively. Expression...

  13. Analgesic Effects of Diluted Bee Venom Acupuncture Mediated by δ-Opioid and α2-Adrenergic Receptors in Osteoarthritic Rats.

    Science.gov (United States)

    Huh, Jeong-Eun; Seo, Byung-Kwan; Lee, Jung-Woo; Kim, Chanyoung; Park, Yeon-Cheol; Lee, Jae-Dong; Baek, Yong-Hyeon

    2017-06-23

    Context • Pain from osteoarthritis is associated with peripheral nociception and central pain processing. Given the unmet need for innovative, effective, and well-tolerated therapies, many patients, after looking for more satisfactory alternatives, decide to use complementary and alternative modalities. The analgesic mechanism of subcutaneous injections of diluted bee venom into an acupoint is thought to be part of an anti-inflammatory effect and the central modulation of pain processing. Objectives • Using the rat model of collagenase-induced osteoarthritis (CIOA), the study intended to investigate the analgesic effects of bee venom acupuncture (BVA) as they are related to the acupuncture points and dosage used and to determine whether the analgesic mechanisms of BVA for pain were mediated by opioid or adrenergic receptors. Design • Male Sprague-Dawley rats were randomly assigned to one of 19 groups, with n = 10 for each group. Setting • The study was conducted at the East-West Bone and Joint Research Institute at Kyung Hee University (Seoul, South Korea). Intervention • All rats were intra-articularly injected with collagenase solution in the left knee, followed by a booster injection performed 4 d after the first injection. For the groups receiving BVA treatments, the treatment was administered into the ST-36 acupoint, except for 1 group that received the treatment into a nonacupoint. Three BVA intervention groups received no pretreatment with agonists or antagonists; 1 of them received a dose of 1 mg/kg of bee venom into acupoint ST-36, 1 received a dose of 2 mg/kg into acupoint ST-36, and 1 received a dose of 1 mg/kg into a nonacupoint location. For the intervention groups receiving pretreatments, the opioid-receptor or adrenergic-receptor agonists or antagonists were injected 20 min before the 1-mg/kg BVA treatments. Outcome Measures • Changes in the rats' pain thresholds were assessed by evaluation of pain-related behavior, using a tail flick

  14. β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat.

    Science.gov (United States)

    Wohleb, Eric S; Hanke, Mark L; Corona, Angela W; Powell, Nicole D; Stiner, La'Tonia M; Bailey, Michael T; Nelson, Randy J; Godbout, Jonathan P; Sheridan, John F

    2011-04-27

    Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression. Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner. Repeated social defeat also significantly increased the number of CD11b(+)/CD45(high)/Ly6C(high) macrophages that trafficked to the brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes [glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)]. The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist. Microglia isolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharide compared with microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1-deficient mice, but did not promote anxiety-like behavior or microglia activation in the absence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergic and IL-1 receptors.

  15. Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus.

    Science.gov (United States)

    Hájos, N; Papp, E C; Acsády, L; Levey, A I; Freund, T F

    1998-01-01

    In previous studies m2 muscarinic acetylcholine receptor-immunoreactive interneurons and various types of m2-positive axon terminals have been described in the hippocampal formation. The aim of the present study was to identify the types of interneurons expressing m2 receptor and to examine whether the somadendritic and axonal m2 immunostaining labels the same or distinct cell populations. In the CA1 subfield, neurons immunoreactive for m2 have horizontal dendrites, they are located at the stratum oriens/alveus border and have an axon that project to the dendritic region of pyramidal cells. In the CA3 subfield and the hilus, m2-positive neurons are multipolar and are scattered in all layers except stratum lacunosum-moleculare. In stratum pyramidale of the CA1 and CA3 regions, striking axon terminal staining for m2 was observed, surrounding the somata and axon initial segments of pyramidal cells in a basket-like manner. The co-localization of m2 with neurochemical markers and GABA was studied using the "mirror" technique and fluorescent double-immunostaining at the light microscopic level and with double-labelling using colloidal gold-conjugated antisera and immunoperoxidase reaction (diaminobenzidine) at the electron microscopic level. GABA was shown to be present in the somata of most m2-immunoreactive interneurons, as well as in the majority of m2-positive terminals in all layers. The calcium-binding protein parvalbumin was absent from practically all m2-immunoreactive cell bodies and dendrites. In contrast, many of the terminals synapsing on pyramidal cell somata and axon initial segments co-localized parvalbumin and m2, suggesting a differential distribution of m2 receptor immunoreactivity on the axonal and somadendritic membrane of parvalbumin-containing basket and axo-axonic cells. The co-existence of m2 receptors with the calcium-binding protein calbindin and the neuropeptides cholecystokinin and vasoactive intestinal polypeptide was rare throughout the

  16. Design and synthesis of aryloxypropanolamine as β3-adrenergic receptor antagonist in cancer and lipolysis.

    Science.gov (United States)

    Jin, Jiyu; Miao, Chunxiao; Wang, Zhilong; Zhang, Wanli; Zhang, Xiongwen; Xie, Xin; Lu, Wei

    2018-04-25

    β-adrenergic receptors (β-ARs) are broadly distributed in various tissues and regulate a panel of important physiological functions and disease states including cancer. Above all, β 3 -adrenergic receptor (β 3 -AR) plays a significant role in regulating lipolysis and thermogenesis in adipose tissue. In this study, we designed and synthesized a series of novel L-748,337 derivatives as selective human β 3 -AR antagonists. Among all the tested L-748,337 analogs, compound 23d was found to display 23-fold more potent β 3 -AR antagonist activity (EC 50  = 0.5117 nM) than L-748,337 (EC 50  = 11.91 nM). In vivo, compound 23d could alleviate weight loss and inhibit tumor growth in C26 tumor cachexia animal model. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  17. Alpha-1 adrenergic receptors gate rapid orientation-specific reduction in visual discrimination.

    Science.gov (United States)

    Treviño, Mario; Frey, Sebastian; Köhr, Georg

    2012-11-01

    Prolonged imbalance in sensory experience leads to dramatic readjustments in cortical representation. Neuromodulatory systems play a critical role in habilitating experience-induced plasticity and regulate memory processes in vivo. Here, we show that a brief period of intense patterned visual stimulation combined with systemic activation of alpha-1 adrenergic neuromodulator receptors (α(1)-ARs) leads to a rapid, reversible, and NMDAR-dependent depression of AMPAR-mediated transmission from ascending inputs to layer II/III pyramidal cells in the visual cortex of young and adult mice. The magnitude of this form of α(1)-AR long-term depression (LTD), measured ex vivo with miniature EPSC recordings, is graded by the number of orientations used during visual experience. Moreover, behavioral tests of visual function following the induction of α(1)-AR LTD reveal that discrimination accuracy of sinusoidal drifting gratings is selectively reduced at high spatial frequencies in a reversible, orientation-specific, and NMDAR-dependent manner. Thus, α(1)-ARs enable rapid cortical synaptic depression which correlates with an orientation-specific decrease in visual discrimination. These findings contribute to our understanding of how adrenergic receptors interact with neuronal networks in response to changes in active sensory experience to produce adaptive behavior.

  18. Effects of superior cervical ganglionectomy on alpha 2 adrenergic receptors in dog cerebral arteries

    International Nuclear Information System (INIS)

    Fujiwara, M.; Tsukahara, T.; Taniguchi, T.; Usui, H.

    1986-01-01

    Norepinephrine (NE)- and clonidine-induced contractions of dog cerebral arteries were attenuated by yohimbine but not affected by prazosin. There was no detectable 3 H-prazosin binding site in the cerebral arteries. On the other hand, 3 H-yohimbine binding studies revealed the presence of two binding sites with high and low affinities in the cerebral arteries. After superior cervical ganglionectomy, NE- and clonidine-induced contractions of the denervated cerebral arteries were not altered compared with the control arteries. The binding study revealed that there was low affinity 3 H-yohimbine binding sites, whereas high affinity sites were not detectable. These results suggest that there are two different NE binding sites in alpha 2 adrenergic receptors, and that the high affinity sites are presynaptically located and low affinity sites are postsynaptic. It is also suggested that NE-induced contractions are mediated by postsynaptic low affinity sites of alpha 2 adrenergic receptors in the dog cerebral arteries

  19. α1b-Adrenergic Receptor Localization and Relationship to the D1-Dopamine Receptor in the Rat Nucleus Accumbens.

    Science.gov (United States)

    Mitrano, Darlene A; Jackson, Kelsey; Finley, Samantha; Seeley, Allison

    2018-02-10

    The α1-adrenergic receptors (α1ARs) have been implicated in numerous actions of the brain, including attention and wakefulness. Additionally, they have been identified as contributing to disorders of the brain, such as drug addiction, and recent work has shown a role of these receptors in relapse to psychostimulants. While some functionality is known, the actual subcellular localization of the subtypes of the α1ARs remains to be elucidated. Further, their anatomical relationship to receptors for other neurotransmitters, such as dopamine (DA), remains unclear. Therefore, using immunohistochemistry and electron microscopy techniques, this study describes the subcellular localization of the α1b-adrenergic receptor (α1bAR), the subtype most tied to relapse behaviors, as well as its relationship to the D1-dopamine receptor (D1R) in both the shell and core of the rat nucleus accumbens (NAc). Overall, α1bARs were found in unmyelinated axons and axon terminals with some labeling in dendrites. In accordance with other studies of the striatum, the D1R was found mainly in dendrites and spines; therefore, colocalization of the D1R with the α1bAR was rare postsynaptically. However, in the NAc shell, when the receptors were co-expressed in the same neuronal elements there was a trend for both receptors to be found on the plasma membrane, as opposed to the intracellular compartment. This study provides valuable anatomical information about the α1bAR and its relationship to the D1R and the regulation of DA and norepinephrine (NE) neurotransmission in the brain which have been examined previously. Published by Elsevier Ltd.

  20. Interaction between Antagonist of Cannabinoid Receptor and Antagonist of Adrenergic Receptor on Anxiety in Male Rat

    Directory of Open Access Journals (Sweden)

    Alireza Komaki

    2014-07-01

    Full Text Available Introduction: Anxiety is among the most common and treatable mental disorders. Adrenergic and cannabinoid systems have an important role in the neurobiology of anxiety. The elevated plus-maze (EPM has broadly been used to investigate anxiolytic and anxiogenic compounds. The present study investigated the effects of intraperitoneal (IP injection of cannabinoid CB1 receptor antagonist (AM251 in the presence of alpha-1 adrenergic antagonist (Prazosin on rat behavior in the EPM. Methods: In this study, the data were obtained from male Wistar rat, which weighing 200- 250 g. Animal behavior in EPM were videotaped and saved in computer for 10 min after IP injection of saline, AM251 (0.3 mg/kg, Prazosin (0.3 mg/kg and AM251 + Prazosin, subsequently scored for conventional indices of anxiety. During the test period, the number of open and closed arms entries, the percentage of entries into the open arms of the EPM, and the spent time in open and closed arms were recorded. Diazepam was considered as a positive control drug with anxiolytic effect (0.3, 0.6, 1.2 mg/kg. Results: Diazepam increased the number of open arm entries and the percentage of spent time on the open arms. IP injection of AM251 before EPM trial decreased open arms exploration and open arm entry. Whereas, Prazosin increased open arms exploration and open arm entry. This study showed that both substances in simultaneous injection have conflicting effects on the responses of each of these two compounds in a single injection. Discussion: Injection of CB1 receptor antagonist may have an anxiogenic profile in rat, whereas adrenergic antagonist has an anxiolytic effect. Further investigations are essential for better understanding of anxiolytic and anxiogenic properties and neurobiological mechanisms of action and probable interactions of the two systems.

  1. Interaction between Antagonist of Cannabinoid Receptor and Antagonist of Adrenergic Receptor on Anxiety in Male Rat.

    Science.gov (United States)

    Komaki, Alireza; Abdollahzadeh, Fatemeh; Sarihi, Abdolrahman; Shahidi, Siamak; Salehi, Iraj

    2014-01-01

    Anxiety is among the most common and treatable mental disorders. Adrenergic and cannabinoid systems have an important role in the neurobiology of anxiety. The elevated plus-maze (EPM) has broadly been used to investigate anxiolytic and anxiogenic compounds. The present study investigated the effects of intraperitoneal (IP) injection of cannabinoid CB1 receptor antagonist (AM251) in the presence of alpha-1 adrenergic antagonist (Prazosin) on rat behavior in the EPM. In this study, the data were obtained from male Wistar rat, which weighing 200- 250 g. Animal behavior in EPM were videotaped and saved in computer for 10 min after IP injection of saline, AM251 (0.3 mg/kg), Prazosin (0.3 mg/kg) and AM251 + Prazosin, subsequently scored for conventional indices of anxiety. During the test period, the number of open and closed arms entries, the percentage of entries into the open arms of the EPM, and the spent time in open and closed arms were recorded. Diazepam was considered as a positive control drug with anxiolytic effect (0.3, 0.6, 1.2 mg/kg). Diazepam increased the number of open arm entries and the percentage of spent time on the open arms. IP injection of AM251 before EPM trial decreased open arms exploration and open arm entry. Whereas, Prazosin increased open arms exploration and open arm entry. This study showed that both substances in simultaneous injection have conflicting effects on the responses of each of these two compounds in a single injection. Injection of CB1 receptor antagonist may have an anxiogenic profile in rat, whereas adrenergic antagonist has an anxiolytic effect. Further investigations are essential for better understanding of anxiolytic and anxiogenic properties and neurobiological mechanisms of action and probable interactions of the two systems.

  2. ESTROGEN RECEPTOR-alpha IMMUNOREACTIVE NEURONS IN THE BRAINSTEM AND SPINAL CORD OF THE FEMALE RHESUS MONKEY : SPECIES-SPECIFIC CHARACTERISTICS

    NARCIS (Netherlands)

    Vanderhorst, V. G. J. M.; Terasawa, E.; Ralston, H. J.

    2009-01-01

    The distribution pattern of estrogen receptors in the rodent CNS has been reported extensively, but mapping of estrogen receptors in primates is incomplete. In this study we describe the distribution of estrogen receptor alpha immunoreactive (ER-alpha 1R) neurons in the brainstem and spinal cord of

  3. Alpha1A-adrenergic receptor-directed autoimmunity induces left ventricular damage and diastolic dysfunction in rats.

    Directory of Open Access Journals (Sweden)

    Katrin Wenzel

    Full Text Available BACKGROUND: Agonistic autoantibodies to the alpha(1-adrenergic receptor occur in nearly half of patients with refractory hypertension; however, their relevance is uncertain. METHODS/PRINCIPAL FINDINGS: We immunized Lewis rats with the second extracellular-loop peptides of the human alpha(1A-adrenergic receptor and maintained them for one year. Alpha(1A-adrenergic antibodies (alpha(1A-AR-AB were monitored with a neonatal cardiomyocyte contraction assay by ELISA, and by ERK1/2 phosphorylation in human alpha(1A-adrenergic receptor transfected Chinese hamster ovary cells. The rats were followed with radiotelemetric blood pressure measurements and echocardiography. At 12 months, the left ventricles of immunized rats had greater wall thickness than control rats. The fractional shortening and dp/dt(max demonstrated preserved systolic function. A decreased E/A ratio in immunized rats indicated a diastolic dysfunction. Invasive hemodynamics revealed increased left ventricular end-diastolic pressures and decreased dp/dt(min. Mean diameter of cardiomyocytes showed hypertrophy in immunized rats. Long-term blood pressure values and heart rates were not different. Genes encoding sarcomeric proteins, collagens, extracellular matrix proteins, calcium regulating proteins, and proteins of energy metabolism in immunized rat hearts were upregulated, compared to controls. Furthermore, fibrosis was present in immunized hearts, but not in control hearts. A subset of immunized and control rats was infused with angiotensin (Ang II. The stressor raised blood pressure to a greater degree and led to more cardiac fibrosis in immunized, than in control rats. CONCLUSIONS/SIGNIFICANCE: We show that alpha(1A-AR-AB cause diastolic dysfunction independent of hypertension, and can increase the sensitivity to Ang II. We suggest that alpha(1A-AR-AB could contribute to cardiovascular endorgan damage.

  4. Dissociation between cardiomyocyte function and remodeling with beta-adrenergic receptor blockade in isolated canine mitral regurgitation.

    Science.gov (United States)

    Pat, Betty; Killingsworth, Cheryl; Denney, Thomas; Zheng, Junying; Powell, Pamela; Tillson, Michael; Dillon, A Ray; Dell'Italia, Louis J

    2008-12-01

    The low-pressure volume overload of isolated mitral regurgitation (MR) is associated with increased adrenergic drive, left ventricular (LV) dilatation, and loss of interstitial collagen. We tested the hypothesis that beta1-adrenergic receptor blockade (beta1-RB) would attenuate LV remodeling after 4 mo of MR in the dog. beta1-RB did not attenuate collagen loss or the increase in LV mass in MR dogs. Using MRI and three-dimensional (3-D) analysis, there was a 70% increase in the LV end-diastolic (LVED) volume-to-LV mass ratio, a 23% decrease in LVED midwall circumferential curvature, and a >50% increase in LVED 3-D radius/wall thickness in MR dogs that was not attenuated by beta1-RB. However, beta1-RB caused a significant increase in LVED length from the base to apex compared with untreated MR dogs. This was associated with an increase in isolated cardiomyocyte length (171+/-5 microm, P<0.05) compared with normal (156+/-3 microm) and MR (165+/-4 microm) dogs. Isolated cardiomyocyte fractional shortening was significantly depressed in MR dogs compared with normal dogs (3.73+/-0.31 vs. 5.02+/-0.26%, P<0.05) and normalized with beta1-RB (4.73+/-0.48%). In addition, stimulation with the beta-adrenergic receptor agonist isoproterenol (25 nM) increased cardiomyocyte fractional shortening by 215% (P<0.05) in beta1-RB dogs compared with normal (56%) and MR (50%) dogs. In summary, beta1-RB improved LV cardiomyocyte function and beta-adrenergic receptor responsiveness despite further cell elongation. The failure to attenuate LV remodeling associated with MR could be due to a failure to improve ultrastructural changes in extracellular matrix organization.

  5. Estrogen receptor-alpha-immunoreactive neurons in the periaqueductal gray of the adult ovariectomized female cat

    NARCIS (Netherlands)

    VanderHorst, Veronique G.J.M.; Meijer, Ellie; Schasfoort, Fabienne C.; Leeuwen, Fred van; Holstege, Gert

    1998-01-01

    Anatomical and physiological studies in rodent and cat have shown that distinct parts of the midbrain periaqueductal gray (FAG) are important for the estrogen dependent, female reproductive behavior. The present study gives a detailed overview of the estrogen receptor-alpha-immunoreactive (ER-IR)

  6. Activation of β-adrenergic receptors is required for elevated α1A-adrenoreceptors expression and signaling in mesenchymal stromal cells

    Science.gov (United States)

    Tyurin-Kuzmin, Pyotr A.; Fadeeva, Julia I.; Kanareikina, Margarita A.; Kalinina, Natalia I.; Sysoeva, Veronika Yu.; Dyikanov, Daniyar T.; Stambolsky, Dmitriy V.; Tkachuk, Vsevolod A.

    2016-01-01

    Sympathetic neurons are important components of mesenchymal stem cells (MSCs) niche and noradrenaline regulates biological activities of these cells. Here we examined the mechanisms of regulation of MSCs responsiveness to noradrenaline. Using flow cytometry, we demonstrated that α1A adrenergic receptors isoform was the most abundant in adipose tissue-derived MSCs. Using calcium imaging in single cells, we demonstrated that only 6.9 ± 0.8% of MSCs responded to noradrenaline by intracellular calcium release. Noradrenaline increases MSCs sensitivity to catecholamines in a transitory mode. Within 6 hrs after incubation with noradrenaline the proportion of cells responding by Ca2+ release to the fresh noradrenaline addition has doubled but declined to the baseline after 24 hrs. Increased sensitivity was due to the elevated quantities of α1A-adrenergic receptors on MSCs. Such elevation depended on the stimulation of β-adrenergic receptors and adenylate cyclase activation. The data for the first time clarify mechanisms of regulation of MSCs sensitivity to noradrenaline. PMID:27596381

  7. Alpha 2-adrenergic receptor stimulation of phospholipase A2 and of adenylate cyclase in transfected Chinese hamster ovary cells is mediated by different mechanisms

    International Nuclear Information System (INIS)

    Jones, S.B.; Halenda, S.P.; Bylund, D.B.

    1991-01-01

    The effect of alpha 2-adrenergic receptor activation on adenylate cyclase activity in Chinese hamster ovary cells stably transfected with the alpha 2A-adrenergic receptor gene is biphasic. At lower concentrations of epinephrine forskolin-stimulated cyclic AMP production is inhibited, but at higher concentrations the inhibition is reversed. Both of these effects are blocked by the alpha 2 antagonist yohimbine but not by the alpha 1 antagonist prazosin. Pretreatment with pertussis toxin attenuates inhibition at lower concentrations of epinephrine and greatly potentiates forskolin-stimulated cyclic AMP production at higher concentrations of epinephrine. alpha 2-Adrenergic receptor stimulation also causes arachidonic acid mobilization, presumably via phospholipase A2. This effect is blocked by yohimbine, quinacrine, removal of extracellular Ca2+, and pretreatment with pertussis toxin. Quinacrine and removal of extracellular Ca2+, in contrast, have no effect on the enhanced forskolin-stimulated cyclic AMP production. Thus, it appears that the alpha 2-adrenergic receptor in these cells can simultaneously activate distinct signal transduction systems; inhibition of adenylate cyclase and stimulation of phospholipase A2, both via G1, and potentiation of cyclic AMP production by a different (pertussis toxin-insensitive) mechanism

  8. Alpha 2-adrenergic receptor stimulation of phospholipase A2 and of adenylate cyclase in transfected Chinese hamster ovary cells is mediated by different mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Jones, S.B.; Halenda, S.P.; Bylund, D.B. (Univ. of Missouri-Columbia (USA))

    1991-02-01

    The effect of alpha 2-adrenergic receptor activation on adenylate cyclase activity in Chinese hamster ovary cells stably transfected with the alpha 2A-adrenergic receptor gene is biphasic. At lower concentrations of epinephrine forskolin-stimulated cyclic AMP production is inhibited, but at higher concentrations the inhibition is reversed. Both of these effects are blocked by the alpha 2 antagonist yohimbine but not by the alpha 1 antagonist prazosin. Pretreatment with pertussis toxin attenuates inhibition at lower concentrations of epinephrine and greatly potentiates forskolin-stimulated cyclic AMP production at higher concentrations of epinephrine. alpha 2-Adrenergic receptor stimulation also causes arachidonic acid mobilization, presumably via phospholipase A2. This effect is blocked by yohimbine, quinacrine, removal of extracellular Ca2+, and pretreatment with pertussis toxin. Quinacrine and removal of extracellular Ca2+, in contrast, have no effect on the enhanced forskolin-stimulated cyclic AMP production. Thus, it appears that the alpha 2-adrenergic receptor in these cells can simultaneously activate distinct signal transduction systems; inhibition of adenylate cyclase and stimulation of phospholipase A2, both via G1, and potentiation of cyclic AMP production by a different (pertussis toxin-insensitive) mechanism.

  9. Differential effects of beta-adrenergic receptor blockade in the medial prefrontal cortex during aversive and incidental taste memory formation.

    Science.gov (United States)

    Reyes-López, J; Nuñez-Jaramillo, L; Morán-Guel, E; Miranda, M I

    2010-08-11

    The medial prefrontal cortex (mPFC) is a brain area crucial for memory, attention, and decision making. Specifically, the noradrenergic system in this cortex is involved in aversive learning, as well as in the retrieval of these memories. Some evidence suggests that this area has an important role during taste memory, particularly during conditioned taste aversion (CTA), a model of aversive memory. Despite some previous evidence, there is scarce information about the role of adrenergic receptors in the mPFC during formation of aversive taste memory and appetitive/incidental taste memory. The goal of this research was to evaluate the role of mPFC beta-adrenergic receptors during CTA acquisition/consolidation or CTA retrieval, as well as during incidental taste memory formation using the model of latent inhibition of CTA. The results showed that infusions in the mPFC of the beta-adrenergic antagonist propranolol before CTA acquisition impaired both short- and long-term aversive taste memory formation, and also that propranolol infusions before the memory test impaired CTA retrieval. However, propranolol infusions before pre-exposure to the taste during the latent inhibition procedure had no effect on incidental taste memory acquisition or consolidation. These data indicate that beta-adrenergic receptors in the mPFC have different functions during taste memory formation: they have an important role during aversive taste association as well as during aversive retrieval but not during incidental taste memory formation. Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Studies on the characterization and regulation of alpha-1 adrenergic receptors and [3H]WB4101 binding sites in the central nervous system

    International Nuclear Information System (INIS)

    Morrow, A.L.

    1985-01-01

    The purpose of these studies has been to resolve the anomalous binding characteristics of two alpha adrenergic receptor ligands, [ 3 H]WB4101 and [ 3 H]prazosin and to study the regulation of the receptors labeled by these compounds after surgical denervation and chronic drug treatments. Preliminary studies indicated that [ 3 H]WB4101 binding sites, which were believed to represent alpha-1 adrenergic receptors, were increased in number following removal of the fimbrial afferents to the hippocampus. This increase was not due to removal of the adrenergic input into this structure since destruction of the locus coeruleus or the dorsal noradrenergic bundle did not produce the up-regulation. Characterization of alpha-1 adrenergic receptors using [ 3 H]prazosin and [ 3 H]WB4101 revealed evidence for subtypes of alpha-1 receptors designated alpha-1A and alpha-1B. The nanomolar affinity component of [ 3 H]WB4101 binding is not adrenergic but serotonergic. The serotonergic agonists, serotonin and 8-hydroxy-dipropylaminotetraline have affinities of 1.5 and 3.0 nM for this site, when studied in the presence of a 30 nM prazosin mask of the alpha-1 component of [ 3 H]WB4101 binding. Fimbria transection or 5,7 dihydroxytryptamine injections produced increases in the Bmax of the nanomolar affinity component of [ 3 H]WB4101 binding in the presence of a prazosin mask. The up-regulated site showed identical serotonergic pharmacology compared to control tissue. Thus, the author concluded that serotonergic denervation of the hippocampus produces the increase in serotonergic binding sites labeled by [ 3 H]WB4101

  11. β2-Adrenergic Receptor Activation Suppresses the Rat Phenethylamine Hallucinogen-Induced Head Twitch Response: Hallucinogen-Induced Excitatory Post-synaptic Potentials as a Potential Substrate

    Science.gov (United States)

    Marek, Gerard J.; Ramos, Brian P.

    2018-01-01

    5-Hydroxytryptamine2A (5-HT2A) receptors are enriched in layers I and Va of the rat prefrontal cortex and neocortex and their activation increases the frequency of glutamatergic excitatory post-synaptic potentials/currents (EPSP/Cs) onto layer V pyramidal cells. A number of other G-protein coupled receptors (GPCRs) are also enriched in cortical layers I and Va and either induce (α1-adrenergic and orexin2) or suppress (metabotropic glutamate2 [mGlu2], adenosine A1, μ-opioid) both 5-HT-induced EPSCs and head twitches or head shakes induced by the phenethylamine hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Another neurotransmitter receptor also localized to apparent thalamocortical afferents to layers I and Va of the rat prefrontal cortex and neocortex is the β2-adrenergic receptor. Therefore, we conducted preliminary electrophysiological experiments with rat brain slices examining the effects of epinephrine on electrically-evoked EPSPs following bath application of DOI (3 μM). Epinephrine (0.3–10 μM) suppressed the late EPSPs produced by electrical stimulation and DOI. The selective β2-adrenergic receptor antagonist ICI-118,551 (300 nM) resulted in a rightward shift of the epinephrine concentration-response relationship. We also tested the selective β2-adrenergic receptor agonist clenbuterol and the antagonist ICI-118,551 on DOI-induced head twitches. Clenbuterol (0.3–3 mg/kg, i.p.) suppressed DOI (1.25 mg/kg, i.p.)-induced head twitches. This clenbuterol effect appeared to be at least partially reversed by the selective β2-adrenergic receptor antagonist ICI-118,553 (0.01–1 mg/kg, i.p.), with significant reversal at doses of 0.1 and 1 mg/kg. Thus, β2-adrenergic receptor activation reverses the effects of phenethylamine hallucinogens in the rat prefrontal cortex. While Gi/Go-coupled GPCRs have previously been shown to suppress both the electrophysiological and behavioral effects of 5-HT2A receptor activation in the mPFC, the present work appears

  12. Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well.

    Science.gov (United States)

    Frishman, William H

    Beta-adrenergic receptor blockers (β-blockers) are an appropriate treatment for patients having systemic hypertension (HTN) who have concomitant ischemic heart disease (IHD), heart failure, obstructive cardiomyopathy, aortic dissection or certain cardiac arrhythmias. β-Blockers can be used in combination with other antiHTN drugs to achieve maximal blood pressure control. Labetalol can be used in HTN emergencies and urgencies. β-Blockers may be useful in HTN patients having a hyperkinetic circulation (palpitations, tachycardia, HTN, and anxiety), migraine headache, and essential tremor. β-Blockers are highly heterogeneous with respect to various pharmacologic properties: degree of intrinsic sympathomimetic activity, membrane stabilizing activity, β 1 selectivity, α 1 -adrenergic blocking effects, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific properties may be important in the selection of a drug for clinical use. β-Blocker usage to reduce perioperative myocardial ischemia and cardiovascular (CV) complications may not benefit as many patients as was once hoped, and may actually cause harm in some individuals. Currently the best evidence supports perioperative β-blocker use in two patient groups: patients undergoing vascular surgery with known IHD or multiple risk factors for it, and for those patients already receiving β-blockers for known CV conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. N-glycosylation of the β2 adrenergic receptor regulates receptor function by modulating dimerization.

    Science.gov (United States)

    Li, Xiaona; Zhou, Mang; Huang, Wei; Yang, Huaiyu

    2017-07-01

    N-glycosylation is a common post-translational modification of G-protein-coupled receptors (GPCRs). However, it remains unknown how N-glycosylation affects GPCR signaling. β 2 adrenergic receptor (β 2 AR) has three N-glycosylation sites: Asn6, Asn15 at the N-terminus, and Asn187 at the second extracellular loop (ECL2). Here, we show that deletion of the N-glycan did not affect receptor expression and ligand binding. Deletion of the N-glycan at the N-terminus rather than Asn187 showed decreased effects on isoproterenol-promoted G-protein-dependent signaling, β-arrestin2 recruitment, and receptor internalization. Both N6Q and N15Q showed decreased receptor dimerization, while N187Q did not influence receptor dimerization. As decreased β 2 AR homodimer accompanied with reduced efficiency for receptor function, we proposed that the N-glycosylation of β 2 AR regulated receptor function by influencing receptor dimerization. To verify this hypothesis, we further paid attention to the residues at the dimerization interface. Studies of Lys60 and Glu338, two residues at the receptor dimerization interface, exhibited that the K60A/E338A showed decreased β 2 AR dimerization and its effects on receptor signaling were similar to N6Q and N15Q, which further supported the importance of receptor dimerization for receptor function. This work provides new insights into the relationship among glycosylation, dimerization, and function of GPCRs. Peptide-N-glycosidase F (PNGase F, EC 3.2.2.11); endo-β-N-acetylglucosaminidase A (Endo-A, EC 3.2.1.96). © 2017 Federation of European Biochemical Societies.

  14. Suppression of the cough reflex by α2-adrenergic receptor agonists in the rabbit

    Science.gov (United States)

    Cinelli, Elenia; Bongianni, Fulvia; Pantaleo, Tito; Mutolo, Donatella

    2013-01-01

    The α2-adrenergic receptor agonist clonidine has been shown to inhibit citric acid-induced cough responses in guinea pigs when administered by aerosol, but not orally. In contrast, oral or inhaled clonidine had no effect on capsaicin-induced cough and reflex bronchoconstriction in humans. In addition, intravenous administration of clonidine has been shown to depress fentanyl-induced cough in humans. We investigated the effects of the α2-adrenergic receptor agonists, clonidine and tizanidine, on cough responses induced by mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. Drugs were microinjected (30–50 nL) into the caudal nucleus tractus solitarii (cNTS) and the caudal ventral respiratory group (cVRG) as well as administered intravenously in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections of clonidine into the cNTS or the cVRG reduced cough responses at 0.5 mmol/L and abolished the cough reflex at 5 mmol/L. Bilateral microinjections of 0.5 mmol/L tizanidine into the cNTS completely suppressed cough responses, whereas bilateral microinjections of 5 mmol/L into the cVRG only caused mild reductions in them. Depressant effects on the cough reflex of clonidine and tizanidine were completely reverted by microinjections of 10 mmol/L yohimbine. Intravenous administration of clonidine (80–120 μg/kg) or tizanidine (150–300 μg/kg) strongly reduced or completely suppressed cough responses. These effects were reverted by intravenous administration of yohimbine (300 μg/kg). The results demonstrate that activation of α2-adrenergic receptors in the rabbit exerts potent inhibitory effects on the central mechanism generating the cough motor pattern with a clear action at the level of the cNTS and the cVRG. PMID:24400133

  15. Photoaffinity labeling of mammalian α1-adrenergic receptors: identification of the ligand binding subunit with a high affinity radioiodinated probe

    International Nuclear Information System (INIS)

    Leeb-Lundberg, L.M.F.; Dickinson, K.E.J.; Heald, S.L.

    1984-01-01

    A description is given of the synthesised and characterization of a novel high affinity radioiodinated α 1 -adrenergic receptor photoaffinity probe, 4-amino-6,7-dimethoxy-2-[4-[5-(4-azido-3-[ 125 I]iodophenyl)pentanoyl]-1-piperazinyl] quinazoline. In the absence of light, this ligand binds with high affinity (K/sub d/ = 130 pm) in a reverisble and saturable manner to sites in rat hepatic plasma membranes. The binding is stereoselective and competitively inhibited by adrenergic agonists and antagonists with an α 1 -adrenergic specificity. Upon photolysis, this ligand incorporates irreversibly into plasma membranes prepared from several mammalian tissues including rat liver, rat, guinea pig, and rabbit spleen, rabbit lung, and rabbit aorta vascular smooth muscle cells, also with typical α 1 -adrenergic specificity. Autoradiograms of such membrane samples subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis reveal a major specifically labeled polypeptide at M/sub 4/ = 78,000-85,000, depending on the tissue used, in addition to some lower molecular weight peptides. Protease inhibitors, in particular EDTA, a metalloprotease inhibitor, dramatically increases the predominance of the M/sub r/ = 78,000-85,000 polypeptide while attenuating the labeling of the lower molecular weight bands. This new high affinity radioiodinated photoaffinity probe should be of great value for the molecular characterization of the α 1 -adrenergic receptor

  16. Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice

    Directory of Open Access Journals (Sweden)

    Nicholas Douris

    2017-08-01

    Conclusions: The response of β-less mice distinguishes at least two distinct categories of physiologic effects in mice consuming KD. In the liver, KD regulates peroxisome proliferator-activated receptor alpha (PPARα-dependent pathways through an action of FGF21 independent of the SNS and beta-adrenergic receptors. In sharp contrast, induction of interscapular brown adipose tissue (BAT and increased energy expenditure absolutely require SNS signals involving action on one or more β-adrenergic receptors. In this way, the key metabolic actions of FGF21 in response to KD have diverse effector mechanisms.

  17. Studies of the associations between functional beta2-adrenergic receptor variants and obesity, hypertension and type 2 diabetes in 7,808 white subjects

    DEFF Research Database (Denmark)

    Gjesing, A P; Andersen, G; Burgdorf, K S

    2007-01-01

    Functional and common Arg16Gly and Gln27Glu polymorphisms have been identified in ADRB2, the gene encoding the beta2-adrenergic receptor. These variants have previously been examined for association with obesity, hypertension and diabetes with inconclusive results.......Functional and common Arg16Gly and Gln27Glu polymorphisms have been identified in ADRB2, the gene encoding the beta2-adrenergic receptor. These variants have previously been examined for association with obesity, hypertension and diabetes with inconclusive results....

  18. cDNA for the human β2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor

    International Nuclear Information System (INIS)

    Kobilka, B.K.; Dixon, R.A.F.; Frielle, T.

    1987-01-01

    The authors have isolated and sequenced a cDNA encoding the human β 2 -adrenergic receptor. The deduced amino acid sequence (413 residues) is that of a protein containing seven clusters of hydrophobic amino acids suggestive of membrane-spanning domains. While the protein is 87% identical overall with the previously cloned hamster β 2 -adrenergic receptor, the most highly conserved regions are the putative transmembrane helices (95% identical) and cytoplasmic loops (93% identical), suggesting that these regions of the molecule harbor important functional domains. Several of the transmembrane helices also share lesser degrees of identity with comparable regions of select members of the opsin family of visual pigments. They have localized the gene for the β 2 -adrenergic receptor to q31-q32 on chromosome 5. This is the same position recently determined for the gene encoding the receptor for platelet-derived growth factor and is adjacent to that for the FMS protooncogene, which encodes the receptor for the macrophage colony-stimulating factor

  19. The role of basolateral amygdala adrenergic receptors in hippocampus dependent spatial memory in rat

    Directory of Open Access Journals (Sweden)

    Vafaei A.L.

    2008-03-01

    Full Text Available Background and the purpose of the study: There are extensive evidences indicating that the noradrenergic system of the basolateral nucleus of the amygdala (BLA is involved in memory processes. The present study investigated the role of the BLA adrenergic receptors (ARs in hippocampus dependent spatial memory in place avoidance task in male rat. Material and Methods: Long Evans rats (n=150 were trained to avoid footshock in a 60° segment while foraging for scattered food on a circular (80-cm diameter arena. The rats were injected bilaterally in the BLA specific ARS (Adrenergic receptors agonist norepinephrine (NE, 0.5 and 1 µg/µl and specific β-ARs antagonist propranolol (PRO, 0.5 and 1 µg/µl before acquisition, after training or before retrieval of the place avoidance task. Control rats received vehicle at the same volume. The learning in a single 30-min session was assessed 24h later by a 30-min extinction trial in which the time to first entrance and the number of entrances to the shocked area measured the avoidance memory. Results: Acquisition and consolidation were enhanced and impaired significantly by NE and PRO when the drugs were injected 10 min before or immediately after training, respectively. In contrast, neither NE nor PRO influenced animal performances when injected before retention testing. Conclusion: Findings of this study indicates that adrenergic system of the BLA plays an important role in regulation of memory storage and show further evidences for the opinion that the BLA plays an important role in integrating hormonal and neurotransmitter influences on memory storage.

  20. Reduced number of alpha- and beta-adrenergic receptors in the myocardium of rats exposed to tobacco smoke

    Energy Technology Data Exchange (ETDEWEB)

    Larue, D.; Kato, G.

    1981-04-09

    The concentration of alpha- and beta-adrenergic receptors--as measured by specific (/sup 3/H)WB-4101 and (-)-(/sup 3/H)dihydroalprenolol binding--was diminished by 60% below control values in the hearts of rats exposed to tobacco smoke. These changes in receptor numbers took place almost immediately after tobacco smoke exposure and were rapidly reversible after termination of the exposure. The dissociation constant, KD, for (/sup 3/H)WB-4101 was identical in exposed (KD . 0.34 +/- 0.09 nM) and control (KD . 0.35 +/- 0.07 nM) hearts but was significantly different in the case of (-)-(3H)dihydroalprenolol binding (exposed, KD . 2.83 +/- 0.30 mM vs. control KD . 5.22 +/- 0.61 nM). For beta-receptor binding there was no significant difference between exposed and control animals in the Ki values for (-)-epinephrine, (-)-norepinephrine, (-)-alprenolol, (+/-)-propranolol or timolol. (-)-Isoproterenol, however, was found to bind with lower affinity in exposed compared with control hearts. For alpha-receptor binding there was no significant difference between control and 'smoked' animals in the Ki values for (-)-epinephrine, (-0)-norepinephrine or phentolamine. The decrease in alpha- and beta-adrenergic receptor concentration may be related to the phenomenon of receptor desensitization resulting from a release of catecholamines in rats exposed to tobacco smoke.

  1. Evidence that shock-induced immune suppression is mediated by adrenal hormones and peripheral beta-adrenergic receptors.

    Science.gov (United States)

    Cunnick, J E; Lysle, D T; Kucinski, B J; Rabin, B S

    1990-07-01

    Our previous work has demonstrated that presentations of mild foot-shock to Lewis rats induces a suppression of splenic and peripheral blood lymphocyte responses to nonspecific T-cell mitogens. The present study demonstrated that adrenalectomy prevented the shock-induced suppression of the mitogenic response of peripheral blood T-cells but did not attenuate the suppression of splenic T-cells. Conversely, the beta-adrenergic receptor antagonists, propranolol and nadolol, attenuated the shock-induced suppression of splenic T-cells in a dose-dependent manner but did not attenuate suppression of the blood mitogen response. These data indicate that distinct mechanisms mediate the shock-induced suppression of T-cell responsiveness to mitogens in the spleen and the peripheral blood. The results indicate that the peripheral release of catecholamines is responsible for splenic immune suppression and that adrenal hormones, which do not interact with beta-adrenergic receptors, are responsible for shock-induced suppression of blood mitogenic responses.

  2. [Studies on the relationship between beta-adrenergic receptor density on cell wall lymphocytes, total serum catecholamine level and heart rate in patients with hyperthyroidism].

    Science.gov (United States)

    Gajek, J; Zieba, I; Zyśko, D

    2000-08-01

    Hyperthyreosis mimics the hyperadrenergic state and its symptoms were though to be dependent on increased level of catecholamines. Another reason for the symptoms could be the increased density or affinity of beta-adrenergic receptors to catecholamines. The aim of the study was to examine the elements of sympathetic nervous system, thyroid hormones level and their influence on heart rate control in patients with hyperthyreosis. The study was carried out in 18 women, mean age 48.9 +/- 8.7 yrs and 6 men, mean age 54.2 +/- 8.7 yrs. The control group consisted of 30 healthy persons matched for age and sex. We examined the density of beta-adrenergic receptors using radioligand labelling method with 125I-cyanopindolol, serum total catecholamines level with radioenzymatic assay kit, the levels of free thyroid hormones using radioimmunoassays and thyreotropine level with immunoradiometric assay. Maximal, minimal and mean heart rate were studied using Holter monitoring system. The density of beta-adrenergic receptors in hyperthyreosis was 37.3 +/- 21.7 vs 37.2 +/- 18.1 fmol/mg in the control group (p = NS). Total catecholamines level was significantly decreased in hyperthyreosis group: 1.5 +/- 0.89 vs 1.9 +/- 0.73 pmol/ml (p < 0.05). There was significantly higher minimal, maximal and mean heart rate in hyperthyreosis group (p < 0.0001, p < 0.0001 and p < 0.05 respectively). There was a weak inverse correlation between minimum heart rate and triiodothyronine level (r = -0.38, p < 0.05). An inverse correlation between triiodothyronine and catecholamines level (r = -0.49, p < 0.05) was observed. Beta-adrenergic receptors density is unchanged and catecholamines level is decreased in hyperthyreosis when compared to normal subjects. There is no correlation between minimal heart rate and adrenergic receptors density or catecholamines level in hyperthyreosis.

  3. CD86 and beta2-adrenergic receptor signaling pathways, respectively, increase Oct-2 and OCA-B Expression and binding to the 3'-IgH enhancer in B cells.

    Science.gov (United States)

    Podojil, Joseph R; Kin, Nicholas W; Sanders, Virginia M

    2004-05-28

    Stimulation of CD86 (formerly known as B7-2) and/or the beta2-adrenergic receptor on a CD40 ligand/interleukin-4-activated B cell increased the rate of mature IgG1 transcription. To identify the mechanism responsible for this effect, we determined whether CD86 and/or beta2-adrenergic receptor stimulation regulated transcription factor expression and binding to the 3'-IgH enhancer in vitro and in vivo. We showed that CD86 stimulation increased the nuclear localization of NF-kappaB1 (p50) and phosphorylated RelA (p65) and increased Oct-2 expression and binding to the 3'-IgH enhancer, in a protein kinase C-dependent manner. These effects were lost when CD86-deficient or NF-kappaB1-deficient B cells were used. CD86 stimulation also increased the level of IkappaB-alpha phosphorylation but in a protein kinase C-independent manner. Beta2-adrenergic receptor stimulation increased CREB phosphorylation, OCA-B expression, and OCA-B binding to the 3'-IgH enhancer in a protein kinase A-dependent manner, an effect lost when beta2-adrenergic receptor-deficient B cells were used. Also, the beta2-adrenergic receptor-induced increase in the level of mature IgG1 transcript was lost when OCA-B-deficient B cells were used. These data are the first to show that CD86 stimulation up-regulates the expression of the transcription factor Oct-2 in a protein kinase C- and NF-kappaB1-dependent manner, and that beta2-adrenergic receptor stimulation up-regulates the expression of the coactivator OCA-B in a protein kinase A-dependent manner to cooperate with Oct-2 binding to the 3'-IgH enhancer.

  4. Regulation of β2-adrenergic receptor function by conformationally selective single-domain intrabodies

    DEFF Research Database (Denmark)

    Staus, Dean P; Wingler, Laura M; Strachan, Ryan T

    2014-01-01

    . However, a monomeric single-domain antibody (nanobody) from the Camelid family was recently found to allosterically bind and stabilize an active conformation of the β2-adrenergic receptor (β2AR). Here, we set out to study the functional interaction of 18 related nanobodies with the β2AR to investigate...... their roles as novel tools for studying GPCR biology. Our studies revealed several sequence-related nanobody families with preferences for active (agonist-occupied) or inactive (antagonist-occupied) receptors. Flow cytometry analysis indicates that all nanobodies bind to epitopes displayed...... on the intracellular receptor surface; therefore, we transiently expressed them intracellularly as "intrabodies" to test their effects on β2AR-dependent signaling. Conformational specificity was preserved after intrabody conversion as demonstrated by the ability for the intracellularly expressed nanobodies...

  5. High-expression β(1) adrenergic receptor/cell membrane chromatography method based on a target receptor to screen active ingredients from traditional Chinese medicines.

    Science.gov (United States)

    Yue, Yuan; Xue, Hui; Wang, Xin; Yang, Qian; Song, Yanhong; Li, Xiaoni

    2014-02-01

    β-Adrenergic receptors are important targets for drug discovery. We have developed a new β1 -adrenergic receptor cell membrane chromatography (β1 AR-CMC) with offline ultra-performance LC (UPLC) and MS method for screening active ingredients from traditional Chinese medicines. In this study, Chinese hamster ovary-S cells with high β1 AR expression levels were established and used to prepare a cell membrane stationary phase in a β1 AR-CMC model. The retention fractions were separated and identified by the UPLC-MS system. The screening results found that isoimperatorin from Rhizoma et Radix Notopterygii was the targeted component that could act on β1 AR in similar manner of metoprolol as a control drug. In addition, the biological effects of active component were also investigated in order to search for a new type of β1 AR antagonist. It will be a useful method for drug discovery as a leading compound resource. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer

    NARCIS (Netherlands)

    C. Poyet (Cédric); T. Hermanns (Thomas); Q. Zhong (Qing); E. Drescher (Eva); D. Eberli (Daniel); M. Burger (Maximilian); F. Hofstaedter (Ferdinand); A. Hartmann (Arndt); R. Stöhr (Robert); E.C. Zwarthoff (Ellen); T. Sulser (Tullio); P.J. Wild (Peter J.)

    2015-01-01

    textabstractIn addition to conventional clinicopathological parameters, molecular markers are also required in order to predict the course of disease in patients with urothelial bladder cancer (BC). Little is known about fibroblast growth factor receptor 3 (FGFR3) immunoreactivity and the clinical

  7. β-adrenergic ([3H] CGP-12177) receptors are elevated in slices of soleus muscle from CHF 147 dystrophic hamsters

    International Nuclear Information System (INIS)

    Watson-Wright, W.M.; Wilkinson, M.

    1987-01-01

    The authors utilized a muscle slice technique to compare the ontogeny of cell surface β-adrenergic receptor binding in soleus and extensor digitorum longus (EDL) muscles of male Golden Syrian (GS) and Canadian Hybrid Farms 147 (CHF 147) dystrophic hamsters. Binding of the β-adrenergic antagonist, [ 3 H] CGP-12177 (CGP), to GS muscle slices was reversible, saturable, stereospecific and of high affinity. Bmax was higher in the soleus (2.57+/-.12 fmol/mg wet wt) than in the EDL (1.61+/-.17 fmol/mg wet wt) of adult animals while affinities were similar (0.35+/-.06 and 0.24+/-.04 nM respectively). No differences in binding characteristics were seen in EDL of GS compared to CHF 147 animals. In soleus slices from GS hamsters, Bmax was highest at 16 days of age (5.72+/-0.26 fmol/mg), decreased between 16 and 29 days and remained constant until 300 days (2.51+/-0.52 fmol/mg). In dystrophic soleus slices, Bmax was also higher at 16 days than at any other age but receptor number decreased gradually, remaining higher than in GS until 90 days of age (p<0.05). The failure of β-adrenergic receptor number to decrease at a normal rate may be implicated in the pathogenesis of hamster polymyopathy. 21 references, 5 figures, 1 table

  8. Investigating β-adrenergic-induced cardiac hypertrophy through computational approach: classical and non-classical pathways.

    Science.gov (United States)

    Khalilimeybodi, Ali; Daneshmehr, Alireza; Sharif-Kashani, Babak

    2018-07-01

    The chronic stimulation of β-adrenergic receptors plays a crucial role in cardiac hypertrophy and its progression to heart failure. In β-adrenergic signaling, in addition to the well-established classical pathway, Gs/AC/cAMP/PKA, activation of non-classical pathways such as Gi/PI3K/Akt/GSK3β and Gi/Ras/Raf/MEK/ERK contribute in cardiac hypertrophy. The signaling network of β-adrenergic-induced hypertrophy is very complex and not fully understood. So, we use a computational approach to investigate the dynamic response and contribution of β-adrenergic mediators in cardiac hypertrophy. The proposed computational model provides insights into the effects of β-adrenergic classical and non-classical pathways on the activity of hypertrophic transcription factors CREB and GATA4. The results illustrate that the model captures the dynamics of the main signaling mediators and reproduces the experimental observations well. The results also show that despite the low portion of β2 receptors out of total cardiac β-adrenergic receptors, their contribution in the activation of hypertrophic mediators and regulation of β-adrenergic-induced hypertrophy is noticeable and variations in β1/β2 receptors ratio greatly affect the ISO-induced hypertrophic response. The model results illustrate that GSK3β deactivation after β-adrenergic receptor stimulation has a major influence on CREB and GATA4 activation and consequent cardiac hypertrophy. Also, it is found through sensitivity analysis that PKB (Akt) activation has both pro-hypertrophic and anti-hypertrophic effects in β-adrenergic signaling.

  9. Localization of the fourth membrane spanning domain as a ligand binding site in the human platelet α2-adrenergic receptor

    International Nuclear Information System (INIS)

    Matsui, Hiroaki; Lefkowitz, R.J.; Caron, M.G.; Regan, J.W.

    1989-01-01

    The human platelet α 2 -adrenergic receptor is an integral membrane protein which binds epinephrine. The gene for this receptor has been cloned, and the primary structure is thus known. A model of its secondary structure predicts that the receptor has seven transmembrane spanning domains. By covalent labeling and peptide mapping, the authors have identified a region of the receptor that is directly involved with ligand binding. Partially purified preparations of the receptor were covalently radiolabeled with either of two specific photoaffinity ligands: [ 3 H]SKF 102229 (an antagonist) or p-azido[ 3 H]clonidine (an agonist). The radiolabeled receptors were then digested with specific endopeptidases, and peptides containing the covalently bound radioligands were identified. Lysylendopeptidase treatment of [ 3 H]SKF 102229 labeled receptor yielded one peptide of M r 2400 as the product of a complete digest. Endopeptidase Arg-C gave a labeled peptide of M r 4000, which was further digested to the M r 2400 peptide by additional treatment with lysylendopeptidase. Using p-azido[ 3 H]clonidine-labeled receptor, a similar M r 2400 peptide was obtained by lysylendopeptidase cleavage. This M r 2400 peptide corresponds to the fourth transmembrane spanning domain of the receptor. These data suggest that this region forms part of the ligand binding domain of the human platelet α 2 -adrenergic receptor

  10. α2-adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression

    Science.gov (United States)

    Lamkin, Donald M.; Sung, Ha Yeon; Yang, Gyu Sik; David, John M.; Ma, Jeffrey C.Y.; Cole, Steve W.; Sloan, Erica K.

    2014-01-01

    Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of β-adrenergic receptors. Catecholamines also signal α-adrenergic receptors, and greater α-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of α-adrenergic receptors can result in elevated catecholamine levels, which may increase β-adrenergic signaling, because pre-synaptic α2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of α-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective α-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective β-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective α2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective α1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that α2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of β-adrenergic signaling on tumor progression-relevant biology. PMID:25462899

  11. Estrogen receptor-alpha-immunoreactive neurons in the mesencephalon, pons and medulla oblongata of the female golden hamster

    NARCIS (Netherlands)

    Boers, J; Gerrits, PO; Holstege, G

    1999-01-01

    Recent studies have revealed brainstem-spinal pathways involved in the generation of receptive behavior in hamster and cat, and the enormous influence of estrogen on these pathways. The present study gives an overview of the location of estrogen receptor-alpha-immunoreactive neurons (ER-alpha-IR) in

  12. Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor

    DEFF Research Database (Denmark)

    Boyhus, Lotte Emilie; Danielsen, Mia; Bengtson, Nina Smidt

    2018-01-01

    A series of Gs protein peptidomimetics were designed and synthesised based on the published X-ray crystal structure of the active state β2-Adrenergic receptor (β2AR) in complex with the Gs protein (PDB 3SN6). We hypothesised that such peptidomimetics may function as allosteric modulators...... that target the intracellular Gs protein binding site of the β2AR. Peptidomimetics were designed to mimic the 15 residue C-Terminal α-helix of the Gs protein and were pre-organised in a helical conformation by (i, i + 4)-stapling using copper catalysed azide alkyne cycloaddition. Linear and stapled...... be able to compete with the native Gs protein for the intracellular binding site to block ISO-induced cAMP formation, but are unable to stabilise an active-like receptor conformation....

  13. Involvement of α(2)-adrenergic receptor in the regulation of the blood glucose level induced by immobilization stress.

    Science.gov (United States)

    Kang, Yu-Jung; Sim, Yun-Beom; Park, Soo-Hyun; Sharma, Naveen; Suh, Hong-Won

    2015-01-01

    The blood glucose profiles were characterized after mice were forced into immobilization stress with various exposure durations. The blood glucose level was significantly enhanced by immobilization stress for 30 min or 1 h, respectively. On the other hand, the blood glucose level was not affected in the groups which were forced into immobilization stress for 2 or 4 h. We further examined the effect of yohimbine (an α2-adrenergic receptor antagonist) administered systemically or centrally in the immobilization stress model. Mice were pretreated intraperitoneally (i.p.; from 0.5 to 5 mg/kg), intracerebroventricularly (i.c.v.; from 1 to 10 µg/5 µl), or intrathecally (i.t.; from 1 to 10 µg/5 µl) with yohimbine for 10 min and then, forced into immobilization stress for 30 min. The blood glucose level was measured right after immobilization stress. We found that up-regulation of the blood glucose level induced by immobilization stress was abolished by i.p. pretreatment with yohimbine. And the immobilization stress-induced blood glucose level was not inhibited by i.c.v. or i.t. pretreatment with yohimbine at a lower dose (1 µg/5 µl). However, immobilization stress-induced blood glucose level was significantly inhibited by i.c.v. or i.t. pretreatment with yohimbine at higher doses (5 and 10 µg/5 µl). In addition, the i.p. (5 mg/kg), i.c.v. (10 µg/5 µl), or i.t. (10 µg/5 µl) pretreatment with yohimbine reduced hypothalamic glucose transporter 4 expression. The involvement of α2-adrenergic receptor in regulation of immobilization stress- induced blood glucose level was further confirmed by the i.p, i.c.v, or i.t pretreatment with idazoxan, another specific α2-adrenergic receptor antagonist. Finally, i.p., i.c.v., or i.t. pretreatment with yohimbine attenuated the blood glucose level in D-glucose-fed model. We suggest that α2-adrenergic receptors located at the peripheral, the brain and the spinal cord play important roles in the up

  14. Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice.

    Directory of Open Access Journals (Sweden)

    Kenji Suita

    Full Text Available Atrial fibrillation (AF is the most common arrhythmias among old people. It causes serious long-term health problems affecting the quality of life. It has been suggested that the autonomic nervous system is involved in the onset and maintenance of AF in human. However, investigation of its pathogenesis and potential treatment has been hampered by the lack of suitable AF models in experimental animals.Our aim was to establish a long-lasting AF model in mice. We also investigated the role of adrenergic receptor (AR subtypes, which may be involved in the onset and duration of AF.Trans-esophageal atrial burst pacing in mice could induce AF, as previously shown, but with only a short duration (29.0 ± 8.1 sec. We found that adrenergic activation by intraperitoneal norepinephrine (NE injection strikingly increased the AF duration. It increased the duration to more than 10 minutes, i.e., by more than 20-fold (656.2 ± 104.8 sec; P<0.001. In this model, a prior injection of a specific β1-AR blocker metoprolol and an α1-AR blocker prazosin both significantly attenuated NE-induced elongation of AF. To further explore the mechanisms underlying these receptors' effects on AF, we assessed the SR Ca(2+ leak, a major trigger of AF, and consequent spontaneous SR Ca(2+ release (SCR in atrial myocytes. Consistent with the results of our in-vivo experiments, both metoprolol and prazosin significantly inhibited the NE-induced SR Ca(2+ leak and SCR. These findings suggest that both β1-AR and α1-AR may play important roles in the development of AF.We have established a long-lasting AF model in mice induced by adrenergic activation, which will be valuable in future AF study using experimental animals, such as transgenic mice. We also revealed the important role of β1- and α1-AR-mediated signaling in the development of AF through in-vivo and in-vitro experiments.

  15. Antithetic regulation by β-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway β-agonist paradox

    OpenAIRE

    McGraw, Dennis W.; Almoosa, Khalid F.; Paul, Richard J.; Kobilka, Brian K.; Liggett, Stephen B.

    2003-01-01

    β-adrenergic receptors (βARs) relax airway smooth muscle and bronchodilate, but chronic β-agonist treatment in asthma causes increased sensitivity to airway constriction (hyperreactivity) and is associated with exacerbations. This paradox was explored using mice with ablated βAR genes (βAR–/–) and transgenic mice overexpressing airway smooth muscle β2AR (β2AR-OE) representing two extremes: absence and persistent activity of airway βAR. Unexpectedly, βAR–/– mice, lacking these bronchodilating ...

  16. Blocking of beta-2 adrenergic receptors hastens recovery from hypoglycemia-associated social withdrawal.

    Science.gov (United States)

    Park, Min Jung; Guest, Christopher B; Barnes, Meredith B; Martin, Jonathan; Ahmad, Uzma; York, Jason M; Freund, Gregory G

    2008-11-01

    Hypoglycemia is associated with a variety of adverse behaviors including fatigue, confusion and social withdrawal. While these clinical symptoms are well characterized, the mechanism of their cause is not understood. Here we investigated how insulin-induced hypoglycemia causes social withdrawal. Male 8-12-week-old C57BL/6J mice were injected intraperitoneally (IP) with or without and/or insulin, norepinephrine (NE) and epinephrine (Epi), terbutaline and butoxamine with subsequent measurement of blood glucose, social withdrawal and plasma catecholamines. Insulin generated (0.75h post-injection) significant hypoglycemia with blood glucose nadirs of 64+/-4 and 48+/-5mg/dl for 0.8 and 1.2units/kg of insulin, respectively. Insulin (0.8 or 1.2units/kg) caused near total social withdrawal at 0.75h with full recovery not occurring until 4h (0.8units/kg) or 8h (1.2units/kg) post-insulin injection. Insulin also caused a marked elevation in plasma catecholamines. Basal 12h fasting NE and Epi were 287+/-38 and 350+/-47pg/ml, respectively. Insulin at 0.8units/kg increased plasma NE and Epi to 994+/-73 and 1842+/-473pg/ml, respectively. Administration of exogenous NE or Epi caused social withdrawal similar in magnitude to insulin. Importantly, administration of the beta-2 adrenergic receptor agonist terbutaline also caused social withdrawal while administration of the beta-2 adrenergic receptor antagonist butoxamine blocked NE-induced social withdrawal. Finally, butoxamine blocked insulin-induced social withdrawal. These data demonstrate that hypoglycemia-associated social withdrawal is dependent on catecholamines via a beta-2 receptor-mediated pathway.

  17. β-Adrenergic enhancement of neuronal excitability in the lateral amygdala is developmentally gated.

    Science.gov (United States)

    Fink, Ann E; LeDoux, Joseph E

    2018-05-01

    Noradrenergic signaling in the amygdala is important for processing threats and other emotionally salient stimuli, and β-adrenergic receptor activation is known to enhance neuronal spiking in the lateral amygdala (LA) of juvenile animals. Nevertheless, intracellular recordings have not yet been conducted to determine the effect of β-adrenergic receptor activation on spike properties in the adult LA, despite the potential significance of developmental changes between adolescence and adulthood. Here we demonstrate that the β-adrenergic agonist isoproterenol (15 μM) enhances spike frequency in dorsal LA principal neurons of juvenile male C57BL/6 mice and fails to do so in strain- and sex-matched adults. Furthermore, we find that the age-dependent effect of isoproterenol on spike frequency is occluded by the GABA A receptor blocker picrotoxin (75 μM), suggesting that β-adrenergic receptors downregulate tonic inhibition specifically in juvenile animals. These findings indicate a significant shift during adolescence in the cellular mechanisms of β-adrenergic modulation in the amygdala. NEW & NOTEWORTHY β-Adrenergic receptors (β-ARs) in amygdala are important in processing emotionally salient stimuli. Most cellular recordings have examined juvenile animals, while behavioral data are often obtained from adults. We replicate findings showing that β-ARs enhance spiking of principal cells in the lateral amygdala of juveniles, but we fail to find this in adults. These findings have notable scientific and clinical implications regarding the noradrenergic modulation of threat processing, alterations of which underlie fear and anxiety disorders.

  18. Sex differences and the effects of ovariectomy on the β-adrenergic contractile response

    Science.gov (United States)

    McIntosh, Victoria J.; Chandrasekera, P. Charukeshi

    2011-01-01

    The presence of sex differences in myocardial β-adrenergic responsiveness is controversial, and limited studies have addressed the mechanism underlying these differences. Studies were performed using isolated perfused hearts from male, intact female and ovariectomized female mice to investigate sex differences and the effects of ovarian hormone withdrawal on β-adrenergic receptor function. Female hearts exhibited blunted contractile responses to the β-adrenergic receptor agonist isoproterenol (ISO) compared with males but not ovariectomized females. There were no sex differences in β1-adrenergic receptor gene or protein expression. To investigate the role of adenylyl cyclase, phosphodiesterase, and the cAMP-signaling cascade in generating sex differences in the β-adrenergic contractile response, dose-response studies were performed in isolated perfused male and female hearts using forskolin, 3-isobutyl-1-methylxanthine (IBMX), and 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate (CPT-cAMP). Males showed a modestly enhanced contractile response to forskolin at 300 nM and 5 μM compared with females, but there were no sex differences in the response to IBMX or CPT-cAMP. The role of the A1 adenosine receptor (A1AR) in antagonizing the β-adrenergic contractile response was investigated using both the A1AR agonist 2-chloro-N6-cyclopentyl-adenosine and A1AR knockout (KO) mice. Intact females showed an enhanced A1AR anti-adrenergic effect compared with males and ovariectomized females. The β-adrenergic contractile response was potentiated in both male and female A1ARKO hearts, with sex differences no longer present above 1 nM ISO. The β-adrenergic contractile response is greater in male hearts than females, and minor differences in the action of adenylyl cyclase or the A1AR may contribute to these sex differences. PMID:21685268

  19. Effect of Increased Cyclic AMP Concentration on Muscle Protein Synthesis and Beta-Adrenergic Receptor Expression in Chicken Skeletal Muscle Cells in Culture

    Science.gov (United States)

    Young, R. B.; Vaughn, J. R.; Bridge, K. Y.; Smith, C. K.

    1998-01-01

    Analogies of epinephrine are known to cause hypertrophy of skeletal muscle when fed to animals. These compounds presumably exert their physiological action through interaction with the P-adrenergic receptor. Since the intracellular signal generated by the Beta-adrenergic receptor is cyclic AMP (cAMP), experiments were initiated in cell culture to determine if artificial elevation of cAMP by treatment with forskolin would alter muscle protein metabolism and P-adrenergic receptor expression. Chicken skeletal muscle cells after 7 days in culture were treated with 0.2-30 micrometers forskolin for a total of three days. At the end of the treatment period, both the concentration of cAMP and the quantity of myosin heavy chain (MHC) were measured. Concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. In contrast, the quantity of MHC was increased approximately 50% above control cells at 0.2 micrometers forskolin, but exhibited a gradual decline at higher levels of forskolin so that the quantity of MHC in cells treated with 30 micrometers forskolin was not significantly different from controls. Curiously, the intracellular concentration of cAMP which elicited the maximum increase in the quantity of MHC was only 40% higher than cAMP concentration in control cells.

  20. The morphological and chemical characteristics of striatal neurons immunoreactive for the alpha1-subunit of the GABA(A) receptor in the rat.

    Science.gov (United States)

    Waldvogel, H J; Kubota, Y; Trevallyan, S C; Kawaguchi, Y; Fritschy, J M; Mohler, H; Faull, R L

    1997-10-01

    The distribution, morphology and chemical characteristics of neurons immunoreactive for the alpha1-subunit of the GABA(A) receptor in the striatum of the basal ganglia in the rat brain were investigated at the light, confocal and electron microscope levels using single, double and triple immunohistochemical labelling techniques. The results showed that alpha1-subunit immunoreactive neurons were sparsely distributed throughout the rat striatum. Double and triple labelling results showed that all the alpha1-subunit-immunoreactive neurons were positive for glutamate decarboxylase and immunoreactive for the beta2,3 and gamma2 subunits of the GABA(A) receptor. Three types of alpha1-subunit-immunoreactive neurons were identified in the striatum on the basis of cellular morphology and chemical characteristics. The most numerous alpha1-subunit-immunoreactive neurons were medium-sized, aspiny neurons with a widely branching dendritic tree. They were parvalbumin-negative and were located mainly in the dorsolateral regions of the striatum. Electron microscopy showed that these neurons had an indented nuclear membrane, typical of striatal interneurons, and were surrounded by small numbers of axon terminals which established alpha1-subunit-immunoreactive synaptic contacts with the soma and dendrites. These cells were classified as type 1 alpha1-subunit-immunoreactive neurons and comprised 75% of the total population of alpha1-subunit-immunoreactive neurons in the striatum. The remaining alpha1-subunit-immunoreactive neurons comprised of a heterogeneous population of large-sized neurons localized in the ventral and medial regions of the striatum. The most numerous large-sized cells were parvalbumin-negative, had two to three relatively short branching dendrites and were designated type 2 alpha1-subunit-immunoreactive neurons. Electron microscopy showed that the type 2 neurons were characterized by a highly convoluted nuclear membrane and were sparsely covered with small axon

  1. Myocardial slice: a physiological approach to beta-adrenergic ([3H] CGP-12177) receptor binding in hamster and guinea pig heart.

    Science.gov (United States)

    Watson-Wright, W M; Armour, J A; Johnstone, D E; Wilkinson, M

    1989-08-01

    A new technique is described for the characterization and quantification of beta-adrenergic receptors in biologically viable slices of myocardium from the hamster right ventricle using the hydrophilic radioligand, [3H]CGP-12177 (CGP). Binding was stereospecific, saturable, of high affinity, reversible, displaceable by appropriate drugs, and highly positively correlated with increasing tissue concentrations. Bmax for CGP binding to myocardial slices from 50-day-old male Golden Syrian hamsters was 3.28 +/- 0.15 fmol/mg wet weight, while Kd was 0.21 +/- 0.02 nM. Freezing resulted in a close to 50% loss of receptor number with no apparent change in affinity. The slice preparation may be utilized to detect in vivo changes in myocardial cell surface receptors, as evidenced by the fact that the number of receptors in slices from ischemic guinea pigs was increased (Bmax = 15.5 +/- 1.25 fmol/mg wet wt) compared with sham-operated controls (Bmax = 10.4 +/- 0.38 fmol/mg wet wt). The minimal tissue disruption associated with this procedure, as well as its speed, simplicity, and relatively low cost, suggest that the myocardial slice preparation provides an important methodology for the study of beta-adrenergic receptor binding in the semiintact myocardium.

  2. Berberine-induced pigment dispersion in Bufo melanostictus melanophores by stimulation of beta-2 adrenergic receptors.

    Science.gov (United States)

    Ali, Sharique A; Naaz, Ishrat; Choudhary, Ram Kumar

    2014-02-01

    Reduced production of melanin by decreased or the absence of melanocytes leads to various hypopigmentation disorders, and the development of melanogenetic agents for photoprotection and hypopigmentation disorders is one of the top priority areas of research. Hence, the present study was carried out to elucidate the ability of berberine, a principal active ingredient present in the roots of the herb Berberis vulgaris to stimulate pigment dispersion in the isolated skin melanophores of the toad Bufo melanostictus. In the present study, mean melanophore size index of the isolated skin melanophores of B. melanostictus was assayed after treating with various concentrations of berberine. A marked melanin dispersion response leading to skin darkening was observed in the isolated melanophores of toad in response to berberine, which was found to be mediated through beta-2 adrenergic receptors. The physiologically significant dose-related melanin dispersion effects of berberine per se were found to be completely abolished by propranolol, which is a specific beta-2 adrenergic receptor blocker. These per se melanin dispersal effects were also found to be markedly potentiated by isoprenaline, which is a specific beta-adrenoceptor agonist. The results indicate that berberine causes a tremendous, dose-dependent, physiologically significant pigment dispersing in the isolated skin melanophores of B. melanostictus.

  3. Role of a guanine nucleotide-binding protein in α1-adrenergic receptor-mediated Ca2+ mobilization in DDT1 MF-2 cells

    International Nuclear Information System (INIS)

    Cornett, L.E.; Norris, J.S.

    1987-01-01

    In this study the mechanisms involved in α 1 -adrenergic receptor-mediated Ca 2+ mobilization at the level of the plasma membrane were investigated. Stimulation of 45 Ca 2+ efflux from saponin-permeabilized DDT 1 MF-2 cells was observed with the addition of either the α 1 -adrenergic agonist phenylephrine and guanosine-5'-triphosphate or the nonhydrolyzable guanine nucleotide guanylyl-imidodiphosphate. In the presence of [ 32 P] NAD, pertussis toxin was found to catalyze ADP-ribosylation of a M/sub r/ = 40,500 (n = 8) peptide in membranes prepared from DDT 1 , MF-2 cells, possibly the α-subunit of N/sub i/. However, stimulation of unidirectional 45 Ca 2+ efflux by phenylephrine was not affected by previous treatment of cells with 100 ng/ml pertussis toxin. These data suggest that the putative guanine nucleotide-binding protein which couples the α 1 -adrenergic receptor to Ca 2+ mobilization in DDT 1 MF-2 cells is not a pertussis toxin substrate and may possibly be an additional member of guanine nucleotide binding protein family

  4. Divergent Label-free Cell Phenotypic Pharmacology of Ligands at the Overexpressed β2-Adrenergic Receptors

    Science.gov (United States)

    Ferrie, Ann M.; Sun, Haiyan; Zaytseva, Natalya; Fang, Ye

    2014-01-01

    We present subclone sensitive cell phenotypic pharmacology of ligands at the β2-adrenergic receptor (β2-AR) stably expressed in HEK-293 cells. The parental cell line was transfected with green fluorescent protein (GFP)-tagged β2-AR. Four stable subclones were established and used to profile a library of sixty-nine AR ligands. Dynamic mass redistribution (DMR) profiling resulted in a pharmacological activity map suggesting that HEK293 endogenously expresses functional Gi-coupled α2-AR and Gs-coupled β2-AR, and the label-free cell phenotypic activity of AR ligands are subclone dependent. Pathway deconvolution revealed that the DMR of epinephrine is originated mostly from the remodeling of actin microfilaments and adhesion complexes, to less extent from the microtubule networks and receptor trafficking, and certain agonists displayed different efficacy towards the cAMP-Epac pathway. We demonstrate that receptor signaling and ligand pharmacology is sensitive to the receptor expression level, and the organization of the receptor and its signaling circuitry.

  5. Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation

    Science.gov (United States)

    Baker, Candice N.; Gidus, Sarah A.; Price, George F.; Peoples, Jessica N. R.

    2014-01-01

    As development proceeds from the embryonic to fetal stages, cardiac energy demands increase substantially, and oxidative phosphorylation of ADP to ATP in mitochondria becomes vital. Relatively little, however, is known about the signaling mechanisms regulating the transition from anaerobic to aerobic metabolism that occurs during the embryonic period. The main objective of this study was to test the hypothesis that adrenergic hormones provide critical stimulation of energy metabolism during embryonic/fetal development. We examined ATP and ADP concentrations in mouse embryos lacking adrenergic hormones due to targeted disruption of the essential dopamine β-hydroxylase (Dbh) gene. Embryonic ATP concentrations decreased dramatically, whereas ADP concentrations rose such that the ATP/ADP ratio in the adrenergic-deficient group was nearly 50-fold less than that found in littermate controls by embryonic day 11.5. We also found that cardiac extracellular acidification and oxygen consumption rates were significantly decreased, and mitochondria were significantly larger and more branched in adrenergic-deficient hearts. Notably, however, the mitochondria were intact with well-formed cristae, and there was no significant difference observed in mitochondrial membrane potential. Maternal administration of the adrenergic receptor agonists isoproterenol or l-phenylephrine significantly ameliorated the decreases in ATP observed in Dbh−/− embryos, suggesting that α- and β-adrenergic receptors were effective modulators of ATP concentrations in mouse embryos in vivo. These data demonstrate that adrenergic hormones stimulate cardiac energy metabolism during a critical period of embryonic development. PMID:25516547

  6. Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation.

    Science.gov (United States)

    Baker, Candice N; Gidus, Sarah A; Price, George F; Peoples, Jessica N R; Ebert, Steven N

    2015-03-01

    As development proceeds from the embryonic to fetal stages, cardiac energy demands increase substantially, and oxidative phosphorylation of ADP to ATP in mitochondria becomes vital. Relatively little, however, is known about the signaling mechanisms regulating the transition from anaerobic to aerobic metabolism that occurs during the embryonic period. The main objective of this study was to test the hypothesis that adrenergic hormones provide critical stimulation of energy metabolism during embryonic/fetal development. We examined ATP and ADP concentrations in mouse embryos lacking adrenergic hormones due to targeted disruption of the essential dopamine β-hydroxylase (Dbh) gene. Embryonic ATP concentrations decreased dramatically, whereas ADP concentrations rose such that the ATP/ADP ratio in the adrenergic-deficient group was nearly 50-fold less than that found in littermate controls by embryonic day 11.5. We also found that cardiac extracellular acidification and oxygen consumption rates were significantly decreased, and mitochondria were significantly larger and more branched in adrenergic-deficient hearts. Notably, however, the mitochondria were intact with well-formed cristae, and there was no significant difference observed in mitochondrial membrane potential. Maternal administration of the adrenergic receptor agonists isoproterenol or l-phenylephrine significantly ameliorated the decreases in ATP observed in Dbh-/- embryos, suggesting that α- and β-adrenergic receptors were effective modulators of ATP concentrations in mouse embryos in vivo. These data demonstrate that adrenergic hormones stimulate cardiac energy metabolism during a critical period of embryonic development. Copyright © 2015 the American Physiological Society.

  7. Angiotensin II potentiates adrenergic and muscarinic modulation of guinea pig intracardiac neurons.

    Science.gov (United States)

    Girasole, Allison E; Palmer, Christopher P; Corrado, Samantha L; Marie Southerland, E; Ardell, Jeffrey L; Hardwick, Jean C

    2011-11-01

    The intrinsic cardiac plexus represents a major peripheral integration site for neuronal, hormonal, and locally produced neuromodulators controlling efferent neuronal output to the heart. This study examined the interdependence of norepinephrine, muscarinic agonists, and ANG II, to modulate intrinsic cardiac neuronal activity. Intracellular voltage recordings from whole-mount preparations of the guinea pig cardiac plexus were used to determine changes in active and passive electrical properties of individual intrinsic cardiac neurons. Application of either adrenergic or muscarinic agonists induced changes in neuronal resting membrane potentials, decreased afterhyperpolarization duration of single action potentials, and increased neuronal excitability. Adrenergic responses were inhibited by removal of extracellular calcium ions, while muscarinic responses were inhibited by application of TEA. The adrenergic responses were heterogeneous, responding to a variety of receptor-specific agonists (phenylephrine, clonidine, dobutamine, and terbutaline), although α-receptor agonists produced the most frequent responses. Application of ANG II alone produced a significant increase in excitability, while application of ANG II in combination with either adrenergic or muscarinic agonists produced a much larger potentiation of excitability. The ANG II-induced modulation of firing was blocked by the angiotensin type 2 (AT(2)) receptor inhibitor PD 123319 and was mimicked by the AT(2) receptor agonist CGP-42112A. AT(1) receptor blockade with telmasartin did not alter neuronal responses to ANG II. These data demonstrate that ANG II potentiates both muscarinically and adrenergically mediated activation of intrinsic cardiac neurons, doing so primarily via AT(2) receptor-dependent mechanisms. These neurohumoral interactions may be fundamental to regulation of neuronal excitability within the intrinsic cardiac nervous system.

  8. β2-Adrenergic receptor activation mobilizes intracellular calcium via a non-canonical cAMP-independent signaling pathway.

    Science.gov (United States)

    Galaz-Montoya, Monica; Wright, Sara J; Rodriguez, Gustavo J; Lichtarge, Olivier; Wensel, Theodore G

    2017-06-16

    Beta adrenergic receptors (βARs) are G-protein-coupled receptors essential for physiological responses to the hormones/neurotransmitters epinephrine and norepinephrine which are found in the nervous system and throughout the body. They are the targets of numerous widely used drugs, especially in the case of the most extensively studied βAR, β 2 AR, whose ligands are used for asthma and cardiovascular disease. βARs signal through Gα s G-proteins and via activation of adenylyl cyclase and cAMP-dependent protein kinase, but some alternative downstream pathways have also been proposed that could be important for understanding normal physiological functioning of βAR signaling and its disruption in disease. Using fluorescence-based Ca 2+ flux assays combined with pharmacology and gene knock-out methods, we discovered a previously unrecognized endogenous pathway in HEK-293 cells whereby β 2 AR activation leads to robust Ca 2+ mobilization from intracellular stores via activation of phospholipase C and opening of inositol trisphosphate (InsP 3 ) receptors. This pathway did not involve cAMP, Gα s , or Gα i or the participation of the other members of the canonical β 2 AR signaling cascade and, therefore, constitutes a novel signaling mechanism for this receptor. This newly uncovered mechanism for Ca 2+ mobilization by β 2 AR has broad implications for adrenergic signaling, cross-talk with other signaling pathways, and the effects of βAR-directed drugs. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Age-associated alterations in hepatic β-adrenergic receptor/adenylate cyclase complex

    International Nuclear Information System (INIS)

    Graham, S.M.; Herring, P.A.; Arinze, I.J.

    1987-01-01

    The effect of age on catecholamine regulation of hepatic glycogenolysis and on hepatic adenylate cyclase was studied in male rats up to 24 mo of age. Epinephrine and norepinephrine stimulated glycogenolysis in isolated hepatocytes at all age groups studied. Isoproterenol, however, stimulated glycogenolysis only at 24 mo. In isolated liver membranes, usual activators of adenylate cyclase increased the activity of the enzyme considerably more in membranes from 24-mo-old rats than in membranes from either 3- or 22-mo-old rats. The Mn 2+ -dependent activity of the cyclase was increased by 2.9-fold in 3-mo-old animals and ∼ 5.7-fold in 24-mo-old rats, indicating a substantial age-dependent increase in the intrinsic activity of the catalytic unit. The density of the β-adrenergic receptor, as measured by the binding of [ 125 I]-iodocyanopindolol to plasma membranes, was 5-8 fmol/mg protein in rats aged 3-12 mo but increased to 19 fmol/mg protein in 24-mo-old rats. Computer-aided analysis of isoproterenol competition of the binding indicated a small age-dependent increase in the proportion of β-receptors in the high-affinity state. These observations suggest that β-receptor-mediated hepatic glycogenolysis in the aged rat is predicated upon increases in the density of β-receptors as well as increased intrinsic activity of the catalytic unit of adenylate cyclase

  10. Role of Peripheral Alpha2 Adrenergic Receptors in Tonic Pain During Different Stages of Estrous Cycle in Rats

    OpenAIRE

    AR Abyazi Shelmani; M Taherianfard

    2007-01-01

    Introduction: Estrogen and progesterone are supposed to modify pain sensitivity. However, the actual role of each of these steroid hormones in this respect is not well known. Plasma concentrations of these hormones show variation during estrous cycle. The role of alpha2 receptors in tonic pain has been pointed out. The aim of the present study was to investigate the agonist and antagonist effect of alpha2 adrenergic receptors on tonic pain sensitivity during all stages of estrous cycle in fem...

  11. Food restriction prevents an age-associated increase in rat liver beta-adrenergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Dax, E.M.; Ingram, D.K.; Partilla, J.S.; Gregerman, R.I.

    1989-05-01

    In male Wistar rats fed ad libitum (24% protein, 4.5 Kcal/gm), the (/sup 125/I)iodopindolol binding capacity of the beta-adrenergic receptors in liver of 24-month-old animals is 3-4 times greater than that of 6-month-old counterparts. In rats fed the same diet, on alternate days from weaning, the receptor capacity did not increase significantly between 6 and 24 months (10.20 +/- 0.55 vs 9.20 +/- 0.72 fmol/mg) or between 24 and 30 months. This was not due to acute dietary deprivation, as rats food-restricted for only 2 weeks, at 23.5 months of age, also showed elevated receptor capacities compared to 6-month-old ad libitum fed animals. Moreover, intermittent feeding produced no significant effects among 6-month-old animals, whether restricted since weaning or for two weeks prior to sacrifice. Many biochemical parameters that decrease with aging in rats fed ad libitum are prevented by dietary restriction. Our results demonstrate that a reproducible biochemical process that increases with aging is also prevented with dietary restriction. The age-related, liver beta-receptor increase may be a potentially reliable marker for studying biochemical perturbations that modify life span.

  12. Food restriction prevents an age-associated increase in rat liver beta-adrenergic receptors

    International Nuclear Information System (INIS)

    Dax, E.M.; Ingram, D.K.; Partilla, J.S.; Gregerman, R.I.

    1989-01-01

    In male Wistar rats fed ad libitum (24% protein, 4.5 Kcal/gm), the [ 125 I]iodopindolol binding capacity of the beta-adrenergic receptors in liver of 24-month-old animals is 3-4 times greater than that of 6-month-old counterparts. In rats fed the same diet, on alternate days from weaning, the receptor capacity did not increase significantly between 6 and 24 months (10.20 +/- 0.55 vs 9.20 +/- 0.72 fmol/mg) or between 24 and 30 months. This was not due to acute dietary deprivation, as rats food-restricted for only 2 weeks, at 23.5 months of age, also showed elevated receptor capacities compared to 6-month-old ad libitum fed animals. Moreover, intermittent feeding produced no significant effects among 6-month-old animals, whether restricted since weaning or for two weeks prior to sacrifice. Many biochemical parameters that decrease with aging in rats fed ad libitum are prevented by dietary restriction. Our results demonstrate that a reproducible biochemical process that increases with aging is also prevented with dietary restriction. The age-related, liver beta-receptor increase may be a potentially reliable marker for studying biochemical perturbations that modify life span

  13. Disappearance of beta(2)-adrenergic receptors on astrocytes in canine distemper encephalitis : possible implications for the pathogenesis of multiple sclerosis

    NARCIS (Netherlands)

    De Keyser, J; Wilczak, N; Zurbriggen, A

    2001-01-01

    It has been reported that astrocytes in the white matter of patients with multiple sclerosis (MS) lack beta (2)-adrenergic receptors. This abnormality might explain why astrocytes in active MS plaques aberrantly express major histocompatibility (MHC) class II molecules, which play an important role

  14. β2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses.

    Science.gov (United States)

    Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure; Moeller, Jesper B; Klose, Christoph S N; Rankin, Lucille C; Yudanin, Naomi A; Monticelli, Laurel A; Putzel, Gregory Garbès; Rodewald, Hans-Reimer; Artis, David

    2018-03-02

    The type 2 inflammatory response is induced by various environmental and infectious stimuli. Although recent studies identified group 2 innate lymphoid cells (ILC2s) as potent sources of type 2 cytokines, the molecular pathways controlling ILC2 responses are incompletely defined. Here we demonstrate that murine ILC2s express the β 2 -adrenergic receptor (β 2 AR) and colocalize with adrenergic neurons in the intestine. β 2 AR deficiency resulted in exaggerated ILC2 responses and type 2 inflammation in intestinal and lung tissues. Conversely, β 2 AR agonist treatment was associated with impaired ILC2 responses and reduced inflammation in vivo. Mechanistically, we demonstrate that the β 2 AR pathway is a cell-intrinsic negative regulator of ILC2 responses through inhibition of cell proliferation and effector function. Collectively, these data provide the first evidence of a neuronal-derived regulatory circuit that limits ILC2-dependent type 2 inflammation. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  15. Blockade of α2-adrenergic receptors in prelimbic cortex: impact on cocaine self-administration in adult spontaneously hypertensive rats following adolescent atomoxetine treatment.

    Science.gov (United States)

    Baskin, Britahny M; Nic Dhonnchadha, Bríd Á; Dwoskin, Linda P; Kantak, Kathleen M

    2017-10-01

    Research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder demonstrated that chronic methylphenidate treatment during adolescence increased cocaine self-administration established during adulthood under a progressive ratio (PR) schedule. Compared to vehicle, chronic atomoxetine treatment during adolescence failed to increase cocaine self-administration under a PR schedule in adult SHR. We determined if enhanced noradrenergic transmission at α2-adrenergic receptors within prefrontal cortex contributes to this neutral effect of adolescent atomoxetine treatment in adult SHR. Following treatment from postnatal days 28-55 with atomoxetine (0.3 mg/kg) or vehicle, adult male SHR and control rats from Wistar-Kyoto (WKY) and Wistar (WIS) strains were trained to self-administer 0.3 mg/kg cocaine. Self-administration performance was evaluated under a PR schedule of cocaine delivery following infusion of the α2-adrenergic receptor antagonist idazoxan (0 and 10-56 μg/side) directly into prelimbic cortex. Adult SHR attained higher PR break points and had greater numbers of active lever responses and infusions than WKY and WIS. Idazoxan dose-dependently increased PR break points and active lever responses in SHR following adolescent atomoxetine vs. vehicle treatment. Behavioral changes were negligible after idazoxan pretreatment in SHR following adolescent vehicle or in WKY and WIS following adolescent atomoxetine or vehicle. α2-Adrenergic receptor blockade in prelimbic cortex of SHR masked the expected neutral effect of adolescent atomoxetine on adult cocaine self-administration behavior. Moreover, greater efficacy of acute idazoxan challenge in adult SHR after adolescent atomoxetine relative to vehicle is consistent with the idea that chronic atomoxetine may downregulate presynaptic α2A-adrenergic autoreceptors in SHR.

  16. Cell-Free Expression, Purification, and Characterization of the Functional β2-Adrenergic Receptor for Multianalyte Detection of β-Agonists.

    Science.gov (United States)

    Wang, Jian; Liu, Yuan; Zhang, Junhua; Han, Zhengzheng; Wang, Wei; Liu, Yang; Wei, Dong; Huang, Wei

    2017-11-01

    Large-scale expression of β 2 -adrenergic receptor (β 2 -AR) in functional form is necessary for establishment of receptor assays for detecting illegally abused β-adrenergic agonists (β-agonists). Cell-based heterologous expression systems have manycritical difficulties in synthesizing this membrane protein, such as low protein yields and aberrant folding. To overcome these challenges, the main objective of the present work was to synthesize large amounts of functional β 2 -AR in a cell-free system based on Escherichia coli extracts. A codon-optimized porcine β 2 -AR gene (codon adaptation index: 0.96) suitable for high expression in E. coli was synthesized and transcribed to the cell-free system, which contributed to increase the expression up to 1.1 mg/ml. After purification using Ni-affinity chromatography, the bioactivity of the purified receptor was measured by novel enzyme-linked receptor assays. It was determined that the relative affinities of the purified β 2 -AR for β-agonists in descending order were as follows: clenbuterol > salbutamol > ractopamine. Moreover, their IC 50 values were 45.99, 60.38, and 78.02 µg/liter, respectively. Although activity of the cell-free system was slightly lower than activity of systems based on insect and mammalian cells, this system should allow production of β 2 -AR in bulk amounts sufficient for the development of multianalyte screening methods for detecting β-agonist residues.

  17. Involvement of β3-adrenergic receptors in the control of food intake in rats.

    Science.gov (United States)

    Kanzler, S A; Januario, A C; Paschoalini, M A

    2011-11-01

    This study examined the food intake changes evoked by intracerebroventricular (icv) injection of a selective agonist (BRL37344, 2 and 20 nmol) or antagonist (SR59230A, 10 and 50 nmol) of β3-adrenergic receptors in 24-h fasted rats (adult male Wistar rats, 200-350 g, N = 6/treatment). The animals were also pretreated with saline icv (SAL) or SR59230A (50 nmol) followed by BRL37344 (20 nmol) or SAL in order to determine the selectivity of the effects evoked by BRL37344 on food intake or the selectivity of the effects evoked by SR59230A on risk assessment (RA) behavior. The highest dose of BRL37344 (N = 7) decreased food intake 1 h after the treatment (6.4 ± 0.5 g in SAL-treated vs 4.2 ± 0.8 g in drug-treated rats). While both doses of SR59230A failed to affect food intake (5.1 ± 1.1 g for 10 nmol and 6.0 ± 1.8 g for 50 nmol), this treatment reduced the RA frequency (number/30 min) (4 ± 2 for SAL-treated vs 1 ± 1 for 10 nmol and 0.5 ± 1 for 50 nmol SR59230A-treated rats), an ethological parameter related to anxiety. While pretreatment with SR59230A (7.0 ± 0.5 g) abolished the hypophagia induced by BRL37344 (3.6 ± 0.9 g), BRL37344 suppressed the reduction in RA frequency caused by SR59230A. These results show that the hypophagia caused by BRL37344 is selectively mediated by β3-adrenergic receptors within the central nervous system. Moreover, they suggest the involvement of these receptors in the control of anxiety.

  18. Involvement of β3-adrenergic receptors in the control of food intake in rats

    Directory of Open Access Journals (Sweden)

    S.A. Kanzler

    2011-11-01

    Full Text Available This study examined the food intake changes evoked by intracerebroventricular (icv injection of a selective agonist (BRL37344, 2 and 20 nmol or antagonist (SR59230A, 10 and 50 nmol of β3-adrenergic receptors in 24-h fasted rats (adult male Wistar rats, 200-350 g, N = 6/treatment. The animals were also pretreated with saline icv (SAL or SR59230A (50 nmol followed by BRL37344 (20 nmol or SAL in order to determine the selectivity of the effects evoked by BRL37344 on food intake or the selectivity of the effects evoked by SR59230A on risk assessment (RA behavior. The highest dose of BRL37344 (N = 7 decreased food intake 1 h after the treatment (6.4 ± 0.5 g in SAL-treated vs 4.2 ± 0.8 g in drug-treated rats. While both doses of SR59230A failed to affect food intake (5.1 ± 1.1 g for 10 nmol and 6.0 ± 1.8 g for 50 nmol, this treatment reduced the RA frequency (number/30 min (4 ± 2 for SAL-treated vs 1 ± 1 for 10 nmol and 0.5 ± 1 for 50 nmol SR59230A-treated rats, an ethological parameter related to anxiety. While pretreatment with SR59230A (7.0 ± 0.5 g abolished the hypophagia induced by BRL37344 (3.6 ± 0.9 g, BRL37344 suppressed the reduction in RA frequency caused by SR59230A. These results show that the hypophagia caused by BRL37344 is selectively mediated by β3-adrenergic receptors within the central nervous system. Moreover, they suggest the involvement of these receptors in the control of anxiety.

  19. Beta2-adrenergic receptor allele frequencies in the Quechua, a high altitude native population.

    Science.gov (United States)

    Rupert, J L; Monsalve, M V; Devine, D V; Hochachka, P W

    2000-03-01

    The beta2-adrenergic receptor is involved in the control of numerous physiological processes and, as the primary catecholamine receptor in the lungs, is of particular importance in the regulation of pulmonary function. There are several polymorphic loci in the beta2-adrenergic receptor gene that have alleles that alter receptor function, including two (A/G46, G/C79) that increase agonist sensitivity. As such a phenotype may increase vaso and bronchial dilation, thereby facilitating air and blood flow through the lungs, we hypothesized that selection may have favoured these alleles in high altitude populations as part of an adaptive strategy to deal with the hypoxic conditions characteristic of such environments. We tested this hypothesis by determining the allele frequencies for these two polymorphisms, as well one additional missense mutation (C/T491) and two silent mutations (G/A252 and C/A523) in 63 Quechua speaking natives from communities located between 3200 and 4200 m on the Peruvian altiplano. These frequencies were compared with those of two lowland populations, one native American (Na-Dene from the west coast of Canada) and one Caucasian of Western European descent. The Quechua manifest many of the pulmonary characteristics of high altitude populations and differences in allele frequencies between the Quechua and lowlanders could be indicative of a selective advantage conferred by certain genotypes in high altitude environments. Allele frequencies varied between populations at some loci and patterns of linkage disequilibrium differed between the old-world and new-world samples; however, as these populations are not closely related, significant variation would be expected due to stochastic effects alone. Neither of the alleles associated with increased receptor sensitivity (A46, G79) was significantly over-represented in the Quechua compared with either lowland group. The Quechua were monomorphic for the C allele at base 79. This variant has been

  20. Projections from estrogen receptor-alpha immunoreactive neurons in the periaqueductal gray to the lateral medulla oblongata in the rhesus monkey

    NARCIS (Netherlands)

    Vanderhorst, VGJM; Terasawa, E; Ralston, HJ

    2004-01-01

    The periaqueductal gray (PAG) contains numerous estrogen receptor-alpha immunoreactive (ER-alpha IR) neurons that are distributed in a species-specific way. These neurons might modulate different types of behavior that are mediated by the PAG such as active and passive coping responses, analgesia,

  1. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells: Involvement of nicotinic acetylcholine receptor (nAChR) and β-adrenergic receptor signaling pathways

    International Nuclear Information System (INIS)

    Shin, Vivian Yvonne; Jin, H.C.; Ng, Enders K.O.; Yu Jun; Leung, W.K.; Cho, C.H.; Sung, J.J.Y.

    2008-01-01

    Induction of cyclooxygenase-2 (COX-2) associates with cigarette smoke exposure in many malignancies. Nicotine and its derivative, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are the two important components in cigarette smoke that contributes to cancer development. However, the molecular mechanism(s) by which nicotine or NNK promotes gastric carcinogenesis remains largely unknown. We found that nicotine and NNK significantly enhanced cell proliferation in AGS cells that expressed both alpha7 nicotinic acetylcholine receptor (α7 nAChR) and β-adrenergic receptors. Treatment of cells with α-bungarotoxin (α-BTX, α7nAChR antagonist) or propranolol (β-adrenergic receptor antagonist) blocked NNK-induced COX-2/PGE 2 and cell proliferation, while nicotine-mediated cell growth and COX-2/PGE 2 induction can only be suppressed by propranolol, but not α-BTX. Moreover, in contrast to the dependence of growth promoting effect of nicotine on Erk activation, inhibitor of p38 mitogen-activated protein kinase (MAPK) repressed NNK-induced COX-2 upregulation and resulted in suppression of cell growth. In addition, nicotine and NNK mediated COX-2 induction via different receptors to modulate several G1/S transition regulatory proteins and promote gastric cancer cell growth. Selective COX-2 inhibitor (SC-236) caused G1 arrest and abrogated nicotine/NNK-induced cell proliferation. Aberrant expression of cyclin D1 and other G1 regulatory proteins are reversed by blockade of COX-2. These results pointed to the importance of adrenergic and nicotinic receptors in gastric tumor growth through MAPK/COX-2 activation, which may perhaps provide a chemoprevention strategy for cigarette smoke-related gastric carcinogenesis

  2. Systemic administration of guanfacine improves food-motivated impulsive choice behavior primarily via direct stimulation of postsynaptic α2A-adrenergic receptors in rats.

    Science.gov (United States)

    Nishitomi, Kouhei; Yano, Koji; Kobayashi, Mika; Jino, Kohei; Kano, Takuya; Horiguchi, Naotaka; Shinohara, Shunji; Hasegawa, Minoru

    2018-06-01

    Impulsive choice behavior, which can be assessed using the delay discounting task, is a characteristic of various psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Guanfacine is a selective α 2A -adrenergic receptor agonist that is clinically effective in treating ADHD. However, there is no clear evidence that systemic guanfacine administration reduces impulsive choice behavior in the delay discounting task in rats. In the present study, we examined the effect of systemic guanfacine administration on food-motivated impulsive choice behavior in rats and the neuronal mechanism underlying this effect. Repeated administration of either guanfacine, methylphenidate, or atomoxetine significantly enhanced impulse control, increasing the number of times the rats chose a large but delayed reward in a dose-dependent manner. The effect of guanfacine was significantly blocked by pretreatment with an α 2A -adrenergic receptor antagonist. Furthermore, the effect of guanfacine remained unaffected in rats pretreated with a selective noradrenergic neurotoxin, consistent with a post-synaptic action. In contrast, the effect of atomoxetine on impulsive choice behavior was attenuated by pretreatment with the noradrenergic neurotoxin. These results provide the first evidence that systemically administered guanfacine reduces impulsive choice behavior in rats and that direct stimulation of postsynaptic, rather than presynaptic, α 2A -adrenergic receptors is involved in this effect. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Alpha 1-adrenergic receptor-mediated phosphoinositide hydrolysis and prostaglandin E2 formation in Madin-Darby canine kidney cells. Possible parallel activation of phospholipase C and phospholipase A2

    International Nuclear Information System (INIS)

    Slivka, S.R.; Insel, P.A.

    1987-01-01

    alpha 1-Adrenergic receptors mediate two effects on phospholipid metabolism in Madin-Darby canine kidney (MDCK-D1) cells: hydrolysis of phosphoinositides and arachidonic acid release with generation of prostaglandin E2 (PGE2). The similarity in concentration dependence for the agonist (-)-epinephrine in eliciting these two responses implies that they are mediated by a single population of alpha 1-adrenergic receptors. However, we find that the kinetics of the two responses are quite different, PGE2 production occurring more rapidly and transiently than the hydrolysis of phosphoinositides. The antibiotic neomycin selectively decreases alpha 1-receptor-mediated phosphatidylinositol 4,5-bisphosphate hydrolysis without decreasing alpha 1-receptor-mediated arachidonic acid release and PGE2 generation. In addition, receptor-mediated inositol trisphosphate formation is independent of extracellular calcium, whereas release of labeled arachidonic acid is largely calcium-dependent. Moreover, based on studies obtained with labeled arachidonic acid, receptor-mediated generation of arachidonic acid cannot be accounted for by breakdown of phosphatidylinositol monophosphate, phosphatidylinositol bisphosphate, or phosphatidic acid. Further studies indicate that epinephrine produces changes in formation or turnover of several classes of membrane phospholipids in MDCK cells. We conclude that alpha 1-adrenergic receptors in MDCK cells appear to regulate phospholipid metabolism by the parallel activation of phospholipase C and phospholipase A2. This parallel activation of phospholipases contrasts with models described in other systems which imply sequential activation of phospholipase C and diacylglycerol lipase or phospholipase A2

  4. Impact of the β-1 adrenergic receptor polymorphism on tolerability and efficacy of bisoprolol therapy in Korean heart failure patients: association between β adrenergic receptor polymorphism and bisoprolol therapy in heart failure (ABBA) study.

    Science.gov (United States)

    Lee, Hae-Young; Chung, Wook-Jin; Jeon, Hui-Kyung; Seo, Hong-Seog; Choi, Dong-Ju; Jeon, Eun-Seok; Kim, Jae-Joong; Shin, Joon Han; Kang, Seok-Min; Lim, Sung Cil; Baek, Sang-Hong

    2016-03-01

    We evaluated the association between coding region variants of adrenergic receptor genes and therapeutic effect in patients with congestive heart failure (CHF). One hundred patients with stable CHF (left ventricular ejection fraction [LVEF] adrenergic receptor gene (ADRB1), the observed minor Gly allele frequency (Gly389Arg + Gly389Gly) was 0.21, and no deviation from Hardy-Weinberg equilibrium was observed in the genotypic distribution of Arg389Gly (p = 0.75). Heart rate was reduced from 80.8 ± 14.3 to 70.0 ± 15.0 beats per minute (p < 0.0001). There was no significant difference in final heart rate across genotypes. However, the Arg389Arg genotype group required significantly more bisoprolol compared to the Gly389X (Gly389Arg + Gly389Gly) group (5.26 ± 2.62 mg vs. 3.96 ± 2.05 mg, p = 0.022). There were no significant differences in LVEF changes or remodeling between two groups. Also, changes in exercise capacity and brain natriuretic peptide level were not significant. However, interestingly, there was a two-fold higher rate of readmission (21.2% vs. 10.0%, p = 0.162) and one CHF-related death in the Arg389Arg group. The ADRB1 Gly389X genotype showed greater response to bisoprolol than the Arg389Arg genotype, suggesting the potential of individually tailoring β-blocker therapy according to genotype.

  5. Corticotropin-releasing factor (CRF) and α 2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats.

    Science.gov (United States)

    Park, Paula E; Vendruscolo, Leandro F; Schlosburg, Joel E; Edwards, Scott; Schulteis, Gery; Koob, George F

    2013-09-01

    Anxiety is one of the early symptoms of opioid withdrawal and contributes to continued drug use and relapse. The acoustic startle response (ASR) is a component of anxiety that has been shown to increase during opioid withdrawal in both humans and animals. We investigated the role of corticotropin-releasing factor (CRF) and norepinephrine (NE), two key mediators of the brain stress system, on acute heroin withdrawal-potentiated ASR. Rats injected with heroin (2 mg/kg s.c.) displayed an increased ASR when tested 4 h after heroin treatment. A similar increase in ASR was found in rats 10-20 h into withdrawal from extended access (12 h) to i.v. heroin self-administration, a model that captures several aspects of heroin addiction in humans. Both the α 2 adrenergic receptor agonist clonidine (10 μg/kg s.c.) and CRF1 receptor antagonist N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5-a] pyrimidin-7-amine (MPZP; 20 mg/kg s.c.) blocked heroin withdrawal-potentiated startle. To investigate the relationship between CRF1 and α 2 adrenergic receptors in the potentiation of the ASR, we tested the effect of MPZP on yohimbine (1.25 mg/kg s.c.)-potentiated startle and clonidine on CRF (2 μg i.c.v.)-potentiated startle. Clonidine blocked CRF-potentiated startle, whereas MPZP partially attenuated but did not reverse yohimbine-potentiated startle, suggesting that CRF may drive NE release to potentiate startle. These results suggest that CRF1 and α 2 receptors play an important role in the heightened anxiety-like behaviour observed during acute withdrawal from heroin, possibly via CRF inducing the release of NE in stress-related brain regions.

  6. Nanoscale organization of {beta}{sub 2}-adrenergic receptor-Venus fusion protein domains on the surface of mammalian cells

    Energy Technology Data Exchange (ETDEWEB)

    Vobornik, Dusan; Rouleau, Yanouchka; Haley, Jennifer [Steacie Institute for Molecular Sciences, National Research Council Canada, Ottawa, ON, Canada K1A 0R6 (Canada); Bani-Yaghoub, Mahmud [Institute for Biological Sciences, National Research Council Canada, Ottawa, ON, Canada K1A 0R6 (Canada); Taylor, Rod [Steacie Institute for Molecular Sciences, National Research Council Canada, Ottawa, ON, Canada K1A 0R6 (Canada); Johnston, Linda J., E-mail: Linda.Johnston@nrc-cnrc.gc.ca [Steacie Institute for Molecular Sciences, National Research Council Canada, Ottawa, ON, Canada K1A 0R6 (Canada); Pezacki, John Paul, E-mail: John.Pezacki@nrc-cnrc.gc.ca [Steacie Institute for Molecular Sciences, National Research Council Canada, Ottawa, ON, Canada K1A 0R6 (Canada)

    2009-04-24

    Adrenergic receptors are a key component of nanoscale multiprotein complexes that are responsible for controlling the beat rate in a mammalian heart. We demonstrate the ability of near-field scanning optical microscopy (NSOM) to visualize {beta}{sub 2}-adrenergic receptors ({beta}{sub 2}AR) fused to the GFP analogue Venus at the nanoscale on HEK293 cells. The expression of the {beta}{sub 2}AR-Venus fusion protein was tightly controlled using a tetracycline-induced promoter. Both the size and density of the observed nanoscale domains are dependent on the level of induction and thus the level of protein expression. At concentrations between 100 and 700 ng/ml of inducer doxycycline, the size of domains containing the {beta}{sub 2}AR-Venus fusion protein appears to remain roughly constant, but the number of domains per cell increase. At 700 ng/ml doxycycline the functional receptors are organized into domains with an average diameter of 150 nm with a density similar to that observed for the native protein on primary murine cells. By contrast, larger micron-sized domains of {beta}{sub 2}AR are observed in the membrane of the HEK293 cells that stably overexpress {beta}{sub 2}AR-GFP and {beta}{sub 2}AR-eYFP. We conclude that precise chemical control of gene expression is highly advantageous for the use {beta}{sub 2}AR-Venus fusion proteins as models for {beta}{sub 2}AR function. These observations are critical for designing future cell models and assays based on {beta}{sub 2}AR, since the receptor biology is consistent with a relatively low density of nanoscale receptor domains.

  7. β-Adrenergic receptor stimulation inhibits proarrhythmic alternans in postinfarction border zone cardiomyocytes: a computational analysis.

    Science.gov (United States)

    Tomek, Jakub; Rodriguez, Blanca; Bub, Gil; Heijman, Jordi

    2017-08-01

    The border zone (BZ) of the viable myocardium adjacent to an infarct undergoes extensive autonomic and electrical remodeling and is prone to repolarization alternans-induced cardiac arrhythmias. BZ remodeling processes may promote or inhibit Ca 2+ and/or repolarization alternans and may differentially affect ventricular arrhythmogenesis. Here, we used a detailed computational model of the canine ventricular cardiomyocyte to study the determinants of alternans in the BZ and their regulation by β-adrenergic receptor (β-AR) stimulation. The BZ model developed Ca 2+ transient alternans at slower pacing cycle lengths than the control model, suggesting that the BZ may promote spatially heterogeneous alternans formation in an infarcted heart. β-AR stimulation abolished alternans. By evaluating all combinations of downstream β-AR stimulation targets, we identified both direct (via ryanodine receptor channels) and indirect [via sarcoplasmic reticulum (SR) Ca 2+ load] modulation of SR Ca 2+ release as critical determinants of Ca 2+ transient alternans. These findings were confirmed in a human ventricular cardiomyocyte model. Cell-to-cell coupling indirectly modulated the likelihood of alternans by affecting the action potential upstroke, reducing the trigger for SR Ca 2+ release in one-dimensional strand simulations. However, β-AR stimulation inhibited alternans in both single and multicellular simulations. Taken together, these data highlight a potential antiarrhythmic role of sympathetic hyperinnervation in the BZ by reducing the likelihood of alternans and provide new insights into the underlying mechanisms controlling Ca 2+ transient and repolarization alternans. NEW & NOTEWORTHY We integrated, for the first time, postmyocardial infarction electrical and autonomic remodeling in a detailed, validated computer model of β-adrenergic stimulation in ventricular cardiomyocytes. Here, we show that β-adrenergic stimulation inhibits alternans and provide novel insights

  8. beta(2)-ADRENERGIC RECEPTORS PROTECT AXONS DURING ENERGETIC STRESS BUT DO NOT INFLUENCE BASAL GLIO-AXONAL LACTATE SHUTTLING IN MOUSE WHITE MATTER

    NARCIS (Netherlands)

    Laureys, G.; Valentino, M.; Demol, F.; Zammit, C.; Muscat, R.; Cambron, M.; Kooijman, R.; De Keyser, J.

    2014-01-01

    In vitro studies have demonstrated that beta 2-adrenergic receptor activation stimulates glycogen degradation in astrocytes, generating lactate as a potential energy source for neurons. Using in vivo microdialysis in mouse cerebellar white matter we demonstrate continuous axonal lactate uptake and

  9. Phosphoinositide metabolism and adrenergic receptors in astrocytes

    International Nuclear Information System (INIS)

    Noble, E.P.; Ritchie, T.; de Vellis, J.

    1986-01-01

    Agonist-induced phosphoinositide (PI) breakdown functions as a signal generating system. Diacylglycerol, one breakdown product of phosphotidylinositol-4,5-diphosphate hydrolysis, can stimulate protein kinase C, whereas inositol triphosphate, the other product, has been proposed to be a second messenger for Ca ++ mobilization. Using purified astrocyte cultures from neonatal rat brain, the effects of adrenergic agonists and antagonists at 10 -5 M were measured on PI breakdown. Astrocytes grown in culture were prelabeled with ( 3 H)inositol, and basal ( 3 H) inositol phosphate (IP 1 ) accumulation was measured in the presence of Li + . Epinephrine > norepinephrine (NE) were the most active stimulants of IP 1 production. The α 1 adrenoreceptor blockers, phentolamine and phenoxybenzamine, added alone had no effect on IP 1 production was reduced below basal levels. Propranolol partially blocked the effects of NE. Clonidine and isoproterenol, separately added, reduced IP 1 below basal levels and when added together diminished IP 1 accumulation even further. The role of adrenergic stimulation in the production of c-AMP

  10. The use of (125I) iodocyanopindolol as a specific probe for beta-adrenergic receptors in differentiating cultured rat skeletal muscle

    International Nuclear Information System (INIS)

    Schonberg, Michael; Morris, S.A.; Krichevsky, Alexander; Bilezikian, J.P.

    1983-01-01

    In order to examine more precisely the role of beta-adrenergic receptors in the process of differentiation the new radioligand iodocyanopindolol was used, and found to be a very useful probe to identify beta receptors. Binding charcteristics conformed to those expected for a physiologically relevant beta receptor. L 6 E 9 cells grown in horse serum, which allows differentiation exhibit increased beta receptor density in intact cells as a function of age. In contrast, cells grown in fetal calf serum, which does not allow differentiation, exhibit constant beta receptor density. In broken cells, however, both differentiating and non-differentiating cells show an increase in beta receptors. These results suggest that the process of differentiation is associated with an unmasking of beta receptors which are increasing but cryptic in undifferentiated cells. (author)

  11. Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor.

    Science.gov (United States)

    Weiss, Dahlia R; Ahn, SeungKirl; Sassano, Maria F; Kleist, Andrew; Zhu, Xiao; Strachan, Ryan; Roth, Bryan L; Lefkowitz, Robert J; Shoichet, Brian K

    2013-05-17

    A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.

  12. Label-free integrative pharmacology on-target of drugs at the β2-adrenergic receptor

    Science.gov (United States)

    Ferrie, Ann M.; Sun, Haiyan; Fang, Ye

    2011-07-01

    We describe a label-free integrative pharmacology on-target (iPOT) method to assess the pharmacology of drugs at the β2-adrenergic receptor. This method combines dynamic mass redistribution (DMR) assays using an array of probe molecule-hijacked cells with similarity analysis. The whole cell DMR assays track cell system-based, ligand-directed, and kinetics-dependent biased activities of the drugs, and translates their on-target pharmacology into numerical descriptors which are subject to similarity analysis. We demonstrate that the approach establishes an effective link between the label-free pharmacology and in vivo therapeutic indications of drugs.

  13. Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism

    DEFF Research Database (Denmark)

    Rao, Fangwen; Wessel, Jennifer; Wen, Gen

    2007-01-01

    biosynthesis (tyrosine hydroxylase), catabolism (monoamine oxidase A), storage/release (chromogranin A), receptor target (dopamine D1 receptor), and postreceptor signal transduction (sorting nexin 13 and rho kinase). Epistasis (gene-by-gene interaction) occurred between alleles at rho kinase, tyrosine...... hydroxylase, chromogranin A, and sorting nexin 13. Dopamine D1 receptor polymorphism showed pleiotropic effects on both albumin and dopamine excretion. These studies establish new roles for heredity and environment in albumin excretion. Urinary excretions of albumin and catecholamines are highly heritable......, and their parallel suggests adrenergic mediation of early glomerular permeability alterations. Albumin excretion is influenced by multiple adrenergic pathway genes and is, thus, polygenic. Such functional links between adrenergic activity and glomerular injury suggest novel approaches to its prediction, prevention...

  14. Beta-adrenergic receptor sensitivity, autonomic balance and serotonergic activity in practitioners of Transcendental Meditation

    International Nuclear Information System (INIS)

    Hill, D.A.

    1989-01-01

    The aim of this thesis was to investigate the acute autonomic effects of the Transcendental Meditation Program (TM) and resolve the conflict arising from discrepant neurochemical and psychophysiological data. Three experimental investigations were performed. The first examined beta 2 -adrenergic receptors (AR's) on peripheral blood lymphocytes, via [I 125 ]iodocyanopindolol binding, in 10 male mediating and 10 age matched non-meditating control subjects, to test the hypothesis that the long-term practice of TM and the TM Sidhi Program (TMSP) reduces end organ sensitivity to adrenergic agonists. The second investigated respiratory sinus arrhythmia (an indirect measure of cardiac Parasympathetic Nervous System tone), and skin resistance (a measure of Sympathetic Nervous System tone) during periods of spontaneous respiratory apneusis, a phenomenon occurring during TM that is known to mark the subjective experience of transcending. The third was within subject investigation of the acute effects of the TMSP on 5-hydroxytryptamine (5-HT) activity. Platelet 5-HT was assayed by high pressure liquid chromatography with electrochemical detection, plasma prolactin (PL) and lutenizing hormone (LH) by radioimmunoassay, tryptophan by spectrofluorimetry, and alpha-1-acid glycoprotein (AGP, a modulator of 5-HT uptake) by radial immunodiffusion assay

  15. Beta Adrenergic Regulation of Intrapulmonary Arteriovenous Anastomoses in Intact Rat and Isolated Rat Lungs

    Directory of Open Access Journals (Sweden)

    Melissa L. Bates

    2017-04-01

    Full Text Available Intrapulmonary arteriovenous anastomoses (IPAVA allow large diameter particles of venous origin to bypass the pulmonary capillary bed and embolize the systemic arterial circulation. IPAVA have been routinely observed in healthy humans with exercise, hypoxia, and catecholamine infusion, but the mechanism by which they are recruited is not well-defined. We hypothesized that beta-adrenergic receptor stimulation recruits IPAVA and that receptor blockade would limit hypoxia-induced IPAVA recruitment. To test our hypothesis, we evaluated the transpulmonary passage of microspheres in intact rats and isolated rats lung infused with the beta-adrenergic receptor agonist isoproterenol. We also evaluated IPAVA recruitment in intact rats with hypoxia and the beta-adrenergic receptor blocker propranolol. We found that IPAVA are recruited in the intact rat by isoproterenol and their recruitment by hypoxia can be minimized by propranolol, suggesting a role for the adrenergic system in the recruitment of IPAVA by hypoxia. IPAVA recruitment is completely abolished by ventilation with 100% oxygen. Isoproterenol also recruits IPAVA in isolated rat lungs. The fact that isoproterenol can recruit IPAVA in isolated lungs, without increased pulmonary flow, suggests that elevated cardiac output is not required for IPAVA recruitment.

  16. The effect of α-, β-adrenergic receptor agonists and antagonists of the efflux of 22Na and uptake of 42K by rat brain cortical slices

    International Nuclear Information System (INIS)

    Phillis, J.W.; Wu, P.H.; Thierry, D.L.

    1982-01-01

    The effects of norepinephrine on ion fluxes in rat brain cortical slices have now been ascertained. 22 Na efflux and 42 K influx are enhanced by norepinephrine. The increase in ion fluxes can be blocked by ouabain, phentolamine and propranolol, suggesting that the catecholamine activates a membrane sodium pump by a receptor-mediated step. The facilitation of 22 Na efflux is stereospecific as demonstrated by the very weak action of D-norepinephrine at 10 -5 M concentration. Various α-adrenergic and β-adrenergic receptor agonists, including oxymetazoline, naphazoline, clonidine, tramazoline, methoxamine, phenylephrine, L-isoproterenol and methoxyphenamine are potent stimulants of the sodium pump as demonstrated by their enhancement of ion fluxes in rat brain cortical slices. The results are consistent with the hypothesis that norepinephrine hyperpolarizes central neurons by activating an ouabain-sensitive, receptor-mediated sodium pump. (Auth.)

  17. Remodeling of intrinsic cardiac neurons: effects of β-adrenergic receptor blockade in guinea pig models of chronic heart disease.

    Science.gov (United States)

    Hardwick, Jean C; Southerland, E Marie; Girasole, Allison E; Ryan, Shannon E; Negrotto, Sara; Ardell, Jeffrey L

    2012-11-01

    Chronic heart disease induces remodeling of cardiac tissue and associated neuronal components. Treatment of chronic heart disease often involves pharmacological blockade of adrenergic receptors. This study examined the specific changes in neuronal sensitivity of guinea pig intrinsic cardiac neurons to autonomic modulators in animals with chronic cardiac disease, in the presence or absence of adrenergic blockage. Myocardial infarction (MI) was produced by ligature of the coronary artery and associated vein on the dorsal surface of the heart. Pressure overload (PO) was induced by a banding of the descending dorsal aorta (∼20% constriction). Animals were allowed to recover for 2 wk and then implanted with an osmotic pump (Alzet) containing either timolol (2 mg·kg(-1)·day(-1)) or vehicle, for a total of 6-7 wk of drug treatment. At termination, intracellular recordings from individual neurons in whole mounts of the cardiac plexus were used to assess changes in physiological responses. Timolol treatment did not inhibit the increased sensitivity to norepinephrine seen in both MI and PO animals, but it did inhibit the stimulatory effects of angiotensin II on the norepinephrine-induced increases in neuronal excitability. Timolol treatment also inhibited the increase in synaptically evoked action potentials observed in PO animals with stimulation of fiber tract bundles. These results demonstrate that β-adrenergic blockade can inhibit specific aspects of remodeling within the intrinsic cardiac plexus. In addition, this effect was preferentially observed with active cardiac disease states, indicating that the β-receptors were more influential on remodeling during dynamic disease progression.

  18. Beta-Adrenergic Receptor Activation during Distinct Patterns of Stimulation Critically Modulates the PKA-Dependence of LTP in the Mouse Hippocampus

    Science.gov (United States)

    Gelinas, Jennifer N.; Tenorio, Gustavo; Lemon, Neal; Abel, Ted; Nguyen, Peter V.

    2008-01-01

    Activation of Beta-adrenergic receptors (Beta-ARs) enhances hippocampal memory consolidation and long-term potentiation (LTP), a likely mechanism for memory storage. One signaling pathway linked to Beta-AR activation is the cAMP-PKA pathway. PKA is critical for the consolidation of hippocampal long-term memory and for the expression of some forms…

  19. Bidirectional modulation of hippocampal gamma (20-80 Hz) frequency activity in vitro via alpha(α)- and beta(β)-adrenergic receptors (AR).

    Science.gov (United States)

    Haggerty, D C; Glykos, V; Adams, N E; Lebeau, F E N

    2013-12-03

    Noradrenaline (NA) in the hippocampus plays an important role in memory function and has been shown to modulate different forms of synaptic plasticity. Oscillations in the gamma frequency (20-80 Hz) band in the hippocampus have also been proposed to play an important role in memory functions and, evidence from both in vitro and in vivo studies, has suggested this activity can be modulated by NA. However, the role of different NA receptor subtypes in the modulation of gamma frequency activity has not been fully elucidated. We have found that NA (30 μM) exerts a bidirectional control on the magnitude of kainate-evoked (50-200 nM) gamma frequency oscillations in the cornu Ammonis (CA3) region of the rat hippocampus in vitro via activation of different receptor subtypes. Activation of alpha-adrenergic receptors (α-AR) reduced the power of the gamma frequency oscillation. In contrast, activation of beta-adrenergic receptors (β-AR) caused an increase in the power of the gamma frequency oscillations. Using specific agonists and antagonists of AR receptor subtypes we demonstrated that these effects are mediated specifically via α1A-AR and β1-AR subtypes. NA activated both receptor subtypes, but the α1A-AR-mediated effect predominated, resulting in a reversible suppression of gamma frequency activity. These results suggest that NA is able to differentially modulate on-going gamma frequency oscillatory activity that could result in either increased or decreased information flow through the hippocampus. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Alpha and beta adrenergic effects on metabolism in contracting, perfused muscle

    DEFF Research Database (Denmark)

    Richter, Erik; Ruderman, N B; Galbo, H

    1982-01-01

    The role of alpha- and beta-adrenergic receptor stimulation for the effect of epinephrine on muscle glycogenolysis, glucose- and oxygen uptake and muscle performance was studied in the perfused rat hindquarter at rest and during electrical stimulation (60 contractions/min). Adrenergic stimulation...... was obtained by epinephrine in a physiological concentration (2.4 X 10(-8) M) and alpha- and beta-adrenergic blockade by 10(-5) M phentolamine and propranolol, respectively. Epinephrine enhanced net glycogenolysis during contractions most markedly in slow-twitch red fibers. In these fibers the effect...... was mediated by alpha- as well as by beta-adrenergic stimulation, the latter involving production of cAMP, phosphorylase activation and synthase inactivation. In contrast, in fast-twitch fibers only beta-adrenergic mechanisms were involved in the glycogenolytic effect of epinephrine. Moreover, inactivation...

  1. Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor β2.

    Science.gov (United States)

    Long, Qiqi; Liu, Xishi; Qi, Qiuming; Guo, Sun-Wei

    2016-11-01

    (a non-specific ADRB agonist), respectively. In all three experiments, the bodyweight and hotplate latency were evaluated before sacrifice 14 days after the induction. In all experimentations, the lesion weight was evaluated and the harvested ectopic endometrial tissue samples were subjected to immunohistochemistry analysis of vascular endothelial growth factor (VEGF), CD31-positive microvessels, proliferating cell nuclear antigen (PCNA), phosphorylated CREB, ADRB1, ADRB2, ADRB3, adrenergic receptor α1 (ADRA1) and ADRA2. Exposure to chronic stress accelerated the development of endometriosis and exacerbated the endometriosis-associated generalized hyperalgesia. This promotional effect is likely to be mediated through the systemic activation of the sympatho-adreno-medullary (SAM) axis, which results in subsequent release of catecholamines. The surging catecholamines may activate ADRB2 and CREB, yielding increased angiogenesis and cellular proliferation in ectopic endometrium in mice with induced endometriosis. In addition, β adrenergic receptor blockade completely abolished the promotional effect of chronic stress, likely through suppression of ADRB2 and CREB activation, thus suppressing angiogenesis and proliferation. Moreover, a non-specific adrenergic β agonist and a specific adrenergic β2 agonist, but not non-specific adrenergic α agonist, acted similarly to chronic stress, accelerating the development of endometriosis and exacerbating the generalized hyperalgesia in mice with pre-existing endometriosis. NA. This study is limited by the use of immunohistochemistry analyses only and the lack of molecular data. The present study provides the experimental evidence that chronic stress can promote the development of endometriosis through the activation of ADRB2. Given ADRB2 is also expressed in human endometriosis and appears to be functional, and in light of recent awareness that adrenergic signaling plays critical roles in tumorigenesis, it is likely that

  2. In vitro study on the effects of some selected agonists and antagonists of alpha(1)-adrenergic receptors on the contractility of the aneurysmally-changed aortic smooth muscle in humans.

    Science.gov (United States)

    Gnus, J; Czerski, A; Ferenc, S; Zawadzki, W; Witkiewicz, W; Hauzer, W; Rusiecka, A; Bujok, J

    2012-02-01

    The study included 18 sections of the aneurysmally-changed abdominal aortas, obtained from patients of the Provincial Specialist Hospital in Wroclaw and 18 sections of normal abdominal aortas obtained from swine. The collected samples were placed horizontally in the incubation chamber. Changes in their transverse section area were registered. They were stretched to a tension of 5 mN. Krebs-Henseleit buffer was used as the incubatory environment. Incubation of the sections was performed at a temperature of 37°C, in the gaseous mixture of oxygen and carbon dioxide used in the following proportion: 95% of O(2) and 5% of CO(2). Contractions of the aorta were registered with isotonic transducers (Letica Scientific Instruments). In the studies, we examined the influence of α(1)-adrenergic receptors (and their subtypes α(1A), α(1B), α(1D)) on the contractility of the aortic muscle in humans and swine by their stimulation or inhibition with some selected agonists or antagonists. This time, it was shown that the stimulation of α(1)-adrenergic receptors leads to contractions of the human and swine aortic muscle; the observed increase in the muscle tone may follow from the stimulation of all subtypes of alpha-1 receptor (α(1A), α(1B), α(1D)). All three subtypes of 1-adrenergic receptor are engaged in vasoconstriction, especially of α(1A) and α(1D) subtypes; the α(1B) subtype is less significant for aortic contractility. The contractile response of the aneurysmally-changed abdominal aorta in humans to agonists of α-adrenergic receptors was significantly less intense than that of the normal porcine aorta. It can be concluded that aneurysms influence the contractile response of the aorta.

  3. Pharmacogenetics of the β2-Adrenergic Receptor Gene

    Science.gov (United States)

    Ortega, Victor E.; Hawkins, Gregory A.; Peters, Stephen P.; Bleecker, Eugene R.

    2009-01-01

    Asthma is a complex genetic disease with multiple genetic and environmental determinants contributing to the observed variability in response to common anti-asthma therapies. Asthma pharmacogenetic research has focused on multiple candidate genes including the β2-adrenergic receptor gene (ADRβ2) and its effect on individual responses to beta agonist therapy. At present, knowledge about the effects of ADRβ2 variation on therapeutic responses is evolving and should not alter current Asthma Guideline approaches consisting of the use of short acting beta agonists for as-needed symptom based therapy and the use of a regular long-acting beta agonist in combination with inhaled corticosteroid therapy for optimal control of asthma symptoms in those asthmatics who are not controlled on inhaled corticosteroid alone. This approach is based upon studies showing a consistent pharmacogenetic response to regular use of short acting beta agonists (SABA) and less consistent findings in studies evaluating long acting beta agonist (LABA). While emerging pharmacogenetic studies are provocative and should lead to functional approaches, conflicting data with responses to LABA therapy may be caused by factors that include small sample sizes of study populations and differences in experimental design that may limit the conclusions that may be drawn from these clinical trials at the present time. PMID:17996583

  4. The adrenergic retulation of the cardiovascular system in the South American rattlesnake, Crotalus durissus

    DEFF Research Database (Denmark)

    Galli, G.L.J.; Jensen, Nini Skovgaard; Abe, A.S.

    2007-01-01

    The present study investigates adrenergic regulation of the systemic and pulmonary circulations of the anaesthetised South American rattlesnake, Crotalus durissus. Haemodynamic measurements were made following bolus injections of adrenaline and adrenergic antagonists administered through a systemic...... arterial catheter. Adrenaline caused a marked systemic vasoconstriction that was abolished by phentolamine, indicating this response was mediated through α-adrenergic receptors. Injection of phentolamine gave rise to a pronounced vasodilatation (systemic conductance (Gsys) more than doubled), while...... injection of propranolol caused a systemic vasoconstriction, pointing to a potent α-adrenergic, and a weaker β-adrenergic tone in the systemic vasculature of Crotalus. Overall, the pulmonary vasculature was far less responsive to adrenergic stimulation than the systemic circulation. Adrenaline caused...

  5. Effect of adrenergic receptor ligands on metaiodobenzylguanidine uptake and storage in neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Babich, J.W. [Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts (United States)]|[Department of Radiology, Harvard Medical School, Boston, Massachusetts (United States); Graham, W. [Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts (United States); Fischman, A.J. [Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts (United States)]|[Department of Radiology, Harvard Medical School, Boston, Massachusetts (United States)

    1997-05-01

    The effects of adrenergic receptor ligands on uptake and storage of the radiopharmaceutical [{sup 125}I]metaiodobenzylguanidine (MIBG) were studied in the human neuroblastoma cell line SK-N-SH. For uptake studies, cells were with varying concentrations of {alpha}-agonist (clonidine, methoxamine, and xylazine), {alpha}-antagonist (phentolamine, tolazoline, phenoxybenzamine, yohimbine, and prazosin), {beta}-antagonist (propranolol, atenolol), {beta}-agonist (isoprenaline and salbutamol), mixed {alpha}/{beta} antagonist (labetalol), or the neuronal blocking agent guanethidine, prior to the addition of [{sup 125}I]MIBG (0.1 {mu}M). The incubation was continued for 2 h and specific cell-associated radioactivity was measured. For the storage studies, cells were incubated with [{sup 125}I]MIBG for 2 h, followed by replacement with fresh medium with or without drug (MIBG, clonidine, or yohimbine). Cell-associated radioactivity was measured at various times over the next 20 h. Propanolol reduced [{sup 125}I]MIBG uptake by approximately 30% (P<0.01) at all concentrations tested, most likely due to nonspecific membrane changes. In conclusion, the results of this study establish that selected adrenergic ligands can significantly influence the pattern of uptake and storage of MIBG in cultured neuroblastoma cells, most likely through inhibition of uptake or through noncompetitive inhibition. The potential inplications of these findings justify further study. (orig./VHE). With 4 figs., 1 tab.

  6. Distribution of beta-adrenergic receptors in failing human myocardium. Implications for mechanisms of down-regulation

    International Nuclear Information System (INIS)

    Murphree, S.S.; Saffitz, J.E.

    1989-01-01

    The density of beta-adrenergic receptors is reduced in crude membranes prepared from failing human myocardium. We used quantitative autoradiography of radioligand binding sites in intact tissue slices to determine whether the total tissue content of receptors is reduced and to characterize the transmural distribution of receptors in cardiac myocytes and the coronary vasculature in hearts obtained from nine cardiac transplant patients with severe congestive failure. Binding of [125Iodo]cyanopindolol to transmural slices of human myocardium was rapid, saturable, stereoselective, and displaceable by agonists and antagonists with an appropriate rank order of potency. Binding isotherms in four normal and nine failing ventricles showed a significant reduction in the total tissue content of beta-receptors in failing myocardium (38.3 +/- 2.0 fmol/mg protein) compared with normal tissue (52.4 +/- 1.7 fmol/mg protein, p = 0.038). In the normal ventricles, the greatest receptor density was observed autoradiographically in myocytic regions of the subendocardium. Receptor density of the coronary arterioles was approximately 70% of that in adjacent myocytic regions. The density of binding sites in both myocytic regions and arterioles was diminished in all regions of the failing ventricles, but down-regulation was due primarily to a selective reduction of beta-receptors of subendocardial myocytes (63 +/- 5% of subepicardial receptor density vs. 115 +/- 6% in controls, p less than 0.0001). These observations indicate that down-regulation occurs nonuniformly in the transmural distribution and thus is likely not related simply to elevated circulating catecholamine levels

  7. Adrenergic manipulation inhibits pavlovian conditioned approach behaviors.

    Science.gov (United States)

    Pasquariello, Kyle Z; Han, Marina; Unal, Cagla; Meyer, Paul J

    2018-02-26

    Environmental rewards and Pavlovian reward cues can acquire incentive salience, thereby eliciting incentive motivational states and instigate reward-seeking. In rats, the incentive salience of food cues can be measured during a Pavlovian conditioned approach paradigm, in which rats engage in cue-directed approach ("sign-tracking") or approach the food delivery location ("goal-tracking"). While it has been shown that dopamine signaling is necessary for sign-tracking, some studies have suggested that norepinephrine is involved in learning to sign-track as well. Thus, in order to investigate the influence of norepinephrine in Pavlovian conditioned approach, we administered three adrenergic drugs while rats learned that a food cue (an illuminated, retractable lever) preceded the delivery of banana-flavored food pellets into a food-cup. We found that pre-session injections of disulfiram (a dopamine-β-hydroxylase inhibitor) inhibited the development of sign-tracking, but goal-tracking was only affected at the high dose. In one experiment, post-session injections of disulfiram blocked the development of sign-tracking, although this effect was not replicated in a separate set of rats. Post-session injections of prazosin (an α1-adrenergic receptor antagonist) and propranolol (a β-adrenergic receptor antagonist) also blocked the development of sign-tracking but not goal-tracking. Taken together, these results suggest that adrenergic transmission mediates the acquisition of sign-tracking but not goal-tracking, and thus plays a selective role in the attribution of incentive salience food cues. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Regulation and function of the alpha2 adrenergic autoreceptor in the central nervous system

    International Nuclear Information System (INIS)

    Spengler, R.N.

    1987-01-01

    The purpose of this investigation was to determine whether changes observed in the number of alpha 2 adrenergic receptors in the brain as measured by radioligand binding experiments reflect changes in the function of alpha 2 autoregulatory receptors which are located on noradrenergic nerve terminals. Inhibition by clonidine of field stimulated 3 H-norepinephrine ( 3 H-NE) release from rat hippocampal slices before and after several drug treatments was analyzed to investigate changes in alpha 2 adrenergic receptor function. Clonidine in a concentration-dependent manner inhibited 3 H-NE release. The effect of clonidine was blocked by the specific alpha 2 adrenergic receptor antagonist, idazoxan. The cumulative administration of clonidine generated a smooth and well-fitted log-concentration-effect curve. Results are presented which demonstrate that this technique can be employed to investigate the role of changes in the function of the alpha 2 autoregulatory receptor. The present investigation also examined representatives of four drug classes which have been shown to alter the specific binding of 3 H-clonidine to neural membranes to determine whether changes in the alpha 2 autoregulatory receptor function also occur

  9. Autonomic receptors in urinary tract: Sex and age differences

    International Nuclear Information System (INIS)

    Latifpour, J.; Kondo, S.; O'Hollaren, B.; Morita, T.; Weiss, R.M.

    1990-01-01

    As age and sex affect the function of the lower urinary tract, we studied the characteristics of adrenergic and cholinergic receptors in various parts of lower urinary tract smooth muscle of young (6 months) and old (4 1/2-5 years) male and female rabbits. Saturation experiments performed with [3H]prazosin, [3H]yohimbine, [3H]dihydroalprenolol and [3H]quinuclidinyl benzylate in rabbit bladder base, bladder dome and urethra indicate the presence of regional, sex- and age-related differences in the density of alpha-1, alpha-2, and beta adrenergic and muscarinic cholinergic receptors. Alpha-2 adrenergic receptor density is considerably higher in the female than in the male urethra of both age groups, whereas the higher density of beta adrenergic receptors in the female than in the male bladder base is observed only in the younger animals. The density of muscarinic receptors is higher in bladder dome than in bladder base or urethra in young rabbits of both sexes. In the old animals, the density of muscarinic receptors in bladder base increases to the level observed in bladder dome. Inhibition experiments with selective adrenergic agonists and antagonists indicate that the pharmacological profiles of alpha-2 adrenergic receptors in the urethra and beta adrenergic receptors in the bladder dome and bladder base are similar in both sexes and at both ages. Beta-2 adrenergic receptors are shown to be predominant in bladder base and bladder dome of rabbits. Parallel studies in rabbit urethra, adult rat cortex and neonatal rat lung show that the urethral alpha-2 adrenergic receptors are of the alpha-2A subtype

  10. Effect of cardiopulmonary bypass on beta adrenergic receptor-adenylate cyclase system on surfaces of peripheral lymphocytes.

    Science.gov (United States)

    Luo, A; Tian, Y; Jin, S

    2000-01-01

    The experimental results showed that the level of CAMP, the ratio of cAPM to cGMP, IL-2R expression and IL-2 production in vitro in lymphocytes immediate and 2 weeks after cardiopulmonary bypass (CPB) were significantly lower than those before anesthetics in the patients undergoing cardiac surgery with CPB. These findings suggested that CPB could cause serious damage to adrenergic beta receptor-adenylate cyclase system on circulating lymphocytes surfaces, which might be one of the mechanisms resulting in immunosuppression after open heart surgery with CPB.

  11. Reversal of propranolol blockade of adrenergic receptors and related toxicity with drugs that increase cyclic AMP.

    Science.gov (United States)

    Whitehurst, V E; Vick, J A; Alleva, F R; Zhang, J; Joseph, X; Balazs, T

    1999-09-01

    An overdose of propranolol, a widely used nonselective beta-adrenergic receptor blocking agent, can result in hypotension and bradycardia leading to irreversible shock and death. In addition, the blockade of adrenergic receptors can lead to alterations in neurotransmitter receptors resulting in the interruption of the activity of other second messengers and the ultimate cellular responses. In the present experiment, three agents, aminophylline, amrinone, and forskolin were tested in an attempt to reverse the potential lethal effects of a propranolol overdose in dogs. Twenty-two anesthetized beagle dogs were given a 10-min infusion of propranolol at a dose of 1 mg/kg/min. Six of the dogs, treated only with intravenous saline, served as controls. Within 15-30 min all six control dogs exhibited profound hypotension and severe bradycardia that led to cardiogenic shock and death. Seven dogs were treated with intravenous aminophylline 20 mg/kg 5 min after the end of the propranolol infusion. Within 10-15 min heart rate and systemic arterial blood pressure returned to near control levels, and all seven dogs survived. Intravenous amrinone (2-3 mg/kg) given to five dogs, and forskolin (1-2 mg/kg) given to four dogs, also increased heart rate and systemic arterial blood pressure but the recovery of these parameters was appreciably slower than that seen with aminophylline. All of these animals also survived with no apparent adverse effects. Histopathologic evaluation of the hearts of the dogs treated with aminophylline showed less damage (vacuolization, inflammation, hemorrhage) than the hearts from animals given propranolol alone. Results of this study showed that these three drugs, all of which increase cyclic AMP, are capable of reversing the otherwise lethal effects of a propranolol overdose in dogs.

  12. Crystal structure of the β2 adrenergic receptor-Gs protein complex

    Energy Technology Data Exchange (ETDEWEB)

    Rasmussen, Søren G.F.; DeVree, Brian T; Zou, Yaozhong; Kruse, Andrew C; Chung, Ka Young; Kobilka, Tong Sun; Thian, Foon Sun; Chae, Pil Seok; Pardon, Els; Calinski, Diane; Mathiesen, Jesper M; Shah, Syed T.A.; Lyons, Joseph A; Caffrey, Martin; Gellman, Samuel H; Steyaert, Jan; Skiniotis, Georgios; Weis, William I; Sunahara, Roger K; Kobilka, Brian K [Brussels; (Trinity); (Michigan); (Stanford-MED); (Michigan-Med); (UW)

    2011-12-07

    G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The β2 adrenergic receptor2AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric β2AR and nucleotide-free Gs heterotrimer. The principal interactions between the β2AR and Gs involve the amino- and carboxy-terminal α-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the β2AR include a 14Å outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an α-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.

  13. β1-adrenergic regulation of rapid component of delayed rectifier K+ currents in guinea-pig cardiac myocytes.

    Science.gov (United States)

    Wang, Sen; Xu, Di; Wu, Ting-Ting; Guo, Yan; Chen, Yan-Hong; Zou, Jian-Gang

    2014-05-01

    Human ether-à-go-go-related gene (hERG) potassium channels conduct the rapid component of the delayed rectifier potassium current (IKr), which is crucial for repolarization of cardiac action potential. Patients with hERG‑associated long QT syndrome usually develop tachyarrhythmias during physical and/or emotional stress, both known to stimulate adrenergic receptors. The present study aimed to investigate a putative functional link between β1-adrenergic stimulation and IKr in guinea-pig left ventricular myocytes and to analyze how IKr is regulated following activation of the β1-adrenergic signaling pathway. The IKr current was measured using a whole-cell patch-clamp technique. A selective β1-adrenergic receptor agonist, xamoterol, at concentrations of 0.01-100 µM decreased IKr in a concentration-dependent manner. The 10 µM xamoterol-induced inhibition of IKr was attenuated by the protein kinase A (PKA) inhibitor KT5720, the protein kinase C (PKC) inhibitor chelerythrine, and the phospholipase (PLC) inhibitor U73122, indicating involvement of PKA, PKC and PLC in β1-adrenergic inhibition of IKr. The results of the present study indicate an association between IKr and the β1-adrenergic receptor in arrhythmogenesis, involving the activation of PKA, PKC and PLC.

  14. β-Adrenergic signaling is required for the induction of a labile state during memory reconsolidation.

    Science.gov (United States)

    Lim, Chae-Seok; Kim, Jae-Ick; Kwak, Chuljung; Lee, Jaehyun; Jang, Eun Hae; Oh, Jihae; Kaang, Bong-Kiun

    2018-04-20

    Memory reconsolidation is the process by which previously consolidated memories reenter a labile state through reactivation of the memory trace and are actively consolidated through de novo protein synthesis. Although extensive studies have shown that β-adrenergic signaling plays a critical role in the restabilization of reactivated memory, its role in the destabilization of long-term memory is not well-studied. In this study, we found that membrane excitability increased in hippocampal CA1 neurons immediately after the retrieval of contextual fear memory. Interestingly, this increase in membrane excitability diminished after treatment with propranolol (a β-adrenergic receptor antagonist), an NMDA receptor antagonist, and a PKA inhibitor. In addition, we found that administration of propranolol prior to, but not after, the retrieval of fear memory ameliorated the memory impairment caused by anisomycin, indicating that inhibition of β-adrenergic signaling blocks the destabilization of contextual fear memory. Taken together, these results indicate that β-adrenergic signaling via NMDA receptors and PKA signaling pathway induces a labile state of long-term memory through increased neuronal membrane excitability. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. The influence of adrenergic stimulation on sex differences in left ventricular twist mechanics.

    Science.gov (United States)

    Williams, Alexandra M; Shave, Rob E; Cheyne, William S; Eves, Neil D

    2017-06-15

    Sex differences in left ventricular (LV) mechanics occur during acute physiological challenges; however, it is unknown whether sex differences in LV mechanics are fundamentally regulated by differences in adrenergic control. Using two-dimensional echocardiography and speckle tracking analysis, this study compared LV mechanics in males and females matched for LV length during post-exercise ischaemia (PEI) and β 1 -adrenergic receptor blockade. Our data demonstrate that while basal rotation was increased in males, LV twist was not significantly different between the sexes during PEI. In contrast, during β 1 -adrenergic receptor blockade, LV apical rotation, twist and untwisting velocity were reduced in males compared to females. Significant relationships were observed between LV twist and LV internal diameter and sphericity index in females, but not males. These findings suggest that LV twist mechanics may be more sensitive to alterations in adrenergic stimulation in males, but more highly influenced by ventricular structure and geometry in females. Sex differences in left ventricular (LV) mechanics exist at rest and during acute physiological stress. Differences in cardiac autonomic and adrenergic control may contribute to sex differences in LV mechanics and LV haemodynamics. Accordingly, this study aimed to investigate sex differences in LV mechanics with altered adrenergic stimulation achieved through post-handgrip-exercise ischaemia (PEI) and β 1 -adrenergic receptor (AR) blockade. Twenty males (23 ± 5 years) and 20 females (22 ± 3 years) were specifically matched for LV length (males: 8.5 ± 0.5 cm, females: 8.2 ± 0.6 cm, P = 0.163), and two-dimensional speckle-tracking echocardiography was used to assess LV structure and function at baseline, during PEI and following administration of 5 mg bisoprolol (β 1 -AR antagonist). During PEI, LV end-diastolic volume and stroke volume were increased in both groups (P adrenergic stimulation

  16. Beta-Adrenergic gene therapy for cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Koch Walter J

    2000-10-01

    Full Text Available Abstract Gene therapy using in vivo recombinant adenovirus-mediated gene transfer is an effective technique that offers great potential to improve existing drug treatments for the complex cardiovascular diseases of heart failure and vascular smooth muscle intimal hyperplasia. Cardiac-specific adenovirus-mediated transfer of the carboxyl-terminus of the β-adrenergic receptor kinase (βARKct, acting as a Gβγ-β-adrenergic receptor kinase (βARK1 inhibitor, improves basal and agonist-induced cardiac performance in both normal and failing rabbit hearts. In addition, βARKct adenovirus infection of vascular smooth muscle is capable of significantly diminishing neointimal proliferation after angioplasty. Therefore, further investigation is warranted to determine whether inhibition of βARK1 activity and sequestration of Gβγ via an adenovirus that encodes the βARKct transgene might be a useful clinical tool for the treatment of cardiovascular pathologies.

  17. Kinetic properties and adrenergic control of TREK-2-like channels in rat medial prefrontal cortex (mPFC) pyramidal neurons.

    Science.gov (United States)

    Ładno, W; Gawlak, M; Szulczyk, P; Nurowska, E

    2017-06-15

    TREK-2-like channels were identified on the basis of electrophysiological and pharmacological tests performed on freshly isolated and enzymatically/mechanically dispersed pyramidal neurons of the rat medial prefrontal cortex (mPFC). Single-channel currents were recorded in cell-attached configuration and the impact of adrenergic receptors (α 1 , α 2 , β) stimulation on spontaneously appearing TREK-2-like channel activity was tested. The obtained results indicate that noradrenaline decreases the mean open probability of TREK-2-like channel currents by activation of β 1 but not of α 1 - and α 2 -adrenergic receptors. Mean open time and channel conductance were not affected. The system of intracellular signaling pathways depends on the activation of protein kinase A. We also show that adrenergic control of TREK-2-like channel currents by adrenergic receptors was similar in pyramidal neurons isolated from young, adolescent, and adult rats. Immunofluorescent confocal scans of mPFC slices confirmed the presence of the TREK-2 protein, which was abundant in layer V pyramidal neurons. The role of TREK-2-like channel control by adrenergic receptors is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. PASSIVE-AVOIDANCE TRAINING INDUCES ENHANCED LEVELS OF IMMUNOREACTIVITY FOR MUSCARINIC ACETYLCHOLINE-RECEPTOR AND COEXPRESSED PKC-GAMMA AND MAP-2 IN RAT CORTICAL-NEURONS

    NARCIS (Netherlands)

    VANDERZEE, EA; DOUMA, BRK; BOHUS, B; LUITEN, PGM

    1994-01-01

    Changes in neocortical immunoreactivity (ir) for muscarinic acetylcholine receptors (mAChRs), protein kinase C gamma (PKC gamma), microtubule-associated protein 2 (MAP-2), and the calcium-binding protein parvalbumin (PARV) induced by the performance of a one-trial passive shock avoidance (PSA) task

  19. Adrenaline rush: the role of adrenergic receptors in stimulant-induced behaviors.

    Science.gov (United States)

    Schmidt, Karl T; Weinshenker, David

    2014-04-01

    Psychostimulants, such as cocaine and amphetamines, act primarily through the monoamine neurotransmitters dopamine (DA), norepinephrine, and serotonin. Although stimulant addiction research has largely focused on DA, medication development efforts targeting the dopaminergic system have thus far been unsuccessful, leading to alternative strategies aimed at abating stimulant abuse. Noradrenergic compounds have shown promise in altering the behavioral effects of stimulants in rodents, nonhuman primates, and humans. In this review, we discuss the contribution of each adrenergic receptor (AR) subtype (α1, α2, and β) to five stimulant-induced behaviors relevant to addiction: locomotor activity, conditioned place preference, anxiety, discrimination, and self-administration. AR manipulation has diverse effects on these behaviors; each subtype profoundly influences outcomes in some paradigms but is inconsequential in others. The functional neuroanatomy and intracellular signaling mechanisms underlying the impact of AR activation/blockade on these behaviors remain largely unknown, presenting a new frontier for research on psychostimulant-AR interactions.

  20. Dissociation between neural and vascular responses to sympathetic stimulation : contribution of local adrenergic receptor function

    Science.gov (United States)

    Jacob, G.; Costa, F.; Shannon, J.; Robertson, D.; Biaggioni, I.

    2000-01-01

    Sympathetic activation produced by various stimuli, eg, mental stress or handgrip, evokes regional vascular responses that are often nonhomogeneous. This phenomenon is believed to be the consequence of the recruitment of differential central neural pathways or of a sympathetically mediated vasodilation. The purpose of this study was to determine whether a similar heterogeneous response occurs with cold pressor stimulation and to test the hypothesis that local differences in adrenergic receptor function could be in part responsible for this diversity. In 8 healthy subjects, local norepinephrine spillover and blood flow were measured in arms and legs at baseline and during sympathetic stimulation induced by baroreflex mechanisms (nitroprusside infusion) or cold pressor stimulation. At baseline, legs had higher vascular resistance (27+/-5 versus 17+/-2 U, P=0.05) despite lower norepinephrine spillover (0.28+/-0.04 versus 0.4+/-0.05 mg. min(-1). dL(-1), P=0.03). Norepinephrine spillover increased similarly in both arms and legs during nitroprusside infusion and cold pressor stimulation. On the other hand, during cold stimulation, vascular resistance increased in arms but not in legs (20+/-9% versus -7+/-4%, P=0.03). Increasing doses of isoproterenol and phenylephrine were infused intra-arterially in arms and legs to estimate beta-mediated vasodilation and alpha-induced vasoconstriction, respectively. beta-Mediated vasodilation was significantly lower in legs compared with arms. Thus, we report a dissociation between norepinephrine spillover and vascular responses to cold stress in lower limbs characterized by a paradoxical decrease in local resistance despite increases in sympathetic activity. The differences observed in adrenergic receptor responses cannot explain this phenomenon.

  1. Renal and femoral venous blood flows are regulated by different mechanisms dependent on α-adrenergic receptor subtypes and nitric oxide in anesthetized rats.

    Science.gov (United States)

    Fioretti, Alexandre C; Ogihara, Cristiana A; Cafarchio, Eduardo M; Venancio, Daniel P; de Almeida, Roberto Lopes; Antonio, Bruno B; Sato, Monica A

    2017-12-01

    Venous and arterial walls are responsive to sympathetic system and circulating substances, nevertheless, very few is known about the venous blood flow regulation simultaneously to arterial vascular beds. In this study, we compared the venous and arterial blood flow regulation in visceral and muscular beds upon injection of different doses of vasoactive drugs which act in arterial vascular beds. Anesthetized adult male Wistar rats underwent to right femoral artery and vein cannulation for hemodynamic recordings and infusion of drugs. Doppler flow probes were placed around the left renal artery and vein, and left femoral artery and vein to evaluate the changes in flood flow. Phenylephrine (PHE) injection (α 1 -adrenergic receptor agonist) elicited vasoconstriction in all arteries and veins. Intravenous prazosin (PZS) (1mg/kg, α 1 -adrenergic receptor blocker) caused renal artery vasodilation, but not in the other beds. Vasoconstrictor effect of PHE was abolished by PZS in all vascular beds, except in femoral vein. Phentolamine (PTL) injection (1mg/kg, α 1 /α 2 -adrenergic receptor blocker) produced renal artery vasodilation with no change in other beds. After PTL, the vasoconstriction evoked by PHE was abolished in all vascular beds. Sodium Nitroprusside (SNP), a nitric oxide donor, elicited vasodilation in all beds, and after PTL but not post PZS injection, SNP enhanced the vasodilatory effect in femoral vein. Our findings suggest that the vasoconstriction in renal and femoral veins is mediated by different subtypes of α-adrenoceptors. The nitric oxide-dependent vasodilation in femoral vein enhances when α 2 -adrenoceptors are not under stimulation, but not in the other vascular beds investigated. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Association of Ovarian Tumor β2-Adrenergic Receptor Status with Ovarian Cancer Risk Factors and Survival.

    Science.gov (United States)

    Huang, Tianyi; Tworoger, Shelley S; Hecht, Jonathan L; Rice, Megan S; Sood, Anil K; Kubzansky, Laura D; Poole, Elizabeth M

    2016-12-01

    The β 2 -adrenergic signaling pathway mediates the effects of chronic stress on ovarian cancer progression in mouse models. The relevance of this pathway to human ovarian cancer remains unknown. We assessed tumor expression of β 2 -adrenergic receptor (ADRB2) using tissue microarrays in 237 ovarian cancer cases from the Nurses' Health Studies (NHS/NHSII). Competing risks Cox regression was used to evaluate whether associations of reproductive, hormonal, and psychosocial factors with ovarian cancer risk differed by ADRB2. We also examined the association between tumor ADRB2 expression and ovarian cancer survival. Forty-five (19%) cases were positive for ADRB2 staining. High levels of anxiety symptoms were positively associated with ADRB2-positive tumors (HR, 2.59; 95% confidence interval [CI], 1.15-5.84) but not with ADRB2-negative tumors (HR, 1.16; 95% CI, 0.81-1.66; P heterogeneity = 0.07). We observed similar results for depression. No associations were observed for job strain, caregiving stress, or widowhood for either positive or negative ADRB2 status. Lifetime ovulatory years were more strongly associated with ADRB2-positive tumors (HR per 5 years, 1.60; 95% CI, 1.15-2.21) compared with ADRB2-negative tumors (HR, 1.11; 95% CI, 0.96-1.27; P heterogeneity = 0.04). Significant heterogeneity by ADRB2 was also observed for parity (P heterogeneity = 0.01), oral contraceptive use (P heterogeneity = 0.03), and age at menopause (P heterogeneity = 0.04). Tumor expression of ADRB2 was not associated with ovarian cancer mortality (HR, 1.05; 95% CI, 0.69-1.59). Several stress- and ovulation-related factors were differentially associated with ovarian tumors responsive to β 2 -adrenergic signaling. Replication in larger studies is warranted to confirm the role of β 2 -adrenergic signaling in ovarian cancer etiology. Cancer Epidemiol Biomarkers Prev; 25(12); 1587-94. ©2016 AACR. ©2016 American Association for Cancer Research.

  3. Amyloid β production is regulated by β2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor.

    Science.gov (United States)

    Bussiere, Renaud; Lacampagne, Alain; Reiken, Steven; Liu, Xiaoping; Scheuerman, Valerie; Zalk, Ran; Martin, Cécile; Checler, Frederic; Marks, Andrew R; Chami, Mounia

    2017-06-16

    Alteration of ryanodine receptor (RyR)-mediated calcium (Ca 2+ ) signaling has been reported in Alzheimer disease (AD) models. However, the molecular mechanisms underlying altered RyR-mediated intracellular Ca 2+ release in AD remain to be fully elucidated. We report here that RyR2 undergoes post-translational modifications (phosphorylation, oxidation, and nitrosylation) in SH-SY5Y neuroblastoma cells expressing the β-amyloid precursor protein (βAPP) harboring the familial double Swedish mutations (APPswe). RyR2 macromolecular complex remodeling, characterized by depletion of the regulatory protein calstabin2, resulted in increased cytosolic Ca 2+ levels and mitochondrial oxidative stress. We also report a functional interplay between amyloid β (Aβ), β-adrenergic signaling, and altered Ca 2+ signaling via leaky RyR2 channels. Thus, post-translational modifications of RyR occur downstream of Aβ through a β2-adrenergic signaling cascade that activates PKA. RyR2 remodeling in turn enhances βAPP processing. Importantly, pharmacological stabilization of the binding of calstabin2 to RyR2 channels, which prevents Ca 2+ leakage, or blocking the β2-adrenergic signaling cascade reduced βAPP processing and the production of Aβ in APPswe-expressing SH-SY5Y cells. We conclude that targeting RyR-mediated Ca 2+ leakage may be a therapeutic approach to treat AD. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Adrenergic effects on renal secretion of epidermal growth factor in the rat

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba

    1985-01-01

    Urinary epidermal growth factor (EGF) has been demonstrated recently to originate from the kidneys. The present study was undertaken to investigate the adrenergic and cholinergic influence on secretion of renal EGF. beta-Adrenergic agonists increased the level of urinary EGF, while propranolol......, a beta-adrenergic blocking agent, decreased basal and beta-adrenergic stimulated total output of urinary EGF. Acetylcholine and the anticholinergic agent atropine had no effect on the output of EGF in urine. Also chemical sympathectomy induced by 6-hydroxydopamine reduced the urinary output of EGF. None...... of the experimental groups had a median serum concentration above the detection limit of the assay. The present study shows that secretion of renal EGF is under the influence of the sympathetic nervous system and release of EGF is stimulated by activation of beta-adrenergic receptors in the kidneys....

  5. Cell-specific expression of calcineurin immunoreactivity within the rat basolateral amygdala complex and colocalization with the neuropeptide Y Y1 receptor.

    Science.gov (United States)

    Leitermann, Randy J; Sajdyk, Tammy J; Urban, Janice H

    2012-10-01

    Neuropeptide Y (NPY) produces potent anxiolytic effects via activation of NPY Y1 receptors (Y1r) within the basolateral amygdaloid complex (BLA). The role of NPY in the BLA was recently expanded to include the ability to produce stress resilience and long-lasting reductions in anxiety-like behavior. These persistent behavioral effects are dependent upon activity of the protein phosphatase, calcineurin (CaN), which has long been associated with shaping long-term synaptic signaling. Furthermore, NPY-induced reductions in anxiety-like behavior persist months after intra-BLA delivery, which together indicate a form of neuronal plasticity had likely occurred. To define a site of action for NPY-induced CaN signaling within the BLA, we employed multi-label immunohistochemistry to determine which cell types express CaN and if CaN colocalizes with the Y1r. We have previously reported that both major neuronal cell populations in the BLA, pyramidal projection neurons and GABAergic interneurons, express the Y1r. Therefore, this current study evaluated CaN immunoreactivity in these cell types, along with Y1r immunoreactivity. Antibodies against calcium-calmodulin kinase II (CaMKII) and GABA were used to identify pyramidal neurons and GABAergic interneurons, respectively. A large population of CaN immunoreactive cells displayed Y1r immunoreactivity (90%). Nearly all (98%) pyramidal neurons displayed CaN immunoreactivity, while only a small percentage of interneurons (10%) contained CaN immunoreactivity. Overall, these anatomical findings provide a model whereby NPY could directly regulate CaN activity in the BLA via activation of the Y1r on CaN-expressing, pyramidal neurons. Importantly, they support BLA pyramidal neurons as prime targets for neuronal plasticity associated with the long-term reductions in anxiety-like behavior produced by NPY injections into the BLA. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Adrenalectomy mediated alterations in adrenergic activation of adenylate cyclase in rat liver

    International Nuclear Information System (INIS)

    El-Refai, M.; Chan, T.

    1986-01-01

    Adrenalectomy caused a large increase in the number of β-adrenergic binding sites on liver plasma membranes as measured by 125 I-iodocyanopindolol (22 and 102 fmol/mg protein for control and adrenalectomized (ADX) rats). Concomitantly an increase in the number of binding sites for 3 H-yohimbine was also observed (104 and 175 fmol/mg protein for control and adx membranes). Epinephrine-stimulated increase in cyclic AMP accumulation in isolated hepatocytes were greater in cells from ADX rats. This increase in β-adrenergic mediated action was much less than what may be expected as a result of the increase in the β-adrenergic binding in ADX membranes. In addition phenoxybenzamine (10 μM) further augmented this action of epinephrine in both control and ADX cells. To test the hypothesis that the increase in the number of the inhibitory α 2 -adrenergic receptors in adrenalectomy is responsible for the muted β-adrenergic response, the authors injected rats with pertussis toxin (PT). This treatment may cause the in vivo ribosylation of the inhibitory binding protein (Ni). Adenylate cyclase (AC) activity in liver plasma membranes prepared from treated and untreated animals was measured. In contrast with control rats, treatment of ADX rats with PT resulted in a significant increase in the basal activity of AC (5.5 and 7.7 pmol/mg protein/min for untreated and treated rats respectively). Isoproterenol (10 μM), caused AC activity to increase to 6.5 and 8.4 pmol/mg protein/min for membranes obtained from ADX untreated and ADX treated rats respectively. The α-adrenergic antagonists had no significant effect on the β-adrenergic-mediated activation of AC in liver plasma membranes from PT treated control and ADX rats. The authors conclude that the β-adrenergic activation of AC is attenuated by Ni protein both directly and as a result of activation of α-adrenergic receptors

  7. Synthesis and biodistribution of R- and S-isomers of [18F]-fluoropropranolol, a lipophilic ligand for the β-adrenergic receptor

    International Nuclear Information System (INIS)

    Tewson, Timothy J.; Stekhova, Svetlana; Kinsey, Berma; Chen, Lay; Wiens, Linda; Barber, Roger

    1999-01-01

    The S and R isomers of [ 18 F]-fluoropropranolol (1-[1-fluoro-2-isopropylamino]-3-naphthalen-1-yloxy-propan-2-ol) have been prepared by reductive alkylation of the appropriate aminoalcohols. The radiosynthesis provides a reasonable yield (∼25%) to give products of 99% enantiomeric excess and specific activities of 1-3 Ci/μmol. The dissociation constants for the β 2 adrenergic receptor are 0.5 and 2.5 nM for the S and the R isomers, respectively. The biodistribution data in rats show that uptake and egress of the tracer is rapid but that the result of blocking studies and the difference between the R and the S isomers suggest receptor-mediated uptake in receptor-rich tissue

  8. Developmental changes in the role of a pertussis toxin sensitive guanine nucleotide binding protein in the rat cardiac alpha1-adrenergic system

    International Nuclear Information System (INIS)

    Han, H.M.

    1989-01-01

    During development, the cardiac alpha 1 -adrenergic chronotropic response changes from positive in the neonate to negative in the adult. This thesis examined the possibility of a developmental change in coupling of a PT-sensitive G-protein to the alpha 1 -adrenergic receptor. Radioligand binding experiments performed with the iodinated alpha 1 -selective radioligand [ 125 I]-I-2-[β-(4-hydroxphenyl)ethylaminomethyl]tetralone ([ 125 I]-IBE 2254) demonstrated that the alpha 1 -adrenergic receptor is coupled to a G-protein in both neonatal and adult rat hearts. However, in the neonate the alpha 1 -adrenergic receptor is coupled to a PT-insensitive G-protein, whereas in the adult the alpha 1 -adrenergic receptor is coupled to both a PT-insensitive and a PT-sensitive G-protein. Consistent with the results from binding experiments, PT did not have any effect on the alpha 1 -mediated positive chronotropic response in the neonate, whereas in the adult the alpha 1 -mediated negative chronotropic response was completely converted to a positive one after PT-treatment. This thesis also examined the possibility of an alteration in coupling of the alpha 1 -adrenergic receptor to its effector under certain circumstances such as high potassium (K + ) depolarization in nerve-muscle (NM) co-cultures, a system which has been previously shown to be a convenient in vitro model to study the mature inhibitory alpha 1 -response

  9. Binding site analysis of full-length α1a adrenergic receptor using homology modeling and molecular docking

    International Nuclear Information System (INIS)

    Pedretti, Alessandro; Elena Silva, Maria; Villa, Luigi; Vistoli, Giulio

    2004-01-01

    The recent availability of crystal structure of bovine rhodopsin offers new opportunities in order to approach the construction of G protein coupled receptors. This study focuses the attention on the modeling of full-length α 1a adrenergic receptor (α 1a -AR) due to its biological role and significant implications in pharmacological treatment of benign prostate hyperplasia. This work could be considered made up by two main steps: (a) the construction of full structure of α 1a -AR, through homology modeling methods; (b) the automated docking of an endogenous agonist, norepinephrine, and of an antagonist, WB-4101, using BioDock program. The obtained results highlight the key residues involved in binding sites of both agonists and antagonists, confirming the mutagenesis data and giving new suggestions for the rational design of selective ligands

  10. Absence of age-related changes in the binding of the beta adrenergic antagonist 125I-iodohydroxybenzylpindolol in rat heart

    International Nuclear Information System (INIS)

    Tumer, N.; Bender, J.; Roberts, J.

    1987-01-01

    The effect of age on the density and the affinity of beta adrenergic receptors was determined in the hearts of Fischer 344 rats at three ages, 6, 12, and 24 months old. The binding of the beta adrenergic antagonist 125 I-iodohydroxybenzylpindolol (IHYP), was used to quantitate and characterize cardiac beta adrenergic receptors. The maximal number of binding sites (B/sub max/ = F moles/mg of protein) were 26.3 +/- 2.5, 25.4 +/- 0.99, and 24.5 +/- 2.4 and the dissociation constants (K/sub d/ = nM) were 0.166 +/- 0.014, 0.126 +/- 0.006, and 0.135 +/- 0.015 for 6, 12, and 24 months old animals, respectively. There were no significant differences among the three ages. These results support the contention that neither beta adrenergic receptor density of affinity changes with age in the ventricles of the rat heart

  11. Beta2-adrenergic receptor homodimers: Role of transmembrane domain 1 and helix 8 in dimerization and cell surface expression.

    Science.gov (United States)

    Parmar, Vikas K; Grinde, Ellinor; Mazurkiewicz, Joseph E; Herrick-Davis, Katharine

    2017-09-01

    Even though there are hundreds of reports in the published literature supporting the hypothesis that G protein-coupled receptors (GPCR) form and function as dimers this remains a highly controversial area of research and mechanisms governing homodimer formation are poorly understood. Crystal structures revealing homodimers have been reported for many different GPCR. For adrenergic receptors, a potential dimer interface involving transmembrane domain 1 (TMD1) and helix 8 (H8) was identified in crystal structures of the beta 1 -adrenergic (β 1 -AR) and β 2 -AR. The purpose of this study was to investigate a potential role for TMD1 and H8 in dimerization and plasma membrane expression of functional β 2 -AR. Charged residues at the base of TMD1 and in the distal portion of H8 were replaced, singly and in combination, with non-polar residues or residues of opposite charge. Wild type and mutant β 2 -AR, tagged with YFP and expressed in HEK293 cells, were evaluated for plasma membrane expression and function. Homodimer formation was evaluated using bioluminescence resonance energy transfer, bimolecular fluorescence complementation, and fluorescence correlation spectroscopy. Amino acid substitutions at the base of TMD1 and in the distal portion of H8 disrupted homodimer formation and caused receptors to be retained in the endoplasmic reticulum. Mutations in the proximal region of H8 did not disrupt dimerization but did interfere with plasma membrane expression. This study provides biophysical evidence linking a potential TMD1/H8 interface with ER export and the expression of functional β 2 -AR on the plasma membrane. This article is part of a Special Issue entitled: Interactions between membrane receptors in cellular membranes edited by Kalina Hristova. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Modulation of receptors and adenylate cyclase activity during sucrose feeding, food deprivation, and cold exposure

    International Nuclear Information System (INIS)

    Scarpace, P.J.; Baresi, L.A.; Morley, J.E.

    1987-01-01

    Thermogenesis in brown adipose tissue (BAT) serves as a regulator of body temperature and weight maintenance. Thermogenesis can be stimulated by catecholamine activation of adenylate cyclase through the β-adrenergic receptor. To investigate the effects of sucrose feeding, food deprivation, and cold exposure on the β-adrenergic pathway, adenylate cyclase activity and β-adrenergic receptors were assessed in rat BAT after 2 wk of sucrose feeding, 2 days of food deprivation, or 2 days of cold exposure. β-Adrenergic receptors were identified in BAT using [ 125 I]iodocyanopindolol. Binding sites had the characteristics of mixed β 1 - and β 2 -type adrenergic receptors at a ratio of 60/40. After sucrose feeding or cold exposure, there was the expected increase in BAT mitochondrial mass as measured by total cytochrome-c oxidase activity but a decrease in β-adrenergic receptor density due to a loss of the β 1 -adrenergic subtype. This BAT β-adrenergic receptor downregulation was tissue specific, since myocardial β-adrenergic receptors were unchanged with either sucrose feeding or cold exposure. Forskolin-stimulated adenylate cyclase activity increased in BAT after sucrose feeding or cold exposure but not after food deprivation. These data suggest that in BAT, sucrose feeding or cold exposure result in downregulation of β-adrenergic receptors and that isoproterenol-stimulated adenylate cyclase activity was limited by receptor availability

  13. Androgen receptor immunoreactivity in rat occipital cortex after callosotomy

    Directory of Open Access Journals (Sweden)

    G Lepore

    2009-08-01

    Full Text Available Gonadal steroidogenesis can be influenced by direct neural links between the central nervous system and the gonads. It is known that androgen receptor (AR is expressed in many areas of the rat brain involved in neuroendocrine control of reproduction, such as the cerebral cortex. It has been recently shown that the occipital cortex exerts an inhibitory effect on testicular stereoidogenesis by a pituitary-independent neural mechanism. Moreover, the complete transection of the corpus callosum leads to an increase in testosterone (T secretion of hemigonadectomized rats. The present study was undertaken to analyze the possible corticocortical influences regulating male reproductive activities. Adult male Wistar rats were divided into 4 groups: 1 intact animals as control; 2 rats undergoing sham callosotomy; 3 posterior callosotomy; 4 gonadectomy and posterior callosotomy. Western blot analysis showed no remarkable variations in cortical AR expression in any of the groups except in group I where a significant decrease in AR levels was found. Similarly, both immunocytochemical study and cell count estimation showed a lower AR immunoreactivity in occipital cortex of callosotomized rats than in other groups. In addition, there was no difference in serum T and LH concentration between sham-callosotomized and callosotomized rats. In conclusion, our results show that posterior callosotomy led to a reduction in AR in the right occipital cortex suggesting a putative inhibiting effect of the contralateral cortical area.

  14. Interaction of sarcolysine with β-adrenergic receptors of tumor cells

    International Nuclear Information System (INIS)

    Belousova, A.K.; Solntseva, T.I.; Khabarov, S.V.

    1986-01-01

    The sites of specific binding of [L- 3 H]dihydroalprenolol ([ 3 H]DHA), possessing the properties of β-adrenergic receptors, coupled with adenylate cyclase, were detected by methods of competitive displacement and binding of β-adrenoblockers: [ 3 H]-DHA and L-propranolol on the surface of ascites sarcoma 37 cells. Specific binding of the ligand occurs rapidly and with saturation. The total number of binding sites in the case of total saturation is (30-40) x 10 3 per cell. An analysis of the results by the Scatchard method permitted the detection of two types of β-adrenoreceptors with high (K/sub d/ = 0.9-1.0 mM) and low (K/sub d/ = 15-20 nM) affinity for [ 3 H]DHA. The number of receptors of the first type is (5.0-7.5) x 10 3 , and of the second (20-30) x 10 3 per cell. Sarcolysine in 1-10 μM concentrations is capable of displacing [ 3 H]DHA bound to the β-adrenoreceptors, competing with it for common binding sites, and, like isoproterenol, inducing a brief increase in the content of cAMP in the tumor cells. Since sarcolysine noncompetitively inhibits cAMP phosphodiesterase of the plasma membranes of ascites sarcoma 37 cells in the same concentration range (2.5-25 μM), a possible functional association between the β-adrenoreceptors, adenylate cyclase, and the membrane cAMP phosphodiesterase and the participation of this complex in the antitumor effect of the cytostatic are suggested

  15. Estrogen alters the diurnal rhythm of alpha 1-adrenergic receptor densities in selected brain regions

    International Nuclear Information System (INIS)

    Weiland, N.G.; Wise, P.M.

    1987-01-01

    Norepinephrine regulates the proestrous and estradiol-induced LH surge by binding to alpha 1-adrenergic receptors. The density of alpha 1-receptors may be regulated by estradiol, photoperiod, and noradrenergic neuronal activity. We wished to determine whether alpha 1-receptors exhibit a diurnal rhythm in ovariectomized and/or estradiol-treated female rats, whether estradiol regulates alpha 1-receptors in those areas of brain involved with LH secretion and/or sexual behavior, and whether the concentrations of alpha-receptors vary inversely relative to previously reported norepinephrine turnover patterns. Young female rats, maintained on a 14:10 light-dark cycle were ovariectomized. One week later, half of them were outfitted sc with Silastic capsules containing estradiol. Groups of animals were decapitated 2 days later at 0300, 1000, 1300, 1500, 1800, and 2300 h. Brains were removed, frozen, and sectioned at 20 micron. Sections were incubated with [ 3 H]prazosin in Tris-HCl buffer, washed, dried, and exposed to LKB Ultrofilm. The densities of alpha 1-receptors were quantitated using a computerized image analysis system. In ovariectomized rats, the density of alpha 1-receptors exhibited a diurnal rhythm in the suprachiasmatic nucleus (SCN), medial preoptic nucleus (MPN), and pineal gland. In SCN and MPN, receptor concentrations were lowest during the middle of the day and rose to peak levels at 1800 h. In the pineal gland, the density of alpha 1-receptors was lowest at middark phase, rose to peak levels before lights on, and remained elevated during the day. Estradiol suppressed the density of alpha 1 binding sites in the SCN, MPN, median eminence, ventromedial nucleus, and the pineal gland but had no effect on the lateral septum. Estrogen treatment altered the rhythm of receptor densities in MPN, median eminence, and the pineal gland

  16. Estrogen alters the diurnal rhythm of alpha 1-adrenergic receptor densities in selected brain regions

    Energy Technology Data Exchange (ETDEWEB)

    Weiland, N.G.; Wise, P.M.

    1987-11-01

    Norepinephrine regulates the proestrous and estradiol-induced LH surge by binding to alpha 1-adrenergic receptors. The density of alpha 1-receptors may be regulated by estradiol, photoperiod, and noradrenergic neuronal activity. We wished to determine whether alpha 1-receptors exhibit a diurnal rhythm in ovariectomized and/or estradiol-treated female rats, whether estradiol regulates alpha 1-receptors in those areas of brain involved with LH secretion and/or sexual behavior, and whether the concentrations of alpha-receptors vary inversely relative to previously reported norepinephrine turnover patterns. Young female rats, maintained on a 14:10 light-dark cycle were ovariectomized. One week later, half of them were outfitted sc with Silastic capsules containing estradiol. Groups of animals were decapitated 2 days later at 0300, 1000, 1300, 1500, 1800, and 2300 h. Brains were removed, frozen, and sectioned at 20 micron. Sections were incubated with (/sup 3/H)prazosin in Tris-HCl buffer, washed, dried, and exposed to LKB Ultrofilm. The densities of alpha 1-receptors were quantitated using a computerized image analysis system. In ovariectomized rats, the density of alpha 1-receptors exhibited a diurnal rhythm in the suprachiasmatic nucleus (SCN), medial preoptic nucleus (MPN), and pineal gland. In SCN and MPN, receptor concentrations were lowest during the middle of the day and rose to peak levels at 1800 h. In the pineal gland, the density of alpha 1-receptors was lowest at middark phase, rose to peak levels before lights on, and remained elevated during the day. Estradiol suppressed the density of alpha 1 binding sites in the SCN, MPN, median eminence, ventromedial nucleus, and the pineal gland but had no effect on the lateral septum. Estrogen treatment altered the rhythm of receptor densities in MPN, median eminence, and the pineal gland.

  17. The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence.

    Directory of Open Access Journals (Sweden)

    Fabrice Trovero

    Full Text Available Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg and cyproheptadine (1 mg/kg (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France and cyproheptadine (1 mg/kg could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.

  18. Effects of thyroid hormone on β-adrenergic responsiveness of aging cardiovascular systems

    International Nuclear Information System (INIS)

    Tsujimoto, G.; Hashimoto, K.; Hoffman, B.B.

    1987-01-01

    The authors have compared the effects of β-adrenergic stimulation on the heart and peripheral vasculature of young (2-mo-old) and older (12-mo-old) rats both in the presence and absence of triiodothyronine (T 3 )-induced hyperthyroidism. The hemodynamic consequences of T 3 treatment were less prominent in the aged hyperthyroid rats compared with young hyperthyroid rats (both in intact and pithed rats). There was a decrease in sensitivity of chronotropic responsiveness to isoproterenol in older pithed rats, which was apparently reversed by T 3 treatment. The number and affinity of myocardial β-adrenergic receptor sites measured by [ 125 I]cyanopindolol were not significantly different in young and older control rats; also, β-receptor density increased to a similar extent in both young and older T 3 -treated rats. The ability of isoproterenol to relax mesenteric arterial rings, markedly blunted in older rats, was partially restored by T 3 treatment without their being any change in isoproterenol-mediated relaxation in the arterial preparation from young rats. The number and affinity of the β-adrenergic receptors measured in the mesenteric arteries was unaffected by either aging or T 3 treatment. The data suggest that effects of thyroid hormone and age-related alterations of cardiovascular responsiveness to β-adrenergic stimulation are interrelated in a complex fashion with a net result that the hyperkinetic cardiovascular manifestations in hyperthyroidism are attenuated in the older animals

  19. Effects of thyroid hormone on. beta. -adrenergic responsiveness of aging cardiovascular systems

    Energy Technology Data Exchange (ETDEWEB)

    Tsujimoto, G.; Hashimoto, K.; Hoffman, B.B.

    1987-03-01

    The authors have compared the effects of ..beta..-adrenergic stimulation on the heart and peripheral vasculature of young (2-mo-old) and older (12-mo-old) rats both in the presence and absence of triiodothyronine (T/sub 3/)-induced hyperthyroidism. The hemodynamic consequences of T/sub 3/ treatment were less prominent in the aged hyperthyroid rats compared with young hyperthyroid rats (both in intact and pithed rats). There was a decrease in sensitivity of chronotropic responsiveness to isoproterenol in older pithed rats, which was apparently reversed by T/sub 3/ treatment. The number and affinity of myocardial ..beta..-adrenergic receptor sites measured by (/sup 125/I)cyanopindolol were not significantly different in young and older control rats; also, ..beta..-receptor density increased to a similar extent in both young and older T/sub 3/-treated rats. The ability of isoproterenol to relax mesenteric arterial rings, markedly blunted in older rats, was partially restored by T/sub 3/ treatment without their being any change in isoproterenol-mediated relaxation in the arterial preparation from young rats. The number and affinity of the ..beta..-adrenergic receptors measured in the mesenteric arteries was unaffected by either aging or T/sub 3/ treatment. The data suggest that effects of thyroid hormone and age-related alterations of cardiovascular responsiveness to ..beta..-adrenergic stimulation are interrelated in a complex fashion with a net result that the hyperkinetic cardiovascular manifestations in hyperthyroidism are attenuated in the older animals.

  20. Pharmacological characterization of a β-adrenergic-like octopamine receptor in Plutella xylostella.

    Science.gov (United States)

    Huang, Qing-Ting; Ma, Hai-Hao; Deng, Xi-Le; Zhu, Hang; Liu, Jia; Zhou, Yong; Zhou, Xiao-Mao

    2018-04-25

    The β-adrenergic-like octopamine receptor (OA2B2) belongs to the class of G-protein coupled receptors. It regulates important physiological functions in insects, thus is potentially a good target for insecticides. In this study, the putative open reading frame sequence of the Pxoa2b2 gene in Plutella xylostella was cloned. Orthologous sequence alignment, phylogenetic tree analysis, and protein sequence analysis all showed that the cloned receptor belongs to the OA2B2 protein family. PxOA2B2 was transiently expressed in HEK-293 cells. It was found that PxOA2B2 could be activated by both octopamine and tyramine, resulting in increased intracellular cyclic AMP (cAMP) levels, whereas dopamine and serotonin were not effective in eliciting cAMP production. Further studies with series of PxOA2B2 agonists and antagonists showed that all four tested agonists (e.g., naphazoline, clonidine, 2-phenylethylamine, and amitraz) could activate the PxOA2B2 receptor, and two of tested antagonists (e.g., phentolamine and mianserin) had significant antagonistic effects. However, antagonist of yohimbine had no effects. Quantitative real-time polymerase chain reaction analysis showed that Pxoa2b2 gene was expressed in all developmental stages of P. xylostella and that the highest expression occurred in male adults. Further analysis with fourth-instar P. xylostella larvae showed that the Pxoa2b2 gene was mainly expressed in Malpighian tubule, epidermal, and head tissues. This study provides both a pharmacological characterization and the gene expression patterns of the OA2B2 in P. xylostella, facilitating further research for insecticides using PxOA2B2 as a target. © 2018 Wiley Periodicals, Inc.

  1. Adrenergic beta 2-selective blocker in isoprenaline-enhanced essential tremor.

    Science.gov (United States)

    Teräväinen, H; Huttunen, J

    1987-01-01

    A beta 2-selective adrenergic-receptor-blocking drug, ICI 118.551, 150 mg/day, prevented almost as effectively as the nonselective antagonist propranolol, 240 mg/day, the isoprenaline enhancement of essential tremor amplitude.

  2. Synthesis and biodistribution of R- and S-isomers of [{sup 18}F]-fluoropropranolol, a lipophilic ligand for the {beta}-adrenergic receptor

    Energy Technology Data Exchange (ETDEWEB)

    Tewson, Timothy J. E-mail: ttewson@u.washington.edu; Stekhova, Svetlana; Kinsey, Berma; Chen, Lay; Wiens, Linda; Barber, Roger

    1999-11-01

    The S and R isomers of [{sup 18}F]-fluoropropranolol (1-[1-fluoro-2-isopropylamino]-3-naphthalen-1-yloxy-propan-2-ol) have been prepared by reductive alkylation of the appropriate aminoalcohols. The radiosynthesis provides a reasonable yield ({approx}25%) to give products of 99% enantiomeric excess and specific activities of 1-3 Ci/{mu}mol. The dissociation constants for the {beta}{sub 2} adrenergic receptor are 0.5 and 2.5 nM for the S and the R isomers, respectively. The biodistribution data in rats show that uptake and egress of the tracer is rapid but that the result of blocking studies and the difference between the R and the S isomers suggest receptor-mediated uptake in receptor-rich tissue.

  3. Insight into partial agonism by observing multiple equilibria for ligand-bound and Gs-mimetic nanobody-bound β1-adrenergic receptor.

    Science.gov (United States)

    Solt, Andras S; Bostock, Mark J; Shrestha, Binesh; Kumar, Prashant; Warne, Tony; Tate, Christopher G; Nietlispach, Daniel

    2017-11-27

    A complex conformational energy landscape determines G-protein-coupled receptor (GPCR) signalling via intracellular binding partners (IBPs), e.g., G s and β-arrestin. Using 13 C methyl methionine NMR for the β 1 -adrenergic receptor, we identify ligand efficacy-dependent equilibria between an inactive and pre-active state and, in complex with G s -mimetic nanobody, between more and less active ternary complexes. Formation of a basal activity complex through ligand-free nanobody-receptor interaction reveals structural differences on the cytoplasmic receptor side compared to the full agonist-bound nanobody-coupled form, suggesting that ligand-induced variations in G-protein interaction underpin partial agonism. Significant differences in receptor dynamics are observed ranging from rigid nanobody-coupled states to extensive μs-to-ms timescale dynamics when bound to a full agonist. We suggest that the mobility of the full agonist-bound form primes the GPCR to couple to IBPs. On formation of the ternary complex, ligand efficacy determines the quality of the interaction between the rigidified receptor and an IBP and consequently the signalling level.

  4. Adrenergic effects on secretion of amylase from the rat salivary glands

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba

    1988-01-01

    The present study was undertaken to investigate the effect of adrenergic agents on secretion of amylase from the salivary glands in vivo. Saliva was collected from the distal oesophagus in conscious rats. Adrenaline increased the concentration of amylase in saliva and serum significantly. The res......The present study was undertaken to investigate the effect of adrenergic agents on secretion of amylase from the salivary glands in vivo. Saliva was collected from the distal oesophagus in conscious rats. Adrenaline increased the concentration of amylase in saliva and serum significantly....... The result of infusion of alpha- and beta-adrenergic antagonists as well as noradrenaline and isoproterenol showed that secretion of salivary amylase is predominantly mediated by stimulation of beta-adrenergic receptors, especially of the beta 1-subtype. Investigation of the isoenzyme pattern in saliva......, pancreatic juice and serum demonstrated that the major component in serum is salivary amylase. This study has shown that beta-adrenergic agents stimulate secretion of amylase from the salivary glands in rats. Though the secretion is mainly exocrine small amounts of amylase is found in serum, which seems...

  5. Structure of the gene for human β2-adrenergic receptor: expression and promoter characterization

    International Nuclear Information System (INIS)

    Emorine, L.J.; Marullo, S.; Delavier-Klutchko, C.; Kaveri, S.V.; Durieu-Trautmann, O.; Strosberg, A.D.

    1987-01-01

    The genomic gene coding for the human β 2 -adrenergic receptor (β 2 AR) from A431 epidermoid cells has been isolated. Transfection of the gene into eukaryotic cells restores a fully active receptor/GTP-binding protein/adenylate cyclase complex with β 2 AR properties. Southern blot analyses with β 2 AR-specific probes show that a single β 2 AR gene is common to various human tissues and that its flanking sequences are highly conserved among humans and between man and rabbit, mouse, and hamster. Functional significance of these regions is supported by the presence of a promoter region (including mRNA cap sites, two TATA boxes, a CAAT box, and three G + C-rich regions that resemble binding sites for transcription factor Sp1) 200-300 base pairs 5' to the translation initiation codon. In the 3' flanking region, sequences homologous to glucocorticoid-response elements might be responsible for the increased expression of the β 2 AR gene observed after treatment of the transfected cells with hydrocortisone. In addition, 5' to the promoter region, an open reading frame encodes a 251-residue polypeptide that displays striking homologies with protein kinases and other nucleotide-binding proteins

  6. Pertussis toxin-sensitive G-protein mediates the alpha 2-adrenergic receptor inhibition of melatonin release in photoreceptive chick pineal cell cultures

    International Nuclear Information System (INIS)

    Pratt, B.L.; Takahashi, J.S.

    1988-01-01

    The avian pineal gland is a photoreceptive organ that has been shown to contain postjunctional alpha 2-adrenoceptors that inhibit melatonin synthesis and/or release upon receptor activation. Physiological response and [32P]ADP ribosylation experiments were performed to investigate whether pertussis toxin-sensitive guanine nucleotide-binding proteins (G-proteins) were involved in the transduction of the alpha 2-adrenergic signal. For physiological response studies, the effects of pertussis toxin on melatonin release in dissociated cell cultures exposed to norepinephrine were assessed. Pertussis toxin blocked alpha 2-adrenergic receptor-mediated inhibition in a dose-dependent manner. Pertussis toxin-induced blockade appeared to be noncompetitive. One and 10 ng/ml doses of pertussis toxin partially blocked and a 100 ng/ml dose completely blocked norepinephrine-induced inhibition. Pertussis toxin-catalyzed [32P]ADP ribosylation of G-proteins in chick pineal cell membranes was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Membranes were prepared from cells that had been pretreated with 0, 1, 10, or 100 ng/ml pertussis toxin. In the absence of pertussis toxin pretreatment, two major proteins of 40K and 41K mol wt (Mr) were labeled by [32P]NAD. Pertussis toxin pretreatment of pineal cells abolished [32P] radiolabeling of the 40K Mr G-protein in a dose-dependent manner. The norepinephrine-induced inhibition of both cAMP efflux and melatonin release, as assessed by RIA of medium samples collected before membrane preparation, was also blocked in a dose-dependent manner by pertussis toxin. Collectively, these results suggest that a pertussis toxin-sensitive 40K Mr G-protein labeled by [32P]NAD may be functionally associated with alpha 2-adrenergic signal transduction in chick pineal cells

  7. Effect of aging on alpha-1 adrenergic stimulation of phosphoinositide hydrolysis in various regions of rat brain

    International Nuclear Information System (INIS)

    Burnett, D.M.; Bowyer, J.F.; Masserano, J.M.; Zahniser, N.R.

    1990-01-01

    The effects of aging were examined on the ability of alpha-1 adrenergic receptor agonists to stimulate phosphoinositide hydrolysis in three brain regions. Tissue minces of thalamus, cerebral cortex and hippocampus from 3-, 18- and 28-month-old male Fischer 344 rats were prelabeled with [ 3 H]myoinositol. Exposure of these prelabeled minces to phenylephrine and (-)-norepinephrine revealed that accumulation of [ 3 H]inositol phosphates was selectively reduced by 20 to 30% in the thalamus and cerebral cortex of the oldest age group. Analysis of concentration-response and competition binding curves indicated that this decrease was due to diminished agonist efficacy rather than diminished receptor affinity. The reduction in responsiveness to phenylephrine and (-)-norepinephrine in the cerebral cortex and the lack of any changes in the hippocampus parallel previously reported changes in the density of alpha-1 adrenergic receptors with aging. These data indicate that the ability of alpha-1 adrenergic receptor agonists to stimulate phosphoinositide hydrolysis is reduced in some, but not all, brain regions of aged Fischer 344 rats

  8. Possible association of β2- and β3-adrenergic receptor gene polymorphisms with susceptibility to breast cancer

    International Nuclear Information System (INIS)

    Huang, Xin-En; Tokudome, Shinkan; Tajima, Kazuo; Hamajima, Nobuyuki; Saito, Toshiko; Matsuo, Keitaro; Mizutani, Mitsuhiro; Iwata, Hiroji; Iwase, Takuji; Miura, Shigeto; Mizuno, Tsutomu

    2001-01-01

    The involvement of β 2 -adrenergic receptor (ADRB2) and β 3 -adrenergic receptor (ADRB3) in both adipocyte lipolysis and thermogenic activity suggests that polymorphisms in the encoding genes might be linked with interindividual variation in obesity, an important risk factor for postmenopausal breast cancer. In order to examine the hypothesis that genetic variations in ADRB2 and ADRB3 represent interindividual susceptibility factors for obesity and breast cancer, we conducted a hospital-based, case-control study in the Aichi Cancer Center, Japan. A self-administered questionnaire was given to 200 breast cancer patients and 182 control individuals, and pertinent information on lifestyle, family history and reproduction was collected. ADRB2 and ADRB3 genotypes were determined by polymerase chain reaction (PCR) restriction fragment length polymorphism assessment. Twenty-five (12.4%) breast cancer patients and 32 (17.6%) control individuals were found to bear a glutamic acid (Glu) allele for the ADRB2 gene (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.38-1.18), and 60 (30.0%) breast cancer patients and 61 (33.5%) control individuals were found to bear an Arg allele for the ADRB3 gene (OR 0.85, 95% CI 0.55-1.31). A significantly lower risk was observed in those who carried the Glu ADRB2 allele and who reported first childbirth when they were younger than 25 years (OR 0.35; 95% CI 0.13-0.99). A potential association may exist between risk of breast cancer and polymorphisms in the ADRB2 and ADRB3 genes; further studies in larger samples and/or in different ethnic groups are warranted to investigate this potential association

  9. Ultrastructural characterization of noradrenergic- and beta-adrenergic receptor-containing profiles in the lateral nucleus of the amygdala

    Directory of Open Access Journals (Sweden)

    Claudia Farb

    2010-10-01

    Full Text Available Norepinephrine (NE is thought to play a key role in fear and anxiety, but its role in amygdala-dependent Pavlovian fear conditioning, a major model for understanding the neural basis of fear, is poorly understood. The lateral nucleus of the amygdala (LA is a critical brain region for fear learning and regulating the effects of stress on memory. To understand better the cellular mechanisms of NE and its adrenergic receptors in the LA, we used antibodies directed against dopamine beta-hydroxylase (DβH, the synthetic enzyme for NE, or against two different isoforms of the beta-adrenergic receptors (βARs, one that predominately recognizes neurons (βAR 248 and the other astrocytes (βAR 404, to characterize the microenvironments of DβH and βAR. By electron microscopy, most DβH terminals did not make synapses, but when they did, they formed both asymmetric and symmetric synapses. By light microscopy, βARs were present in both neurons and astrocytes. Confocal microscopy revealed that both excitatory and inhibitory neurons express βAR248. By electron microscopy, βAR 248 was present in neuronal cell bodies, dendritic shafts and spines, and some axon terminals and astrocytes. When in dendrites and spines, βAR 248 was frequently concentrated along plasma membranes and at post-synaptic densities of asymmetric (excitatory synapses. βAR 404 was expressed predominately in astrocytic cell bodies and processes. These astrocytic processes were frequently interposed between unlabeled terminals or ensheathed asymmetric synapses. Our findings provide a morphological basis for understanding ways in which NE may modulate transmission by acting via synaptic or non-synaptic mechanisms in the LA.

  10. Preliminary evidence for a role of the adrenergic nervous system in generalized anxiety disorder.

    Science.gov (United States)

    Zhang, Xiaobin; Norton, Joanna; Carrière, Isabelle; Ritchie, Karen; Chaudieu, Isabelle; Ryan, Joanne; Ancelin, Marie-Laure

    2017-02-15

    Generalized anxiety disorder (GAD) is a common chronic condition that is understudied compared to other psychiatric disorders. An altered adrenergic function has been reported in GAD, however direct evidence for genetic susceptibility is missing. This study evaluated the associations of gene variants in adrenergic receptors (ADRs) with GAD, with the involvement of stressful events. Data were obtained from 844 French community-dwelling elderly aged 65 or over. Anxiety disorders were assessed using the Mini-International Neuropsychiatry Interview, according to DSM-IV criteria. Eight single-nucleotide polymorphisms (SNPs) involved with adrenergic function were genotyped; adrenergic receptors alpha(1A) (ADRA1A), alpha(2A) (ADRA2A), and beta2 (ADRB2) and transcription factor TCF7L2. Questionnaires evaluated recent stressful life events as well as early environment during childhood and adolescence. Using multivariate logistic regression analyses four SNPs were significantly associated with GAD. A 4-fold modified risk was found with ADRA1A rs17426222 and rs573514, and ADRB2 rs1042713 which remained significant after Bonferroni correction. Certain variants may moderate the effect of adverse life events on the risk of GAD. Replication in larger samples is needed due to the small case number. This is the first study showing that ADR variants are susceptibility factors for GAD, further highlighting the critical role of the adrenergic nervous system in this disorder.

  11. Effects of central imidazolinergic and alpha2-adrenergic activation on water intake

    Directory of Open Access Journals (Sweden)

    Sugawara A.M.

    2001-01-01

    Full Text Available Non-adrenergic ligands that bind to imidazoline receptors (I-R, a selective ligand that binds to alpha2-adrenoceptors (alpha2-AR and mixed ligands that bind to both receptors were tested for their action on water intake behavior of 24-h water-deprived rats. All drugs were injected into the third cerebral ventricle. Except for agmatine (80 nmol, mixed ligands binding to I-R/alpha2-AR such as guanabenz (40 nmol and UK 14304 (20 nmol inhibited water intake by 65% and up to 95%, respectively. The selective non-imidazoline alpha2-AR agonist, alpha-methylnoradrenaline, produced inhibition of water intake similar to that obtained with guanabenz, but at higher doses (80 nmol. The non-adrenergic I-R ligands histamine (160 nmol, mixed histaminergic and imidazoline ligand and imidazole-4-acetic acid (80 nmol, imidazoline ligand did not alter water intake. The results show that selective, non-imidazoline alpha2-AR activation suppresses water intake, and suggest that the action on imidazoline sites by non-adrenergic ligands is not sufficient to inhibit water intake.

  12. Characterization of phosphorylated beta-adrenergic receptors from desensitized turkey erythrocytes

    International Nuclear Information System (INIS)

    Rebar, R.; Crooke, S.T.; Stadel, J.M.

    1986-01-01

    Catecholamine-induced desensitization of turkey erythrocyte (TE) adenylate cyclase results in a 40-50 percent decrease in agonist stimulated cyclase activity. Desensitization is accompanied by decreased mobility on SDS-PAGE of beta-adrenergic receptor (BAR) proteins photoaffinity labeled with [ 125 I]-p-azidobenzylcarazolol compared to control. Using a low crosslinked gel, the M/sub r/ = 42,000 band of BAR from desensitized TE was further resolved into a doublet compared to a single M/sub r/ = 38,000 band for control. The formation of the doublet appears to correlate with the amount of adenylate cyclase desensitization. Preincubating TE for 20 hr at 37 0 C with 32 P-/sub i/ labels BAR. 32 P-BAR was partially purified by affinity chromatography over alprenolol-Sepharose. Limited digest peptide maps of 32 P-BAR using papain identified a unique peptide (M/sub r/ = 2800) from BAR of desensitized TE which was absent in control. This unique 32 P-peptide was found only in the upper band of the doublet of BAR from desensitized TE. These data indicate that BAR is not uniformly phosphorylated following agonist-induced desensitization of TE and identify a peptide of BAR which is a site of phosphorylation correlating with desensitization of TE adenylate cyclase

  13. Subjective social status predicts in vivo responsiveness of β-adrenergic receptors.

    Science.gov (United States)

    Euteneuer, Frank; Mills, Paul J; Rief, Winfried; Ziegler, Michael G; Dimsdale, Joel E

    2012-07-01

    Several poor health outcomes, including cardiovascular risk, have been associated with both subjective social status (SSS) and sympathetic overactivity. Because prolonged sympathetic overactivation down regulates beta adrenergic receptor (β-AR) function, reduced β-AR responsiveness is considered an indicator of sympathetic overactivity and a cardiovascular risk factor. Though prior research has focused on objective social status and β-AR function, no studies have examined the association between SSS and β-AR function. We aimed to learn whether SSS predicts the in vivo responsiveness of β-ARs. We assessed the chronotropic 25 dose (CD25), an in vivo marker of β-AR responsiveness, in 94 healthy participants. The MacArthur scales of subjective social status were used to assess SSS in the U.S.A. (SSS-USA) and in the local community (SSS-C). Objective social status was analyzed by calculating the Hollingshead two-factor index. β-AR responsiveness was reduced (as indicated by higher CD25 values) in participants with lower SSS-USA (p = .007) and lower SSS-C (p social status. Our results indicate that β-AR function may be an important component of the link between SSS and health.

  14. Synthesis of the sup 11 C-labelled. beta. -adrenergic receptor ligands atenolol, metoprolol and propanolol

    Energy Technology Data Exchange (ETDEWEB)

    Antoni, G.; Ulin, J.; Laangstroem, B. (Uppsala Univ. (Sweden). Dept. of Organic Chemistry)

    1989-01-01

    The {sup 11}C-labelled {beta}-adrenergic receptor ligands atenolol 1, metoprolol 2 and propranolol 3 have been synthesized by an N-alkylation reaction using (2-{sup 11}C)isopropyl iodide. The labelled isopropyl iodide was prepared in a one-pot reactor system from ({sup 11}C)carbon dioxide and obtained in 40% radiochemical yield within 14 min reaction time. The total reaction times for compounds 1-3, counted from the start of the isopropyl iodide synthesis and including purification were 45-55 min. The products were obtained in 5-15% radiochemical yields and with radiochemical purities higher than 98%. The specific activity ranged from 0.4 to 4 GBq/{mu}mol. In a typical experiment starting with 4 GBq around 75 MBq of product was obtained. (author).

  15. β2‑adrenergic receptor functionality and genotype in two different models of chronic inflammatory disease: Liver cirrhosis and osteoarthritis.

    Science.gov (United States)

    Roca, Reyes; Esteban, Pablo; Zapater, Pedro; Inda, María-Del-Mar; Conte, Anna Lucia; Gómez-Escolar, Laura; Martínez, Helena; Horga, José F; Palazon, José M; Peiró, Ana M

    2018-06-01

    The present study was designed to investigate the functional status of β2 adrenoceptors (β2AR) in two models of chronic inflammatory disease: liver cirrhosis (LC) and osteoarthritis (OA). The β2AR gene contains three single nucleotide polymorphisms at amino acid positions 16, 27 and 164. The aim of the present study was to investigate the potential influence of lymphocyte β2AR receptor functionality and genotype in LC and OA patients. Blood samples from cirrhotic patients (n=52, hepatic venous pressure gradient 13±4 mmHg, CHILD 7±2 and MELD 11±4 scores), OA patients (n=30, 84% Kellgren‑Lawrence severity 4 grade, 14% knee replacement joint) and healthy volunteers as control group (n=26) were analyzed. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood and basal and isoproterenol induced adenylate cyclase activity (isoproterenol stimulus from 10‑9 to 10‑4 mM), and β2AR allelic variants (rs1042713, rs1042714, rs1800888) were determined. β2AR functionality was decreased in the two different models of chronic inflammatory disease studied, OA (50% vs. control) and LC (85% vs. control). In these patients, the strength of the β2AR response to adrenergic stimulation was very limited. Adrenergic modulation of PBMC function through the β2AR stimulus is decreased in chronic inflammatory processes including LC and OA, suggesting that the adrenergic system may be important in the development of these processes.

  16. Modifying influence of incorporated 137Cs upon the mechanisms of adrenergic control over contractile myucard function

    International Nuclear Information System (INIS)

    Lobanok, L.M.; Bulanova, K.Ya.; Gerasimovich, N.V.; Sineleva, M.V.; Milyutin, A.A.

    1994-01-01

    Incorporated 137 Cs (absorbed dose of 0.26 Gy) causes decrease of myocard's contractile function and intropic response to β-adrenagonists effect, isoproterenol-stimulated adenylate cyclase activity and β-adrenoreceptors affinity. Adrenergic effects, mediated by α-adrenergic structures on heart contractile function, on the contrary, become stronger, that is due to the increase of the receptors' dencity on sarcolemma surface

  17. Adrenergic control of swimbladder deflation in the zebrafish (Danio rerio).

    Science.gov (United States)

    Dumbarton, Tristan C; Stoyek, Matthew; Croll, Roger P; Smith, Frank M

    2010-07-15

    Many teleosts actively regulate buoyancy by adjusting gas volume in the swimbladder. In physostomous fishes such as the zebrafish, a connection is maintained between the swimbladder and the oesophagus via the pneumatic duct for the inflation and deflation of this organ. Here we investigated the role of adrenergic stimulation of swimbladder wall musculature in deflation of the swimbladder. Noradrenaline (NA), the sympathetic neurotransmitter (dosage 10(-6) to 10(-5) mol l(-1)), doubled the force of smooth muscle contraction in isolated tissue rings from the anterior chamber, caused a doubling of pressure in this chamber in situ, and evoked gas expulsion through the pneumatic duct, deflating the swimbladder to approximately 85% of the pre-NA volume. These effects were mediated by beta-adrenergic receptors, representing a novel role for these receptors in vertebrates. No effects of adrenergic stimulation were detected in the posterior chamber. In a detailed examination of the musculature and innervation of the swimbladder to determine the anatomical substrate for these functional results, we found that the anterior chamber contained an extensive ventral band of smooth muscle with fibres organized into putative motor units, richly innervated by tyrosine hydroxylase-positive axons. Additionally, a novel arrangement of folds in the lumenal connective tissue in the wall of the anterior chamber was described that may permit small changes in muscle length to cause large changes in effective wall distensibility and hence chamber volume. Taken together, these data strongly suggest that deflation of the zebrafish swimbladder occurs primarily by beta-adrenergically mediated contraction of smooth muscle in the anterior chamber and is under the control of the sympathetic limb of the autonomic nervous system.

  18. β adrenergic receptor/cAMP/PKA signaling contributes to the intracellular Ca2+ release by tentacle extract from the jellyfish Cyanea capillata.

    Science.gov (United States)

    Wang, Qianqian; Zhang, Hui; Wang, Bo; Wang, Chao; Xiao, Liang; Zhang, Liming

    2017-07-25

    Intracellular Ca 2+ overload induced by extracellular Ca 2+ entry has previously been confirmed to be an important mechanism for the cardiotoxicity as well as the acute heart dysfunction induced by jellyfish venom, while the underlying mechanism remains to be elucidated. Under extracellular Ca 2+ -free or Ca 2+ -containing conditions, the Ca 2+ fluorescence in isolated adult mouse cardiomyocytes pre-incubated with tentacle extract (TE) from the jellyfish Cyanea capillata and β blockers was scanned by laser scanning confocal microscope. Then, the cyclic adenosine monophosphate (cAMP) concentration and protein kinase A (PKA) activity in primary neonatal rat ventricular cardiomyocytes were determined by ELISA assay. Furthermore, the effect of propranolol against the cardiotoxicity of TE was evaluated in Langendorff-perfused rat hearts and intact rats. The increase of intracellular Ca 2+ fluorescence signal by TE was significantly attenuated and delayed when the extracellular Ca 2+ was removed. The β adrenergic blockers, including propranolol, atenolol and esmolol, partially inhibited the increase of intracellular Ca 2+ in the presence of 1.8 mM extracellular Ca 2+ and completely abolished the Ca 2+ increase under an extracellular Ca 2+ -free condition. Both cAMP concentration and PKA activity were stimulated by TE, and were inhibited by the β adrenergic blockers. Cardiomyocyte toxicity of TE was antagonized by β adrenergic blockers and the PKA inhibitor H89. Finally, the acute heart dysfuction by TE was antagonized by propranolol in Langendorff-perfused rat hearts and intact rats. Our findings indicate that β adrenergic receptor/cAMP/PKA signaling contributes to the intracellular Ca 2+ overload through intracellular Ca 2+ release by TE from the jellyfish C. capillata.

  19. β-Adrenergic Receptors Regulate the Acquisition and Consolidation Phases of Aversive Memory Formation Through Distinct, Temporally Regulated Signaling Pathways.

    Science.gov (United States)

    Schiff, Hillary C; Johansen, Joshua P; Hou, Mian; Bush, David E A; Smith, Emily K; Klein, JoAnna E; LeDoux, Joseph E; Sears, Robert M

    2017-03-01

    Memory formation requires the temporal coordination of molecular events and cellular processes following a learned event. During Pavlovian threat (fear) conditioning (PTC), sensory and neuromodulatory inputs converge on post-synaptic neurons within the lateral nucleus of the amygdala (LA). By activating an intracellular cascade of signaling molecules, these G-protein-coupled neuromodulatory receptors are capable of recruiting a diverse profile of plasticity-related proteins. Here we report that norepinephrine, through its actions on β-adrenergic receptors (βARs), modulates aversive memory formation following PTC through two molecularly and temporally distinct signaling mechanisms. Specifically, using behavioral pharmacology and biochemistry in adult rats, we determined that βAR activity during, but not after PTC training initiates the activation of two plasticity-related targets: AMPA receptors (AMPARs) for memory acquisition and short-term memory and extracellular regulated kinase (ERK) for consolidating the learned association into a long-term memory. These findings reveal that βAR activity during, but not following PTC sets in motion cascading molecular events for the acquisition (AMPARs) and subsequent consolidation (ERK) of learned associations.

  20. Rotifer neuropharmacology--III. Adrenergic drug effects on Brachionus plicatilis.

    Science.gov (United States)

    Keshmirian, J; Nogrady, T

    1987-01-01

    Norepinephrine (NE) induces three pharmacological effects in Brachionus plicatilis. As a result of excitation the rate of ciliary motion and swimming increases, and the animals flip their foot constantly at a rapid rate. This rapid foot flipping was used as a specific model to measure adrenergic effects in B. plicatilis. Phenylephrine induces the same effect at identical efficacy, while isoproterenol and salbutamol, two beta-agonists, show one-half and one-tenth NE efficacy. The beta blocker propranolol and the alpha blocker tolazoline both antagonize foot flipping induced by NE. However, propranolol shows antagonism because it causes foot paralysis by itself. Timolol, another beta blocker but without the membrane effect of propranolol, does not antagonize the alpha receptor mediated NE effect, nor does it cause foot paralysis. Propranolol, timolol and tolazoline also show agonist activity, inducing foot flipping. NE does not antagonize the foot paralysis induced by propranolol, only its anesthetic effect by delaying its onset. These results indicate that the foot flipping induced by NE is a receptor-mediated alpha adrenergic effect, while the foot paralysis is caused by membrane phenomena.

  1. Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.

    Science.gov (United States)

    Maruyama, Tatsuya; Onda, Kenichi; Hayakawa, Masahiko; Matsui, Tetsuo; Takasu, Toshiyuki; Ohta, Mitsuaki

    2009-06-01

    In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.

  2. Adrenergic bronchodilator overdose

    Science.gov (United States)

    Adrenergic bronchodilators are inhaled medicines that help open up the airways. They are used to treat asthma and chronic bronchitis. Adrenergic bronchodilator overdose occurs when someone accidentally or intentionally ...

  3. An investigation into the receptor-regulating effects of the acute administration of opioid agonists and an antagonist on beta adrenergic receptors in the rat cerebral cortex

    International Nuclear Information System (INIS)

    Roper, I.

    1987-01-01

    Past and current research indicated that biochemical deviations which might be involved in the etiology and pathophysiology of depression, included abnormalities or imbalances in the noradrenergic, serotonergic, hormonal and possibly in the endogenous opioid, dopaminergic, histaminergic, cholinergic and trace amine systems. In order to investigate a possible link between the noradrenergic system and opioids, it was decided to test the acute effects of opioid administration on cortical beta adrenoceptor numbers and affinity. As these receptors have been most consistently downregulated by antidepressant treatment, they may be involved in the mechanism of antidepressant action of these agents. It was decided to investigate beta adrenoceptor-regulatory effects of opioid treatment. Naloxone was tested alone, with a view to suppressing any possible endogenous opioid influences upon beta receptor status and revealing an effect which would possibly be the opposite of that brought about by the administration of opioid agonists. Naloxone was administered together with morphine to demonstrate that any beta receptor up- or downregulation which might be measured, had indeed been opioid-receptor mediated. It was found that the acute administration of four different mu opioid agonists, naloxone and naloxone plus morphine, did not cause any statistically significant alterations in cortical beta adrenergic receptor numbers or affinity in the rat. A radioactive ligand, the beta adrenoceptor-labelling compound referred to as DHA (L-dihydroalprenolol HCI) was used in this study

  4. Nicotinic receptor blockade decreases fos immunoreactivity within orexin/hypocretin-expressing neurons of nicotine-exposed rats.

    Science.gov (United States)

    Simmons, Steven J; Gentile, Taylor A; Mo, Lili; Tran, Fionya H; Ma, Sisi; Muschamp, John W

    2016-11-01

    Tobacco smoking is the leading cause of preventable death in the United States. Nicotine is the principal psychoactive ingredient in tobacco that causes addiction. The structures governing nicotine addiction, including those underlying withdrawal, are still being explored. Nicotine withdrawal is characterized by negative affective and cognitive symptoms that enhance relapse susceptibility, and suppressed dopaminergic transmission from ventral tegmental area (VTA) to target structures underlies behavioral symptoms of nicotine withdrawal. Agonist and partial agonist therapies help 1 in 4 treatment-seeking smokers at one-year post-cessation, and new targets are needed to more effectively aid smokers attempting to quit. Hypothalamic orexin/hypocretin neurons send excitatory projections to dopamine (DA)-producing neurons of VTA and modulate mesoaccumbal DA release. The effects of nicotinic receptor blockade, which is commonly used to precipitate withdrawal, on orexin neurons remain poorly investigated and present an attractive target for intervention. The present study sought to investigate the effects of nicotinic receptor blockade on hypothalamic orexin neurons using mecamylamine to precipitate withdrawal in rats. Separate groups of rats were treated with either chronic nicotine or saline for 7-days at which point effects of mecamylamine or saline on somatic signs and anxiety-like behavior were assessed. Finally, tissue from rats was harvested for immunofluorescent analysis of Fos within orexin neurons. Results demonstrate that nicotinic receptor blockade leads to reduced orexin cell activity, as indicated by lowered Fos-immunoreactivity, and suggest that this underlying cellular activity may be associated with symptoms of nicotine withdrawal as effects were most prominently observed in rats given chronic nicotine. We conclude from this study that orexin transmission becomes suppressed in rats upon nicotinic receptor blockade, and that behavioral symptoms associated

  5. Redistribution of Cerebral Blood Flow during Severe Hypovolemia and Reperfusion in a Sheep Model: Critical Role of α1-Adrenergic Signaling

    Directory of Open Access Journals (Sweden)

    René Schiffner

    2017-05-01

    Full Text Available Background: Maintenance of brain circulation during shock is sufficient to prevent subcortical injury but the cerebral cortex is not spared. This suggests area-specific regulation of cerebral blood flow (CBF during hemorrhage. Methods: Cortical and subcortical CBF were continuously measured during blood loss (≤50% and subsequent reperfusion using laser Doppler flowmetry. Blood gases, mean arterial blood pressure (MABP, heart rate and renal blood flow were also monitored. Urapidil was used for α1A-adrenergic receptor blockade in dosages, which did not modify the MABP-response to blood loss. Western blot and quantitative reverse transcription polymerase chain reactions were used to determine adrenergic receptor expression in brain arterioles. Results: During hypovolemia subcortical CBF was maintained at 81 ± 6% of baseline, whereas cortical CBF decreased to 40 ± 4% (p < 0.001. Reperfusion led to peak CBFs of about 70% above baseline in both brain regions. α1A-Adrenergic blockade massively reduced subcortical CBF during hemorrhage and reperfusion, and prevented hyperperfusion during reperfusion in the cortex. α1A-mRNA expression was significantly higher in the cortex, whereas α1D-mRNA expression was higher in the subcortex (p < 0.001. Conclusions: α1-Adrenergic receptors are critical for perfusion redistribution: activity of the α1A-receptor subtype is a prerequisite for redistribution of CBF, whereas the α1D-receptor subtype may determine the magnitude of redistribution responses.

  6. Expression of inwardly rectifying potassium channels (GIRKs) and beta-adrenergic regulation of breast cancer cell lines

    International Nuclear Information System (INIS)

    Plummer, Howard K III; Yu, Qiang; Cakir, Yavuz; Schuller, Hildegard M

    2004-01-01

    Previous research has indicated that at various organ sites there is a subset of adenocarcinomas that is regulated by beta-adrenergic and arachidonic acid-mediated signal transduction pathways. We wished to determine if this regulation exists in breast adenocarcinomas. Expression of mRNA that encodes a G-protein coupled inwardly rectifying potassium channel (GIRK1) has been shown in tissue samples from approximately 40% of primary human breast cancers. Previously, GIRK channels have been associated with beta-adrenergic signaling. Breast cancer cell lines were screened for GIRK channels by RT-PCR. Cell cultures of breast cancer cells were treated with beta-adrenergic agonists and antagonists, and changes in gene expression were determined by both relative competitive and real time PCR. Potassium flux was determined by flow cytometry and cell signaling was determined by western blotting. Breast cancer cell lines MCF-7, MDA-MB-361 MDA-MB 453, and ZR-75-1 expressed mRNA for the GIRK1 channel, while MDA-MB-468 and MDA-MB-435S did not. GIRK4 was expressed in all six breast cancer cell lines, and GIRK2 was expressed in all but ZR-75-1 and MDA-MB-435. Exposure of MDA-MB-453 cells for 6 days to the beta-blocker propranolol (1 μM) increased the GIRK1 mRNA levels and decreased beta 2 -adrenergic mRNA levels, while treatment for 30 minutes daily for 7 days had no effect. Exposure to a beta-adrenergic agonist and antagonist for 24 hours had no effect on gene expression. The beta adrenergic agonist, formoterol hemifumarate, led to increases in K + flux into MDA-MB-453 cells, and this increase was inhibited by the GIRK channel inhibitor clozapine. The tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a high affinity agonist for beta-adrenergic receptors stimulated activation of Erk 1/2 in MDA-MB-453 cells. Our data suggests β-adrenergic receptors and GIRK channels may play a role in breast cancer

  7. The Trp64Arg amino acid polymorphism of the beta3-adrenergic receptor gene does not contribute to the genetic susceptibility of diabetic microvascular complications in Caucasian type 1 diabetic patients

    DEFF Research Database (Denmark)

    Tarnow, L; Urhammer, S A; Mottlau, B

    1999-01-01

    OBJECTIVE: The beta3-adrenergic receptor is involved in regulation of microvascular blood flow. A missense mutation (Trp64Arg) in the beta3-adrenergic receptor gene has been suggested as a risk factor for proliferative retinopathy in Japanese type 2 diabetic patients. The aim of the present study...... was to evaluate the contribution of this polymorphism to the development of microangiopathic complications in Caucasian type 1 diabetic patients. SUBJECTS AND METHODS: We studied the relationship between the Trp64Arg polymorphism in type 1 diabetic patients with nephropathy (204 men/132 women, age 42.8 +/- 11.......0 years, diabetes duration 28 +/- 9 years) and in type 1 diabetic patients with persistent normoalbuminuria (118 men/73 women, age 42.6 +/- 10.2 years, diabetes duration 27 +/- 8 years). Proliferative retinopathy was present in 254 patients (48%), while 66 patients (13%) had no diabetic retinopathy...

  8. Changes in blood pressure and vascular adrenergic receptor numbers after isolation stress or dihydrotestosterone (DHT) treatment in the male SHR

    International Nuclear Information System (INIS)

    Iams, S.G.; McConnaughey, M.M.

    1986-01-01

    The authors have previously reported that treatment with testosterone increased blood pressure and alpha adrenergic receptor numbers in tail artery preparations from male SHRs, while gonadectomy had the opposite effect. In this study, they compared the effects of isolation stress and DHT treatment (800 mg/100 B Wt 3X/wk SC) on blood pressure and alpha and beta receptor numbers in tail artery and abdominal aorta preparations. Blood pressures were significantly higher (P 3 H]DHA) from the tail arteries or abdominal aortas after DHT, 151 +/- 7 and 119 +/- 1 vs. sham values 155 +/- 5 and 120 +/- 8. Beta receptor numbers were lower in the tail arteries and abdominal aortas from the stressed rats, 139 +/- 5 and 107 +/- 1. Alpha 1 receptor density (fmol/mg [ 3 H] prazosin) was increased in the DHT treated and stressed animals in both tail arteries 270 +/- 16 and 279 +/- 17 and abdominal aortas 231 +/- 13 and 212 +/- 9 when compared to DHT and non-stressed controls, 255 +/- 6 and 206 +/- 5. These results suggest that the alpha 1 receptor changes seen after androgen treatment may be a result of the increased blood pressure rather than a direct effect of the androgens on vascular smooth muscle

  9. An alpha-adrenergic receptor mechanism controlling potassium permeability in the rat lacrimal gland acinar cell

    International Nuclear Information System (INIS)

    Parod, R.J.; Putney, J.W. Jr.

    1978-01-01

    Rat lacrimal gland slices, incubated in a balanced, buffered salt solution, were found to be physiologically stable for up to 2 hr with respect to 0 2 consumption, extracellular space, and water and ion content. The release of 86 Rb serves as a good substitute for 42 K in monitoring the movement of K through the cell membrane. Adrenaline appears to increase membrane permeability to K as evidenced by an increase in the rate of 86 Rb efflux. This response to adrenaline was blocked by phentolamine but not by propranolol and was mimicked by phenylephrine but not by isoprenaline. The magnitude of the 86 Rb release indicates that it is being released, at least in part, from the lacrimal gland acinar cell. It is concluded that the lacrimal gland acinar cell has an α-adrenergic receptor, activation of which leads to an increase in membrane permeability to K. (author)

  10. Adrenergic influence on gastric mucosal blood flow in gastric fistula dogs

    DEFF Research Database (Denmark)

    Hovendal, C P; Bech, K; Gottrup, F

    1984-01-01

    micrograms/kg/min) induced an increase in mucosal blood flow and a similar increase in acid secretion. If the dopamine infusion was preceded by alpha-receptor blockade, a pronounced increase in mucosal blood flow was observed without a similar increase in acid secretion. beta-adrenergic stimulation...

  11. Beta-adrenergic control of plasma glucose and free fatty acid levels in the air-breathing African catfish Clarias gariepinus Burchell 1822

    NARCIS (Netherlands)

    van Heeswijk, JCF; Vianen, GJ; van den Thillart, GEEJM; Zaagsma, J

    In several water-breathing fish species, P-adrenergic receptor stimulation by noradrenaline leads to a decrease in plasma free fatty acid (FFA) levels, as opposed to an increase in air-breathing mammals. We hypothesised that this change in adrenergic control is related to the mode of breathing.

  12. Historical Overview of the Effect of -Adrenergic Agonists on Beef Cattle Production

    Directory of Open Access Journals (Sweden)

    Bradley J. Johnson

    2014-05-01

    Full Text Available Postnatal muscle hypertrophy of beef cattle is the result of enhanced myofibrillar protein synthesis and reduced protein turnover. Skeletal muscle hypertrophy has been studied in cattle fed β-adrenergic agonists (β-AA, which are receptor-mediated enhancers of protein synthesis and inhibitors of protein degradation. Feeding β-AA to beef cattle increases longissimus muscle cross-sectional area 6% to 40% compared to non-treated cattle. The β-AA have been reported to improve live animal performance, including average daily gain, feed efficiency, hot carcass weight, and dressing percentage. Treatment with β-AA increased mRNA concentration of the β2 or β1-adrenergic receptor and myosin heavy chain IIX in bovine skeletal muscle tissue. This review will examine the effects of skeletal muscle and adipose development with β-AA, and will interpret how the use of β-AA affects performance, body composition, and growth in beef cattle.

  13. Selective survival of β1-adenergic receptors in rat cerebellum following neonatal X-irradiation

    International Nuclear Information System (INIS)

    Minneman, K.P.; Pittman, R.N.; Wolfe, B.B.; Molinoff, P.B.

    1981-01-01

    To investigate the cellular localization of β 1 - and β 2 -adrenergic receptors, the effects of intermittent neonatal X-irradiation focused on the cerebellum were determined on the densities of the two subtypes of β-adrenergic receptor. This treatment destroys the late-maturing cerebellar interneurons including the granule, basket and stellate cells. The total number of β 2 -adrenergic receptors per cerebellum was reduced by 81-83% in 6- and 12-week-old X-irradiated rats. However, the number of β 1 -adrenergic receptors per cerebellum in 6- and 12-week-old X-irradiated rats was not significantly different from that in control animals. The results suggest that β 2 receptors in the rat cerebellum are primarily associated with the small interneurons destroyed by neonatal X-irradiation. The β 1 receptors may be located on a cell population which is unaffected by this treatment, possibly on cerebellar Purkinje cells. (Auth.)

  14. Characterization of a β-Adrenergic-Like Octopamine Receptor in the Oriental Fruit Fly, Bactrocera dorsalis (Hendel

    Directory of Open Access Journals (Sweden)

    Hui-Min Li

    2016-09-01

    Full Text Available The biogenic amine octopamine plays a critical role in the regulation of many physiological processes in insects. Octopamine transmits its action through a set of specific G-protein coupled receptors (GPCRs, namely octopamine receptors. Here, we report on a β-adrenergic-like octopamine receptor gene (BdOctβR1 from the oriental fruit fly, Bactrocera dorsalis (Hendel, a destructive agricultural pest that occurs in North America and the Asia-Pacific region. As indicated by RT-qPCR, BdOctβR1 was highly expressed in the central nervous system (CNS and Malpighian tubules (MT in the adult flies, suggesting it may undertake important roles in neural signaling in the CNS as well as physiological functions in the MT of this fly. Furthermore, its ligand specificities were tested in a heterologous expression system where BdOctβR1 was expressed in HEK-293 cells. Based on cyclic AMP response assays, we found that BdOctβR1 could be activated by octopamine in a concentration-dependent manner, confirming that this receptor was functional, while tyramine and dopamine had much less potency than octopamine. Naphazoline possessed the highest agonistic activity among the tested agonists. In antagonistic assays, mianserin had the strongest activity and was followed by phentolamine and chlorpromazine. Furthermore, when the flies were kept under starvation, there was a corresponding increase in the transcript level of BdOctβR1, while high or low temperature stress could not induce significant expression changes. The above results suggest that BdOctβR1 may be involved in the regulation of feeding processes in Bactrocera dorsalis and may provide new potential insecticide leads targeting octopamine receptors.

  15. Structural basis for activation of G-protein-coupled receptors

    DEFF Research Database (Denmark)

    Gether, Ulrik; Asmar, Fazila; Meinild, Anne Kristine

    2002-01-01

    into conformational changes accompanying GPCR activation and the underlying molecular mechanism governing transition of the receptor between its active and inactive states. Using the beta2-adrenergic receptor as a model system we have obtained evidence for an evolutionary conserved activation mechanism where...... changes and receptor activation. At the current stage we are exploring the possibility of reaching this goal by direct in situ labeling of the beta2-adrenergic receptor in Xenopus laevis oocytes with conformationally sensitive fluorescent probes and parallel detection of receptor activation by co...

  16. Neurokinin-1 Receptor Immunoreactive Neuronal Elements in the Superficial Dorsal Horn of the Chicken Spinal Cord: With Special Reference to Their Relationship with the Tachykinin-containing Central Axon Terminals in Synaptic Glomeruli

    International Nuclear Information System (INIS)

    Sakamoto, Hiroshi; Kawate, Toyoko; Li, Yongnan; Atsumi, Saoko

    2009-01-01

    Synaptic glomeruli that involve tachykinin-containing primary afferent central terminals are numerous in lamina II of the chicken spinal cord. Therefore, a certain amount of noxious information is likely to be modulated in these structures in chickens. In this study, we used immunohistochemistry with confocal and electron microscopy to investigate whether neurokinin-1 receptor (NK-1R)-expressing neuronal elements are in contact with the central primary afferent terminals in synaptic glomeruli of the chicken spinal cord. We also investigated which neuronal elements (axon terminals, dendrites, cell bodies) and which neurons in the spinal cord possess NK-1R, and are possibly influenced by tachykinin in the glomeruli. By confocal microscopy, NK-1R immunoreactivities were seen in a variety of neuronal cell bodies, their dendrites and smaller fibers of unknown origin. Some of the NK-1R immunoreactive profiles also expressed GABA immunoreactivities. A close association was observed between the NK-1R-immunoreactive neurons and tachykinin-immunoreactive axonal varicosities. By electron microscopy, NK-1R immunoreactivity was seen in cell bodies, conventional dendrites and vesicle-containing dendrites in laminae I and II. Among these elements, dendrites and vesicle-containing dendrites made contact with tachykinin-containing central terminals in the synaptic glomeruli. These results indicate that tachykinin-containing central terminals in the chicken spinal cord can modulate second-order neuronal elements in the synaptic glomeruli

  17. Identification of an endogenous alpha-adrenergic receptor antagonist: studies on its possible role in endocrine and cardiovascular function

    International Nuclear Information System (INIS)

    Dunbar, J.C.; Wider, M.; House, F.; Campbell, R.

    1986-01-01

    The concept of α and β adrenergic receptors that are regulated by epinephrine or norepinephrine (NE) is well established. The reported receptor antagonists have been synthetic. A peptide extracted from the duodenal mucosa with α-2 antagonist properties has been identified. It specifically inhibits 3 H-yohimbine binding (α-2) but not 3 H dihydroalprenolol (β) binding in whole brain membranes. Partially purified preparations of the alpha receptor binding inhibitor (ABI) were tested for endocrine pancreatic and cardiovascular effects. When isolated islets were incubated in the presence of ABI with and without NE, ABI along did not alter insulin secretion but completely reversed the NE suppression of glucose stimulated insulin release. Glucagon secretion by these same islets was enhanced by ABI and augmented the stimulatory effect of NE. Intravenous (I.V.) infusion of ABI increased serum insulin in the presence of NE and decreased the serum glucose response to a glucose load. Infusion of ABI into the 4th ventricle, or I.V. resulted in a decrease (50-60%) in systolic and diastolic blood pressure as well as a decrease (10-20%) in heart rate. From these studies the authors conclude that a duodenal peptide with the capacity to inhibit α-2 agonist binding may play a role in endocrine and cardiovascular functions

  18. Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

    Science.gov (United States)

    O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

    2014-01-01

    Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

  19. Conformational entropic maps of functional coupling domains in GPCR activation: A case study with beta2 adrenergic receptor

    Science.gov (United States)

    Liu, Fan; Abrol, Ravinder; Goddard, William, III; Dougherty, Dennis

    2014-03-01

    Entropic effect in GPCR activation is poorly understood. Based on the recent solved structures, researchers in the GPCR structural biology field have proposed several ``local activating switches'' that consisted of a few number of conserved residues, but have long ignored the collective dynamical effect (conformational entropy) of a domain comprised of an ensemble of residues. A new paradigm has been proposed recently that a GPCR can be viewed as a composition of several functional coupling domains, each of which undergoes order-to-disorder or disorder-to-order transitions upon activation. Here we identified and studied these functional coupling domains by comparing the local entropy changes of each residue between the inactive and active states of the β2 adrenergic receptor from computational simulation. We found that agonist and G-protein binding increases the heterogeneity of the entropy distribution in the receptor. This new activation paradigm and computational entropy analysis scheme provides novel ways to design functionally modified mutant and identify new allosteric sites for GPCRs. The authors thank NIH and Sanofi for funding this project.

  20. β-Adrenergic regulation of the cardiac Na+-K+ ATPase mediated by oxidative signaling

    DEFF Research Database (Denmark)

    Galougahi, Keyvan Karimi; Liu, Chia-Chi; Bundgaard, Henning

    2012-01-01

    Activation of β-adrenergic receptors (ARs) elicits responses arising from protein kinase A (PKA)-mediated phosphorylation of target proteins that regulate Ca(2+)-dependent excitation-contraction coupling. Some important targets for β-AR- and PKA-dependent pathways, including the sarcolemmal Na(+)...

  1. Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.

    Science.gov (United States)

    Abekawa, Tomohiro; Ito, Koki; Nakagawa, Shin; Koyama, Tsukasa

    2007-06-01

    Neurodevelopmental deficits of parvalbumin-immunoreactive gamma-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-D-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Prenatal exposure (E15-E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.

  2. Food restriction modulates β-adrenergic-sensitive adenylate cyclase in rat liver during aging

    International Nuclear Information System (INIS)

    Katz, M.S.

    1988-01-01

    Adenylate cyclase activities were studied in rat liver during postmaturational aging of male Fischer 344 rats fed ad libitum or restricted to 60% of the ad libitum intake. Catecholamine-stimulated adenylate cyclase activity increased by 200-300% between 6 and 24-27 mo of age in ad libitum-fed rats, whereas in food-restricted rats catecholamine response increased by only 58-84% between 6 and 30 mo. In ad libitum-fed rats, glucagon-stimulated enzyme activity also increased by 40% between 6 and 12 mo and in restricted rats a similar age-related increase was delayed until 18 mo. β-Adrenergic receptor density increased by 50% between 6 and 24 mo in livers from ad libitum-fed but not food-restricted rats and showed a highly significant correlation with maximal isoproterenol-stimulated adenylate cyclase activity over the postmaturational life span. Age-related increases in unstimulated (basal) adenylate cyclase activity and nonreceptor-mediated enzyme activation were retarded by food restriction. The results demonstrate that food restriction diminishes a marked age-related increase in β-adrenergic-sensitive adenylate cyclase activity of rat liver. Alterations of adrenergic-responsive adenylate cyclase with age and the modulatory effects of food restriction appear to be mediated by changes in both receptor and nonreceptor components of adenylate cyclase

  3. Bone marrow adipocytes resist lipolysis and remodeling in response to β-adrenergic stimulation.

    Science.gov (United States)

    Scheller, Erica L; Khandaker, Shaima; Learman, Brian S; Cawthorn, William P; Anderson, Lindsay M; Pham, H A; Robles, Hero; Wang, Zhaohua; Li, Ziru; Parlee, Sebastian D; Simon, Becky R; Mori, Hiroyuki; Bree, Adam J; Craft, Clarissa S; MacDougald, Ormond A

    2018-01-26

    Bone marrow adipose tissue (BMAT) is preserved or increased in states of caloric restriction. Similarly, we found that BMAT in the tail vertebrae, but not the red marrow in the tibia, resists loss of neutral lipid with acute, 48-hour fasting in rats. The mechanisms underlying this phenomenon and its seemingly distinct regulation from peripheral white adipose tissue (WAT) remain unknown. To test the role of β-adrenergic stimulation, a major regulator of adipose tissue lipolysis, we examined the responses of BMAT to β-adrenergic agonists. Relative to inguinal WAT, BMAT had reduced phosphorylation of hormone sensitive lipase (HSL) after treatment with pan-β-adrenergic agonist isoproterenol. Phosphorylation of HSL in response to β3-adrenergic agonist CL316,243 was decreased by an additional ~90% (distal tibia BMAT) or could not be detected (tail vertebrae). Ex vivo, adrenergic stimulation of lipolysis in purified BMAT adipocytes was also substantially less than iWAT adipocytes and had site-specific properties. Specifically, regulated bone marrow adipocytes (rBMAs) from proximal tibia and femur underwent lipolysis in response to both CL316,243 and forskolin, while constitutive BMAs from the tail responded only to forskolin. This occurred independently of changes in gene expression of β-adrenergic receptors, which were similar between adipocytes from iWAT and BMAT, and could not be explained by defective coupling of β-adrenergic receptors to lipolytic machinery through caveolin 1. Specifically, we found that whereas caveolin 1 was necessary to mediate maximal stimulation of lipolysis in iWAT, overexpression of caveolin 1 was insufficient to rescue impaired BMAT signaling. Lastly, we tested the ability of BMAT to respond to 72-hour treatment with CL316,243 in vivo. This was sufficient to cause beiging of iWAT adipocytes and a decrease in iWAT adipocyte cell size. By contrast, adipocyte size in the tail BMAT and distal tibia remained unchanged. However, within the

  4. [Beta]-Adrenergic Receptors in the Insular Cortex are Differentially Involved in Aversive vs. Incidental Context Memory Formation

    Science.gov (United States)

    Miranda, Maria Isabel; Sabath, Elizabeth; Nunez-Jaramillo, Luis; Puron-Sierra, Liliana

    2011-01-01

    The goal of this research was to determine the effects of [beta]-adrenergic antagonism in the IC before or after inhibitory avoidance (IA) training or context pre-exposure in a latent inhibition protocol. Pretraining intra-IC infusion of the [beta]-adrenergic antagonist propranolol disrupted subsequent IA retention and impaired latent inhibition…

  5. Evidence for Alpha Receptors in the Human Ureter

    Science.gov (United States)

    Madeb, Ralph; Knopf, Joy; Golijanin, Dragan; Bourne, Patricia; Erturk, Erdal

    2007-04-01

    An immunohistochemical and western blot expression analysis of human ureters was performed in order to characterize the alpha-1-adrenergic receptor distribution along the length of the human ureteral wall. Mapping the distribution will assist in understanding the potential role alpha -1-adrenergic receptors and their subtype density might have in the pathophysiology of ureteral colic and stone passage. Patients diagnosed with renal cancer or bladder cancer undergoing nephrectomy, nephroureterectomy, or cystectomy had ureteral specimens taken from the proximal, mid, distal and tunneled ureter. Tissues were processed for fresh frozen examination and fixed in formalin. None of the ureteral specimens were involved with cancer. Serial histologic sections and immunohistochemical studies were performed using antibodies specific for alpha-1-adrenergic receptor subtypes (alpha 1a, alpha 1b, alpha 1d). The sections were examined under a light microscope and scored as positive or negative. In order to validate and quantify the alpha receptor subtypes along the human ureter. Western blotting techniques were applied. Human ureter stained positively for alpha -1-adrenergic receptors. Immunostaining appeared red, with intense reaction in the smooth muscle of the ureter and endothelium of the neighboring blood vessels. There was differential expression between all the receptors with the highest staining for alpha-1D subtype. The highest protein expression for all three subtypes was in the renal pelvis and decreased with advancement along the ureter to the distal ureter. At the distal ureter, there was marked increase in expression as one progressed towards the ureteral orifice. The same pattern of protein expression was exhibited for all three alpha -1-adrenergic receptor subtypes. We provide preliminary evidence for the ability to detect and quantify the alpha-1-receptor subtypes along the human ureter which to the best of our knowledge has never been done with

  6. Carvedilol and adrenergic agonists suppress the lipopolysaccharide-induced NO production in RAW 264.7 macrophages via the adrenergic receptors

    Czech Academy of Sciences Publication Activity Database

    Pekarová, Michaela; Králová, Jana; Kubala, Lukáš; Číž, Milan; Papežíková, Ivana; Mačičková, T.; Pečivová, J.; Nosál, R.; Lojek, Antonín

    2009-01-01

    Roč. 60, č. 1 (2009), s. 143-150 ISSN 0867-5910 R&D Projects: GA AV ČR(CZ) 1QS500040507; GA ČR(CZ) GA524/08/1753 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : carvedilol * adrenergic agonists * nitric oxide Subject RIV: BO - Biophysics Impact factor: 1.489, year: 2009

  7. Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the β2-adrenergic receptor in neurons.

    Science.gov (United States)

    Qian, Hai; Patriarchi, Tommaso; Price, Jennifer L; Matt, Lucas; Lee, Boram; Nieves-Cintrón, Madeline; Buonarati, Olivia R; Chowdhury, Dhrubajyoti; Nanou, Evanthia; Nystoriak, Matthew A; Catterall, William A; Poomvanicha, Montatip; Hofmann, Franz; Navedo, Manuel F; Hell, Johannes W

    2017-01-24

    The L-type Ca 2+ channel Ca v 1.2 controls multiple functions throughout the body including heart rate and neuronal excitability. It is a key mediator of fight-or-flight stress responses triggered by a signaling pathway involving β-adrenergic receptors (βARs), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). PKA readily phosphorylates Ser 1928 in Ca v 1.2 in vitro and in vivo, including in rodents and humans. However, S1928A knock-in (KI) mice have normal PKA-mediated L-type channel regulation in the heart, indicating that Ser 1928 is not required for regulation of cardiac Ca v 1.2 by PKA in this tissue. We report that augmentation of L-type currents by PKA in neurons was absent in S1928A KI mice. Furthermore, S1928A KI mice failed to induce long-term potentiation in response to prolonged theta-tetanus (PTT-LTP), a form of synaptic plasticity that requires Ca v 1.2 and enhancement of its activity by the β 2 -adrenergic receptor (β 2 AR)-cAMP-PKA cascade. Thus, there is an unexpected dichotomy in the control of Ca v 1.2 by PKA in cardiomyocytes and hippocampal neurons. Copyright © 2017, American Association for the Advancement of Science.

  8. Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens.

    Science.gov (United States)

    Ovadia, H; Wohlman, A; Mechoulam, R; Weidenfeld, J

    1995-02-01

    In the present study we have characterized the hypothermic effect of the psychoactive cannabinoid HU-210, by investigating its interaction with the endogenous pyrogens, IL-1 and PGE2. We also studied the involvement of the adrenergic system in mediation of this hypothermic effect. Injection of HU-210 directly into the preoptic area caused a dose dependent reduction of rectal temperature from 37 to 32.1 degrees C. Injection of the non-psychoactive analog, HU-211 which does not bind to brain cannabinoid receptor, did not affect body temperature. Injection of the adrenergic agonists, CGP-12177 and clonidine (beta, and alpha adrenergic agonists, respectively) abrogated the hypothermia induced by HU-210. Injection of the adrenergic antagonists, prazosin (alpha 1) and propranolol (beta) enhanced the hypothermic effect of HU-210. Intracerebral administration of IL-1 or PGE2 to rats pretreated with HU-210 caused a transient inhibition of the hypothermia. The ex vivo rate of basal or bacterial endotoxin-induced synthesis of PGE2 by different brain regions, including the preoptic area was not affected by HU-210 administration. These results suggest that the synthetic cannabinoid HU-210 acts in the preoptic area, probably via the brain cannabinoid receptor to induce hypothermia. The hypothermic effect can be antagonized by adrenergic agonists and enhanced by adrenergic antagonists. HU-210 does not interfere with the pyrogenic effect of IL-1 or PGE2.

  9. The Gly16 allele of the G16R single nucleotide polymorphism in the β2-adrenergic receptor gene augments the glycemic response to adrenaline in humans

    DEFF Research Database (Denmark)

    Rokamp, Kim Z.; Staalsø, Jonatan M.; Zaar, Morten

    2017-01-01

    Cerebral non-oxidative carbohydrate consumption may be driven by a ß2-adrenergic mechanism. This study tested whether the 46G > A (G16R) single nucleotide polymorphism of the ß2-adrenergic receptor gene (ADRB2) influences the metabolic and cerebrovascular responses to administration of adrenaline....... Forty healthy Caucasian men were included from a group of genotyped individuals. Cardio- and cerebrovascular variables at baseline and during a 60-min adrenaline infusion (0.06 μg kg-1 min-1) were measured by Model flow, near-infrared spectroscopy and transcranial Doppler sonography. Blood samples were...... obtained from an artery and a retrograde catheter in the right internal jugular vein. The ADRB2 G16R variation had no effect on baseline arterial glucose, but during adrenaline infusion plasma glucose was up to 1.2 mM (CI95: 0.36-2.1, P

  10. Evidence for thymopoietin and thymopoietin/α-bungarotoxin/nicotinic receptors within the brain

    International Nuclear Information System (INIS)

    Quik, M.; Babu, U.; Audhya, T.; Goldstein, G.

    1991-01-01

    Thymopoietin, a polypeptide hormone of the thymus that has pleiotropic actions on the immune, endocrine, and nervous systems, potently interacts with the neuromuscular nicotinic acetylcholine receptor. Thymopoietin binds to the nicotinic α-bungarotoxin (α-BGT) receptor in muscle and, like αBGT, inhibits cholinergic transmission at this site. Evidence is given that radiolabeled thymopoietin similarly binds to a nicotinic α-BGT-binding site within the brain and does so with the characteristics of a specific receptor ligand. Thus specific binding to neuronal membranes was saturable, of high affinity linear with increased tissue concentration, and readily reversible; half-time was ∼5 min for association and 10 min for dissociation. Binding of 125 I-labeled thymopoietin was displaced not only by unlabeled thymopoietin but also by α-BGT and the nicotinic receptor ligands d-tubocurarine and nicotine; various other receptor ligands (muscarinic, adrenergic, and dopaminergic) did not affect binding of 125 I-labeled thymopoietin. Thymopoietin was shown by ELISA to be present in brain extracts, displacement curves of thymus and brain extracts being parallel to the standard thymopoietin curve, and Western (immuno) blot identified in brain and thymus extracts a thymopoietin-immunoreactive polypeptide of the same molecular mass as purified thymopoietin polypeptide. The authors conclude that thymopoietin and thymopoietin-binding sites are present within the brain and that the receptor for thymopoietin is the previously identified nicotinic α-BGT-binding site of neuronal tissue

  11. β-adrenergic-stimulated macrophages: Comprehensive localization in the M1–M2 spectrum

    Science.gov (United States)

    Lamkin, Donald M.; Ho, Hsin-Yun; Ong, Tiffany H.; Kawanishi, Carly K.; Stoffers, Victoria L.; Ahlawat, Nivedita; Ma, Jeffrey C.Y.; Arevalo, Jesusa M. G.; Cole, Steve W.; Sloan, Erica K.

    2016-01-01

    β-adrenergic signaling can regulate macrophage involvement in several diseases and often produces anti-inflammatory properties in macrophages, which are similar to M2 properties in a dichotomous M1 vs. M2 macrophage taxonomy. However, it is not clear that β-adrenergic-stimulated macrophages may be classified strictly as M2. In this in vitro study, we utilized recently published criteria and transcriptome-wide bioinformatics methods to map the relative polarity of murine β-adrenergic-stimulated macrophages within a wider M1–M2 spectrum. Results show that β-adrenergic-stimulated macrophages did not fit entirely into any one predefined category of the M1–M2 spectrum but did express genes that are representative of some M2 side categories. Moreover, transcript origin analysis of genome-wide transcriptional profiles located β-adrenergic-stimulated macrophages firmly on the M2 side of the M1–M2 spectrum and found active suppression of M1 side gene transcripts. The signal transduction pathways involved were mapped through blocking experiments and bioinformatics analysis of transcription factor binding motifs. M2-promoting effects were mediated specifically through β2-adrenergic receptors and were associated with CREB, C/EBPβ, and ATF transcription factor pathways but not with established M1–M2 STAT pathways. Thus, β-adrenergic-signaling induces a macrophage transcriptome that locates on the M2 side of the M1–M2 spectrum but likely accomplishes this effect through a signaling pathway that is atypical for M2-spectrum macrophages. PMID:27485040

  12. Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-Kinase

    Directory of Open Access Journals (Sweden)

    Julie Simard

    2009-01-01

    Full Text Available An agonist-occupied β2-adrenergic receptor (β2-AR recruits G protein receptor kinase-2 (GRK2 which is recruited to the membrane. Thus, the physical proximity of activated β2-AR and PI-3K allows the activation of the latter. In contrast, it has been observed that the β1-AR is unable to activate the PI-3K/Akt pathway. We hypothesized that the difference might be due to molecular determinants present in the carboxy termini of the two β-AR subtypes. Using transiently transfected HEK 293 cells expressing either β1- or β2-AR, we also observed that in presence of an agonist, β2-AR, but not β1-AR, is able to activate the PI-3K/Akt pathway. Switching the seventh transmembrane domain and the carboxy tail between the two receptors reverses this phenotype; that is, β1×β2-AR can activate the PI-3K/Akt pathway whereas β2×β1-AR cannot. Pretreatment with pertussis toxin abolished the activation of PI-3K by β2- or β1×β2-AR stimulation. Ligand-mediated internalization of the β2-AR induced by a 15-minute stimulation with agonist was abolished in the presence of a dominant negative of PI-3K or following pertussis toxin pretreatment. These results indicate that the subtype-specific differences in the coupling to PI-3K/Akt pathway are due to molecular determinants present in the carboxy tail of the receptor and further that β2-AR activates PI-3K via a pertussis toxin-sensitive mechanism.

  13. Effect of β2-adrenergic receptor gene (ADRB2 3′ untranslated region polymorphisms on inhaled corticosteroid/long-acting β2-adrenergic agonist response

    Directory of Open Access Journals (Sweden)

    Ambrose Helen J

    2012-05-01

    Full Text Available Abstract Background Evidence suggests that variation in the length of the poly-C repeat in the 3′ untranslated region (3′UTR of the β2-adrenergic receptor gene (ADRB2 may contribute to interindividual variation in β-agonist response. However, methodology in previous studies limited the assessment of the effect of sequence variation in the context of poly-C repeat length. The objectives of this study were to design a novel genotyping method to fully characterize sequence variation in the ADRB2 3′UTR poly-C repeat in asthma patients treated with inhaled corticosteroid and long-acting β2-adrenergic agonist (ICS/LABA combination therapy, and to analyze the effect of the poly-C repeat polymorphism on clinical response. Methods In 2,250 asthma patients randomized to treatment with budesonide/formoterol or fluticasone/salmeterol in a six-month study (AstraZeneca study code: SD-039-0735, sequence diversity in the ADRB2 poly-C repeat region was determined using a novel sequencing-based genotyping method. The relationship between the poly-C repeat polymorphism and the incidence of severe asthma exacerbations, and changes in pulmonary function and asthma symptoms from baseline to the average during the treatment period, were analyzed. Results Poly-C repeat genotypes were assigned in 97% (2,192/2,250 of patients. Of the 13 different poly-C repeat alleles identified, six alleles occurred at a frequency of >5% in one or more population in this study. The repeat length of these six common alleles ranged from 10 to 14 nucleotides. Twelve poly-C repeat genotypes were observed at a frequency of >1%. No evidence of an association between poly-C repeat genotype and the incidence of severe asthma exacerbations was observed. Patients’ pulmonary function measurements improved and asthma symptoms declined when treated with ICS/LABA combination therapy regardless of poly-C repeat genotype. Conclusions The extensive sequence diversity present in the poly

  14. adrenergic receptor with preeclampsia

    African Journals Online (AJOL)

    User

    2011-05-09

    May 9, 2011 ... due to a post- receptor defect (Karadas et al., 2007). Several polymorphisms have ... the detection of the Arg16Gly polymorphism, overnight digestion at. 37°C with 10 U ..... DW, Wood AJ, Stein CM (2004). Beta2-adrenoceptor ...

  15. Role of Peripheral Alpha2 Adrenergic Receptors in Tonic Pain During Different Stages of Estrous Cycle in Rats

    Directory of Open Access Journals (Sweden)

    AR Abyazi Shelmani

    2007-12-01

    Full Text Available Introduction: Estrogen and progesterone are supposed to modify pain sensitivity. However, the actual role of each of these steroid hormones in this respect is not well known. Plasma concentrations of these hormones show variation during estrous cycle. The role of alpha2 receptors in tonic pain has been pointed out. The aim of the present study was to investigate the agonist and antagonist effect of alpha2 adrenergic receptors on tonic pain sensitivity during all stages of estrous cycle in female rats. Methods: Xylasine as alpha2 agonist and yohimbin as alpha2 antagonist were used via intraperitoneal route (IP. Adult rats weighing 180-200 grams were used. Animals were maintained on 12h reverse light/dark cycle for 7 days prior to the experiment. Water and food was available ad libitum. Formalin test was performed by subcutaneous injection of 50 l formalin (2.5% solution into the hind paw. Formalin test was performed in all stages of estrous cycle for 60 minutes. Animals were divided into four groups; 1- control group (intact animal, 2- Sham group (animals received 0.2 ml normal saline by IP route, 3- Agonist groups (animals received 0.2 ml xylasine 1, 3 mg/kg body weight by IP route and 4- Antagonist group (animals received 0.2 ml yohimbine 1, 3 mg/kg body weight by IP route. Data were statistically analyzed using 2 way ANOVA test followed by Tukey's test as post-hoc test. P<0.05 was considered significant. Results: Results showed that xylasine significantly (p<0.05 decreases pain sensitivity in all stages of estrous cycle. Analgesic effect of xylasine was maximum in estrus stage of estrous cycle and minimum in metestrus stage of estrous cycle. Yohimbine significantly (p<0.05 increases pain sensitivity in all stages of estrous cycle. Hyperalgesic effect of yohimbine was maximum in metestrus stage of estrous cycle and minimum in estrus stage of estrous cycle. Conclusion: These results indicate that alpha2 adrenergic system and endogenous

  16. A new Drosophila octopamine receptor responds to serotonin.

    Science.gov (United States)

    Qi, Yi-Xiang; Xu, Gang; Gu, Gui-Xiang; Mao, Fen; Ye, Gong-Yin; Liu, Weiwei; Huang, Jia

    2017-11-01

    As the counterparts of the vertebrate adrenergic transmitters, octopamine and tyramine are important physiological regulators in invertebrates. They control and modulate many physiological and behavioral functions in insects. In this study, we reported the pharmacological properties of a new α2-adrenergic-like octopamine receptor (CG18208) from Drosophila melanogaster, named DmOctα2R. This new receptor gene encodes two transcripts by alternative splicing. The long isoform DmOctα2R-L differs from the short isoform DmOctα2R-S by the presence of an additional 29 amino acids within the third intracellular loop. When heterologously expressed in mammalian cell lines, both receptors were activated by octopamine, tyramine, epinephrine and norepinephrine, resulting in the inhibition of cAMP production in a dose-dependent manner. The long form is more sensitive to the above ligands than the short form. The adrenergic agonists naphazoline, tolazoline and clonidine can stimulate DmOctα2R as full agonists. Surprisingly, serotonin and serotoninergic agonists can also activate DmOctα2R. Several tested adrenergic antagonists and serotonin antagonists blocked the action of octopamine or serotonin on DmOctα2R. The data presented here reported an adrenergic-like G protein-coupled receptor activated by serotonin, suggesting that the neurotransmission and neuromodulation in the nervous system could be more complex than previously thought. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Delayed internalization and lack of recycling in a beta2-adrenergic receptor fused to the G protein alpha-subunit

    Directory of Open Access Journals (Sweden)

    Floridi Aristide

    2008-10-01

    Full Text Available Abstract Background Chimeric proteins obtained by the fusion of a G protein-coupled receptor (GPCR sequence to the N-terminus of the G protein α-subunit have been extensively used to investigate several aspects of GPCR signalling. Although both the receptor and the G protein generally maintain a fully functional state in such polypeptides, original observations made using a chimera between the β2-adrenergic receptor (β2AR and Gαs indicated that the fusion to the α-subunit resulted in a marked reduction of receptor desensitization and down-regulation. To further investigate this phenomenon, we have compared the rates of internalization and recycling between wild-type and Gαs-fused β2AR. Results The rate of agonist-induced internalization, measured as the disappearance of cell surface immunofluorescence in HEK293 cells permanently expressing N-terminus tagged receptors, was reduced three-fold by receptor-G protein fusion. However, both fused and non-fused receptors translocated to the same endocytic compartment, as determined by dual-label confocal analysis of cells co-expressing both proteins and transferrin co-localization. Receptor recycling, determined as the reversion of surface immunofluorescence following the addition of antagonist to cells that were previously exposed to agonist, markedly differed between wild-type and fused receptors. While most of the internalized β2AR returned rapidly to the plasma membrane, β2AR-Gαs did not recycle, and the observed slow recovery for the fusion protein immunofluorescence was entirely accounted for by protein synthesis. Conclusion The covalent linkage between β2AR and Gαs does not appear to alter the initial endocytic translocation of the two proteins, although there is reduced efficiency. It does, however, completely disrupt the process of receptor and G protein recycling. We conclude that the physical separation between receptor and Gα is not necessary for the transit to early endosomes

  18. The association of eight potentially functional polymorphisms in five adrenergic receptor-encoding genes with myocardial infarction risk in Han Chinese.

    Science.gov (United States)

    Xia, Kun; Ding, Rongjing; Zhang, Zhiyong; Li, Weiming; Shang, Xiaoming; Yang, Xinchun; Wang, Lefeng; Zhang, Qi

    2017-08-15

    Adrenergic receptors play a key role in activating the sympathetic nervous system, which often accompanies with the development of myocardial infarction (MI). Here, we aimed to test the association of eight potentially functional polymorphisms in five adrenergic receptor-encoding genes with MI risk. Genotypes were available for 717 MI patients and 612 controls. There were no detectable deviations from the Hardy-Weinberg equilibrium for all study polymorphisms. Allele frequencies differed remarkably for ADRA2B D/I (P<0.001), ADRB1 Ser49Gly (P=0.002), ADRB2 Gln27Glu (P=0.005), and ADRB3 Trp64Arg (P<0.001) polymorphisms, even after the Bonferroni correction. Systolic blood pressure was significantly lower in ADRA2B II genotype carriers than in the DD genotype carriers (P=0.006), while plasma high-density lipoprotein cholesterol was significantly higher in patients carrying ADRA2B I allele and ADRB1 49Ser allele than in patients with the DD genotype and 49Gly/49Gly genotype, respectively (P=0.018 and 0.033). Overall best interaction model consisted of ADRA2B D/I, ADRB1 Ser49Gly, dyslipidemia and hypertension, with the highest testing accuracy of 0.627 and the maximal 10-fold cross-validation consistency (P=0.017). Finally, a nomogram was depicted based on four significant polymorphisms and metabolic risk factors, and it had a better predictive utility and was internally validated with a discrimination C-index of 0.723 (P<0.001). Altogether, we identified two polymorphisms, ADRA2B D/I and ADRB1 Ser49Arg, which not only altered genetic susceptibility to MI, but also impacted on blood pressure and plasma lipid changes, and their combination with metabolic risk factors constituted the overall best interaction model. Copyright © 2017. Published by Elsevier B.V.

  19. Astrocytic beta 2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice

    NARCIS (Netherlands)

    Jensen, Cathy Joanna; Demol, Frauke; Bauwens, Romy; Kooijman, Ron; Massie, Ann; Villers, Agnes; Ris, Laurence; De Keyser, Jacques

    2016-01-01

    In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the beta

  20. alpha-adrenergic Blockade Unmasks a Greater Compensatory Vasodilation in Hypoperfused Contracting Muscle

    Directory of Open Access Journals (Sweden)

    Darren P. Casey

    2012-07-01

    Full Text Available We previously demonstrated that acute hypoperfusion in exercising human muscle causes an immediate increase in vascular resistance that is followed by a partial restoration (less than 100% recovery of flow. In the current study we examined the contribution of alpha-adrenergic vasoconstriction in the initial changes in vascular resistance at the onset of hypoperfusion as well as in the recovery of flow over time. Nine healthy male subjects (29 ± 2 performed rhythmic forearm exercise (20% of maximum during hypoperfusion evoked by intra-arterial balloon inflation. Each trial included; baseline, exercise prior to inflation, exercise with inflation, and exercise after deflation (3 min each. Forearm blood flow (FBF; ultrasound, local (brachial artery, and systemic arterial pressure (MAP; Finometer were measured. The trial was repeated during phentolamine infusion (alpha-adrenergic receptor blockade. Forearm vascular conductance (FVC; ml min-1 100 mmHg-1 and resistance (mmHg ml min-1 was calculated from BF (ml min-1 and local MAP (mmHg. Recovery of FBF and FVC (steady state inflation plus exercise value – nadir/ [steady state exercise (control value-nadir] with phentolamine was enhanced compared with the respective control (no drug trial (FBF = 97 ± 5% vs. 81 ± 6%, P < 0.05; FVC = 126 ± 9% vs. 91 ± 5%, P < 0.01. However, the absolute (0.05 ± 0.01 vs. 0.06 ± 0.01 mmHg ml min-1; P = 0.17 and relative (35 ± 5% vs. 31 ± 2%; P = 0.41 increase in vascular resistance at the onset of balloon inflation was not different between the alpha-adrenergic receptor inhibition and control (no drug trials. Therefore, our data indicate that alpha-adrenergic mediated vasoconstriction restricts compensatory vasodilation during forearm exercise with hypoperfusion, but is not responsible for the initial increase in vascular resistance at the onset of hypoperfusion.

  1. Binding-Site Compatible Fragment Growing Applied to the Design of β2-Adrenergic Receptor Ligands.

    Science.gov (United States)

    Chevillard, Florent; Rimmer, Helena; Betti, Cecilia; Pardon, Els; Ballet, Steven; van Hilten, Niek; Steyaert, Jan; Diederich, Wibke E; Kolb, Peter

    2018-02-08

    Fragment-based drug discovery is intimately linked to fragment extension approaches that can be accelerated using software for de novo design. Although computers allow for the facile generation of millions of suggestions, synthetic feasibility is however often neglected. In this study we computationally extended, chemically synthesized, and experimentally assayed new ligands for the β 2 -adrenergic receptor (β 2 AR) by growing fragment-sized ligands. In order to address the synthetic tractability issue, our in silico workflow aims at derivatized products based on robust organic reactions. The study started from the predicted binding modes of five fragments. We suggested a total of eight diverse extensions that were easily synthesized, and further assays showed that four products had an improved affinity (up to 40-fold) compared to their respective initial fragment. The described workflow, which we call "growing via merging" and for which the key tools are available online, can improve early fragment-based drug discovery projects, making it a useful creative tool for medicinal chemists during structure-activity relationship (SAR) studies.

  2. Synthesis of [18F]-labelled nebivolol as a β1-adrenergic receptor antagonist for PET imaging agent

    International Nuclear Information System (INIS)

    Kim, Taek Soo; Park, Jeong Hoon; Lee, Jun Young; Yang, Seung Dae; Chang, Dong Jo

    2017-01-01

    Selective β 1 -agonist and antagonists are used for the treatment of cardiac diseases including congestive heart failure, angina pectoris and arrhythmia. Selective β 1 -antagonists including nebivolol have high binding affinity on β 1 -adrenergic receptor, not β 2 -receptor mainly expressed in smooth muscle. Nebivolol is one of most selective β 1 -blockers in clinically used β 1 - blockers including atenolol and bisoprolol. We tried to develop clinically useful cardiac PET tracers using a selective β 1 -blocker. Nebivolol is C 2 -symmetric and has two chromane moiety with a secondary amino alcohol and aromatic fluorine. We adopted the general synthetic strategy using epoxide ring opening reaction. Unlike formal synthesis of nebivolol, we prepared two chromane building blocks with fluorine and iodine which was transformed to diaryliodonium salt for labelling of 18 F. Two epoxide building blocks were readily prepared from commercially available chromene carboxylic acids (1, 8). Then, the amino alcohol building block (15) was prepared by ammonolysis of epoxide (14) followed by coupling reaction with the other building block, epoxide (7). Diaryliodonium salt, a precursor for 18 F-aromatic substitution, was synthesized in moderate yield which was readily subjected to 18 F-aromatic substitution to give 18 F-labelled nebivolol

  3. Change of expression of renal alpha1-adrenergic receptor and angiotensin II receptor subtypes with aging in rats.

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    Li, Yan-Fang; Cao, Xiao-Jing; Bai, Xue-Yuan; Lin, Shu-Peng; Shi, Shu-Tian

    2010-04-01

    It has been considered that the functional decline of renal vasoconstriction during senescence is associated with an alteration in renal alpha1-adrenergic receptor (alpha1-AR) expression. While alterations in renal angiotensin II receptor (ATR) expression was considered to have an effect on renal structure and function, until now little information has been available concerning alpha1-AR and ATR expression variations over the entire aging continuum. The present study was undertaken to examine the expression levels of alpha1-AR and ATR subtypes in renal tissue during the spectrum running from young adulthood, to middle age, to the presenium, and to the senium. Semiquantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Western Blot were used to quantify the messenger RNA (mRNA) and protein levels of alpha1-AR and ATR subtypes in renal tissue in 3-month-old (young adult), 12-month-old (middle age), 18-month-old (presenium) and 24-month-old (senium) Wistar rats. alpha1A-AR expression decreased gradually with aging: it was decreased during middle age, the presenium and the senium, compared, respectively, with young adult values (page and in the senium with respect to the presenium. alpha1B-AR and alpha1D-AR expression were unmodified during senescence. AT1R expression was unaffected by aging during young adulthood and middle age, but exhibited a remarkable downregulation in the presenium and senium periods (prenal alpha1-AR and ATR subtypes during aging. alpha1A-AR expression downregulation may account for the reduced reactivity of renal alpha1-AR to vasoconstrictors and to renal function decline in the senium. Both the downregulation of AT1R and the upregulation of AT2R may be influential in maintaining normal physiological renal function during aging.

  4. Simultaneous evaluation of the pre- and postsynaptic interactions of alpha-2 adrenergic agents in the phenoxybenzamine-treated dog saphenous vein

    International Nuclear Information System (INIS)

    Buckner, S.; Morse, P.; DeBernardis, J.; Kyncyl, J.

    1986-01-01

    Functional alpha-2 adrenergic receptors can be demonstrated on both the neuronal and muscular sides of the sympathetic synapse in the superfused, electrically stimulated, 3 H-NE-loaded dog saphenous vein (DSV). Selective alkylation of the alpha-1 subtype in this tissue by phenoxybenzamine produced a preparation which contained functional alpha adrenergic receptors of only the alpha-2 subtype at both locations and provided an experimental model suitable for differentiating alpha-2 selective compounds according to their pre- vs postsynaptic preference. A number of standard alpha-2 selective agonists and antagonists were tested in this model. None of these agents exhibited any significant degree of presynaptic or postsynaptic selectivity

  5. Individual Responsiveness to Exercise-Induced Fat Loss and Improvement of Metabolic Profile in Young Women is Associated with Polymorphisms of Adrenergic Receptor Genes

    Directory of Open Access Journals (Sweden)

    Agata Leońska-Duniec, Zbigniew Jastrzębski, Aleksandra Jażdżewska, Waldemar Moska, Ewelina Lulińska-Kuklik, Marek Sawczuk, Svetlana I. Gubaydullina, Alsu T. Shakirova, Pawel Cięszczyk, Adam Maszczyk, Ildus I. Ahmetov

    2018-03-01

    Full Text Available The effectiveness of physical exercise on fat loss and improvement of aerobic capacity varies considerably between individuals. A strong linkage exists between common allelic variants of the adrenergic receptor genes and weight gain, as well as changes in body composition. Therefore we aimed to check if body composition and metabolic variables were modulated by the ADRB2 (Gly16Arg and Glu27Gln, ADRB3 (Trp64Arg and ADRA2A (rs553668 G/A gene polymorphisms in 163 Polish sedentary women (age 19-24; body mass index (BMI 21.7 ± 0.2 kg·m-2 involved in a 12-week aerobic training program. Only 74.8% of participants lost fat mass. On average, participants lost 5.8 (10.4% of their relative fat mass with training (range: +28.3 to -63.6%. The improvement of VO2max was significantly greater in women who could lose their fat mass compared to women who were unsuccessful in fat loss (4.5 (5.6% vs. 1.5 (3.8%; p = 0.0045. The carriers of a low number (0-3 of obesity-related risk alleles (ADRB2 Gly16, ADRB2 Glu27, ADRA2A rs553668 G were more successful in fat mass loss compared to the carriers of a high number (5-6 of risk alleles (7.7 (9.8 vs 4.0 (9.4%, p = 0.0362. The presented results support the assumption that variation within adrenergic receptor genes contributes to interindividual changes of body composition in response to physical exercise.

  6. Effects of exercise training on cardiovascular adrenergic system.

    Science.gov (United States)

    Leosco, Dario; Parisi, Valentina; Femminella, Grazia D; Formisano, Roberto; Petraglia, Laura; Allocca, Elena; Bonaduce, Domenico

    2013-11-28

    In heart failure (HF), exercise has been shown to modulate cardiac sympathetic hyperactivation which is one of the earliest features of neurohormonal derangement in this syndrome and correlates with adverse outcome. An important molecular alteration related to chronic sympathetic overstimulation in HF is represented by cardiac β-adrenergic receptor (β-AR) dysfunction. It has been demonstrated that exercise reverses β-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation. In particular, several evidence indicate that exercise reduces levels of cardiac G-protein coupled receptor kinase-2 (GRK2) which is known to be involved in both β1-AR and β2-AR dysregulation in HF. Similar alterations of β-AR system have been described also in the senescent heart. It has also been demonstrated that exercise training restores adrenal GRK2/α-2AR/catecholamine (CA) production axis. At vascular level, exercise shows a therapeutic effect on age-related impairment of vascular reactivity to adrenergic stimulation and restores β-AR-dependent vasodilatation by increasing vascular β-AR responsiveness and reducing endothelial GRK2 activity. Sympathetic nervous system overdrive is thought to account for >50% of all cases of hypertension and a lack of balance between parasympathetic and sympathetic modulation has been observed in hypertensive subjects. Non-pharmacological, lifestyle interventions have been associated with reductions in SNS overactivity and blood pressure in hypertension. Several evidence have highlighted the blood pressure lowering effects of aerobic endurance exercise in patients with hypertension and the significant reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining the favorable effects of exercise on blood pressure control.

  7. EFFECTS OF EXERCISE TRAINING ON CARDIOVASCULAR ADRENERGIC SYSTEM

    Directory of Open Access Journals (Sweden)

    Dario eLeosco

    2013-11-01

    Full Text Available In heart failure (HF, exercise has been shown to modulate cardiac sympathetic hyperactivation which is one of the earliest features of neurohormonal derangement in this syndrome and correlates with adverse outcome. An important molecular alteration related to chronic sympathetic overstimulation in HF is represented by cardiac β-adrenergic receptor (β-AR dysfunction . It has been demonstrated that exercise reverses β-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation. In particular, several evidence indicate that exercise reduces levels of cardiac G-protein coupled receptor kinase-2 (GRK2 which is known to be involved in both β1-AR and β2-AR dysregulation in HF. Similar alterations of β-AR system have been described also in the senescent heart. It has also been demonstrated that exercise training restores adrenal GRK2/α-2AR/cathecolamine (CA production axis. At vascular level, exercise shows a therapeutic effect on age-related impairment of vascular reactivity to adrenergic stimulation and restores β-AR-dependent vasodilatation by increasing vascular β-AR responsiveness and reducing endothelial GRK2 activity. Sympathetic nervous system overdrive is thought to account for >50 % of all cases of hypertension and a lack of balance between parasympathetic and sympathetic modulation has been observed in hypertensive subjects. Non-pharmacological, lifestyle interventions have been associated with reductions in SNS overactivity and blood pressure in hypertension. Several evidence have highlighted the blood pressure lowering effects of aerobic endurance exercise in patients with hypertension and the significant reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining the favourable effects of exercise on blood pressure control.

  8. Association between Selective Beta-adrenergic Drugs and Blood Pressure Elevation: Data Mining of the Japanese Adverse Drug Event Report (JADER) Database.

    Science.gov (United States)

    Ohyama, Katsuhiro; Inoue, Michiko

    2016-01-01

    Selective beta-adrenergic drugs are used clinically to treat various diseases. Because of imperfect receptor selectivity, beta-adrenergic drugs cause some adverse drug events by stimulating other adrenergic receptors. To examine the association between selective beta-adrenergic drugs and blood pressure elevation, we reviewed the Japanese Adverse Drug Event Reports (JADERs) submitted to the Japan Pharmaceuticals and Medical Devices Agency. We used the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms extracted from Standardized MedDRA queries for hypertension to identify events related to blood pressure elevation. Spontaneous adverse event reports from April 2004 through May 2015 in JADERs, a data mining algorithm, and the reporting odds ratio (ROR) were used for quantitative signal detection, and assessed by the case/non-case method. Safety signals are considered significant if the ROR estimates and lower bound of the 95% confidence interval (CI) exceed 1. A total of 2021 reports were included in this study. Among the nine drugs examined, significant signals were found, based on the 95%CI for salbutamol (ROR: 9.94, 95%CI: 3.09-31.93) and mirabegron (ROR: 7.52, 95%CI: 4.89-11.55). The results of this study indicate that some selective beta-adrenergic drugs are associated with blood pressure elevation. Considering the frequency of their indications, attention should be paid to their use in elderly patients to avoid adverse events.

  9. Orexin A-induced anxiety-like behavior is mediated through GABA-ergic, α- and β-adrenergic neurotransmissions in mice.

    Science.gov (United States)

    Palotai, Miklós; Telegdy, Gyula; Jászberényi, Miklós

    2014-07-01

    Orexins are hypothalamic neuropeptides, which are involved in several physiological functions of the central nervous system, including anxiety and stress. Several studies provide biochemical and behavioral evidence about the anxiogenic action of orexin A. However, we have little evidence about the underlying neuromodulation. Therefore, the aim of the present study was to investigate the involvement of neurotransmitters in the orexin A-induced anxiety-like behavior in elevated plus maze (EPM) test in mice. Accordingly, mice were pretreated with a non-selective muscarinic cholinergic antagonist, atropine; a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline; a D2, D3, D4 dopamine receptor antagonist, haloperidol; a non-specific nitric oxide synthase (NOS) inhibitor, nitro-l-arginine; a nonselective α-adrenergic receptor antagonist, phenoxybenzamine and a β-adrenergic receptor antagonist, propranolol 30min prior to the intracerebroventricular administration of orexin A. The EPM test started 30min after the i.c.v. injection of the neuropeptide. Our results show that orexin A decreases significantly the time spent in the arms (open/open+closed) and this action is reversed by bicuculline, phenoxybenzamine and propranolol, but not by atropine, haloperidol or nitro-l-arginine. Our results provide evidence for the first time that the orexin A-induced anxiety-like behavior is mediated through GABA-A-ergic, α- and β-adrenergic neurotransmissions, whereas muscarinic cholinergic, dopaminergic and nitrergic neurotransmissions may not be implicated. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Cooperative regulation of non-small cell lung carcinoma by nicotinic and beta-adrenergic receptors: a novel target for intervention.

    Directory of Open Access Journals (Sweden)

    Hussein A N Al-Wadei

    Full Text Available Lung cancer is the leading cause of cancer death; 80-85% of lung cancer cases are non-small cell lung cancer (NSCLC. Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299, we identified the cooperation of nicotinic acetylcholine receptors (nAChRs and β-adrenergic receptors (β-ARs as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the α7nAChR and α4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the α7nAChR antagonist α-BTX or the β-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing β-adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by β blocker may

  11. Effects of adrenergic agents on the expression of zebrafish (Danio rerio) vitellogenin Ao1

    International Nuclear Information System (INIS)

    Yin Naida; Jin Xia; He Jiangyan; Yin Zhan

    2009-01-01

    Teleost vitellogenins (VTGs) are large multidomain apolipoproteins, traditionally considered to be estrogen-responsive precursors of the major egg yolk proteins, expressed and synthesized mainly in hepatic tissue. The inducibility of VTGs has made them one of the most frequently used in vivo and in vitro biomarkers of exposure to estrogen-active substances. A significant level of zebrafish vtgAo1, a major estrogen responsive form, has been unexpectedly found in heart tissue in our present studies. Our studies on zebrafish cardiomyopathy, caused by adrenergic agonist treatment, suggest a similar protective function of the cardiac expressed vtgAo1. We hypothesize that its function is to unload surplus intracellular lipids in cardiomyocytes for 'reverse triglyceride transportation' similar to that found in lipid transport proteins in mammals. Our results also demonstrated that zebrafish vtgAo1 mRNA expression in heart can be suppressed by both α-adrenergic agonist, phenylephrine (PE) and β-adrenergic agonist, isoproterenol (ISO). Furthermore, the strong stimulation of zebrafish vtgAo1 expression in plasma induced by the β-adrenergic antagonist, MOXIsylyl, was detected by Enzyme-Linked ImmunoSorbent Assay (ELISA). Such stimulation cannot be suppressed by taMOXIfen, an antagonist to estrogen receptors. Thus, our present data indicate that the production of teleost VTG in vivo can be regulated not only by estrogenic agents, but by adrenergic signals as well.

  12. Morphology and kainate-receptor immunoreactivity of identified neurons within the entorhinal cortex projecting to superior temporal sulcus in the cynomolgus monkey

    Science.gov (United States)

    Good, P. F.; Morrison, J. H.; Bloom, F. E. (Principal Investigator)

    1995-01-01

    Projections of the entorhinal cortex to the hippocampus are well known from the classical studies of Cajal (Ramon y Cajal, 1904) and Lorente de No (1933). Projections from the entorhinal cortex to neocortical areas are less well understood. Such connectivity is likely to underlie the consolidation of long-term declarative memory in neocortical sites. In the present study, a projection arising in layer V of the entorhinal cortex and terminating in a polymodal association area of the superior temporal gyrus has been identified with the use of retrograde tracing. The dendritic arbors of neurons giving rise to this projection were further investigated by cell filling and confocal microscopy with computer reconstruction. This analysis demonstrated that the dendritic arbor of identified projection neurons was largely confined to layer V, with the exception of a solitary, simple apical dendrite occasionally ascending to superficial laminae but often confined to the lamina dissecans (layer IV). Finally, immunoreactivity for glutamate-receptor subunit proteins GluR 5/6/7 of the dendritic arbor of identified entorhinal projection neurons was examined. The solitary apical dendrite of identified entorhinal projection neurons was prominently immunolabeled for GluR 5/6/7, as was the dendritic arbor of basilar dendrites of these neurons. The restriction of the large bulk of the dendritic arbor of identified entorhinal projection neurons to layer V implies that these neurons are likely to be heavily influenced by hippocampal output arriving in the deep layers of the entorhinal cortex. Immunoreactivity for GluR 5/6/7 throughout the dendritic arbor of such neurons indicates that this class of glutamate receptor is in a position to play a prominent role in mediating excitatory neurotransmission within hippocampal-entorhinal circuits.

  13. Ganglionic adrenergic action modulates ovarian steroids and nitric oxide in prepubertal rat.

    Science.gov (United States)

    Delgado, Silvia Marcela; Casais, Marilina; Sosa, Zulema; Rastrilla, Ana María

    2006-08-01

    Both peripheral innervation and nitric oxide (NO) participate in ovarian steroidogenesis. The purpose of this work was to analyse the ganglionic adrenergic influence on the ovarian release of steroids and NO and the possible steroids/NO relationship. The experiments were carried out in the ex vivo coeliac ganglion-superior ovarian nerve (SON)-ovary system of prepubertal rats. The coeliac ganglion-SON-ovary system was incubated in Krebs Ringer-bicarbonate buffer in presence of adrenergic agents in the ganglionic compartment. The accumulation of progesterone, androstenedione, oestradiol and NO in the ovarian incubation liquid was measured. Norepinephrine in coeliac ganglion inhibited the liberation of progesterone and increased androstenedione, oestradiol and NO in ovary. The addition of alpha and beta adrenergic antagonists also showed different responses in the liberation of the substances mentioned before, which, from a physiological point of view, reveals the presence of adrenergic receptors in coeliac ganglion. In relation to propranolol, it does not revert the effect of noradrenaline on the liberation of progesterone, which leads us to think that it might also have a "per se" effect on the ganglion, responsible for the ovarian response observed for progesterone. Finally, we can conclude that the ganglionic adrenergic action via SON participates on the regulation of the prepubertal ovary in one of two ways: either increasing the NO, a gaseous neurotransmitter with cytostatic characteristics, to favour the immature follicles to remain dormant or increasing the liberation of androstenedione and oestradiol, the steroids necessary for the beginning of the near first estral cycle.

  14. Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance

    Science.gov (United States)

    Jacob, G.; Shannon, J. R.; Costa, F.; Furlan, R.; Biaggioni, I.; Mosqueda-Garcia, R.; Robertson, R. M.; Robertson, D.

    1999-01-01

    BACKGROUND: Chronic orthostatic intolerance (OI) is characterized by symptoms of inadequate cerebral perfusion with standing, in the absence of significant orthostatic hypotension. A heart rate increase of >/=30 bpm is typical. Possible underlying pathophysiologies include hypovolemia, partial dysautonomia, or a primary hyperadrenergic state. We tested the hypothesis that patients with OI have functional abnormalities in autonomic neurons regulating cardiovascular responses. METHODS AND RESULTS: Thirteen patients with chronic OI and 10 control subjects underwent a battery of autonomic tests. Systemic norepinephrine (NE) kinetics were determined with the patients supine and standing before and after tyramine administration. In addition, baroreflex sensitivity, hemodynamic responses to bolus injections of adrenergic agonists, and intrinsic heart rate were determined. Resting supine NE spillover and clearance were similar in both groups. With standing, patients had a greater decrease in NE clearance than control subjects (55+/-5% versus 30+/-7%, Pheart rate 25 bpm was lower in patients than in control subjects (0.5+/-0.05 versus 1.0+/-0.1 microg, Pheart rate was similar in both groups. CONCLUSIONS: The decreased NE clearance with standing, resistance to the NE-releasing effect of tyramine, and increased sensitivity to adrenergic agonists demonstrate dramatically disordered sympathetic cardiovascular regulation in patients with chronic OI.

  15. Impaired modulation of postjunctional α1 - but not α2 -adrenergic vasoconstriction in contracting forearm muscle of postmenopausal women.

    Science.gov (United States)

    Kruse, Nicholas T; Hughes, William E; Ueda, Kenichi; Hanada, Satoshi; Feider, Andrew J; Iwamoto, Erika; Bock, Joshua M; Casey, Darren P

    2018-04-30

    Contraction-mediated blunting of postjunctional α-adrenergic vasoconstriction (functional sympatholysis) is attenuated in skeletal muscle of ageing males, brought on by altered postjunctional α 1 - and α 2 -adrenergic receptor sensitivity. The extent to which postjunctional α-adrenergic vasoconstriction occurs in the forearms at rest and during exercise in postmenopausal women remains unknown. The novel findings indicate that contraction-mediated blunting of α 1 - (via intra-arterial infusion of phenylephrine) but not α 2 -adrenergic (via intra-arterial infusion of dexmedetomidine) vasoconstriction was attenuated in postmenopausal women compared to young women. Additional important findings revealed that postjunctional α-adrenergic vasoconstrictor responsiveness at rest does not appear to be affected by age in women. Collectively, these results contribute to our understanding of local neurovascular control at rest and during exercise with age in women. Contraction-mediated blunting of postjunctional α-adrenergic vasoconstriction (functional sympatholysis) is attenuated in older males; however, direct confirmation of this effect remains unknown in postmenopausal women (PMW). The present study examined whether PMW exhibit augmented postjunctional α-adrenergic receptor vasoconstriction at rest and during forearm exercise compared to young women (YW). Eight YW (24 ± 1 years) and eight PMW (65 ± 1 years) completed a series of randomized experimental trials: (1) at rest, (2) under high flow (adenosine infusion) conditions and (3) during 6 min of forearm exercise at relative (20% of maximum) and absolute (7 kg) intensities. Phenylephrine (α 1 -agonist) or dexmedetomidine (α 2 -agonist) was administered during the last 3 min of each trial to elicit α-adrenergic vasoconstriction. Forearm vascular conductance (FVC) was calculated from blood flow and blood pressure. Vasoconstrictor responsiveness was identified as the change in FVC (%) during α-adrenergic

  16. The role of adrenergic activation on murine luteal cell viability and progesterone production.

    Science.gov (United States)

    Wang, Jing; Tang, Min; Jiang, Huaide; Wu, Bing; Cai, Wei; Hu, Chuan; Bao, Riqiang; Dong, Qiming; Xiao, Li; Li, Gang; Zhang, Chunping

    2016-09-15

    Sympathetic innervations exist in mammalian CL. The action of catecholaminergic system on luteal cells has been the focus of a variety of studies. Norepinephrine (NE) increased progesterone secretion of cattle luteal cells by activating β-adrenoceptors. In this study, murine luteal cells were treated with NE and isoprenaline (ISO). We found that NE increased the viability of murine luteal cells and ISO decreased the viability of luteal cells. Both NE and ISO promoted the progesterone production. Nonselective β-adrenergic antagonist, propranolol reversed the effect of ISO on cell viability but did not reverse the effect of NE on cell viability. Propranolol blocked the influence of NE and ISO on progesterone production. These results reveal that the increase of luteal cell viability induced by NE is not dependent on β-adrenergic activation. α-Adrenergic activation possibly contributes to it. Both NE and ISO increased progesterone production through activating β-adrenergic receptor. Further study showed that CyclinD2 is involved in the increase of luteal cell induced by NE. 3β-Hydroxysteroid dehydrogenase, LHR, steroidogenic acute regulatory protein (StAR), and PGF2α contribute to the progesterone production induced by NE and ISO. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Enteral tranexamic acid attenuates vasopressor resistance and changes in α1-adrenergic receptor expression in hemorrhagic shock.

    Science.gov (United States)

    Santamaria, Marco Henry; Aletti, Federico; Li, Joyce B; Tan, Aaron; Chang, Monica; Leon, Jessica; Schmid-Schönbein, Geert W; Kistler, Erik B

    2017-08-01

    Irreversible hemorrhagic shock is characterized by hyporesponsiveness to vasopressor and fluid therapy. Little is known, however, about the mechanisms that contribute to this phenomenon. Previous studies have shown that decreased intestinal perfusion in hemorrhagic shock leads to proteolytically mediated increases in gut permeability, with subsequent egress of vasoactive substances systemically. Maintenance of blood pressure is achieved in part by α1 receptor modulation, which may be affected by vasoactive factors; we thus hypothesized that decreases in hemodynamic stability and vasopressor response in shock can be prevented by enteral protease inhibition. Rats were exposed to experimental hemorrhagic shock (35 mm Hg mean arterial blood pressure for 2 hours, followed by reperfusion for 2 hours) and challenged with phenylephrine (2 μg/kg) at discrete intervals to measure vasopressor responsiveness. A second group of animals received enteral injections with the protease inhibitor tranexamic acid (TXA) (127 mM) along the small intestine and cecum 1 hour after induction of hemorrhagic shock. Blood pressure response (duration and amplitude) to phenylephrine after reperfusion was significantly attenuated in animals subjected to hemorrhagic shock compared with baseline and control nonshocked animals and was restored to near baseline by enteral TXA. Arteries from shocked animals also displayed decreased α1 receptor density with restoration to baseline after enteral TXA treatment. In vitro, rat shock plasma decreased α1 receptor density in smooth muscle cells, which was also abrogated by enteral TXA treatment. Results from this study demonstrate that experimental hemorrhagic shock leads to decreased response to the α1-selective agonist phenylephrine and decreased α1 receptor density via circulating shock factors. These changes are mitigated by enteral TXA with correspondingly improved hemodynamics. Proteolytic inhibition in the lumen of the small intestine improves

  18. Robust experiment design for estimating myocardial β adrenergic receptor concentration using PET

    International Nuclear Information System (INIS)

    Salinas, Cristian; Muzic, Raymond F. Jr.; Ernsberger, Paul; Saidel, Gerald M.

    2007-01-01

    Myocardial β adrenergic receptor (β-AR) concentration can substantially decrease in congestive heart failure and significantly increase in chronic volume overload, such as in severe aortic valve regurgitation. Positron emission tomography (PET) with an appropriate ligand-receptor model can be used for noninvasive estimation of myocardial β-AR concentration in vivo. An optimal design of the experiment protocol, however, is needed for sufficiently precise estimates of β-AR concentration in a heterogeneous population. Standard methods of optimal design do not account for a heterogeneous population with a wide range of β-AR concentrations and other physiological parameters and consequently are inadequate. To address this, we have developed a methodology to design a robust two-injection protocol that provides reliable estimates of myocardial β-AR concentration in normal and pathologic states. A two-injection protocol of the high affinity β-AR antagonist [ 18 F]-(S)-fluorocarazolol was designed based on a computer-generated (or synthetic) population incorporating a wide range of β-AR concentrations. Timing and dosage of the ligand injections were optimally designed with minimax criterion to provide the least bad β-AR estimates for the worst case in the synthetic population. This robust experiment design for PET was applied to experiments with pigs before and after β-AR upregulation by chemical sympathectomy. Estimates of β-AR concentration were found by minimizing the difference between the model-predicted and experimental PET data. With this robust protocol, estimates of β-AR concentration showed high precision in both normal and pathologic states. The increase in β-AR concentration after sympathectomy predicted noninvasively with PET is consistent with the increase shown by in vitro assays in pig myocardium. A robust experiment protocol was designed for PET that yields reliable estimates of β-AR concentration in a population with normal and pathologic

  19. Calcium/calmodulin-dependent kinase II and nitric oxide synthase 1-dependent modulation of ryanodine receptors during β-adrenergic stimulation is restricted to the dyadic cleft.

    Science.gov (United States)

    Dries, Eef; Santiago, Demetrio J; Johnson, Daniel M; Gilbert, Guillaume; Holemans, Patricia; Korte, Sanne M; Roderick, H Llewelyn; Sipido, Karin R

    2016-10-15

    The dyadic cleft, where coupled ryanodine receptors (RyRs) reside, is thought to serve as a microdomain for local signalling, as supported by distinct modulation of coupled RyRs dependent on Ca 2+ /calmodulin-dependent kinase II (CaMKII) activation during high-frequency stimulation. Sympathetic stimulation through β-adrenergic receptors activates an integrated signalling cascade, enhancing Ca 2+ cycling and is at least partially mediated through CaMKII. Here we report that CaMKII activation during β-adrenergic signalling is restricted to the dyadic cleft, where it enhances activity of coupled RyRs thereby contributing to the increase in diastolic events. Nitric oxide synthase 1 equally participates in the local modulation of coupled RyRs. In contrast, the increase in the Ca 2+ content of the sarcoplasmic reticulum and related increase in the amplitude of the Ca 2+ transient are primarily protein kinase A-dependent. The present data extend the concept of microdomain signalling in the dyadic cleft and give perspectives for selective modulation of RyR subpopulations and diastolic events. In cardiac myocytes, β-adrenergic stimulation enhances Ca 2+ cycling through an integrated signalling cascade modulating L-type Ca 2+ channels (LTCCs), phospholamban and ryanodine receptors (RyRs). Ca 2+ /calmodulin-dependent kinase II (CaMKII) and nitric oxide synthase 1 (NOS1) are proposed as prime mediators for increasing RyR open probability. We investigate whether this pathway is confined to the high Ca 2+ microdomain of the dyadic cleft and thus to coupled RyRs. Pig ventricular myocytes are studied under whole-cell voltage-clamp and confocal line-scan imaging with Fluo-4 as a [Ca 2+ ] i indicator. Following conditioning depolarizing pulses, spontaneous RyR activity is recorded as Ca 2+ sparks, which are assigned to coupled and non-coupled RyR clusters. Isoproterenol (ISO) (10 nm) increases Ca 2+ spark frequency in both populations of RyRs. However, CaMKII inhibition reduces

  20. Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation

    Science.gov (United States)

    Eng, Jason W.-L.; Reed, Chelsey B.; Kokolus, Kathleen M.; Pitoniak, Rosemarie; Utley, Adam; Bucsek, Mark J.; Ma, Wen Wee; Repasky, Elizabeth A.; Hylander, Bonnie L.

    2015-03-01

    Cancer research relies heavily on murine models for evaluating the anti-tumour efficacy of therapies. Here we show that the sensitivity of several pancreatic tumour models to cytotoxic therapies is significantly increased when mice are housed at a thermoneutral ambient temperature of 30 °C compared with the standard temperature of 22 °C. Further, we find that baseline levels of norepinephrine as well as the levels of several anti-apoptotic molecules are elevated in tumours from mice housed at 22 °C. The sensitivity of tumours to cytotoxic therapies is also enhanced by administering a β-adrenergic receptor antagonist to mice housed at 22 °C. These data demonstrate that standard housing causes a degree of cold stress sufficient to impact the signalling pathways related to tumour-cell survival and affect the outcome of pre-clinical experiments. Furthermore, these data highlight the significant role of host physiological factors in regulating the sensitivity of tumours to therapy.

  1. Effect of skin temperature on cutaneous vasodilator response to the β-adrenergic agonist isoproterenol

    OpenAIRE

    Hodges, Gary J.; Kellogg, Dean L.; Johnson, John M.

    2015-01-01

    The vascular response to local skin cooling is dependent in part on a cold-induced translocation of α2C-receptors and an increased α-adrenoreceptor function. To discover whether β-adrenergic function might contribute, we examined whether β-receptor sensitivity to the β-agonist isoproterenol was affected by local skin temperature. In seven healthy volunteers, skin blood flow was measured from the forearm by laser-Doppler flowmetry and blood pressure was measured by finger photoplethysmography....

  2. In brown adipocytes, adrenergically induced β1-/β3-(Gs)-, α2-(Gi)- and α1-(Gq)-signalling to Erk1/2 activation is not mediated via EGF receptor transactivation

    International Nuclear Information System (INIS)

    Wang, Yanling; Fälting, Johanna M.; Mattsson, Charlotte L.; Holmström, Therése E.; Nedergaard, Jan

    2013-01-01

    Brown adipose tissue is unusual in that the neurotransmitter norepinephrine influences cell destiny in ways generally associated with effects of classical growth factors: regulation of cell proliferation, of apoptosis, and progression of differentiation. The norepinephrine effects are mediated through G-protein-coupled receptors; further mediation of such stimulation to e.g. Erk1/2 activation is in cell biology in general accepted to occur through transactivation of the EGF receptor (by external or internal pathways). We have examined here the significance of such transactivation in brown adipocytes. Stimulation of mature brown adipocytes with cirazoline (α 1 -adrenoceptor coupled via G q ), clonidine (α 2 via G i ) or CL316243 (β 3 via G s ) or via β 1 -receptors significantly activated Erk1/2. Pretreatment with the EGF receptor kinase inhibitor AG1478 had, remarkably, no significant effect on Erk1/2 activation induced by any of these adrenergic agonists (although it fully abolished EGF-induced Erk1/2 activation), demonstrating absence of EGF receptor-mediated transactivation. Results with brown preadipocytes (cells in more proliferative states) were not qualitatively different. Joint stimulation of all adrenoceptors with norepinephrine did not result in synergism on Erk1/2 activation. AG1478 action on EGF-stimulated Erk1/2 phosphorylation showed a sharp concentration–response relationship (IC 50 0.3 µM); a minor apparent effect of AG1478 on norepinephrine-stimulated Erk1/2 phosphorylation showed nonspecific kinetics, implying caution in interpretation of partial effects of AG1478 as reported in other systems. Transactivation of the EGF receptor is clearly not a universal prerequisite for coupling of G-protein coupled receptors to Erk1/2 signalling cascades. - Highlights: • In brown adipocytes, norepinephrine regulates proliferation, apoptosis, differentiation. • EGF receptor transactivation is supposed to mediate GPCR-induced Erk1/2 activation. •

  3. Terbutaline causes immobilization of single β2-adrenergic receptor-ligand complexes in the plasma membrane of living A549 cells as revealed by single-molecule microscopy

    Science.gov (United States)

    Sieben, Anne; Kaminski, Tim; Kubitscheck, Ulrich; Häberlein, Hanns

    2011-02-01

    G-protein-coupled receptors are important targets for various drugs. After signal transduction, regulatory processes, such as receptor desensitization and internalization, change the lateral receptor mobility. In order to study the lateral diffusion of β2-adrenergic receptors (β2AR) complexed with fluorescently labeled noradrenaline (Alexa-NA) in plasma membranes of A549 cells, trajectories of single receptor-ligand complexes were monitored using single-particle tracking. We found that a fraction of 18% of all β2ARs are constitutively immobile. About 2/3 of the β2ARs moved with a diffusion constant of D2 = 0.03+/-0.001 μm2/s and about 17% were diffusing five-fold faster (D3 = 0.15+/-0.02 μm2/s). The mobile receptors moved within restricted domains and also showed a discontinuous diffusion behavior. Analysis of the trajectory lengths revealed two different binding durations with τ1 = 77+/-1 ms and τ2 = 388+/-11 ms. Agonistic stimulation of the β2AR-Alexa-NA complexes with 1 μM terbutaline caused immobilization of almost 50% of the receptors within 35 min. Simultaneously, the mean area covered by the mobile receptors decreased significantly. Thus, we demonstrated that agonistic stimulation followed by cell regulatory processes results in a change in β2AR mobility suggesting that different receptor dynamics characterize different receptor states.

  4. Beta-Adrenergic Receptor Polymorphisms and Cardiac Graft Function in Potential Organ Donors

    Science.gov (United States)

    Khush, K.K.; Pawlikowska, L.; Menza, R.L.; Goldstein, B.A.; Hayden, V.; Nguyen, J.; Kim, H.; Poon, A.; Sapru, A.; Matthay, M.A.; Kwok, P.Y.; Young, W.L.; Baxter-Lowe, L.A.; Zaroff, J.G.

    2012-01-01

    Prior studies have demonstrated associations between β-adrenergic receptor polymorphisms and left ventricular dysfunction—an important cause of allograft non-utilization for transplantation. We hypothesized that βAR polymorphisms predispose donor hearts to LV dysfunction after brain death. 1,043 organ donors managed from 2001-2006 were initially studied. The following βAR single nucleotide polymorphisms were genotyped: β1AR 1165C/G (Arg389Gly), β1AR 145A/G (Ser49Gly), β2AR 46G/A (Gly16Arg), and β2AR 79C/G (Gln27Glu). In multivariable regression analyses, the β2AR46 SNP was significantly associated with LV systolic dysfunction, with each minor allele additively decreasing the odds for LV ejection fractiondonor management period: donors with the GG and AA genotypes had ORs of 2.64 (95% CI 1.52-4.57) and 2.70 (1.07-2.74) respectively for requiring >10 mcg/kg/min of dopamine compared to those with the CC and GG genotypes. However, no significant associations were found between βAR SNPs and cardiac dysfunction in 364 donors managed from 2007-2008, perhaps due to changes in donor management, lack of power in this validation cohort, or the absence of a true association. βAR polymorphisms may be associated with cardiac dysfunction after brain death, but these relationships require further study in independent donor cohorts. PMID:22994654

  5. ß-Adrenergic stimulation increases RyR2 activity via intracellular Ca2+ and Mg2+ regulation.

    Directory of Open Access Journals (Sweden)

    Jiao Li

    Full Text Available Here we investigate how ß-adrenergic stimulation of the heart alters regulation of ryanodine receptors (RyRs by intracellular Ca(2+ and Mg(2+ and the role of these changes in SR Ca(2+ release. RyRs were isolated from rat hearts, perfused in a Langendorff apparatus for 5 min and subject to 1 min perfusion with 1 µM isoproterenol or without (control and snap frozen in liquid N2 to capture their phosphorylation state. Western Blots show that RyR2 phosphorylation was increased by isoproterenol, confirming that RyR2 were subject to normal ß-adrenergic signaling. Under basal conditions, S2808 and S2814 had phosphorylation levels of 69% and 15%, respectively. These levels were increased to 83% and 60%, respectively, after 60 s of ß-adrenergic stimulation consistent with other reports that ß-adrenergic stimulation of the heart can phosphorylate RyRs at specific residues including S2808 and S2814 causing an increase in RyR activity. At cytoplasmic [Ca(2+] 1 µM, ß-adrenergic stimulation only decreased cytoplasmic Mg(2+ and Ca(2+ inhibition of RyRs. The Ka and maximum levels of cytoplasmic Ca(2+ activation site were not affected by ß-adrenergic stimulation. Our RyR2 gating model was fitted to the single channel data. It predicted that in diastole, ß-adrenergic stimulation is mediated by 1 increasing the activating potency of Ca(2+ binding to the luminal Ca(2+ site and decreasing its affinity for luminal Mg(2+ and 2 decreasing affinity of the low-affinity Ca(2+/Mg(2+ cytoplasmic inhibition site. However in systole, ß-adrenergic stimulation is mediated mainly by the latter.

  6. In utero Exposure to beta-2-Adrenergic Receptor Agonist Drugs and Risk for Autism Spectrum Disorders

    DEFF Research Database (Denmark)

    Gidaya, Nicole B.; Lee, Brian K.; Burstyn, Igor

    2016-01-01

    OBJECTIVES: The purpose of this study was to investigate associations between use of β-2-adrenergic receptor (B2AR) agonist drugs during pregnancy and risk for autism spectrum disorders (ASD). METHODS: A case-control study was conducted by using Denmark’s health and population registers. Among...... exposure during pregnancy, preconception, and by trimester. RESULTS: In total, 3.7% of cases and 2.9% of controls were exposed to B2ARs during pregnancy. Use of B2ARs during pregnancy was associated with increased risk of ASD, even after adjustment for maternal asthma and other covariates (OR: 1.3, 95% CI......: 1.1–1.5). The elevated risk was observed with use of B2AR during preconception (OR: 1.3, 95% CI: 1.0–1.6), first trimester (OR: 1.3, 95% CI: 1.1–1.5), second trimester (OR: 1.5, 95% CI: 1.1–1.7), and the third trimester (OR: 1.4, 95% CI: 1.1–1.7). There was some evidence that longer B2AR within-pregnancy...

  7. Defective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma.

    Directory of Open Access Journals (Sweden)

    Manveen K Gupta

    Full Text Available β2-adrenergic receptor (β2AR agonists (β2-agonist are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. Activation of βARs by β-agonist leads to desensitization (inactivation by phosphorylation through G-protein coupled receptor kinases (GRKs which mediate β-arrestin binding and βAR internalization. Resensitization occurs by dephosphorylation of the endosomal βARs which recycle back to the plasma membrane as agonist-ready receptors. To determine whether the loss in β-agonist response in asthma is due to altered βAR desensitization and/or resensitization, we used primary human airway smooth muscle cells (HASMCs isolated from the lungs of non-asthmatic and fatal-asthmatic subjects. Asthmatic HASMCs have diminished adenylyl cyclase activity and cAMP response to β-agonist as compared to non-asthmatic HASMCs. Confocal microscopy showed significant accumulation of phosphorylated β2ARs in asthmatic HASMCs. Systematic analysis of desensitization components including GRKs and β-arrestin showed no appreciable differences between asthmatic and non-asthmatic HASMCs. However, asthmatic HASMC showed significant increase in PI3Kγ activity and was associated with reduction in PP2A activity. Since reduction in PP2A activity could alter receptor resensitization, endosomal fractions were isolated to assess the agonist ready β2ARs as a measure of resensitization. Despite significant accumulation of β2ARs in the endosomes of asthmatic HASMCs, endosomal β2ARs cannot robustly activate adenylyl cyclase. Furthermore, endosomes from asthmatic HASMCs are associated with significant increase in PI3Kγ and reduced PP2A activity that inhibits β2AR resensitization. Our study shows that resensitization, a process considered to be a homeostasis maintaining passive process is inhibited in asthmatic HASMCs contributing to β2AR dysfunction which may underlie

  8. β-adrenergic receptor-dependent alterations in murine cardiac transcript expression are differentially regulated by gefitinib in vivo.

    Directory of Open Access Journals (Sweden)

    Jennifer A Talarico

    Full Text Available β-adrenergic receptor (βAR-mediated transactivation of epidermal growth factor receptor (EGFR has been shown to promote cardioprotection in a mouse model of heart failure and we recently showed that this mechanism leads to enhanced cell survival in part via regulation of apoptotic transcript expression in isolated primary rat neonatal cardiomyocytes. Thus, we hypothesized that this process could regulate cardiac transcript expression in vivo. To comprehensively assess cardiac transcript alterations in response to acute βAR-dependent EGFR transactivation, we performed whole transcriptome analysis of hearts from C57BL/6 mice given i.p. injections of the βAR agonist isoproterenol in the presence or absence of the EGFR antagonist gefitinib for 1 hour. Total cardiac RNA from each treatment group underwent transcriptome analysis, revealing a substantial number of transcripts regulated by each treatment. Gefitinib alone significantly altered the expression of 405 transcripts, while isoproterenol either alone or in conjunction with gefitinib significantly altered 493 and 698 distinct transcripts, respectively. Further statistical analysis was performed, confirming 473 transcripts whose regulation by isoproterenol were significantly altered by gefitinib (isoproterenol-induced up/downregulation antagonized/promoted by gefinitib, including several known to be involved in the regulation of numerous processes including cell death and survival. Thus, βAR-dependent regulation of cardiac transcript expression in vivo can be modulated by the EGFR antagonist gefitinib.

  9. Glycyrrhetic acid synergistically enhances β₂-adrenergic receptor-Gs signaling by changing the location of Gαs in lipid rafts.

    Directory of Open Access Journals (Sweden)

    Qian Shi

    Full Text Available Glycyrrhetic acid (GA exerts synergistic anti-asthmatic effects via a β₂-adrenergic receptor (β₂AR-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the β₂AR-Gs-adenylate cyclase (AC-mediated signaling pathway. Owing to the structural similarities between GA and cholesterol, we investigated the possibility that GA enhances β₂AR signaling by altering cholesterol distribution. Azide-terminal GA (ATGA was synthesized and applied to human embryonic kidney 293 (HEK293 cells expressing fusion β₂AR, and the electron spin resonance (ESR technique was utilized. GA was determined to be localized predominantly on membrane and decreased their cholesterol contents. Thus, the fluidity of the hydrophobic region increased but not the polar surface of the cell membrane. The conformations of membrane proteins were also changed. GA further changed the localization of Gαs from lipid rafts to non-raft regions, resulting the binding of β₂AR and Gαs, as well as in reduced β₂AR internalization. Co-localization of β₂AR, Gαs, and AC increased isoproterenol-induced cAMP production and cholesterol reloading attenuated this effect. A speculation wherein GA enhances beta-adrenergic activity by increasing the functional linkage between the subcomponents of the membrane β₂AR-protein kinase A (PKA signaling pathway was proposed. The enhanced efficacy of β₂AR agonists by this novel mechanism could prevent tachyphylaxis.

  10. β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

    Science.gov (United States)

    Mani, Bharath K.; Osborne-Lawrence, Sherri; Vijayaraghavan, Prasanna; Hepler, Chelsea; Zigman, Jeffrey M.

    2016-01-01

    Ghrelin is an orexigenic gastric peptide hormone secreted when caloric intake is limited. Ghrelin also regulates blood glucose, as emphasized by the hypoglycemia that is induced by caloric restriction in mouse models of deficient ghrelin signaling. Here, we hypothesized that activation of β1-adrenergic receptors (β1ARs) localized to ghrelin cells is required for caloric restriction–associated ghrelin release and the ensuing protective glucoregulatory response. In mice lacking the β1AR specifically in ghrelin-expressing cells, ghrelin secretion was markedly blunted, resulting in profound hypoglycemia and prevalent mortality upon severe caloric restriction. Replacement of ghrelin blocked the effects of caloric restriction in β1AR-deficient mice. We also determined that treating calorically restricted juvenile WT mice with beta blockers led to reduced plasma ghrelin and hypoglycemia, the latter of which is similar to the life-threatening, fasting-induced hypoglycemia observed in infants treated with beta blockers. These findings highlight the critical functions of ghrelin in preventing hypoglycemia and promoting survival during severe caloric restriction and the requirement for ghrelin cell–expressed β1ARs in these processes. Moreover, these results indicate a potential role for ghrelin in mediating beta blocker–associated hypoglycemia in susceptible individuals, such as young children. PMID:27548523

  11. Agonist-induced alterations in lymphocyte β-adrenergic receptor photoaffintiy labelling: effects of phenylarsine oxide

    International Nuclear Information System (INIS)

    Feldman, R.D.; McArdle, W.; Lai, C.

    1986-01-01

    In several models, desensitization of the β-adrenergic receptor (βAR) is associated with a decrease in binding of hydrophilic but not hydrophobic βAR ligands. This suggests a sequestration of cell surface βAR. Desensitization of the lymphobyte βAR is also associated with a selective reduction in the photoaffinity labelling of a 55K βAR protein as compared to a 68K βAR protein. In order to examine the relationship between sequestration and reduction in labelling of the 55K peptide, the authors have studied the effect of phenylarsine oxide (PAO; an inhibitor of sequestration) on lymphocyte βAR desensitization. Incubation of cells with PAO prior to desensitization did not block the consequent reduction in isoproterenol-stimulated adenylate cyclase activity. However, the agonist-induced reduction in binding of the hydrophilic βAR ligand CGP-12177 was blocked by PAO (without PAO:57 +/- 4% of control, with PAO: 97 +/- 2% of control). Photolabelling studies with [ 125 I] iodocyanopindolol diazirine revealed that PAO pretreatment also blocked the selective loss in labelling of the 55K βAR protein seen with desensitization. These data suggest that loss of labelling of the 55K protein of the βAR is closely coupled to βAR sequestration

  12. The effects of N-methyl D-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: a meta-analysis.

    Science.gov (United States)

    Das, Ravi K; Freeman, Tom P; Kamboj, Sunjeev K

    2013-03-01

    Pharmacological memory reconsolidation blockade provides a potential mechanism for ameliorating the maladaptive reward memories underlying relapse in addiction. Two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-D-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. We used meta-analysis and meta-regression to assess the effects of these drugs on the reconsolidation of reward memory in preclinical models of addiction. Pharmacokinetic, mnemonic and methodological factors were assessed for their moderating impact on effect sizes. An analysis of 52 independent effect sizes (NMDAR=30, B-AR=22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. Significant moderating effects of drug dose, relapse process and primary reinforcer were found. The findings suggest that reward memory reconsolidation can be robustly targeted by NMDAR antagonists and to a lesser extent, by B-AR antagonists. Implications for future clinical work are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Circulating sex hormones and gene expression of subcutaneous adipose tissue oestrogen and alpha-adrenergic receptors in HIV-lipodystrophy: implications for fat distribution

    DEFF Research Database (Denmark)

    Andersen, Ove; Pedersen, Steen B; Svenstrup, Birgit

    2007-01-01

    in lipodystrophic patients compared to nonlipodystrophic patients, whereas luteinizing hormone, follicle-stimulating hormone and prolactin were similar and normal in both study groups. Ratio of subcutaneous to total abdominal fat mass, limb fat, and insulin sensitivity, which were all decreased in lipodystrophic...... patients, correlated positively with both plasma oestradiol and testosterone (n = 31). Glycerol concentration during clamp (a marker of lipolysis) correlated inversely with expression of alpha2A-adrenergic-receptor, ratio of subcutaneous to total abdominal fat mass, and limb fat, respectively. Expression......OBJECTIVE: Circulating oestradiol and testosterone, which have been shown to increase in human immunodeficiency virus (HIV)-infected patients following highly active antiretroviral therapy (HAART), may influence fat distribution and insulin sensitivity. Oestradiol increases subcutaneous adipose...

  14. ß-Adrenergic Stimulation Increases RyR2 Activity via Intracellular Ca2+ and Mg2+ Regulation

    Science.gov (United States)

    Li, Jiao; Imtiaz, Mohammad S.; Beard, Nicole A.; Dulhunty, Angela F.; Thorne, Rick; vanHelden, Dirk F.; Laver, Derek R.

    2013-01-01

    Here we investigate how ß-adrenergic stimulation of the heart alters regulation of ryanodine receptors (RyRs) by intracellular Ca2+ and Mg2+ and the role of these changes in SR Ca2+ release. RyRs were isolated from rat hearts, perfused in a Langendorff apparatus for 5 min and subject to 1 min perfusion with 1 µM isoproterenol or without (control) and snap frozen in liquid N2 to capture their phosphorylation state. Western Blots show that RyR2 phosphorylation was increased by isoproterenol, confirming that RyR2 were subject to normal ß-adrenergic signaling. Under basal conditions, S2808 and S2814 had phosphorylation levels of 69% and 15%, respectively. These levels were increased to 83% and 60%, respectively, after 60 s of ß-adrenergic stimulation consistent with other reports that ß-adrenergic stimulation of the heart can phosphorylate RyRs at specific residues including S2808 and S2814 causing an increase in RyR activity. At cytoplasmic [Ca2+] adrenergic stimulation increased luminal Ca2+ activation of single RyR channels, decreased luminal Mg2+ inhibition and decreased inhibition of RyRs by mM cytoplasmic Mg2+. At cytoplasmic [Ca2+] >1 µM, ß-adrenergic stimulation only decreased cytoplasmic Mg2+ and Ca2+ inhibition of RyRs. The Ka and maximum levels of cytoplasmic Ca2+ activation site were not affected by ß-adrenergic stimulation. Our RyR2 gating model was fitted to the single channel data. It predicted that in diastole, ß-adrenergic stimulation is mediated by 1) increasing the activating potency of Ca2+ binding to the luminal Ca2+ site and decreasing its affinity for luminal Mg2+ and 2) decreasing affinity of the low-affinity Ca2+/Mg2+ cytoplasmic inhibition site. However in systole, ß-adrenergic stimulation is mediated mainly by the latter. PMID:23533585

  15. Enhanced expression of contractile endothelin ET(B) receptors in rat coronary artery after organ culture

    DEFF Research Database (Denmark)

    Johnsson, E.; Maddahi, A.; Wackenfors, A.

    2008-01-01

    . In cardiovascular disease and in organ culture in vitro, endothelin ET(B) receptors are up-regulated on smooth muscle cells. The objectives of the present study were to characterise the endothelin receptor-induced vasoconstriction and quantify the endothelin receptor mRNA levels and immunoreactivity in fresh...... and cultured rat coronary arteries. We demonstrate that endothelin-1 induces strong and equal concentration-dependent contractions in fresh and cultured segments from the left anterior descending coronary artery. Sarafotoxin 6c, an endothelin ET(B) receptor agonist, had negligible effect in fresh arteries...... but produced significant vasoconstriction after organ culture. The endothelin ET(B) receptor mRNA level and the receptor protein immunoreactivity were increased, whereas the level of endothelin ET(A) receptor mRNA was down-regulated but not its receptor protein immunoreactivity after organ culture...

  16. Ghrelin potentiates cardiac reactivity to stress by modulating sympathetic control and beta-adrenergic response.

    Science.gov (United States)

    Camargo-Silva, Gabriel; Turones, Larissa Córdova; da Cruz, Kellen Rosa; Gomes, Karina Pereira; Mendonça, Michelle Mendanha; Nunes, Allancer; de Jesus, Itamar Guedes; Colugnati, Diego Basile; Pansani, Aline Priscila; Pobbe, Roger Luis Henschel; Santos, Robson; Fontes, Marco Antônio Peliky; Guatimosim, Silvia; de Castro, Carlos Henrique; Ianzer, Danielle; Ferreira, Reginaldo Nassar; Xavier, Carlos Henrique

    2018-03-01

    Prior evidence indicates that ghrelin is involved in the integration of cardiovascular functions and behavioral responses. Ghrelin actions are mediated by the growth hormone secretagogue receptor subtype 1a (GHS-R1a), which is expressed in peripheral tissues and central areas involved in the control of cardiovascular responses to stress. In the present study, we assessed the role of ghrelin - GHS-R1a axis in the cardiovascular reactivity to acute emotional stress in rats. Ghrelin potentiated the tachycardia evoked by restraint and air jet stresses, which was reverted by GHS-R1a blockade. Evaluation of the autonomic balance revealed that the sympathetic branch modulates the ghrelin-evoked positive chronotropy. In isolated hearts, the perfusion with ghrelin potentiated the contractile responses caused by stimulation of the beta-adrenergic receptor, without altering the amplitude of the responses evoked by acetylcholine. Experiments in isolated cardiomyocytes revealed that ghrelin amplified the increases in calcium transient changes evoked by isoproterenol. Taken together, our results indicate that the Ghrelin-GHS-R1a axis potentiates the magnitude of stress-evoked tachycardia by modulating the autonomic nervous system and peripheral mechanisms, strongly relying on the activation of cardiac calcium transient and beta-adrenergic receptors. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Beta-Adrenergic signaling in rat heart is similarly affected by continuous and intermittent normobaric hypoxia

    Czech Academy of Sciences Publication Activity Database

    Hahnová, K.; Kašparová, D.; Žurmanová, J.; Neckář, Jan; Kolář, František; Novotný, J.

    2016-01-01

    Roč. 35, č. 2 (2016), s. 165-173 ISSN 0231-5882 R&D Projects: GA ČR(CZ) GAP303/12/1162 Institutional support: RVO:67985823 Keywords : rat myocardium * chronic hypoxia * beta-adrenergic receptors * adenylyl cyclase Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.170, year: 2016

  18. Effect of Zingiber officinale Supplementation on Obesity Management with Respect to the Uncoupling Protein 1 -3826A>G and ß3-adrenergic Receptor Trp64Arg Polymorphism.

    Science.gov (United States)

    Ebrahimzadeh Attari, Vahideh; Asghari Jafarabadi, Mohammad; Zemestani, Maryam; Ostadrahimi, Alireza

    2015-07-01

    The present study aimed to investigate the effect of ginger (Zingiber officinale) supplementation on some obesity-associated parameters, with nutrigenetics approach. Accordingly, 80 eligible obese women (aged 18-45 years) were randomly assigned to receive either ginger (2-g ginger rhizomes powder as two 1-g tablets per day) or placebo supplements (corn starch with the same amount) for 12 weeks. Subjects were tested for changes in body weight, body mass index, waist and hip circumferences, body composition, appetite score, and dietary intake. Moreover, participants were genotyped for the -3826A>G and Trp64Arg polymorphisms of uncoupling protein 1 and ß3-adrenergic receptor genes, respectively. Over 12 weeks, ginger supplementation resulted in a slight but statistically significant decrease in all anthropometric measurements and total appetite score as compared with placebo group, which were more pronounced in subjects with the AA genotype for uncoupling protein 1 and Trp64Trp genotype for ß3-adrenergic receptor gene. However, there was no significant difference in changes of body composition and total energy and macronutrients intake between groups. In conclusion, our findings suggest that ginger consumption has potential in managing obesity, accompanying with an intervention-genotype interaction effect. However, further clinical trials need to explore ginger's efficacy as an anti-obesity agent in the form of powder, extract, or its active components. Copyright © 2015 John Wiley & Sons, Ltd.

  19. Function of brain α2B-adrenergic receptor characterized with subtype-selective α2B antagonist and KO mice.

    Science.gov (United States)

    Luhrs, Lauren; Manlapaz, Cynthia; Kedzie, Karen; Rao, Sandhya; Cabrera-Ghayouri, Sara; Donello, John; Gil, Daniel

    2016-12-17

    Noradrenergic signaling, through the α 2A and α 2C adrenergic receptors modulates the cognitive and behavioral symptoms of disorders such as schizophrenia, attention deficit hyperactivity disorder (ADHD), and addiction. However, it is unknown whether the α 2B receptor has any significant role in CNS function. The present study elucidates the potential role of the α 2B receptor in CNS function via the discovery and use of the first subtype-selective α 2B antagonist (AGN-209419), and behavioral analyses of α-receptor knockout (KO) mice. Using AGN-209419 as radioligand, α 2B receptor binding sites were identified within the olfactory bulb, cortex, thalamus, cerebellum, and striatum. Based on the observed expression patterns of α 2 subtypes in the brain, we compared α 2B KO, α 2A KO and α 2C KO mice behavioral phenotypes with their respective wild-type lines in anxiety (plus maze), compulsive (marble burying), and sensorimotor (prepulse inhibition) tasks. α 2B KO mice exhibited increased marble burying and α 2C KO mice exhibited an increased startle response to a pulse stimulus, but otherwise intact prepulse inhibition. To further explore compulsive behavior, we evaluated novelty-induced locomotor hyperactivity and found that α 2B KO and α 2C KO mice exhibited increased locomotion in the open field. Interestingly, when challenged with amphetamine, α 2C KO mice increased activity at lower doses relative to either α 2A KO or WT mice. However, α 2B KO mice exhibited stereotypy at doses of amphetamine that were only locomotor stimulatory to all other genotypes. Following co-administration of AGN-209419 with low-dose amphetamine in WT mice, stereotypy was observed, mimicking the α 2B KO phenotype. These findings suggest that the α 2B receptor is involved in CNS behaviors associated with sensorimotor gating and compulsivity, and may be therapeutically relevant for disorders such as schizophrenia, ADHD, post-traumatic stress disorder, addiction, and

  20. Blood flow distribution with adrenergic and histaminergic antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.

    1989-03-01

    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects.

  1. Blood flow distribution with adrenergic and histaminergic antagonists

    International Nuclear Information System (INIS)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.

    1989-01-01

    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects

  2. Beta-adrenergic receptors in the lateral nucleus of the amygdala contribute to the acquisition but not the consolidation of auditory fear conditioning.

    Science.gov (United States)

    Bush, David E A; Caparosa, Ellen M; Gekker, Anna; Ledoux, Joseph

    2010-01-01

    Beta-adrenergic receptors (βARs) have long been associated with fear disorders and with learning and memory. However, the contribution of these receptors to Pavlovian fear conditioning, a leading behavioral model for studying fear learning and memory, is still poorly understood. The aim of this study was to investigate the involvement of βAR activation in the acquisition, consolidation and expression of fear conditioning. We focused on manipulations of βARs in the lateral nucleus of the amygdala (LA) because of the well-established contribution of this area to fear conditioning. Specifically, we tested the effects of intra-LA microinfusions of the βAR antagonist, propranolol, on learning and memory for auditory Pavlovian fear conditioning in rats. Pre-training propranolol infusions disrupted the initial acquisition, short-term memory (STM), and long-term memory (LTM) for fear conditioning, but infusions immediately after training had no effect. Further, infusion of propranolol prior to testing fear responses did not affect fear memory expression. These findings indicate that amygdala βARs are important for the acquisition but not the consolidation of fear conditioning.

  3. Ventricular action potential adaptation to regular exercise: role of β-adrenergic and KATP channel function.

    Science.gov (United States)

    Wang, Xinrui; Fitts, Robert H

    2017-08-01

    Regular exercise training is known to affect the action potential duration (APD) and improve heart function, but involvement of β-adrenergic receptor (β-AR) subtypes and/or the ATP-sensitive K + (K ATP ) channel is unknown. To address this, female and male Sprague-Dawley rats were randomly assigned to voluntary wheel-running or control groups; they were anesthetized after 6-8 wk of training, and myocytes were isolated. Exercise training significantly increased APD of apex and base myocytes at 1 Hz and decreased APD at 10 Hz. Ca 2+ transient durations reflected the changes in APD, while Ca 2+ transient amplitudes were unaffected by wheel running. The nonselective β-AR agonist isoproterenol shortened the myocyte APD, an effect reduced by wheel running. The isoproterenol-induced shortening of APD was largely reversed by the selective β 1 -AR blocker atenolol, but not the β 2 -AR blocker ICI 118,551, providing evidence that wheel running reduced the sensitivity of the β 1 -AR. At 10 Hz, the K ATP channel inhibitor glibenclamide prolonged the myocyte APD more in exercise-trained than control rats, implicating a role for this channel in the exercise-induced APD shortening at 10 Hz. A novel finding of this work was the dual importance of altered β 1 -AR responsiveness and K ATP channel function in the training-induced regulation of APD. Of physiological importance to the beating heart, the reduced response to adrenergic agonists would enhance cardiac contractility at resting rates, where sympathetic drive is low, by prolonging APD and Ca 2+ influx; during exercise, an increase in K ATP channel activity would shorten APD and, thus, protect the heart against Ca 2+ overload or inadequate filling. NEW & NOTEWORTHY Our data demonstrated that regular exercise prolonged the action potential and Ca 2+ transient durations in myocytes isolated from apex and base regions at 1-Hz and shortened both at 10-Hz stimulation. Novel findings were that wheel running shifted the β-adrenergic

  4. Beta-1 vs. beta-2 adrenergic control of coronary blood flow during isometric handgrip exercise in humans.

    Science.gov (United States)

    Maman, Stephan R; Vargas, Alvaro F; Ahmad, Tariq Ali; Miller, Amanda J; Gao, Zhaohui; Leuenberger, Urs A; Proctor, David N; Muller, Matthew D

    2017-08-01

    During exercise, β-adrenergic receptors are activated throughout the body. In healthy humans, the net effect of β-adrenergic stimulation is an increase in coronary blood flow. However, the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia is not clear. In this study, we simultaneously measured noninvasive indexes of myocardial oxygen supply (i.e., blood velocity in the left anterior descending coronary artery; Doppler echocardiography) and demand [i.e., rate pressure product (RPP) = heart rate × systolic blood pressure) and tested the hypothesis that β1 blockade with esmolol improves coronary exercise hyperemia compared with nonselective β-blockade with propranolol. Eight healthy young men received intravenous infusions of esmolol, propranolol, and saline on three separate days in a single-blind, randomized, crossover design. During each infusion, subjects performed isometric handgrip exercise until fatigue. Blood pressure, heart rate, and coronary blood velocity (CBV) were measured continuously, and RPP was calculated. Changes in parameters from baseline were compared with paired t -tests. Esmolol (Δ = 3296 ± 1204) and propranolol (Δ = 2997 ± 699) caused similar reductions in peak RPP compared with saline (Δ = 5384 ± 1865). In support of our hypothesis, ΔCBV with esmolol was significantly greater than with propranolol (7.3 ± 2.4 vs. 4.5 ± 1.6 cm/s; P = 0.002). This effect was also evident when normalizing ΔCBV to ΔRPP. In summary, not only does selective β1 blockade reduce myocardial oxygen demand during exercise, but it also unveils β2-receptor-mediated coronary exercise hyperemia. NEW & NOTEWORTHY In this study, we evaluated the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia in a single-blind, randomized, crossover study in healthy men. In response to isometric handgrip exercise, blood flow velocity in the left anterior descending coronary artery was significantly greater with esmolol compared with

  5. Effects of electroacupuncture on orphanin FQ immunoreactivity and preproorphanin FQ mRNA in nucleus of raphe magnus in the neuropathic pain rats.

    Science.gov (United States)

    Ma, Fei; Xie, Hong; Dong, Zhi-Qiang; Wang, Yan-Qing; Wu, Gen-Cheng

    2004-07-15

    Orphanin FQ (OFQ) is an endogenous ligand for opioid receptor-like-1 (ORL1) receptor. Previous studies have shown that both OFQ immunoreactivity and preproorphanin FQ (ppOFQ) mRNA expression could be observed in the brain regions involved in pain modulation, e.g., nucleus of raphe magnus (NRM), dorsal raphe nucleus (DRN), and ventrolateral periaqueductal gray (vlPAG). It was reported that electroacupuncture (EA) has analgesic effect on neuropathic pain, and the analgesic effect was mediated by the endogenous opioid peptides. In the present study, we investigated the effects of EA on the changes of OFQ in the neuropathic pain rats. In the sciatic nerve chronic constriction injury (CCI) model, we investigated the changes of ppOFQ mRNA and OFQ immunoreactivity in NRM after EA by in situ hybridization (ISH) and immunohistochemistry methods, respectively. Then, the ppOFQ mRNA-positive and OFQ immunoreactive cells were counted under a computerized image analysis system. The results showed that expression of ppOFQ mRNA decreased and OFQ immunoreactivity increased after EA treatment in the neuropathic pain rats. These results indicated that EA modulated OFQ synthesis and OFQ peptide level in NRM of the neuropathic pain rats. Copyright 2004 Elsevier Inc.

  6. Role of neuropsin in parvalbumin immunoreactivity changes in hippocampal basket terminals of mice reared in various environments

    Directory of Open Access Journals (Sweden)

    Harumitsu eSuzuki

    2014-12-01

    Full Text Available In vitro approaches have suggested that neuropsin (or kallikrein 8/KLK8, which controls gamma-aminobutyric acid (GABA neurotransmission through neuregulin-1 and its receptor (ErbB4, is involved in neural plasticity (Tamura et al., 2012, 2013. In the present study, we examined whether parvalbumin (PV-positive neuronal networks, the majority of which are ErbB4-positive GABAergic interneurons, are controlled by neuropsin in tranquil and stimulated voluntarily behaving mice.PV-immunoreactive fibers surrounding hippocampal pyramidal and granular neurons in mice reared in their home cage were decreased in neuropsin-deficient mice, suggesting that neuropsin controls PV immunoreactivity. One- or two-week exposures of wild mice to novel environments, in which they could behave freely and run voluntarily in a wheel resulted in a marked upregulation of both neuropsin mRNA and protein in the hippocampus. To elucidate the functional relevance of the increase in neuropsin during exposure to a rich environment, the intensities of PV-immunoreactive fibers were compared between neuropsin-deficient and wild-type mice under environmental stimuli. When mice were transferred into novel cages (large cages with toys, the intensity of PV-immunoreactive fibers increased in wild-type mice and neuropsin-deficient mice. Therefore, behavioral stimuli control a neuropsin-independent form of PV immunoreactivity. However, the neuropsin-dependent part of the change in PV-immunoreactive fibers may occur in the stimulated hippocampus because increased levels of neuropsin continued during these enriched conditions.

  7. Hypoxia-induced increases in serotonin-immunoreactive nerve fibers in the medulla oblongata of the rat.

    Science.gov (United States)

    Morinaga, Ryosuke; Nakamuta, Nobuaki; Yamamoto, Yoshio

    2016-10-01

    Hypoxia induces respiratory responses in mammals and serotonergic neurons in the medulla oblongata participate in respiratory control. However, the morphological changes in serotonergic neurons induced by hypoxia have not yet been examined and respiratory controls of serotonergic neurons have not been clarified. We herein investigated the distribution of immunoreactivity for serotonin (5-hydroxytryptamine; 5-HT) in the medulla oblongata of control rats and rats exposed to 1-6h of hypoxia (10% O 2 ). We also examined the medulla oblongata by multiple immunofluorescence labeling for 5-HT, neurokinin 1 receptors (NK1R), a marker for some respiratory neurons in the pre-Bötzinger complex (PBC), and dopamine β-hydroxylase (DBH), a marker for catecholaminergic neurons. The number of 5-HT-immunoreactive nerve cell bodies in the raphe nuclei was higher in rats exposed to hypoxia than in control rats. The number of 5-HT-immunoreactive nerve fibers significantly increased in the rostral ventrolateral medulla of rats exposed to 1-6h of hypoxia, caudal ventrolateral medulla of rats exposed to 2-6h of hypoxia, and lateral part of the nucleus of the solitary tract and dorsal motor nucleus of the vagus nerve of rats exposed to 1-2h of hypoxia. Multiple immunofluorescence labeling showed that 5-HT-immunoreactive nerve fibers were close to NK1R-immunoreactive neurons in ventrolateral medulla and to DBH-immunoreactive neurons in the medulla. These results suggest that serotonergic neurons partly regulate respiratory control under hypoxic conditions by modulating the activity of NK1R-expressing and catecholaminergic neurons. Copyright © 2016 Elsevier GmbH. All rights reserved.

  8. Does alpha 1-acid glycoprotein act as a non-functional receptor for alpha 1-adrenergic antagonists?

    Science.gov (United States)

    Qin, M; Oie, S

    1994-11-01

    The ability of a variety of alpha 1-acid glycoproteins (AAG) to affect the intrinsic activity of the alpha 1-adrenergic antagonist prazosin was studied in rabbit aortic strip preparations. From these studies, the activity of AAG appears to be linked to their ability to bind the antagonist. However, a capability to bind prazosin was not the only requirement for this effect. The removal of sialic acid and partial removal of the galactose and mannose residues by periodate oxidation of human AAG all but eliminated the ability of AAG to affect the intrinsic pharmacologic activity of prazosin, although the binding of prazosin was not significantly affected. The presence of bovine AAG, a protein that has a low ability to bind prazosin, reduced the effect of human AAG on prazosin activity. Based upon these results, we propose that AAG is able to bind in the vicinity of the alpha 1-adrenoceptors, therefore extending the binding region for antagonists in such a way as to decrease the ability of the antagonist to interact with the receptor. The carbohydrate side-chains are important for the binding of AAG in the region of the adrenoceptor.

  9. Energy expenditure, body composition and insulin response to glucose in male twins discordant for the Trp64Arg polymorphism of the β3-adrenergic receptor gene

    DEFF Research Database (Denmark)

    Højlund, Kurt; Christiansen, Christian; Bjørnsbo, K.S.

    2006-01-01

    AIM: The tryptophan to arginine change in position 64 (Trp64Arg) polymorphism of the beta3-adrenergic receptor (beta3AR) gene has been associated with an increased prevalence of obesity, insulin resistance and type 2 diabetes. In this, decreased rates of energy expenditure and impaired insulin...... and environmental background, the Trp64Arg polymorphism of the beta3AR gene is associated with lower fat mass, fasting insulin levels and an appropriate insulin response to glucose. Thus, heterozygosity for the Trp64Arg variant is unlikely to increase the risk of obesity, insulin resistance or type 2 diabetes....

  10. CL316,243, a β3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength.

    Science.gov (United States)

    Puzzo, Daniela; Raiteri, Roberto; Castaldo, Clotilde; Capasso, Raffaele; Pagano, Ester; Tedesco, Mariateresa; Gulisano, Walter; Drozd, Lisaveta; Lippiello, Pellegrino; Palmeri, Agostino; Scotto, Pietro; Miniaci, Maria Concetta

    2016-11-22

    Studies in vitro have demonstrated that β3-adrenergic receptors (β3-ARs) regulate protein metabolism in skeletal muscle by promoting protein synthesis and inhibiting protein degradation. In this study, we evaluated whether activation of β3-ARs by the selective agonist CL316,243 modifies the functional and structural properties of skeletal muscles of healthy mice. Daily injections of CL316,243 for 15 days resulted in a significant improvement in muscle force production, assessed by grip strength and weight tests, and an increased myofiber cross-sectional area, indicative of muscle hypertrophy. In addition, atomic force microscopy revealed a significant effect of CL316,243 on the transversal stiffness of isolated muscle fibers. Interestingly, the expression level of mammalian target of rapamycin (mTOR) downstream targets and neuronal nitric oxide synthase (NOS) was also found to be enhanced in tibialis anterior and soleus muscles of CL316,243 treated mice, in accordance with previous data linking β3-ARs to mTOR and NOS signaling pathways. In conclusion, our data suggest that CL316,243 systemic administration might be a novel therapeutic strategy worthy of further investigations in conditions of muscle wasting and weakness associated with aging and muscular diseases.

  11. β(3) adrenergic stimulation of the cardiac Na+-K+ pump by reversal of an inhibitory oxidative modification

    DEFF Research Database (Denmark)

    Bundgaard, Henning; Liu, Chia-Chi; Garcia, Alvaro

    2010-01-01

    inhibition of L-type Ca(2+) current contributes to negative inotropy of β(3) adrenergic receptor (β(3) AR) activation, but effects on other determinants of excitation-contraction coupling are not known. Of these, the Na(+)-K(+) pump is of particular interest because of adverse effects attributed ...

  12. ß(3) adrenergic stimulation of the cardiac Na+-K+ pump by reversal of an inhibitory oxidative modification

    DEFF Research Database (Denmark)

    Bundgaard, Henning; Liu, Chia-Chi; Garcia, Alvaro

    2010-01-01

    inhibition of L-type Ca(2+) current contributes to negative inotropy of ß(3) adrenergic receptor (ß(3) AR) activation, but effects on other determinants of excitation-contraction coupling are not known. Of these, the Na(+)-K(+) pump is of particular interest because of adverse effects attributed ...

  13. Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia.

    Science.gov (United States)

    Spalink, Christy L; Barnes, Erin; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio

    2017-08-01

    To report the use of intranasal dexmedetomidine, an α 2 -adrenergic agonist for the acute treatment of refractory adrenergic crisis in patients with familial dysautonomia. Case series. Three patients with genetically confirmed familial dysautonomia (case 1: 20-year-old male; case 2: 43-year-old male; case 3: 26-year-old female) received intranasal dexmedetomidine 2 mcg/kg, half of the dose in each nostril, for the acute treatment of adrenergic crisis. Within 8-17 min of administering the intranasal dose, the adrenergic crisis symptoms abated, and blood pressure and heart rate returned to pre-crises values. Adrenergic crises eventually resumed, and all three patients required hospitalization for investigation of the cause of the crises. Intranasal dexmedetomidine is a feasible and safe acute treatment for adrenergic crisis in patients with familial dysautonomia. Further controlled studies are required to confirm the safety and efficacy in this population.

  14. Meta-analysis of the association between the Trp64Arg polymorphism of the beta-3 adrenergic receptor and susceptibility to gestational diabetes mellitus.

    Science.gov (United States)

    Guan, Lianyue; Cui, Xiaofeng; Zhou, Hui

    2018-02-01

    The study aimed to explore the associations between Trp64Arg polymorphism of Beta-3 Adrenergic receptor (ADRB3) and susceptibility to gestational diabetes mellitus (GDM). Relevant studies till December 2013 were identified through searching electronic databases. A meta-analysis was conducted on associations between Trp64Arg polymorphism in ADRB3 and susceptibility to GDM. We found no association between Trp64Arg polymorphism in ADRB3 and susceptibility to GDM in overall population (Arg vs. Trp: OR = 1.20, 95%CI = 0.99-1.47, p = .16; Trp/Arg + Arg/Arg vs. Trp/Trp: OR = 1.22, 95%CI = 0.99-1.50, p = .11). In subgroup analysis on European Caucasian population, Trp64Arg in ADRB3 was associated with susceptibility to GDM. Trp64Arg polymorphism in ADRB3 had certain association with susceptibility to GDM in the European Caucasian population. Impact statement What is already known on this subject: Gestational diabetes mellitus (GDM) is recognised as carbohydrate intolerance of varied severity that begins or is first recognised during pregnancy. A missense mutation in the codon 64 of the Beta-3 adrenergic receptor (ADRB3), Trp64Arg, leads to the substitution of tryptophan by arginine in the first intracellular loop of the ADRB3 receptor. Trp64Arg Polymorphism has also been reportedly associated with increased body weight, type 2 diabetes mellitus, insulin resistance and obesity. However, other investigators have found that the Trp64Arg polymorphism of ADRB3 has no effect on insulin resistance, obesity or type 2 diabetes mellitus. What the results of the study add: Our present meta-analysis demonstrated that Trp64Arg polymorphism in ADRB3 was associated with susceptibility to GDM in the European Caucasian population. Trp64Arg polymorphism in ADRB3 may be able to predict the occurrence of GDM and used for the diagnosis of it in clinic. What the implications are of these findings for clinical practice and future research: The findings in this study

  15. Reproduction phase-related expression of GnRH-like immunoreactivity in the olfactory receptor neurons, their projections to the olfactory bulb and in the nervus terminalis in the female Indian major carp Cirrhinus mrigala (Ham.).

    Science.gov (United States)

    Biju, K C; Singru, Praful S; Schreibman, Martin P; Subhedar, Nishikant

    2003-10-01

    The reproductive biology of the Indian major carp Cirrhinus mrigala is tightly synchronized with the seasonal changes in the environment. While the ovaries show growth from February through June, the fish spawn in July-August to coincide with the monsoon; thereafter the fish pass into the postspawning and resting phases. We investigated the pattern of GnRH immunoreactivity in the olfactory system at regular intervals extending over a period of 35 months. Although no signal was detected in the olfactory organ of fish collected from April through February following year, distinct GnRH-like immunoreactivity appeared in the fish collected in March. Intense immunoreactivity was noticed in several olfactory receptor neurons (ORNs) and their axonal fibers as they extend over the olfactory nerve, spread in the periphery of the olfactory bulb (OB), and terminate in the glomerular layer. Strong immunoreactivity was seen in some fascicles of the medial olfactory tracts extending from the OB to the telencephalon. Some neurons of the ganglion cells of nervus terminalis showed GnRH immunostaining during March; no immunoreactivity was detected at other times of the year. Plexus of GnRH immunoreactive fibers extending throughout the bulb represented a different component of the olfactory system; the fiber density showed a seasonal pattern that could be related to the status of gonadal maturity. While it was highest in the prespawning phase, significant reduction in the fiber density was noticed in the fish of spawning and the following regressive phases. Taken together the data suggest that the GnRH in the olfactory system of C. mrigala may play a major role in translation of the environmental cues and influence the downstream signals leading to the stimulation of the brain-pituitary-ovary axis.

  16. Different pathways of [3H]inositol phosphate formation mediated by α 1a- and α 1b-adrenergic receptors

    International Nuclear Information System (INIS)

    Wilson, K.M.; Minneman, K.P.

    1990-01-01

    The types of inositol phosphates (InsPs) formed in response to activation of alpha 1-adrenergic receptor subtypes were determined in collagenase-dispersed renal cells and hepatocytes by high pressure liquid chromatography separation. In hepatocytes, which contain only the alpha 1b subtype, norepinephrine stimulated rapid (10-s) formation of [3H]Ins(1,4,5)P3 and [3H]Ins(1,3,4)P3 and slower (5-min) formation of Ins(1,4)P2 and Ins(1)P. Selective inactivation of alpha 1b receptors by chloroethylclonidine almost completely blocked the effects of norepinephrine in hepatocytes. In renal cells, which contain both alpha 1a and alpha 1b receptors in a 60:40 ratio, norepinephrine did not significantly increase the size of any peaks until 5 min after agonist activation. At this time, only a peak eluting with Ins(1)P and one eluting shortly after Ins(1,4)P2 were significantly elevated. Incubation with norepinephrine for 2 h caused small but significant increases in peaks co-eluting with Ins(1)P and Ins(1,4,5)P3 in renal cells; however, only the increase in Ins(1)P was inhibited by chloroethylclonidine pretreatment. Extraction under neutral conditions suggested that cyclic InsPs may be the primary compounds formed in response to norepinephrine in renal cells. Removal of extracellular Ca2+ caused a 60% reduction in the InsP response to norepinephrine in renal cells but had no effect in hepatocytes. These results suggest that activation of alpha 1a and alpha 1b receptor subtypes results in formation of different InsPs and that the response to alpha 1a activation may require influx of extracellular Ca2+

  17. Beta adrenergic receptors in dog heart characterised in vivo by sup 11 C-CGP 12117 and positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Seto, Mikito [Kanazawa Univ. (Japan). School of Medicine

    1989-06-01

    Beta adrenergic receptors in the dog heart were demonstrated in vivo using a potent antagonist, {sup 11}C-CGP 12117 (Kd=0.2 nmol/kg, in vitro), and positron emission tomography (PET). {sup 11}C-CGP at a high specific radioactivity (approximately 500 Ci/mmol) was intravenously injectd in dogs. Axial transverse slices of the heart were obtained. The concentration of {sup 11}C-CGP 12177 in the myocardium rapidly increased and then remained nearly constant for about 30 minutes, before decreasing slowly. Designing a new method to distinguish specific receptor binding from the total ligand concentration in the heart measured by PET, beta adrenoceptor density in the dog myocardium (Bmax) was found to be 113 pmol/cm{sup 3}. Displacement and pre-saturation studies were performed to demonstrate the specifity of {sup 11}C-CGP 12177 binding for noradrenaline binding sites. The bolus injection of unlabeled CGP 12177 25 min following {sup 11}C-CGP 12177 injection led to a rapid decrease in the myocardial ligand concentration and a rapid fall in the heart rate. Both the pharmacological effect of CGP 12177 and the binding inhibition of radioligand were synchronous with the increasing amount of antagonist injected for displacement. In experiments of presaturation with an excessive dose of unlabeled antagonist injection 10 min before {sup 11}C-CGP 12177 injection, the heart/blood radioligand concentration ratio as a function of time was significantly lower than that in the control study. Thus, specific receptor binding of {sup 11}C-CGP 12177 for noradrenaline binding sites in the living heart was proved by PET, which might be the ideal method to study the physiologically active form of receptors in vivo. (author).

  18. Reduced Numbers of Somatostatin Receptors in the Cerebral Cortex in Alzheimer's Disease

    Science.gov (United States)

    Flint Beal, M.; Mazurek, Michael F.; Tran, Vinh T.; Chattha, Geetinder; Bird, Edward D.; Martin, Joseph B.

    1985-07-01

    Somatostatin receptor concentrations were measured in patients with Alzheimer's disease and controls. In the frontal cortex (Brodmann areas 6, 9, and 10) and temporal cortex (Brodmann area 21), the concentrations of somatostatin in receptors in the patients were reduced to approximately 50 percent of control values. A 40 percent reduction was seen in the hippocampus, while no significant changes were found in the cingulate cortex, postcentral gyrus, temporal pole, and superior temporal gyrus. Scatchard analysis showed a reduction in receptor number rather than a change in affinity. Somatostatin-like immunoreactivity was significantly reduced in both the frontal and temporal cortex. Somatostatin-like immunoreactivity was linearly related to somatostatin-receptor binding in the cortices of Alzheimer's patients. These findings may reflect degeneration of postsynaptic neurons or cortical afferents in the patients' cerebral cortices. Alternatively, decreased somatostatinlike immunoreactivity in Alzheimer's disease might indicate increased release of somatostatin and down regulation of postsynaptic receptors.

  19. Early postnatal maternal separation causes alterations in the expression of β3-adrenergic receptor in rat adipose tissue suggesting long-term influence on obesity

    International Nuclear Information System (INIS)

    Miki, Takanori; Liu, Jun-Qian; Ohta, Ken-ichi; Suzuki, Shingo; Kusaka, Takashi; Warita, Katsuhiko; Yokoyama, Toshifumi; Jamal, Mostofa; Ueki, Masaaki; Yakura, Tomiko; Tamai, Motoki; Sumitani, Kazunori; Hosomi, Naohisa; Takeuchi, Yoshiki

    2013-01-01

    Highlights: •High-fat diet intake following maternal separation did not cause body weight gain. •However, levels of metabolism-related molecules in adipose tissue were altered. •Increased levels of prohibitin mRNA in white fat were observed. •Attenuated levels of β3-adrenergic receptor mRNA were observed in brown fat. •Such alterations in adipose tissue may contribute to obesity later in life. -- Abstract: The effects of early postnatal maternal deprivation on the biological characteristics of the adipose tissue later in life were investigated in the present study. Sprague–Dawley rats were classified as either maternal deprivation (MD) or mother-reared control (MRC) groups. MD was achieved by separating the rat pups from their mothers for 3 h each day during the 10–15 postnatal days. mRNA levels of mitochondrial uncoupling protein 1 (UCP-1), β3-adrenergic receptor (β3-AR), and prohibitin (PHB) in the brown and white adipose tissue were determined using real-time RT-PCR analysis. UCP-1, which is mediated through β3-AR, is closely involved in the energy metabolism and expenditure. PHB is highly expressed in the proliferating tissues/cells. At 10 weeks of age, the body weight of the MRC and MD rats was similar. However, the levels of the key molecules in the adipose tissue were substantially altered. There was a significant increase in the expression of PHB mRNA in the white adipose tissue, while the β3-AR mRNA expression decreased significantly, and the UCP-1 mRNA expression remained unchanged in the brown adipose tissue. Given that these molecules influence the mitochondrial metabolism, our study indicates that early postnatal maternal deprivation can influence the fate of adipose tissue proliferation, presumably leading to obesity later in life

  20. Early postnatal maternal separation causes alterations in the expression of β3-adrenergic receptor in rat adipose tissue suggesting long-term influence on obesity

    Energy Technology Data Exchange (ETDEWEB)

    Miki, Takanori, E-mail: mikit@med.kagawa-u.ac.jp [Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University (Japan); Liu, Jun-Qian; Ohta, Ken-ichi; Suzuki, Shingo [Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University (Japan); Kusaka, Takashi [Department of Pediatrics, Faculty of Medicine, Kagawa University (Japan); Warita, Katsuhiko [Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University (Japan); Yokoyama, Toshifumi [Department of Bioresource and Agrobiosciences, Graduate School of Science and Technology, Kobe University (Japan); Jamal, Mostofa [Department of Forensic Medicine, Faculty of Medicine, Kagawa University (Japan); Ueki, Masaaki [Department of Anesthesia, Nishiwaki Municipal Hospital (Japan); Yakura, Tomiko; Tamai, Motoki [Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University (Japan); Sumitani, Kazunori [Department of Medical Education, Faculty of Medicine, Kagawa University (Japan); Hosomi, Naohisa [Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical Sciences (Japan); Takeuchi, Yoshiki [Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University (Japan)

    2013-12-06

    Highlights: •High-fat diet intake following maternal separation did not cause body weight gain. •However, levels of metabolism-related molecules in adipose tissue were altered. •Increased levels of prohibitin mRNA in white fat were observed. •Attenuated levels of β3-adrenergic receptor mRNA were observed in brown fat. •Such alterations in adipose tissue may contribute to obesity later in life. -- Abstract: The effects of early postnatal maternal deprivation on the biological characteristics of the adipose tissue later in life were investigated in the present study. Sprague–Dawley rats were classified as either maternal deprivation (MD) or mother-reared control (MRC) groups. MD was achieved by separating the rat pups from their mothers for 3 h each day during the 10–15 postnatal days. mRNA levels of mitochondrial uncoupling protein 1 (UCP-1), β3-adrenergic receptor (β3-AR), and prohibitin (PHB) in the brown and white adipose tissue were determined using real-time RT-PCR analysis. UCP-1, which is mediated through β3-AR, is closely involved in the energy metabolism and expenditure. PHB is highly expressed in the proliferating tissues/cells. At 10 weeks of age, the body weight of the MRC and MD rats was similar. However, the levels of the key molecules in the adipose tissue were substantially altered. There was a significant increase in the expression of PHB mRNA in the white adipose tissue, while the β3-AR mRNA expression decreased significantly, and the UCP-1 mRNA expression remained unchanged in the brown adipose tissue. Given that these molecules influence the mitochondrial metabolism, our study indicates that early postnatal maternal deprivation can influence the fate of adipose tissue proliferation, presumably leading to obesity later in life.

  1. Dwarfism and insulin resistance in male offspring caused by α1-adrenergic antagonism during pregnancy.

    Science.gov (United States)

    Oelkrug, Rebecca; Herrmann, Beate; Geissler, Cathleen; Harder, Lisbeth; Koch, Christiane; Lehnert, Hendrik; Oster, Henrik; Kirchner, Henriette; Mittag, Jens

    2017-10-01

    Maternal and environmental factors control the epigenetic fetal programming of the embryo, thereby defining the susceptibility for metabolic or endocrine disorders in the offspring. Pharmacological interventions required as a consequence of gestational problems, e.g. hypertension, can potentially interfere with correct fetal programming. As epigenetic alterations are usually only revealed later in life and not detected in studies focusing on early perinatal outcomes, little is known about the long-term epigenetic effects of gestational drug treatments. We sought to test the consequences of maternal α1-adrenergic antagonism during pregnancy, which can occur e.g. during hypertension treatment, for the endocrine and metabolic phenotype of the offspring. We treated C57BL/6NCrl female mice with the α1-adrenergic antagonist prazosin during pregnancy and analyzed the male and female offspring for endocrine and metabolic abnormalities. Our data revealed that maternal α1-adrenergic blockade caused dwarfism, elevated body temperature, and insulin resistance in male offspring, accompanied by reduced IGF-1 serum concentrations as the result of reduced hepatic growth hormone receptor (Ghr) expression. We subsequently identified increased CpG DNA methylation at the transcriptional start site of the alternative Ghr promotor caused by the maternal treatment, which showed a strong inverse correlation to hepatic Ghr expression. Our results demonstrate that maternal α1-adrenergic blockade can constitute an epigenetic cause for dwarfism and insulin resistance. The findings are of immediate clinical relevance as combined α/β-adrenergic blockers are first-line treatment of maternal hypertension. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

  2. Endothelin in human brain and pituitary gland: Presence of immunoreactive endothelin, endothelin messenger ribonucleic acid, and endothelin receptors

    International Nuclear Information System (INIS)

    Takahashi, K.; Ghatei, M.A.; Jones, P.M.; Murphy, J.K.; Lam, H.C.; O'Halloran, D.J.; Bloom, S.R.

    1991-01-01

    The presence of immunoreactive (IR) endothelin, endothelin mRNA, and endothelin receptors in human brain and pituitary gland has been studied by RIA, Northern blot hybridization, and receptor assay. IR endothelin was detected in all five brain regions examined (cerebral cortex, cerebellum, brain stem, basal ganglia, and hypothalamus) (6-10 fmol/g wet wt) and spinal cord (22 +/- 6 fmol/g wet wt, n = 7, mean +/- SEM). Higher concentrations of IR endothelin were found in the pituitary gland (147 +/- 30 fmol/g wet wt). Fast protein liquid chromatographic analysis of the IR endothelin in pituitary gland showed a large IR peak in the position of endothelin-3 and a smaller peak in the position of endothelin-1, whereas IR endothelin in the hypothalamus and brain stem was mainly endothelin-1. Endothelin messenger RNA was detected by Northern blot hybridization in the pituitary but not in hypothalamus. The receptor assay showed that 125I-endothelin-1 binding sites were present in large numbers in all five brain regions but were much less abundant in the pituitary gland. Binding capacity and dissociation constant were 5052 +/- 740 fmol/mg protein and 0.045 +/- 0.007 nM in brain stem and 963 +/- 181 fmol/mg protein and 0.034 +/- 0.009 nM in hypothalamus. In the pituitary gland, there were two classes of binding sites for endothelin with dissociation constants of 0.059 +/- 0.002 nM (binding capacity = 418 +/- 63 fmol/mg protein) and 0.652 +/- 0.103 nM (binding capacity = 1717 +/- 200 fmol/mg protein). Endothelin-1, -2 and -3 were almost equipotent in displacing the binding (IC50 approximately 0.04 nM). These findings are in accord with the possibility that endothelin acts as a neurotransmitter, neuromodulator or neurohormone in man

  3. Enhanced Y1-receptor-mediated vasoconstrictive action of neuropeptide Y (NPY) in superior mesenteric arteries in portal hypertension.

    Science.gov (United States)

    Wiest, Reiner; Jurzik, Lars; Moleda, Lukas; Froh, Matthias; Schnabl, Bernd; von Hörsten, Stephan; Schölmerich, Juergen; Straub, Rainer H

    2006-03-01

    Vascular hyporeactivity to catecholamines contributes to arterial vasodilation and hemodynamic dysregulation in portal hypertension. Neuropeptide Y (NPY) is a sympathetic neurotransmitter facilitating adrenergic vasoconstriction via Y1-receptors on the vascular smooth muscle. Therefore, we investigated its role for vascular reactivity in the superior mesenteric artery (SMA) of portal vein ligated (PVL) and sham operated rats. In vitro perfused SMA vascular beds of rats were tested for the cumulative dose-response to NPY dependent on the presence and level of alpha1-adrenergic vascular tone (methoxamine MT: 0.3-10 microM). Moreover, the effect of NPY (50 nM) on vascular responsiveness to alpha1-adrenergic stimulation (MT: 0.3-300 microM) was evaluated. Y1-receptor function was tested by Y1-selective inhibition using BIBP-3226 (1 microM). NPY dose-dependently and endothelium-independently enhanced MT-pre-constriction in SMA. This potentiation was increasingly effective with increasing adrenergic pre-stimulation and being more pronounced in PVL rats as compared to sham rats at high MT concentrations. NPY enhanced vascular contractility only in PVL rats correcting the adrenergic vascular hyporeactivity. Y1-receptor inhibition completely abolished NPY-evoked vasoconstrictive effects. NPY endothelium-independently potentiates adrenergic vasoconstriction via Y1-receptors being more pronounced in portal hypertension improving mesenteric vascular contractility and thereby correcting the splanchnic vascular hyporeactivity. This makes NPY a superior vasoconstrictor counterbalancing arterial vasodilation in portal hypertension.

  4. Development of antibodies against the rat brain somatostatin receptor.

    Science.gov (United States)

    Theveniau, M; Rens-Domiano, S; Law, S F; Rougon, G; Reisine, T

    1992-05-15

    Somatostatin (SRIF) is a neurotransmitter in the brain involved in the regulation of motor activity and cognition. It induces its physiological actions by interacting with receptors. We have developed antibodies against the receptor to investigate its structural properties. Rabbit polyclonal antibodies were generated against the rat brain SRIF receptor. These antibodies (F4) were able to immunoprecipitate solubilized SRIF receptors from rat brain and the cell line AtT-20. The specificity of the interaction of these antibodies with SRIF receptors was further demonstrated by immunoblotting. F4 detected SRIF receptors of 60 kDa from rat brain and adrenal cortex and the cell lines AtT-20, GH3, and NG-108, which express high densities of SRIF receptors. They did not detect immunoreactive material from rat liver or COS-1, HEPG, or CRL cells, which do not express functional SRIF receptors. In rat brain, 60-kDa immunoreactivity was detected by F4 in the hippocampus, cerebral cortex, and striatum, which have high densities of SRIF receptors. However, F4 did not interact with proteins from cerebellum and brain stem, which express few SRIF receptors. Immunoreactive material cannot be detected in rat pancreas or pituitary, which have been reported to express a 90-kDa SRIF receptor subtype. The selective detection of 60-kDa SRIF receptors by F4 indicates that the 60- and 90-kDa SRIF receptor subtypes are immunologically distinct. The availability of antibodies that selectively detect native and denatured brain SRIF receptors provides us with a feasible approach to clone the brain SRIF receptor gene(s).

  5. Protocol for evaluating Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension

    OpenAIRE

    sprotocols

    2015-01-01

    Authors: ShengYu Mu, Tatsuo Shimosawa & Toshiro Fujita ### Abstract In the current study, we found that β2 adrenergic receptor (β2AR) stimulation induced histone acetylation through HDAC8 inhibition, and then decreased transcription of the WNK4 gene by enhancing the binding of glucocorticoid receptor (GR) and negative-GR-responsive-element (nGRE) in WNK4 promoter region. Infusion of isoproterenol decreased WNK4 expression and activated the Na+-Cl- co-transporter in mice, which develop...

  6. Morphological Features of Tyrosine Hydroxylase Immunoreactive ...

    African Journals Online (AJOL)

    The current immunohistochemical study used the antibody against tyrosine hydroxylase (TH) to observe the immunoreactive elements in the mouse pancreas. The results indicated the presence of immunoreactive nerve fibers and endocrine cells. The immunopositive nerve fibers appeared as thick and thin bundles; thick ...

  7. Synthesis of [{sup 18}F]-labelled nebivolol as a β{sub 1}-adrenergic receptor antagonist for PET imaging agent

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Taek Soo; Park, Jeong Hoon; Lee, Jun Young; Yang, Seung Dae [Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute (KAERI), Jeongeup (Korea, Republic of); Chang, Dong Jo [College of pharmacy, Sunchon National University, Suncheon (Korea, Republic of)

    2017-02-15

    Selective β{sub 1}-agonist and antagonists are used for the treatment of cardiac diseases including congestive heart failure, angina pectoris and arrhythmia. Selective β{sub 1}-antagonists including nebivolol have high binding affinity on β{sub 1}-adrenergic receptor, not β{sub 2}-receptor mainly expressed in smooth muscle. Nebivolol is one of most selective β{sub 1}-blockers in clinically used β{sub 1}- blockers including atenolol and bisoprolol. We tried to develop clinically useful cardiac PET tracers using a selective β{sub 1}-blocker. Nebivolol is C{sub 2}-symmetric and has two chromane moiety with a secondary amino alcohol and aromatic fluorine. We adopted the general synthetic strategy using epoxide ring opening reaction. Unlike formal synthesis of nebivolol, we prepared two chromane building blocks with fluorine and iodine which was transformed to diaryliodonium salt for labelling of {sup 18}F. Two epoxide building blocks were readily prepared from commercially available chromene carboxylic acids (1, 8). Then, the amino alcohol building block (15) was prepared by ammonolysis of epoxide (14) followed by coupling reaction with the other building block, epoxide (7). Diaryliodonium salt, a precursor for {sup 18}F-aromatic substitution, was synthesized in moderate yield which was readily subjected to {sup 18}F-aromatic substitution to give {sup 18}F-labelled nebivolol.

  8. Characterization of beta-adrenergic receptors and adenylate cyclase activity in rat brown fat

    International Nuclear Information System (INIS)

    Baresi, L.A.; Morley, J.E.; Scarpace, P.J.

    1986-01-01

    Catecholamines stimulate thermogenesis in rat brown fat through a mechanism which involves binding to the beta-adrenergic receptor (BAR), stimulation of adenylate cyclase (AC) and culminating with uncoupling of mitochondrial respiration from ATP synthesis. The authors characterized BAR, AC and cytochrome (cyt) c oxidase in CDF (F-344) interscapular brown fat. Scatchard analysis of [ 125 ]Iodopindolol binding yields a straight line consistent with a single class of antagonist binding sites with 41.8 +/- 12.0 fmol BAR/mg protein and a K/sub d/ of 118 +/- 15 pM. Binding was both specific and stereospecific. Competition with 1-propranolol (K/sub d/ = 6.7 nM) was 15 times more potent than d-propranolol (K/sub d/ = 103 nM). Competition with isoproterenol (K/sub d/ = 79 nM) was 10 times more potent than epinephrine (K/sub d/ = 820 nM) which was 35 times more potent than norepinephrine (K/sub d/ = 2.9 x 10 -5 M) suggesting predominate beta 2 -type BAR. Cyt c oxidase activity was assessed in brown fat mitochrondrial preparations. The ratio of BAR to cyt c activity was 959 +/- 275 nmol BAR/mol cyc c/min. Isoproterenol (0.1 mM) stimulated AC activity was 24 times GTP (0.1 mM) stimulated AC (98.5 vs 40.7 pmol cAMP/min/mg). NaF-stimulated AC was nine times basal activity (90.5 vs 11.3 pmol cAMP/min/mg). These data demonstrate the presence of a beta- 2 -type BAR coupled to adenylate cyclase in rat brown fat

  9. G Protein-coupled Receptor Kinases of the GRK4 Protein Subfamily Phosphorylate Inactive G Protein-coupled Receptors (GPCRs).

    Science.gov (United States)

    Li, Lingyong; Homan, Kristoff T; Vishnivetskiy, Sergey A; Manglik, Aashish; Tesmer, John J G; Gurevich, Vsevolod V; Gurevich, Eugenia V

    2015-04-24

    G protein-coupled receptor (GPCR) kinases (GRKs) play a key role in homologous desensitization of GPCRs. It is widely assumed that most GRKs selectively phosphorylate only active GPCRs. Here, we show that although this seems to be the case for the GRK2/3 subfamily, GRK5/6 effectively phosphorylate inactive forms of several GPCRs, including β2-adrenergic and M2 muscarinic receptors, which are commonly used as representative models for GPCRs. Agonist-independent GPCR phosphorylation cannot be explained by constitutive activity of the receptor or membrane association of the GRK, suggesting that it is an inherent ability of GRK5/6. Importantly, phosphorylation of the inactive β2-adrenergic receptor enhanced its interactions with arrestins. Arrestin-3 was able to discriminate between phosphorylation of the same receptor by GRK2 and GRK5, demonstrating preference for the latter. Arrestin recruitment to inactive phosphorylated GPCRs suggests that not only agonist activation but also the complement of GRKs in the cell regulate formation of the arrestin-receptor complex and thereby G protein-independent signaling. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Non-selective beta-adrenergic blockade prevents reduction of the cerebral metabolic ratio during exhaustive exercise in humans

    DEFF Research Database (Denmark)

    Larsen, T.S.; Rasmussen, P.; Overgaard, M.

    2008-01-01

    Intense exercise decreases the cerebral metabolic ratio of oxygen to carbohydrates [O(2)/(glucose + (1/2)lactate)], but whether this ratio is influenced by adrenergic stimulation is not known. In eight males, incremental cycle ergometry increased arterial lactate to 15.3 +/- 4.2 mm (mean +/- s.......d.) and the arterial-jugular venous (a-v) difference from -0.02 +/- 0.03 mm at rest to 1.0 +/- 0.5 mm (P cerebral metabolic ratio decreased from 5.5 +/- 1.4 to 3.0 +/- 0.3 (P ... of a non-selective beta-adrenergic (beta(1) + beta(2)) receptor antagonist (propranolol) reduced heart rate (69 +/- 8 to 58 +/- 6 beats min(-1)) and exercise capacity (239 +/- 42 to 209 +/- 31 W; P

  11. In vivo autoradiographic demonstration of β-adrenergic binding sites in adult rat type II alveolar epithelial cells

    International Nuclear Information System (INIS)

    Smith, D.M.; Sidhu, M.K.

    1984-01-01

    Adult male rats were injected intravenously with the muscarinic binding probe 3 H-Quinuclidinyl benzilate (QNB) or the β-adrenergic probe 3 H-dihydroalprenolol (DHA). Other rats were pre-treated with an intraperitoneal injection of a 500-fold excess of L-isoproterenol prior to the DHA. Light microscopic autoradiography of 0.5 μm sections of lung from the QNB group demonstrated very little labelling even after 6 months of exposure. In constrast, trachealis smooth muscle from these animals contained substantial labelling. Autoradiographs of lung from rats injected with DHA demonstrated labelling which was well localized over alveolar septa and concentrated over the cytoplasm of type II cells. Quantitative analysis of labelling in the DHA groups indicated a significant reduction of labelling in animals treated with L-isoproterenol prior to DHA, in both the alveolar parenchyma in general and over type II cells. The results of this study provide morphologic evidence for the uptake and specific binding of β-adrenergic antagonists by the adult lung in vivo, while failing to demonstrate similar binding of a muscarinic probe. In addition, the results demonstrate specific β-adrenergic receptors on type II cells in vivo and substantiate the view of a direct effect of β-adrenergic agonists on alveolar type II cells

  12. Sexual behavior reduces hypothalamic androgen receptor immunoreactivity

    NARCIS (Netherlands)

    Fernandez-Guasti, Alonso; Swaab, Dick; Rodríguez-Manzo, Gabriela

    2003-01-01

    Male sexual behavior is regulated by limbic areas like the medial preoptic nucleus (MPN), the bed nucleus of the stria terminalis (BST), the nucleus accumbens (nAcc) and the ventromedial hypothalamic nucleus (VMN). Neurons in these brain areas are rich in androgen receptors (AR) and express

  13. Molecular Mechanisms Underlying β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells

    Directory of Open Access Journals (Sweden)

    Dianne Lorton

    2015-03-01

    Full Text Available Cross-talk between the sympathetic nervous system (SNS and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs in immune cells activates the cAMP-protein kinase A (PKA intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune–SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP–PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP–PKA to mitogen-activated protein kinase (MAPK pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for “signal switching” in immune cells.

  14. Cardiac voltage gated calcium channels and their regulation by β-adrenergic signaling.

    Science.gov (United States)

    Kumari, Neema; Gaur, Himanshu; Bhargava, Anamika

    2018-02-01

    Voltage-gated calcium channels (VGCCs) are the predominant source of calcium influx in the heart leading to calcium-induced calcium release and ultimately excitation-contraction coupling. In the heart, VGCCs are modulated by the β-adrenergic signaling. Signaling through β-adrenergic receptors (βARs) and modulation of VGCCs by β-adrenergic signaling in the heart are critical signaling and changes to these have been significantly implicated in heart failure. However, data related to calcium channel dysfunction in heart failure is divergent and contradictory ranging from reduced function to no change in the calcium current. Many recent studies have highlighted the importance of functional and spatial microdomains in the heart and that may be the key to answer several puzzling questions. In this review, we have briefly discussed the types of VGCCs found in heart tissues, their structure, and significance in the normal and pathological condition of the heart. More importantly, we have reviewed the modulation of VGCCs by βARs in normal and pathological conditions incorporating functional and structural aspects. There are different types of βARs, each having their own significance in the functioning of the heart. Finally, we emphasize the importance of location of proteins as it relates to their function and modulation by co-signaling molecules. Its implication on the studies of heart failure is speculated. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. The adrenergic alpha2 receptor and sexual incentive motivation in male rats.

    Science.gov (United States)

    Viitamaa, Timo; Haapalinna, Antti; Agmo, Anders

    2006-03-01

    The purpose of the present series of experiments was to determine whether drugs acting at the alpha2-adrenoceptor modify unconditioned sexual incentive motivation in the male rat. To that end a highly specific agonist, dexmedetomidine, a corresponding antagonist, atipamezole, and a less specific antagonist, yohimbine, were administered to groups of sexually inexperienced male rats. The subjects were tested in a large rectangular arena, where a sexually receptive female and an intact male were employed as incentives. The incentive animals were confined behind a wire mesh in opposite corners of the arena. The animals could see, hear and smell each other, but no sexual interaction was possible. Approach to the incentives constituted the measure of incentive motivation. In addition, the test provided data on ambulatory activity and general arousal. Dexmedetomidine, at a dose of 8 microg/kg, produced a slight reduction of sexual incentive motivation. Ambulatory activity and general arousal were also inhibited. Atipamezole, in doses of 0.1 and 0.3mg/kg enhanced the positive incentive properties of the receptive female. A high dose of 1mg/kg did not have any significant effect. Ambulatory activity was slightly reduced by the two larger doses of atipamezole. Yohimbine had a slight stimulatory effect on sexual incentive motivation at a dose (4 mg/kg) that also reduced ambulatory activity and general arousal. It is concluded that blockade of the adrenergic alpha2 receptor stimulates sexual incentive motivation in the male rat whereas stimulation of it has the opposite effect. At present it is not clear if these drug effects are caused by pre- or postsynaptic actions of the drugs, and the importance of secondary changes in other neurotransmitter systems remains unknown.

  16. Alpha-Amylase Activity in Blood Increases after Pharmacological, But Not Psychological, Activation of the Adrenergic System.

    Directory of Open Access Journals (Sweden)

    Urs M Nater

    Full Text Available Alpha-amylase in both blood and saliva has been used as a diagnostic parameter. While studies examining alpha-amylase activity in saliva have shown that it is sensitive to physiological and psychological challenge of the adrenergic system, no challenge studies have attempted to elucidate the role of the adrenergic system in alpha-amylase activity in blood. We set out to examine the impact of psychological and pharmacological challenge on alpha-amylase in blood in two separate studies.In study 1, healthy subjects were examined in a placebo-controlled, double-blind paradigm using yohimbine, an alpha2-adrenergic antagonist. In study 2, subjects were examined in a standardized rest-controlled psychosocial stress protocol. Alpha-amylase activity in blood was repeatedly measured in both studies.Results of study 1 showed that alpha-amylase in blood is subject to stronger increases after injection of yohimbine compared to placebo. In study 2, results showed that there was no significant effect of psychological stress compared to rest.Alpha-amylase in blood increases after pharmacological activation of the adrenergic pathways suggesting that sympathetic receptors are responsible for these changes. Psychological stress, however, does not seem to have an impact on alpha-amylase in blood. Our findings provide insight into the mechanisms underlying activity changes in alpha-amylase in blood in healthy individuals.

  17. Immunoreactive transforming growth factor alpha and epidermal growth factor in oral squamous cell carcinomas

    DEFF Research Database (Denmark)

    Therkildsen, M H; Poulsen, Steen Seier; Bretlau, P

    1993-01-01

    Forty oral squamous cell carcinomas have been investigated immunohistochemically for the presence of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF). The same cases were recently characterized for the expression of EGF-receptors. TGF-alpha was detected...... previous results confirms the existence of TGF-alpha, EGF, and EGF-receptors in the majority of oral squamous cell carcinomas and their metastases......., the cells above the basal cell layer were positive for both TGF-alpha and EGF. The same staining pattern was observed in oral mucosa obtained from healthy persons. In moderately to well differentiated carcinomas, the immunoreactivity was mainly confined to the cytologically more differentiated cells, thus...

  18. Adrenergic blockade in diabetic and uninephrectomized rats

    DEFF Research Database (Denmark)

    Thulesen, J; Poulsen, Steen Seier; Jørgensen, P E

    1999-01-01

    The present study reports on the effects of adrenergic blocking agents on the renal growth and on the renal content and urinary excretion of epidermal growth factor (EGF) in streptozotocin-induced diabetic or uninephrectomized rats. Diabetic and uninephrectomized rats were allocated to groups...... treated with either saline or adrenergic antagonists and compared to controls and sham-operated controls, respectively. 24-hour urine samples were obtained on days 7, 14, and 21 and renal tissue samples on day 21. The 24-hour urinary excretion of EGF from controls and saline-treated diabetic rats...... was comparable. In adrenergic antagonist treated diabetic rats, it was reduced by at least 40% throughout the study period. Uninephrectomy caused a 50% reduction in the urinary excretion of EGF. This was not influenced by treatment with an adrenergic antagonist. After 3 weeks, saline-treated diabetic rats had...

  19. Osmotic versus adrenergic control of ion transport by ionocytes of Fundulus heteroclitus in the cold.

    Science.gov (United States)

    Tait, Janet C; Mercer, Evan W; Gerber, Lucie; Robertson, George N; Marshall, William S

    2017-01-01

    In eurythermic vertebrates, acclimation to the cold may produce changes in physiological control systems. We hypothesize that relatively direct osmosensitive control will operate better than adrenergic receptor mediated control of ion transport in cold vs. warm conditions. Fish were acclimated to full strength seawater (SW) at 21°C and 5°C for four weeks, gill samples and blood were taken and opercular epithelia mounted in Ussing style chambers. Short-circuit current (I sc ) at 21°C and 5°C (measured at acclimation temperature), was significantly inhibited by the α 2 -adrenergic agonist clonidine but the ED 50 dose was significantly higher in cold conditions (93.8±16.4nM) than in warm epithelia (47.8±8.1nM) and the maximum inhibition was significantly lower in cold (-66.1±2.2%) vs. warm conditions (-85.6±1.3%), indicating lower sensitivity in the cold. β-Adrenergic responses were unchanged. Hypotonic inhibition of I sc , was higher in warm acclimated (-95%), compared to cold acclimated fish (-75%), while hypertonic stimulations were the same, indicating equal responsiveness to hyperosmotic stimuli. Plasma osmolality was significantly elevated in cold acclimated fish and, by TEM, gill ionocytes from cold acclimated fish had significantly shorter mitochondria. These data are consistent with a shift in these eurythermic animals from complex adrenergic control to relatively simple biomechanical osmotic control of ion secretion in the cold. Copyright © 2016. Published by Elsevier Inc.

  20. White-matter connectivity and methylphenidate-induced changes in attentional performance according to α2A-adrenergic receptor gene polymorphisms in Korean children with attention-deficit hyperactivity disorder.

    Science.gov (United States)

    Park, Subin; Hong, Soon-Beom; Kim, Jae-Won; Yang, Young-Hui; Park, Min-Hyeon; Kim, Boong-Nyun; Shin, Min-Sup; Yoo, Hee-Jeong; Cho, Soo-Churl

    2013-01-01

    The authors examined the association between the MspI C/G and DraI C/T genotypes of the α2A-adrenergic receptor gene and white-matter connectivity and attentional performance before and after medication in 53 children with attention-deficit hyperactivity disorder. Subjects who carried the T allele at the DraI polymorphism showed fewer changes in the mean commission error scores after 8 weeks of medication and decreased fractional anisotropy (FA) values in the right middle frontal cortex than subjects without the T allele. Subjects with the C allele at the MspI polymorphism showed decreased FA values in the right postcentral gyrus than subjects without.

  1. Neural modulation of salt secretion in teleostopercular epithelium by 2-adrenergic receptors and inositol 1,4,5-trisphosphate

    Science.gov (United States)

    Marshall; Duquesnay; Gillis; Bryson; Liedtke

    1998-05-21

    Opercular epithelia from seawater-adapted killifish (Fundulus heteroclitus) were dissected with the nerve intact, mounted in Ussing-style membrane chambers and bathed in symmetrical saline solutions. Nerve stimulation rapidly inhibited transepithelial current (a measure of Cl- secretion rate) by 27.3+/-3.3 % (N=22), and the effect could be sustained for more than 10 min using intermittent pulse trains at 10 Hz. The effect was blocked in a dose-dependent manner by yohimbine, but not by propranolol, atropine or tubocurarine, indicating mediation by 2-adrenergic receptors. The effect was also present, but significantly diminished, in opercular membranes from animals that had been transferred to sea water for 48 h (18+/-8.6 % inhibition, N=14). The resting current and the effect were absent in membranes from freshwater-adapted animals. The addition of clonidine (1.0 micromol l-1 serosal side) started to inhibit Cl- current after 40-60 s; immediately before this, at 30 s, there was a significant rise (Plevel, but no change at later times, compared with LiCl-treated control membranes and measured by radiolabeled receptor assay. The results indicate that seawater-adapted killifish can decrease their Cl- secretion rate through the action of the sympathetic nervous system, a response appropriate for the entry of estuarine fish to fresh water, and that the effect is mediated by 2-adrenoceptors via InsP3. The results imply that euryhaline fish entering fresh water can undergo an autonomic reflex reduction in salt secretion that does not require a stress response.

  2. Reversible exacerbation of obstructive sleep apnea by α1-adrenergic blockade with tamsulosin: A case report.

    Science.gov (United States)

    Moran, Mark

    2016-01-01

    Obstructive sleep apnea (OSA) is characterized by repeated involuntary closure of the pharyngeal airspace during sleep. Normal activity of the genioglossus (GG) muscle is important in maintaining airway patency, and inhibition of GG activity can contribute to airway closure. Neurons in the hypoglossal motor nucleus (HMN) regulate GG activity. Adrenergic tone is an important regulator of HMN neuronal excitability. In laboratory models α 1 -adrenergic antagonists inhibit HMN neurons and GG activity, suggesting that α 1 -adrenergic antagonism might adversely affect patients with OSA. To date there has been no report of such a case. The patient was a 67-year old man with a 27-month history of obstructive sleep apnea. Diagnostic polysomnography demonstrated a baseline apnea-hypopnea index (AHI) of 21.3 and a trough oxygen saturation of 84%. Treatment with continuous positive airway pressure (CPAP) was initiated. The AHI in year 1 averaged 1.0 ± 0.1 (mean ± SD) and 0.8 ± 0.1 in year 2. Other medical conditions included hypertension controlled with losartan and benign prostatic hypertrophy not well controlled by finasteride monotherapy. The α 1 -adrenergic receptor antagonist tamsulosin 0.4 mg daily was added. Shortly after initiation of tamsulosin, subjective sleep quality deteriorated. Significant surges in obstructive events, apneic episodes, and AHI were also recorded, and nocturnal airway pressure was frequently sustained at the CPAP device maximum of 20 cm H 2 O. Tamsulosin was discontinued. CPAP parameters and sleep quality returned to the pre-tamsulosin baselines within 10 days. These findings suggest that α 1 -adrenergic blockade with tamsulosin may exacerbate sleep-disordered breathing in susceptible patients.

  3. Alpha 1-adrenergic stimulation of phosphatidylinositol turnover and respiration of brown fat cells

    International Nuclear Information System (INIS)

    Mohell, N.; Wallace, M.; Fain, J.N.

    1984-01-01

    The alpha-adrenergic agonist phenylephrine (in the presence of the beta-adrenergic antagonist alprenolol) stimulated respiration and incorporation of [ 3 H]glycerol and [ 32 P] P/sub i/ into phosphatidylinositol of hamster brown fat cells in a concentration-dependent manner. Both responses were preferentially inhibited by prazosin as compared with yohimbine, indicating alpha 1 specificity. Uniquely, prazosin inhibition of phenylephrine-stimulated phosphatidylinositol metabolism had two components, since 30% of the response was inhibited by less than 1 nM prazosin, 10 nM gave no further inhibition, and 100 nM prazosin completely inhibited the response. The phosphatidylinositol response was still present in Ca 2 +-free buffer, although reduced in magnitude. The concentration relationships of the effects of agonists and antagonists were compared with those of previous results of [ 3 H]prazosin binding and with phenylephrine potency to compete for binding. On the basis of these comparisons, it is suggested that the highly prazosin-sensitive part of the phosphatidylinositol response may be closely associated with receptor occupation

  4. Evidence for β-adrenergic modulation of sweating during incremental exercise in habitually trained males.

    Science.gov (United States)

    Amano, Tatsuro; Shitara, Yosuke; Fujii, Naoto; Inoue, Yoshimitsu; Kondo, Narihiko

    2017-07-01

    The aim of the present study was to determine the β-adrenergic contribution to sweating during incremental exercise in habitually trained males. Nine habitually trained and 11 untrained males performed incremental cycling until exhaustion (20 W/min). Bilateral forearm sweat rates (ventilated capsule) were measured at two skin sites that were transdermally administered via iontophoresis with either 1% propranolol (Propranolol, a nonselective β-adrenergic receptor antagonist) or saline (Control). The sweat rate was evaluated as a function of both relative (percentage of maximum workload) and absolute exercise intensities. The sweat rate at the Propranolol site was lower than the control during exercise at 80 (0.57 ± 0.21 and 0.45 ± 0.19 mg·cm -2 ·min -1 for Control and Propranolol, respectively) and 90% (0.74 ± 0.22 and 0.65 ± 0.17 mg·cm -2 ·min -1 , respectively) of maximum workload in trained males (all P 0.05). At the same absolute intensity, higher sweat rates on the control site were observed in trained males relative to the untrained during exercise at 160 (0.23 ± 0.20 and 0.04 ± 0.05 mg·cm -2 ·min -1 for trained and untrained, respectively) and 180 W (0.40 ± 0.20 and 0.13 ± 0.13 mg·cm -2 ·min -1 , respectively) (all P 0.05). We show that the β-adrenergic mechanism does modulate sweating during exercise at a submaximal high relative intensity in habitually trained males. The β-adrenergic mechanism may in part contribute to the greater sweat production in habitually trained males than in untrained counterparts during exercise. NEW & NOTEWORTHY We demonstrated for the first time that the β-adrenergic mechanism does modulate sweating (i.e., β-adrenergic sweating) during exercise using a localized β-adrenoceptor blockade in humans in vivo. β-Adrenergic sweating was evident in habitually trained individuals during exercise at a submaximal high relative intensity (80-90% maximal work). This observation advances

  5. Stress-induced enhancement of mouse amygdalar synaptic plasticity depends on glucocorticoid and ß-adrenergic activity.

    Directory of Open Access Journals (Sweden)

    Ratna Angela Sarabdjitsingh

    Full Text Available BACKGROUND: Glucocorticoid hormones, in interaction with noradrenaline, enable the consolidation of emotionally arousing and stressful experiences in rodents and humans. Such interaction is thought to occur at least partly in the basolateral nucleus of the amygdala (BLA which is crucially involved in emotional memory formation. Extensive evidence points to long-term synaptic potentiation (LTP as a mechanism contributing to memory formation. Here we determined in adolescent C57/Bl6 mice the effects of stress on LTP in the LA-BLA pathway and the specific roles of corticosteroid and β-adrenergic receptor activation in this process. PRINCIPAL FINDINGS: Exposure to 20 min of restraint stress (compared to control treatment prior to slice preparation enhanced subsequent LTP induction in vitro, without affecting baseline fEPSP responses. The role of glucocorticoid receptors, mineralocorticoid receptors and β2-adrenoceptors in the effects of stress was studied by treating mice with the antagonists mifepristone, spironolactone or propranolol respectively (or the corresponding vehicles prior to stress or control treatment. In undisturbed controls, mifepristone and propranolol administration in vivo did not influence LTP induced in vitro. By contrast, spironolactone caused a gradually attenuating form of LTP, both in unstressed and stressed mice. Mifepristone treatment prior to stress strongly reduced the ability to induce LTP in vitro. Propranolol normalized the stress-induced enhancement of LTP to control levels during the first 10 min after high frequency stimulation, after which synaptic responses further declined. CONCLUSIONS: Acute stress changes BLA electrical properties such that subsequent LTP induction is facilitated. Both β-adrenergic and glucocorticoid receptors are involved in the development of these changes. Mineralocorticoid receptors are important for the maintenance of LTP in the BLA, irrespective of stress-induced changes in the

  6. Reciprocal modulation of helper Th1 and Th17 cells by the β2-adrenergic receptor agonist drug terbutaline.

    Science.gov (United States)

    Carvajal Gonczi, Catalina M; Tabatabaei Shafiei, Mahdieh; East, Ashley; Martire, Erika; Maurice-Ventouris, Meagane H I; Darlington, Peter J

    2017-09-01

    Catecholamine hormones are powerful regulators of the immune system produced by the sympathetic nervous system (SNS). They regulate the adaptive immune system by altering T-cell differentiation into T helper (Th) 1 and Th2 cell subsets, but the effect on Th17 cells is not known. Th17 cells, defined, in part, by chemokine receptor CCR6 and cytokine interleukin (IL)-17A, are crucial for mediating certain pathogen-specific responses and are linked with several autoimmune diseases. We demonstrated that a proportion of human Th17 cells express beta 2-adrenergic receptor (β2AR), a G protein-coupled receptor that responds to catecholamines. Activation of peripheral blood mononuclear cells, which were obtained from venous blood drawn from healthy volunteers, with anti-cluster of differentiation 3 (CD3) and anti-CD28 and with a β2-agonist drug, terbutaline (TERB), augmented IL-17A levels (P < 0.01) in the majority of samples. TERB reduced interferon gamma (IFNγ) indicating that IL-17A and IFNγ are reciprocally regulated. Similar reciprocal regulation was observed with dbcAMP. Proliferation of Th cells was monitored by carboxyfluorescein diacetate N-succinimidyl ester labeling and flow cytometry with antibody staining for CD3 and CD4. TERB increased proliferation by a small but significant margin (P < 0.001). Next, Th17 cells (CD4 + CXCR3 - CCR6 + ) were purified using an immunomagnetic positive selection kit, which removes all other mononuclear cells. TERB increased IL-17A from purified Th17 cells, which argues that TERB acts directly on Th17 cells. Thus, hormone signals from the SNS maintain a balance of Th cells subtypes through the β2AR. © 2017 Federation of European Biochemical Societies.

  7. Administration of a selective β2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Branca, Caterina; Wisely, Elena V; Hartman, Lauren K; Caccamo, Antonella; Oddo, Salvatore

    2014-12-01

    Currently, there are no available approaches to cure or slow down the progression of Alzheimer's disease (AD), which is characterized by the accumulation of extracellular amyloid-β (Aβ) deposits and intraneuronal tangles that comprised hyperphosphorylated tau. The β2 adrenergic receptors (β2ARs) are expressed throughout the cortex and hippocampus and play a key role in cognitive functions. Alterations in the function of these receptors have been linked to AD; however, these data remain controversial as apparent contradicting reports have been published. Given the current demographics of growing elderly population and the high likelihood of concurrent β-blocker use for other chronic conditions, more studies into the role of this receptor in AD animal models are needed. Here, we show that administration of ICI 118,551 (ICI), a selective β2AR antagonist, exacerbates cognitive deficits in a mouse model of AD, the 3xTg-AD mice. Neuropathologically, ICI increased Aβ levels and Aβ plaque burden. Concomitantly, ICI-treated 3xTg-AD mice showed an increase in tau phosphorylation and accumulation. Mechanistically, these changes were linked to an increase in amyloidogenic amyloid precursor protein processing. These results suggest that under the conditions used here, selective pharmacologic inhibition of β2ARs has detrimental effects on AD-like pathology in mice. Overall, these studies strengthen the notion that the link between β2ARs and AD is likely highly complex and suggest caution in generalizing the beneficial effects of β blockers on AD. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Acute orexigenic effect of agmatine involves interaction between central α2-adrenergic and GABAergic receptors.

    Science.gov (United States)

    Taksande, Brijesh Gulabrao; Sharma, Omi; Aglawe, Manish Manohar; Kale, Mayur Bhimrao; Gawande, Dinesh Yugraj; Umekar, Milind Janraoji; Kotagale, Nandkishor Ramdas

    2017-09-01

    Agmatine and GABA have been abundantly expressed in brain nuclei involved in regulation of energy homeostasis and promoting stimulation of food intake in rodents. However, their mutual interaction, if any, in the elicitation of feeding behavior is largely remains unclear. The current study provides experimental evidence for the possible interaction of agmatine, adrenergic and GABAergic systems in stimulation of feeding in satiated rats. Satiated rats fitted with intracerebroventricular (i.c.v.) cannulae and were administered agmatine, alone or jointly with (a) GABA A receptor agonist, muscimol, diazepam or antagonist bicuculline and flumazenil, GABA A positive modulator, allopregnanolone or negative modulator of GABA A receptor, dehydroepiandrosterone (b) In view of the high affinity of agmatine for α 2 -adrenoceptors and the close association between α 2 -adrenoceptors and GABAergic system, the effect of their modulators on feeding elicited by agmatine/GABAergic agonists were also examined. I.c.v. administration of agmatine (40-80μg/rat) induces the significant orexigenic effect in satiated rats. The orexigenic effect of agmatine was potentiated by muscimol (25ng/rat, i.c.v.); diazepam (0.5mg/kg, i.p.); allopregnanolone (0.5mg/kg, s.c.) and blocked by bicuculline (1mg/kg, i.p.) and dehydroepiandrosterone (4mg/kg,s.c.). However, it remained unaffected in presence of flumazenil (25ng/rat, i.c.v.). The orexigenic effect of agmatine and GABAergic agonists was potentiated by a α 2 -adrenoceptors agonist, clonidine (10ng/rat, i.c.v.) and blocked by its antagonist, yohimbine (5μg/rat, i.c.v.). Yohimbine also blocked the hyperphagic effect elicited by ineffective dose combination of agmatine (5μg/rat, i.c.v.) with muscimol (25ng/rat, i.c.v.) or diazepam (0.5mg/kg, i.p.) or allopregnanolone (0.5mg/kg,s.c.). The results of the present study suggest that agmatine induced α 2 -adrenoceptors activation might facilitate GABAergic activity to stimulate food intake in

  9. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.

    2003-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

  10. The alpha(2a)-adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety.

    Science.gov (United States)

    Schramm, N L; McDonald, M P; Limbird, L E

    2001-07-01

    The noradrenergic system is involved in the regulation of many physiological and psychological processes, including the modulation of mood. The alpha(2)-adrenergic receptors (alpha(2)-ARs) modulate norepinephrine release, as well as the release of serotonin and other neurotransmitters, and are therefore potential targets for antidepressant and anxiolytic drug development. The current studies were undertaken to examine the role of the alpha(2A) subtype of alpha(2)-AR in mouse behavioral models of depression and anxiety. We have observed that the genetic knock-out of the alpha(2A)-AR makes mice less active in a modified version of Porsolt's forced swim test and insensitive to the antidepressant effects of the tricyclic drug imipramine in this paradigm. Furthermore, alpha(2A)-AR knock-out mice appear more anxious than wild-type C57 Bl/6 mice in the rearing and light-dark models of anxiety after injection stress. These findings suggest that the alpha(2A)-AR may play a protective role in some forms of depression and anxiety and that the antidepressant effects of imipramine may be mediated by the alpha(2A)-AR.

  11. Norepinephrine regulates cocaine-primed reinstatement via α1-adrenergic receptors in the medial prefrontal cortex.

    Science.gov (United States)

    Schmidt, Karl T; Schroeder, Jason P; Foster, Stephanie L; Squires, Katherine; Smith, Brilee M; Pitts, Elizabeth G; Epstein, Michael P; Weinshenker, David

    2017-06-01

    Drug-primed reinstatement of cocaine seeking in rats is thought to reflect relapse-like behavior and is mediated by the integration of signals from mesocorticolimbic dopaminergic projections and corticostriatal glutamatergic innervation. Cocaine-primed reinstatement can also be attenuated by systemic administration of dopamine β-hydroxylase (DBH) inhibitors, which prevent norepinephrine (NE) synthesis, or by α1-adrenergic receptor (α1AR) antagonists, indicating functional modulation by the noradrenergic system. In the present study, we sought to further discern the role of NE in cocaine-seeking behavior by determining whether α1AR activation can induce reinstatement on its own or is sufficient to permit cocaine-primed reinstatement in the absence of all other AR signaling, and identifying the neuroanatomical substrate within the mesocorticolimbic reward system harboring the critical α1ARs. We found that while intracerebroventricular infusion of the α1AR agonist phenylephrine did not induce reinstatement on its own, it did overcome the blockade of cocaine-primed reinstatement by the DBH inhibitor nepicastat. Furthermore, administration of the α1AR antagonist terazosin in the medial prefrontal cortex (mPFC), but not the ventral tegmental area (VTA) or nucleus accumbens (NAc) shell, attenuated cocaine-primed reinstatement. Combined, these data indicate that α1AR activation in the mPFC is required for cocaine-primed reinstatement, and suggest that α1AR antagonists merit further investigation as pharmacotherapies for cocaine dependence. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Pharmacodynamic Study of Interaction of Aqueous Leaf Extract of Psidium Guajava Linn. (Myrtaceae) with Receptor Systems Using Isolated Tissue Preparations.

    Science.gov (United States)

    Mahaseth, R K; Kumar, S; Dutta, Shagun; Sehgal, Ratika; Rajora, Preety; Mathur, Rajani

    2015-01-01

    The present study investigates the interaction of aqueous leaf extract of Psidium guajava with muscarinic, serotonergic and adrenergic receptor system using isolated rat ileum, gastric fundus and trachea, respectively. The concentration-dependent contractile response of aqueous leaf extract of Psidium guajava was parallel and rightward of standard agonists, ACh and 5-HT indicating agonistic activity on muscarinic and serotonergic receptor systems. The inhibition of aqueous leaf extract of Psidium guajava mediated contractions in presence of atropine (10(-7) M) and ketanserin (10(-6) M) confirmed the activity. Relaxant effect of PG (0.2 mg/ml) on carbachol induced pre-contracted rat tracheal chain indicated its agonistic action on adrenergic receptor system. Inhibition (P<0.05) of the action in the presence of propranolol (1 ng/ml) confirmed the activity. It may be concluded that PG possesses agonistic action on muscarinic, serotonergic and adrenergic receptor systems.

  13. Partial agonism through a zinc-Ion switch constructed between transmembrane domains III and VII in the tachykinin NK(1) receptor

    DEFF Research Database (Denmark)

    Holst, B; Elling, C E; Schwartz, T W

    2000-01-01

    switch located exactly one helical turn below the two previously identified interaction points for Substance P in, respectively, TM-III and -VII. The metal-ion chelator, phenantroline, which in the beta(2)-adrenergic receptor increased both the potency and the agonistic efficacy of Zn(2+) or Cu(2......Partly due to lack of detailed knowledge of the molecular recognition of ligands the structural basis for partial versus full agonism is not known. In the beta(2)-adrenergic receptor the agonist binding site has previously been structurally and functionally exchanged with an activating metal....... In contrast to the similarly mutated beta(2)-adrenergic receptor, signal transduction-i.e., inositol phosphate turnover-could be stimulated by both Zn(2+) and by the natural agonist, Substance P in the mutated NK(1) receptor. The metal-ion acted as a 25% partial agonist through binding to the bidentate zinc...

  14. Enhanced Striatal β1-Adrenergic Receptor Expression Following Hormone Loss in Adulthood Is Programmed by Both Early Sexual Differentiation and Puberty: A Study of Humans and Rats

    Science.gov (United States)

    Perry, Adam N.; Westenbroek, Christel; Hedges, Valerie L.; Becker, Jill B.; Mermelstein, Paul G.

    2013-01-01

    After reproductive senescence or gonadectomy, changes occur in neural gene expression, ultimately altering brain function. The endocrine mechanisms underlying these changes in gene expression beyond immediate hormone loss are poorly understood. To investigate this, we measured changes in gene expression the dorsal striatum, where 17β-estradiol modulates catecholamine signaling. In human caudate, quantitative PCR determined a significant elevation in β1-adrenergic receptor (β1AR) expression in menopausal females when compared with similarly aged males. No differences were detected in β2-adrenergic and D1- and D2-dopamine receptor expression. Consistent with humans, adult ovariectomized female rats exhibited a similar increase in β1AR expression when compared with gonadectomized males. No sex difference in β1AR expression was detected between intact adults, prepubertal juveniles, or adults gonadectomized before puberty, indicating the necessity of pubertal development and adult ovariectomy. Additionally, increased β1AR expression in adult ovariectomized females was not observed if animals were masculinized/defeminized with testosterone injections as neonates. To generate a model system for assessing functional impact, increased β1AR expression was induced in female-derived cultured striatal neurons via exposure to and then removal of hormone-containing serum. Increased β1AR action on cAMP formation, cAMP response element-binding protein phosphorylation and gene expression was observed. This up-regulation of β1AR action was eliminated with 17β-estradiol addition to the media, directly implicating this hormone as a regulator of β1AR expression. Beyond having implications for the known sex differences in striatal function and pathologies, these data collectively demonstrate that critical periods early in life and at puberty program adult gene responsiveness to hormone loss after gonadectomy and potentially reproductive senescence. PMID:23533220

  15. A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure.

    Science.gov (United States)

    Zhang, Xiaojian; Shen, Chengwu; Zhai, Shujun; Liu, Yukun; Yue, Wen-Wei; Han, Li

    2016-10-01

    Adrenergic β-blockers are drugs that bind to, but do not activate β-adrenergic receptors. Instead they block the actions of β-adrenergic agonists and are used for the treatment of various diseases such as cardiac arrhythmias, angina pectoris, myocardial infarction, hypertension, headache, migraines, stress, anxiety, prostate cancer, and heart failure. Several meta-analysis studies have shown that β-blockers improve the heart function and reduce the risks of cardiovascular events, rate of mortality, and sudden death through chronic heart failure (CHF) of patients. The present study identified results from recent meta-analyses of β-adrenergic blockers and their usefulness in CHF. Databases including Medline/Embase/Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched for the periods May, 1985 to March, 2011 and June, 2013 to August, 2015, and a number of studies identified. Results of those studies showed that use of β-blockers was associated with decreased sudden cardiac death in patients with heart failure. However, contradictory results have also been reported. The present meta-analysis aimed to determine the efficacy of β-blockers on mortality and morbidity in patients with heart failure. The results showed that mortality was significantly reduced by β-blocker treatment prior to the surgery of heart failure patients. The results from the meta-analysis studies showed that β-blocker treatment in heart failure patients correlated with a significant decrease in long-term mortality, even in patients that meet one or more exclusion criteria of the MERIT-HF study. In summary, the findings of the current meta-analysis revealed beneficial effects different β-blockers have on patients with heart failure or related heart disease.

  16. Skeletal muscle beta-receptors and isoproterenol-stimulated vasodilation in canine heart failure

    International Nuclear Information System (INIS)

    Frey, M.J.; Lanoce, V.; Molinoff, P.B.; Wilson, J.R.

    1989-01-01

    To investigate whether heart failure alters beta-adrenergic receptors on skeletal muscle and its associated vasculature, the density of beta-adrenergic receptors, isoproterenol-stimulated adenylate cyclase activity, and coupling of the guanine nucleotide-binding regulatory protein were compared in 18 control dogs and 16 dogs with heart failure induced by 5-8 wk of ventricular pacing at 260 beats/min. Hindlimb vascular responses to isoproterenol were compared in eight controls and eight of the dogs with heart failure. In dogs with heart failure, the density of beta-receptors on skeletal muscle was reduced in both gastrocnemius (control: 50 +/- 5; heart failure: 33 +/- 8 fmol/mg of protein) and semitendinosus muscle (control: 43 +/- 9; heart failure: 27 +/- 9 fmol/mg of protein, both P less than 0.05). Receptor coupling to the ternary complex, as determined by isoproterenol competition curves with and without guanosine 5'-triphosphate (GTP), was unchanged. Isoproterenol-stimulated adenylate cyclase activity was significantly decreased in semitendinosus muscle (control: 52.4 +/- 4.6; heart failure: 36.5 +/- 9.5 pmol.mg-1.min-1; P less than 0.05) and tended to be decreased in gastrocnemius muscle (control: 40.1 +/- 8.5; heart failure: 33.5 +/- 4.5 pmol.mg-1.min-1; P = NS). Isoproterenol-induced hindlimb vasodilation was not significantly different in controls and in dogs with heart failure. These findings suggest that heart failure causes downregulation of skeletal muscle beta-adrenergic receptors, probably due to receptor exposure to elevated catecholamine levels, but does not reduce beta-receptor-mediated vasodilation in muscle

  17. Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat

    Directory of Open Access Journals (Sweden)

    Juan Suárez

    2014-01-01

    Full Text Available β-adrenergic receptor activation promotes brown adipose tissue (BAT β-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-α (PPARα in white adipose tissue (WAT. Here we explore whether PPARα activation potentiates the effect of β3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association on feeding, thermogenesis, β-oxidation, and lipid and cholesterol metabolism in epididymal (eWAT was monitored. CL316243 (1 mg/kg and OEA (5 mg/kg co-administration over 6 days enhanced the reduction of both food intake and body weight gain, increased the energy expenditure and reduced the respiratory quotient (VCO2/VO2. This negative energy balance agreed with decreased fat mass and increased BAT weight and temperature, as well as with lowered plasma levels of triglycerides, cholesterol, nonessential fatty acids (NEFAs, and the adipokines leptin and TNF-α. Regarding eWAT, CL316243 and OEA treatment elevated levels of the thermogenic factors PPARα and UCP1, reduced p38-MAPK phosphorylation, and promoted brown-like features in the white adipocytes: the mitochondrial (Cox4i1, Cox4i2 and BAT (Fgf21, Prdm16 genes were overexpressed in eWAT. The enhancement of the fatty-acid β-oxidation factors Cpt1b and Acox1 in eWAT was accompanied by an upregulation of de novo lipogenesis and reduced expression of the unsaturated-fatty-acid-synthesis enzyme gene, Scd1. We propose that the combination of β-adrenergic and PPARα receptor agonists promotes therapeutic adipocyte remodelling in eWAT, and therefore has a potential clinical utility in the treatment of obesity.

  18. Possible involvements of glutamate and adrenergic receptors on acute toxicity of methylphenidate in isolated hippocampus and cerebral cortex of adult rats.

    Science.gov (United States)

    Motaghinejad, Majid; Motevalian, Manijeh; Shabab, Behnaz

    2017-04-01

    Neurodegeneration induced by methylphenidate (MPH), as a central stimulant with unknown long-term consequences, in adult rats' brain and the possible mechanisms involved were studied. Rats were acutely treated with MPH in the presence and absence of some receptor antagonists such as ketamine, topiramate, yohimbine, and haloperidol. Motor activity and anxiety level in rats were monitored. Antioxidant and inflammatory parameters were also measured in isolated hippocampus and cerebral cortex. MPH-treated groups (10 and 20 mg/kg) demonstrated anxiety-like behavior and increased motor activity. MPH significantly increased lipid peroxidation, GSSG content, IL-1β and TNF-α levels in isolated tissues, and also significantly reduced GSH content, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) activities in hippocampus and cerebral cortex. Pretreatment of animals by receptor antagonists caused inhibition of MPH-induced motor activity disturbances and anxiety-like behavior. Pretreatment of animals by ketamine, topiramate, and yohimbine inhibited the MPH-induced oxidative stress and inflammation; it significantly decreased lipid peroxidation, GSSG level, IL-1β and TNF-α levels and increased GSH content, SOD, GPx, and GR activities in hippocampus and cerebral cortex of acutely MPH-treated rats. Pretreatment with haloperidol did not cause any change in MPH-induced oxidative stress and inflammation. In conclusion, acute administration of high doses of MPH can cause oxidative and inflammatory changes in brain cells and induce neurodegeneration in hippocampus and cerebral cortex of adult rats and these changes might probably be mediated by glutamate (NMDA or AMPA) and/or α 2 -adrenergic receptors. © 2016 Société Française de Pharmacologie et de Thérapeutique.

  19. Chronic stress enhances progression of periodontitis via α1-adrenergic signaling: a potential target for periodontal disease therapy.

    Science.gov (United States)

    Lu, Huaixiu; Xu, Minguang; Wang, Feng; Liu, Shisen; Gu, Jing; Lin, Songshan

    2014-10-17

    This study assessed the roles of chronic stress (CS) in the stimulation of the sympathetic nervous system and explored the underlying mechanisms of periodontitis. Using an animal model of periodontitis and CS, the expression of tyrosine hydroxylase (TH) and the protein levels of the α1-adrenergic receptor (α1-AR) and β2-adrenergic receptor (β2-AR) were assessed. Furthermore, human periodontal ligament fibroblasts (HPDLFs) were stimulated with lipopolysaccharide (LPS) to mimic the process of inflammation. The proliferation of the HPDLFs and the expression of α1-AR and β2-AR were assessed. The inflammatory-related cytokines interleukin (IL)-1β, IL-6 and IL-8 were detected after pretreatment with the α1/β2-AR blockers phentolamine/propranolol, both in vitro and in vivo. Results show that periodontitis under CS conditions enhanced the expression of TH, α1-AR and β2-AR. Phentolamine significantly reduced the inflammatory cytokine levels. Furthermore, we observed a marked decrease in HPDLF proliferation and the increased expression of α1-ARfollowing LPS pretreatment. Pretreatment with phentolamine dramatically ameliorated LPS-inhibited cell proliferation. In addition, the blocking of α1-ARsignaling also hindered the upregulation of the inflammatory-related cytokines IL-1β, IL-6 and IL-8. These results suggest that CS can significantly enhance the pathological progression of periodontitis by an α1-adrenergic signaling-mediated inflammatory response. We have identified a potential therapeutic target for the treatment of periodontal disease, particularly in those patients suffering from concurrent CS.

  20. Evidence of changes in alpha-1/AT1 receptor function generated by diet-induced obesity.

    Science.gov (United States)

    Juarez, Esther; Tufiño, Cecilia; Querejeta, Enrique; Bracho-Valdes, Ismael; Bobadilla-Lugo, Rosa A

    2017-11-01

    To study whether hypercaloric diet-induced obesity deteriorates vascular contractility of rat aorta through functional changes in α 1 adrenergic and/or AT1 Angiotensin II receptors. Angiotensin II- or phenylephrine-induced contraction was tested on isolated aorta rings with and without endothelium from female Wistar rats fed for 7 weeks with hypercaloric diet or standard diet. Vascular expression of Angiotensin II Receptor type 1 (AT1R), Angiotensin II Receptor type 2 (AT2R), Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), inducible Nitric Oxide Synthase (iNOS) and endothelial Nitric Oxide Synthase (eNOS), as well as blood pressure, glucose, insulin and angiotensin II blood levels were measured. Diet-induced obesity did not significantly change agonist-induced contractions (Emax and pD 2 hypercaloric diet vs standard diet n.s.d.) of both intact (e+) or endothelium free (e-) vessels but significantly decrease both phenylephrine and angiotensin II contraction (Emax p obesity did not change angiotensin II AT1, AT2 receptor proteins expression but reduced COX-1 and NOS2 ( p obesity produces alterations in vascular adrenergic and angiotensin II receptor dynamics that suggest an endothelium-dependent adrenergic/angiotensin II crosstalk. These changes reflect early-stage vascular responses to obesity.

  1. Physiological and biochemical characteristics of adrenergic receptors and pathways in brown adipocytes

    Science.gov (United States)

    Horwitz, B. A.

    1975-01-01

    Mechanisms involved in the thermogenic response of brown adipose tissue (BAT) to sympathetic nervous stimulation (e.g., by cold exposure) and to norepinephrine (NE) release are investigated. Three effects appear to play a role in the increased oxygen consumption (and heat production) of the adipocytes: increased membrane permeability, activation of the beta-adrenergic pathway, and enhancement of Na(+)/K(+) membrane pump activity. Increased passive influx of Na(+) and efflux of K(+) due to greater permeability raise the energy demands of the Na/K pump; the pump is also stimulated by increased cyclic AMP synthesis resulting from activation by NE of membrane-bound adenyl cyclase. Studies with inhibitors such as propanolol, phentolamine, and ouabain support this hypothesis.

  2. Subtype-dependent postnatal development of taste receptor cells in mouse fungiform taste buds.

    Science.gov (United States)

    Ohtubo, Yoshitaka; Iwamoto, Masafumi; Yoshii, Kiyonori

    2012-06-01

    Taste buds contain two types of taste receptor cells, inositol 1,4,5-triphosphate receptor type 3-immunoreactive cells (type II cells) and synaptosomal-associating protein-25-immunoreactive cells (type III cells). We investigated their postnatal development in mouse fungiform taste buds immunohistochemically and electrophysiologically. The cell density, i.e. the number of cells per taste bud divided by the maximal area of the horizontal cross-section of the taste bud, of type II cells increased by postnatal day (PD)49, where as that of type III cells was unchanged throughout the postnatal observation period and was equal to that of the adult cells at PD1. The immunoreactivity of taste bud cell subtypes was the same as that of their respective subtypes in adult mice throughout the postnatal observation period. Almost all type II cells were immunoreactive to gustducin at PD1, and then the ratio of gustducin-immunoreactive type II cells to all type II cells decreased to a saturation level, ∼60% of all type II cells, by PD15. Type II and III cells generated voltage-gated currents similar to their respective adult cells even at PD3. These results show that infant taste receptor cells are as excitable as those of adults and propagate in a subtype-dependent manner. The relationship between the ratio of each taste receptor cell subtype to all cells and taste nerve responses are discussed. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  3. Quetiapine reverse paclitaxel-induced neuropathic pain in mice: Role of Alpha2- adrenergic receptors

    Directory of Open Access Journals (Sweden)

    Alireza Abed

    2017-11-01

    Full Text Available Objective(s: Paclitaxel-induced peripheral neuropathy is a common adverse effect of cancer chemo -therapy. This neuropathy has a profound impact on quality of life and patient’s survival. Preventing and treating paclitaxel-induced peripheral neuropathy is a major concern. First- and second-generation antipsychotics have shown analgesic effects both in humans and animals. Quetiapine is a novel atypical antipsychotic with low propensity to induce extrapyramidal or hyperprolactinemia side effects. The present study was designed to investigate the effects of quetiapine on the development and expression of neuropathic pain induced by paclitaxel in mice and the role of α2-adrenoceptors on its antinociception. Materials and Methods: Paclitaxel (2 mg/kg IP was injected for five consecutive days which resulted in thermal hyperalgesia and mechanical and cold allodynia. Results: Early administration of quetiapine from the 1st day until the 5th day (5, 10, and 15 mg/kg PO did not affect thermal, mechanical, and cold stimuli and could not prevent the development of neuropathic pain. In contrast, when quetiapine (10 and 15 mg/kg PO administration was started on the 6th day after the first paclitaxel injections, once the model had been established, and given daily until the 10th day, heat hyperalgesia and mechanical and cold allodynia were significantly attenuated. Also, the effect of quetiapine on heat hyperalgesia was reversed by pretreatment with yohimbine, as an alpha-2 adrenergic receptor antagonist. Conclusion: These results indicate that quetiapine, when administered after nerve injury can reverse the expression of neuropathic pain. Also, we conclude that α2-adrenoceptors participate in the antinociceptive effects of quetiapine.

  4. Alpha1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses.

    Science.gov (United States)

    Solecki, Wojciech B; Szklarczyk, Klaudia; Klasa, Adam; Pradel, Kamil; Dobrzański, Grzegorz; Przewłocki, Ryszard

    2017-08-01

    Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha 1 -adrenergic receptor (α 1 -AR) signaling in the VTA affects conditioned fear. The role of α 1 -AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α 1 -AR blockade in the mammillary bodies (MB) - a brain region with α 1 -AR expression adjacent to the VTA. Intra-VTA but not intra-MB α 1 -AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α 1 -AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α 1 -AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α 1 -AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α 1 -AR signaling in the regulation of stress responsiveness and fear memory. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

  5. DA1 receptors modulation in rat isolated trachea.

    Science.gov (United States)

    Cabezas, Gloria A; Velasco, Manuel

    2010-01-01

    We have previously demonstrated that low dose of inhaled dopamine (0.5-2 microg kg(-1) min(-1)) induces broncodilatacion in patients with acute asthma attack, suggesting that this dopamine effect is mediated by dopaminergic rather than by adrenergic receptors. To understand better these dopamine effect, rat tracheal smooth muscle was used as a model to evaluate the responses of beta2-, alpha1-, alpha2-adrenergic and DA1 and DA2 dopaminergic antagonists. Tracheal rings from male Sprague-Dawley rats (n = 90) were excised and placed in an organ bath containing modified Krebs-Ringer bicarbonate buffer at 37 degrees C, and gassed with O2 (95%) and CO2 (5%). Contractile responses were recorded with an isometric transducer in a polygraph (Letica, Spain). Contraction was induced by accumulative doses of acetylcholine (0.1, 0.3, 1, 3, 10 mM) or by electric field stimulation (10 Hz at 2 milliseconds), and accumulative doses of dopamine were added to the bath. Low concentration (0.1-0.3 mM) elicited a small initial contraction, followed by a marked relaxation. Cholinergic contraction was completely reversed at 6 mM of dopamine. This biphasic dopaminergic response was not blocked by incubation with beta2-adrenergic antagonist propranolol (0.1 microM), alpha1-antagonist, terazosin (0.1 mM), alpha2-antagonist, yohimbine (0.1 mM), or by DA2 antagonist metoclopramide (1-8 mM); DA1 antagonist SCH23390 (0.1 microM) produced a sustained increase of basal tone but did not block initial dopaminergic contraction and partially inhibited bronchodilator effect of dopamine. Dopaminergic relaxation in rat trachea is mediated by DA1 rather than by DA2 receptors; and adrenergic receptors are not involved in such dopamine-induced response. Finally, DA1 antagonist SCH23390 exerts intrinsic contractile activity on airway smooth muscle that deserves further research.

  6. In brown adipocytes, adrenergically induced β{sub 1}-/β{sub 3}-(G{sub s})-, α{sub 2}-(G{sub i})- and α{sub 1}-(G{sub q})-signalling to Erk1/2 activation is not mediated via EGF receptor transactivation

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yanling; Fälting, Johanna M.; Mattsson, Charlotte L.; Holmström, Therése E.; Nedergaard, Jan, E-mail: jan@metabol.su.se

    2013-10-15

    Brown adipose tissue is unusual in that the neurotransmitter norepinephrine influences cell destiny in ways generally associated with effects of classical growth factors: regulation of cell proliferation, of apoptosis, and progression of differentiation. The norepinephrine effects are mediated through G-protein-coupled receptors; further mediation of such stimulation to e.g. Erk1/2 activation is in cell biology in general accepted to occur through transactivation of the EGF receptor (by external or internal pathways). We have examined here the significance of such transactivation in brown adipocytes. Stimulation of mature brown adipocytes with cirazoline (α{sub 1}-adrenoceptor coupled via G{sub q}), clonidine (α{sub 2} via G{sub i}) or CL316243 (β{sub 3} via G{sub s}) or via β{sub 1}-receptors significantly activated Erk1/2. Pretreatment with the EGF receptor kinase inhibitor AG1478 had, remarkably, no significant effect on Erk1/2 activation induced by any of these adrenergic agonists (although it fully abolished EGF-induced Erk1/2 activation), demonstrating absence of EGF receptor-mediated transactivation. Results with brown preadipocytes (cells in more proliferative states) were not qualitatively different. Joint stimulation of all adrenoceptors with norepinephrine did not result in synergism on Erk1/2 activation. AG1478 action on EGF-stimulated Erk1/2 phosphorylation showed a sharp concentration–response relationship (IC{sub 50} 0.3 µM); a minor apparent effect of AG1478 on norepinephrine-stimulated Erk1/2 phosphorylation showed nonspecific kinetics, implying caution in interpretation of partial effects of AG1478 as reported in other systems. Transactivation of the EGF receptor is clearly not a universal prerequisite for coupling of G-protein coupled receptors to Erk1/2 signalling cascades. - Highlights: • In brown adipocytes, norepinephrine regulates proliferation, apoptosis, differentiation. • EGF receptor transactivation is supposed to mediate GPCR

  7. Specificity and impact of adrenergic projections to the midbrain dopamine system

    Science.gov (United States)

    Mejias-Aponte, Carlos A.

    2016-01-01

    Dopamine (DA) is a neuromodulator that regulates different brain circuits involved in cognitive functions, motor coordination, and emotions. Dysregulation of DA is associated with many neurological and psychiatric disorders such as Parkinson’s disease and substance abuse. Several lines of research have shown that the midbrain DA system is regulated by the central adrenergic system. This review focuses on adrenergic interactions with midbrain DA neurons. It discusses the current neuroanatomy including source of adrenergic innervation, type of synapses, and adrenoceptors expression. It also discusses adrenergic regulation of DA cell activity and neurotransmitter release. Finally, it reviews several neurological and psychiatric disorders where changes in adrenergic system are associated with dysregulation of the midbrain DA system. PMID:26820641

  8. Adrenergic effects on exocrine secretion of rat submandibular epidermal growth factor

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba

    1984-01-01

    The present study was undertaken to investigate the effect of alpha- and beta-adrenergic agonists on secretion of epidermal growth factor (EGF) from the rat submandibular glands and to test the possibility of intestinal absorption of EGF. Alpha-adrenergic agonists increased the concentration...... of salivary EGF by approximately a hundred times, while the serum concentration of EGF was unchanged. The contents of EGF in the submandibular glands decreased upon administration of the alpha-adrenergic agonist noradrenaline, and this was confirmed on immunohistochemical investigation of the glands. Beta-adrenergic....... This study shows that alpha-adrenergic agonists stimulate exocrine secretion of submandibular EGF and that EGF in physiological amounts are not absorbed in the gastrointestinal tract....

  9. Central beta-adrenergic modulation of cognitive flexibility.

    Science.gov (United States)

    Beversdorf, David Q; White, Dawn M; Chever, Daquesha C; Hughes, John D; Bornstein, Robert A

    2002-12-20

    Situational stressors and anxiety impede performance on creativity tests requiring cognitive flexibility. Preliminary research revealed better performance on a task requiring cognitive flexibility, the anagram task, after propranolol (beta-adrenergic antagonist) than after ephedrine (beta-adrenergic agonist). However, propranolol and ephedrine have both peripheral and central beta-adrenergic effects. In order to determine whether noradrenergic modulation of cognitive flexibility is a centrally or peripherally mediated phenomenon, we compared the effects of propranolol (peripheral and central beta-blocker), nadolol (peripheral beta-blocker), and placebo on anagram task performance. Solution latency scores for each subject were compared across the drug conditions. Anagram solution latency scores after propranolol were significantly lower than after nadolol. This suggests a centrally mediated modulatory influence of the noradrenergic system on cognitive flexibility.

  10. G16R single nucleotide polymorphism but not haplotypes of the ß2-adrenergic receptor gene alters cardiac output in humans

    DEFF Research Database (Denmark)

    Rokamp, Kim Z; Staalsø, Jonatan M; Gartmann, Martin

    2013-01-01

    Variation in genes encoding the ß2-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) may influence Q¿ (cardiac output). The 46G>A (G16R) SNP (single nucleotide polymorphism) has been associated with ß2-mediated vasodilation, but the effect of ADRB2 haplotypes on Q¿ has not been...... studied. Five SNPs within ADRB2 (46G>A, 79C>G, 491C>T, 523C>A and 1053G>C by a pairwise tagging principle) and the I/D (insertion/deletion) polymorphism in ACE were genotyped in 143 subjects. Cardiovascular variables were evaluated by the Model flow method at rest and during incremental cycling exercise...... V¿O2 (oxygen uptake) in G16G subjects, but the increase was 0.5 (0.0-0.9) l/min lower in Arg16 carriers (P=0.035). A similar effect size was observed for the Arg16 haplotypes ACCCG and ACCCC. No interaction was found between ADRB2 and ACE polymorphisms. During exercise, the increase in Q¿ was 0...

  11. Modulation of haloperidol-induced patterns of the transcription factor Nur77 and Nor-1 expression by serotonergic and adrenergic drugs in the mouse brain

    Science.gov (United States)

    Maheux, Jérôme; Vuillier, Laura; Mahfouz, Mylène; Rouillard, Claude; Lévesque, Daniel

    2015-01-01

    Different patterns of expression of the transcription factors of Nur77 and Nor-1 are induced following acute administration of typical and atypical antipsychotic drugs. The pharmacological profile of atypical antipsychotics suggests that serotonergic and/or adrenergic receptors might contribute to these reported differences. In order to test this possibility, we examined the abilities of serotonin 5-HT1A and 5-HT2A/2C, and α1- and α2-adrenergic receptor drugs to modify the pattern of Nur77 (NR4A1) and Nor-1 (NR4A3) mRNA expression induced by haloperidol. Various groups of mice were treated with either saline, DOI, a 5-HT2A/2C agonist, MDL11939, a 5-HT2A antagonist, 8-OH-DPAT, a 5-HT1A agonist, prazosin, an α1-adrenergic antagonist and idazoxan, an α2-adrenergic antagonist, alone or in combination with haloperidol. The 5-HT2A/2C agonist DOI alone significantly increased Nur77 expression in the medial striatum and nucleus accumbens. DOI reduced Nor-1 expression, while MDL11939 increased the expression of this transcript in the cortex. Prazosin reduced Nur77 expression in the dorsal striatum and nucleus accumbens. Interestingly, 8-OH-DPAT and MDL11939 partially prevented haloperidol-induced Nur77 up-regulation, while MDL11939 completely abolished Nor-1 expression in the striatum. In addition, MDL11939 decreased haloperidol-induced Nur77 and Nor-1 mRNA levels in the ventral tegmental area. On the contrary, idazoxan (α2 antagonist) consistently potentiated haloperidol-induced Nur77, but not Nor-1 mRNA levels in the striatum, whereas prazosin (α1 antagonist) remained without effect. Taken together, these results show the ability of a 5-HT1A agonist or a 5-HT2A antagonist to reduce haloperidol-induced Nur77 and Nor-1 striatal expression, suggesting that these serotonin receptor subtypes participate in the differential pattern of gene expression induced by typical and atypical antipsychotic drugs. PMID:21524335

  12. The Biogenic Amine Tyramine and its Receptor (AmTyr1 in Olfactory Neuropils in the Honey Bee (Apis mellifera Brain

    Directory of Open Access Journals (Sweden)

    Irina T. Sinakevitch

    2017-10-01

    Full Text Available This article describes the cellular sources for tyramine and the cellular targets of tyramine via the Tyramine Receptor 1 (AmTyr1 in the olfactory learning and memory neuropils of the honey bee brain. Clusters of approximately 160 tyramine immunoreactive neurons are the source of tyraminergic fibers with small varicosities in the optic lobes, antennal lobes, lateral protocerebrum, mushroom body (calyces and gamma lobes, tritocerebrum and subesophageal ganglion (SEG. Our tyramine mapping study shows that the primary sources of tyramine in the antennal lobe and calyx of the mushroom body are from at least two Ventral Unpaired Median neurons (VUMmd and VUMmx with cell bodies in the SEG. To reveal AmTyr1 receptors in the brain, we used newly characterized anti-AmTyr1 antibodies. Immunolocalization studies in the antennal lobe with anti-AmTyr1 antibodies showed that the AmTyr1 expression pattern is mostly in the presynaptic sites of olfactory receptor neurons (ORNs. In the mushroom body calyx, anti-AmTyr1 mapped the presynaptic sites of uniglomerular Projection Neurons (PNs located primarily in the microglomeruli of the lip and basal ring calyx area. Release of tyramine/octopamine from VUM (md and mx neurons in the antennal lobe and mushroom body calyx would target AmTyr1 expressed on ORN and uniglomerular PN presynaptic terminals. The presynaptic location of AmTyr1, its structural similarity with vertebrate alpha-2 adrenergic receptors, and previous pharmacological evidence suggests that it has an important role in the presynaptic inhibitory control of neurotransmitter release.

  13. Mice Lacking the β2 Adrenergic Receptor Have a Unique Genetic Profile before and after Focal Brain Ischaemia

    Directory of Open Access Journals (Sweden)

    Robin E White

    2012-08-01

    Full Text Available The role of the β2AR (β2 adrenergic receptor after stroke is unclear as pharmacological manipulations of the β2AR have produced contradictory results. We previously showed that mice deficient in the β2AR (β2KO had smaller infarcts compared with WT (wild-type mice (FVB after MCAO (middle cerebral artery occlusion, a model of stroke. To elucidate mechanisms of this neuroprotection, we evaluated changes in gene expression using microarrays comparing differences before and after MCAO, and differences between genotypes. Genes associated with inflammation and cell deaths were enriched after MCAO in both genotypes, and we identified several genes not previously shown to increase following ischaemia (Ccl9, Gem and Prg4. In addition to networks that were similar between genotypes, one network with a central core of GPCR (G-protein-coupled receptor and including biological functions such as carbohydrate metabolism, small molecule biochemistry and inflammation was identified in FVB mice but not in β2KO mice. Analysis of differences between genotypes revealed 11 genes differentially expressed by genotype both before and after ischaemia. We demonstrate greater Glo1 protein levels and lower Pmaip/Noxa mRNA levels in β2KO mice in both sham and MCAO conditions. As both genes are implicated in NF-κB (nuclear factor κB signalling, we measured p65 activity and TNFα (tumour necrosis factor α levels 24 h after MCAO. MCAO-induced p65 activation and post-ischaemic TNFα production were both greater in FVB compared with β2KO mice. These results suggest that loss of β2AR signaling results in a neuroprotective phenotype in part due to decreased NF-κB signalling, decreased inflammation and decreased apoptotic signalling in the brain.

  14. Expression of VEGF receptors VEFGR-1 and VEGFR-2, angiopoietin receptors Tie-1 and Tie-2 in chorionic villi tree during early pregnancy.

    Directory of Open Access Journals (Sweden)

    Ramazan Demir

    2010-02-01

    Full Text Available The aim of this study was to determine the expression of VEGF and its receptors in placentas from normal pregnancies between 22 days p.c. and 48 days p.c. of very early pregnancy. Placental tissues carried out from 19 pregnant women were examined. Immunohistochemical technique, electron microscopy were employed to evaluate the factors expression. In the new developing mesenchymal villi and immature intermediate villi VEGF and its receptors VEGFR-1 and VEGFR-2 immunoreactivity was detected in all the placental components, while in the stem villi and in the chorionic plate with large vessels only in some components. In the mesenchymal villi and immature intermediate villi VEGFR-1 and -2, and angiopoietin receptors Tie-1 and -2 immunoreactivity was dominantly observed in the heamangiogenic cells and cells cords, whereas the matured villi showed immunoreactivity only in other components. The ultrastructural findings were higher in respect to the all of the early pregnancy days. The placental samples from all of pregnancies, showed the VEGF and its receptors in optimal expression levels, whereas the angiopoietin receptors Tie-1 and -2 showed a higher expression levels in respect to other study factors. The receptors protein levels increased from the early days to the advanced days of gestation, but this alteration was not significant. The intensity of the immunolabeling for these proteins were not significant compared to to each other of gestatin days were examined. These findings demonstrated that a dysregulation of the placental expression of the VEGF and its receptors related to the different degrees of the gestational periods. Probably, this event may be related to complete vasculugenesis and angiogenesis in placental villi.

  15. Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion -- interaction with the sensory system

    DEFF Research Database (Denmark)

    Csati, Anett; Tajti, Janos; Tuka, Bernadett

    2012-01-01

    , Western blot technique was used to demonstrate the existence of CGRP receptor components in rat SPG. CGRP immunoreactive fibers were frequently found intraganglionic in the SPG in the vicinity of neurons. CLR immunoreactivity was observed in satellite glial cells (SGCs) as well as in nerve fibers......, but not in neurons. RAMP1 immunoreactivity was localized in many neurons and SGCs. Thus, the two CGRP receptor components together were found in the SGCs. In addition, Western blot revealed the presence of RAMP1 and CLR in rat SPG. Our results suggest a possible sensory influence in the parasympathetic cranial...

  16. Intact calcium signaling in adrenergic-deficient embryonic mouse hearts.

    Science.gov (United States)

    Peoples, Jessica N; Taylor, David G; Katchman, Alexander N; Ebert, Steven N

    2018-01-22

    Mouse embryos that lack the ability to produce the adrenergic hormones, norepinephrine (NE) and epinephrine (EPI), due to disruption of the dopamine beta-hydroxylase (Dbh -/- ) gene inevitably perish from heart failure during mid-gestation. Since adrenergic stimulation is well-known to enhance calcium signaling in developing as well as adult myocardium, and impairments in calcium signaling are typically associated with heart failure, we hypothesized that adrenergic-deficient embryonic hearts would display deficiencies in cardiac calcium signaling relative to adrenergic-competent controls at a developmental stage immediately preceding the onset of heart failure, which first appears beginning or shortly after mouse embryonic day 10.5 (E10.5). To test this hypothesis, we used ratiometric fluorescent calcium imaging techniques to measure cytosolic calcium transients, [Ca 2+ ] i in isolated E10.5 mouse hearts. Our results show that spontaneous [Ca 2+ ] i oscillations were intact and robustly responded to a variety of stimuli including extracellular calcium (5 mM), caffeine (5 mM), and NE (100 nM) in a manner that was indistinguishable from controls. Further, we show similar patterns of distribution (via immunofluorescent histochemical staining) and activity (via patch-clamp recording techniques) for the major voltage-gated plasma membrane calcium channel responsible for the L-type calcium current, I Ca,L , in adrenergic-deficient and control embryonic cardiac cells. These results demonstrate that despite the absence of vital adrenergic hormones that consistently leads to embryonic lethality in vivo, intracellular and extracellular calcium signaling remain essentially intact and functional in embryonic mouse hearts through E10.5. These findings suggest that adrenergic stimulation is not required for the development of intracellular calcium oscillations or extracellular calcium signaling through I Ca,L and that aberrant calcium signaling does not likely contribute

  17. Neural correlate of resting-state functional connectivity under α2 adrenergic receptor agonist, medetomidine.

    Science.gov (United States)

    Nasrallah, Fatima A; Lew, Si Kang; Low, Amanda Si-Min; Chuang, Kai-Hsiang

    2014-01-01

    Correlative fluctuations in functional MRI (fMRI) signals across the brain at rest have been taken as a measure of functional connectivity, but the neural basis of this resting-state MRI (rsMRI) signal is not clear. Previously, we found that the α2 adrenergic agonist, medetomidine, suppressed the rsMRI correlation dose-dependently but not the stimulus evoked activation. To understand the underlying electrophysiology and neurovascular coupling, which might be altered due to the vasoconstrictive nature of medetomidine, somatosensory evoked potential (SEP) and resting electroencephalography (EEG) were measured and correlated with corresponding BOLD signals in rat brains under three dosages of medetomidine. The SEP elicited by electrical stimulation to both forepaws was unchanged regardless of medetomidine dosage, which was consistent with the BOLD activation. Identical relationship between the SEP and BOLD signal under different medetomidine dosages indicates that the neurovascular coupling was not affected. Under resting state, EEG power was the same but a depression of inter-hemispheric EEG coherence in the gamma band was observed at higher medetomidine dosage. Different from medetomidine, both resting EEG power and BOLD power and coherence were significantly suppressed with increased isoflurane level. Such reduction was likely due to suppressed neural activity as shown by diminished SEP and BOLD activation under isoflurane, suggesting different mechanisms of losing synchrony at resting-state. Even though, similarity between electrophysiology and BOLD under stimulation and resting-state implicates a tight neurovascular coupling in both medetomidine and isoflurane. Our results confirm that medetomidine does not suppress neural activity but dissociates connectivity in the somatosensory cortex. The differential effect of medetomidine and its receptor specific action supports the neuronal origin of functional connectivity and implicates the mechanism of its sedative

  18. Beta 1- and beta 2-adrenergic 125I-pindolol binding sites in the interpeduncular nucleus of the rat: Normal distribution and the effects of deafferentation

    International Nuclear Information System (INIS)

    Battisti, W.P.; Artymyshyn, R.P.; Murray, M.

    1989-01-01

    The plasticity of the beta 1- and beta 2-adrenergic receptor subtypes was examined in the interpeduncular nucleus (IPN) of the adult rat. The beta-adrenergic receptor antagonist 125I-pindolol (125I-PIN) was used in conjunction with the selective subtype antagonists ICI 118,551 and ICI 89,406 to determine the subnuclear distribution of beta 1- and beta 2-adrenergic receptors in this nucleus and to correlate the receptor distribution with the distribution of both noradrenergic afferents from the locus coeruleus (LC) and non-noradrenergic afferents from the fasiculus retroflexus (FR). The density of these binding sites was examined following lesions that decreased (LC lesions) or increased (FR lesions) the density of the noradrenergic projection in the IPN. Quantitative radioautography indicated that beta 1-labeled binding sites account for the larger percentage of binding sites in the IPN. The beta 1-binding sites are densest in those subnuclei that receive a noradrenergic projection from the LC: the central, rostral, and intermediate subnuclei. beta 1-binding sites are algo homogeneously distributed throughout the lateral subnuclei, where there is no detectable noradrenergic innervation. beta 2-binding sites have a more restricted distribution. They are concentrated in the ventral half of the lateral subnuclei, where they account for 70% of total 125I-PIN binding sites. beta 2-binding sites are also present along the ventral border of the IPN. Some of this labeling extends into the central and intermediate subnuclei. Bilateral lesions of the LC, which selectively remove noradrenergic innervation to the IPN, result in an increase in the beta 1-binding sites. Bilateral lesions of the FR, which remove the major cholinergic and peptidergic input from the IPN, elicit an increase in noradrenergic projections and a decrease in beta 1-binding sites

  19. NCBI nr-aa BLAST: CBRC-DMEL-06-0067 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-DMEL-06-0067 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  20. NCBI nr-aa BLAST: CBRC-OLAT-01-0012 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-OLAT-01-0012 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  1. NCBI nr-aa BLAST: CBRC-PABE-21-0006 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PABE-21-0006 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  2. NCBI nr-aa BLAST: CBRC-TNIG-22-0186 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-TNIG-22-0186 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  3. NCBI nr-aa BLAST: CBRC-OCUN-01-1614 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-OCUN-01-1614 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  4. NCBI nr-aa BLAST: CBRC-CJAC-01-0998 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CJAC-01-0998 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  5. NCBI nr-aa BLAST: CBRC-TGUT-06-0022 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-TGUT-06-0022 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  6. NCBI nr-aa BLAST: CBRC-PTRO-21-0002 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PTRO-21-0002 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  7. NCBI nr-aa BLAST: CBRC-GGAL-04-0044 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-GGAL-04-0044 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  8. NCBI nr-aa BLAST: CBRC-RNOR-03-0467 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-RNOR-03-0467 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  9. NCBI nr-aa BLAST: CBRC-SARA-01-1942 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-SARA-01-1942 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  10. NCBI nr-aa BLAST: CBRC-MMUS-02-0386 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-MMUS-02-0386 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  11. NCBI nr-aa BLAST: CBRC-PMAR-01-0862 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-PMAR-01-0862 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  12. NCBI nr-aa BLAST: CBRC-FRUB-02-0703 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-FRUB-02-0703 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  13. NCBI nr-aa BLAST: CBRC-GACU-09-0018 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-GACU-09-0018 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  14. NCBI nr-aa BLAST: CBRC-OCUN-01-0599 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-OCUN-01-0599 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  15. NCBI nr-aa BLAST: CBRC-DSIM-06-0034 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-DSIM-06-0034 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  16. NCBI nr-aa BLAST: CBRC-FRUB-02-0406 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-FRUB-02-0406 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  17. NCBI nr-aa BLAST: CBRC-ACAR-01-0377 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-ACAR-01-0377 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  18. NCBI nr-aa BLAST: CBRC-HSAP-20-0001 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-HSAP-20-0001 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  19. NCBI nr-aa BLAST: CBRC-CFAM-24-0001 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-CFAM-24-0001 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

  20. Nitric oxide and the non-adrenergic non-cholinergic neurotransmission

    NARCIS (Netherlands)

    Boeckxstaens, G. E.; Pelckmans, P. A.

    1997-01-01

    In the early 1960s, the first evidence was reported demonstrating neurally mediated responses in the presence of adrenergic and cholinergic antagonists, leading to the introduction of the concept of non-adrenergic non-cholinergic neurotransmission. The inhibitory component of this part of the

  1. Effect of skin temperature on cutaneous vasodilator response to the β-adrenergic agonist isoproterenol.

    Science.gov (United States)

    Hodges, Gary J; Kellogg, Dean L; Johnson, John M

    2015-04-01

    The vascular response to local skin cooling is dependent in part on a cold-induced translocation of α2C-receptors and an increased α-adrenoreceptor function. To discover whether β-adrenergic function might contribute, we examined whether β-receptor sensitivity to the β-agonist isoproterenol was affected by local skin temperature. In seven healthy volunteers, skin blood flow was measured from the forearm by laser-Doppler flowmetry and blood pressure was measured by finger photoplethysmography. Data were expressed as cutaneous vascular conductance (CVC; laser-Doppler flux/mean arterial blood pressure). Pharmacological agents were administered via intradermal microdialysis. We prepared four skin sites: one site was maintained at a thermoneutral temperature of 34°C (32 ± 10%CVCmax) one site was heated to 39°C (38 ± 11%CVCmax); and two sites were cooled, one to 29°C (22 ± 7%CVCmax) and the other 24°C (16 ± 4%CVCmax). After 20 min at these temperatures to allow stabilization of skin blood flow, isoproterenol was perfused in concentrations of 10, 30, 100, and 300 μM. Each concentration was perfused for 15 min. Relative to the CVC responses to isoproterenol at the thermoneutral skin temperature (34°C) (+21 ± 10%max), low skin temperatures reduced (at 29°C) (+17 ± 6%max) or abolished (at 24°C) (+1 ± 5%max) the vasodilator response, and warm (39°C) skin temperatures enhanced the vasodilator response (+40 ± 9%max) to isoproterenol. These data indicate that β-adrenergic function was influenced by local skin temperature. This finding raises the possibility that a part of the vasoconstrictor response to direct skin cooling could include reduced background β-receptor mediated vasodilation. Copyright © 2015 the American Physiological Society.

  2. Uncoupling of the beta-adrenergic receptor as a mechanism of in vitro neutrophil desensitization

    International Nuclear Information System (INIS)

    Galant, S.P.; Britt, S.

    1984-01-01

    Human leukocytes have been useful in studying desensitization phenomena to beta-adrenergic agonists in a number of clinical conditions. In the present in vitro study the authors have explored the mechanism for beta-adrenergic desensitization and have compared conditions for homologous and heterologous desensitization, using the intact PMN model. PMN preincubated with isoproterenol (10 -4 M), washed thoroughly, then restimulated, desensitized rapidly so that within 10 min 80% of control isoproterenol-induced cyclic AMP stimulation is lost. Cells washed free of isoproterenol recover full responsiveness in 1 to 2 hr. The estimated isoproterenol desensitization EC 50 in cells washed and then restimulated is 1 x 10 -5 M, and EC 50 in unwashed cells that are restimulated is 9 x 10 -8 M. Rank-order potency studies of catecholamine desensitization show isoproterenol > epinephrine > norepinephrine, a beta-2 pattern. Isoproterenol-induced desensitization results in a small reduction in [ 3 H]DHA binding sites, which becomes statistically significant (p 50 of 6.6 +/- 2.6 x 10 - (M, which is significantly different (p 50 of 38.1 +/- 9.1 x 10 -1 M found when cells are previously desensitized with isoproterenol for 10 min. GTP does not affect the EC 50 of desensitized cells. Finally, prolonged (3 hr) isoproterenol preincubation results in a small but significant (p 1 (59.3% +/- 7.4), suggesting heterologous desensitization. These studies suggest that the human PMN is a suitable model to study both homologous and heterologous desensitization in vitro. 22 references. 6 figures. 3 tables

  3. Dopaminergic and beta-adrenergic effects on gastric antral motility

    DEFF Research Database (Denmark)

    Bech, K; Hovendal, C P; Gottrup, F

    1984-01-01

    of bethanechol or pentagastrin inducing motor activity patterns as in the phase III of the MMC and the digestive state respectively. The stimulated antral motility was dose-dependently inhibited by dopamine. The effect was significantly blocked by specifically acting dopaminergic blockers, while alpha- and beta......-adrenergic blockers were without any significant effects. Dose-response experiments with bethanechol and dopamine showed inhibition of a non-competitive type. Isoprenaline was used alone and in conjunction with selective blockade of beta 1- and beta 2-receptors during infusion of bethanechol which induces a pattern...... similar to phase III in the migrating myoelectric complex. The stimulated antral motility was dose-dependently inhibited by isoprenaline. The effect could be significantly blocked by propranolol (beta 1 + beta 2-adrenoceptor blocker) and by using in conjunction the beta 1-adrenoceptor blocker practolol...

  4. Roles of beta2-adrenergic receptor gene polymorphisms in a Turkish population with obstructive sleep apnea syndrome or obesity.

    Science.gov (United States)

    Gök, I; Celebi, I; Hüseyinoğlu, N; Ozic, C

    2014-10-20

    We determined the distribution of the Arg16Gly and Gln27Glu polymorphisms of the beta-2 adrenergic receptor gene (ADRB2) in patients with obstructive sleep apnea syndrome as well as a control group in Northeastern Turkey. A total of 52 patients diagnosed with obstructive sleep apnea in a sleep laboratory and 78 control subjects were examined. Peripheral blood samples were taken from patients diagnosed with obstructive sleep apnea by polysomnography. DNA was extracted from blood samples and amplified using polymerase chain reaction. Amplification products were digested with restriction enzymes to investigate gene polymorphisms. Restriction products were extracted from agarose gel electrophoresis and polymorphisms were analyzed using gel images. The Arg16Gly polymorphism was observed in 18 of 52 patients and in 23 of 78 controls. The Gln27Glu polymorphism was observed in 21 of 52 patients and in 28 of 78 controls. In conclusion, there was no correlation among polymorphic frequencies between patient and control groups. Based on the results, these polymorphisms do not contribute to the clinical diagnosis of this syndrome. However, the distribution of Arg16Gly vs Gln27Glu polymorphisms may contribute to obesity in patients with a body mass index greater than 30 (P sleep apnea disease are changed.

  5. MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac hypertrophy induced by α1-adrenergic receptors.

    Science.gov (United States)

    Ogata, Takehiro; Naito, Daisuke; Nakanishi, Naohiko; Hayashi, Yukiko K; Taniguchi, Takuya; Miyagawa, Kotaro; Hamaoka, Tetsuro; Maruyama, Naoki; Matoba, Satoaki; Ikeda, Koji; Yamada, Hiroyuki; Oh, Hidemasa; Ueyama, Tomomi

    2014-03-11

    The actions of catecholamines on adrenergic receptors (ARs) induce sympathetic responses, and sustained activation of the sympathetic nervous system results in disrupted circulatory homeostasis. In cardiomyocytes, α1-ARs localize to flask-shaped membrane microdomains known as "caveolae." Caveolae require both caveolin and cavin proteins for their biogenesis and function. However, the functional roles and molecular interactions of caveolar components in cardiomyocytes are poorly understood. Here, we showed that muscle-restricted coiled-coil protein (MURC)/Cavin-4 regulated α1-AR-induced cardiomyocyte hypertrophy through enhancement of ERK1/2 activation in caveolae. MURC/Cavin-4 was expressed in the caveolae and T tubules of cardiomyocytes. MURC/Cavin-4 overexpression distended the caveolae, whereas MURC/Cavin-4 was not essential for their formation. MURC/Cavin-4 deficiency attenuated cardiac hypertrophy induced by α1-AR stimulation in the presence of caveolae. Interestingly, MURC/Cavin-4 bound to α1A- and α1B-ARs as well as ERK1/2 in caveolae, and spatiotemporally modulated MEK/ERK signaling in response to α1-AR stimulation. Thus, MURC/Cavin-4 facilitates ERK1/2 recruitment to caveolae and efficient α1-AR signaling mediated by caveolae in cardiomyocytes, which provides a unique insight into the molecular mechanisms underlying caveola-mediated signaling in cardiac hypertrophy.

  6. 2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R-2-((2-(1H-Indol-2-ylethylamino-1-Phenylethan-1-ol with Human β3-Adrenergic Activity

    Directory of Open Access Journals (Sweden)

    Gastón Apablaza

    2017-03-01

    Full Text Available The β3 adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration in USA and the MHRA (Medicines and Healthcare products Regulatory Agency in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis study on a series of potent β3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β3 adrenergic activity is given.

  7. Adenosine deaminase complexing protein (ADCP) immunoreactivity in colorectal adenocarcinoma.

    Science.gov (United States)

    ten Kate, J; van den Ingh, H F; Khan, P M; Bosman, F T

    1986-04-15

    Immunoreactive adenosine deaminase complexing protein (ADCP) was studied in 91 human colorectal adenocarcinomas. The expression of ADCP was correlated with that of secretory component (SC) and carcinoembryonic antigen (CEA), with the histological grade and the Dukes' stage of the carcinomas. The histological grade was scored semi-quantitatively according to 5 structural and 4 cytological variables. ADCP expression was observed in 3 different staining patterns, namely: (1) diffuse cytoplasmic (77% of the carcinomas); (2) granular cytoplasmic (13%); and (3) membrane-associated (66%). These patterns were observed alone or in combination. Eleven percent of the carcinomas exhibited no ADCP immunoreactivity. Linear regression analysis showed that the expression of ADCP correlates with that of SC and CEA. However, no significant correlation emerged between the histological parameters or the Dukes' stage and any of the immunohistological parameters. Comparison of the histological characteristics of carcinomas exhibiting little or no ADCP immunoreactivity with those showing extensive immunoreactivity, showed that membranous ADCP immunoreactivity occurs more frequently in well-differentiated carcinomas. Structural parameters showed a better correlation with membranous ADCP expression than the cytological variables. It is concluded that membranous expression of ADCP and CEA are indicators of a high level of differentiation as reflected primarily in the structural characteristics of the tumor.

  8. β3-adrenergic receptor activation induces TGFβ1 expression in cardiomyocytes via the PKG/JNK/c-Jun pathway.

    Science.gov (United States)

    Xu, Zhongcheng; Wu, Jimin; Xin, Junzhou; Feng, Yenan; Hu, Guomin; Shen, Jing; Li, Mingzhe; Zhang, Youyi; Xiao, Han; Wang, Li

    2018-06-05

    In heart failure, the expression of cardiac β 3 -adrenergic receptors (β 3 -ARs) increases. However, the precise role of β 3 -AR signaling within cardiomyocytes remains unclear. Transforming growth factor β1 (TGFβ1) is a crucial cytokine mediating the cardiac remodeling that plays a causal role in the progression of heart failure. Here, we set out to determine the effect of β 3 -AR activation on TGFβ1 expression in rat cardiomyocytes and examine the underlying mechanism. The selective β 3 -AR agonist BRL37344 induced an increase in TGFβ1 expression and the phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun in β 3 -AR-overexpressing cardiomyocytes. Those effects of BRL37344 were suppressed by a β 3 -AR antagonist. Moreover, the inhibition of JNK and c-Jun activity by a JNK inhibitor and c-Jun siRNA blocked the increase in TGFβ1 expression upon β 3 -AR activation. A protein kinase G (PKG) inhibitor also attenuated β 3 -AR-agonist-induced TGFβ1 expression and the phosphorylation of JNK and c-Jun. In conclusion, the β 3 -AR activation in cardiomyocytes increases the expression of TGFβ1 via the PKG/JNK/c-Jun pathway. These results help us further understand the role of β 3 -AR signaling in heart failure. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Linking γ-aminobutyric acid A receptor to epidermal growth factor receptor pathways activation in human prostate cancer.

    Science.gov (United States)

    Wu, Weijuan; Yang, Qing; Fung, Kar-Ming; Humphreys, Mitchell R; Brame, Lacy S; Cao, Amy; Fang, Yu-Ting; Shih, Pin-Tsen; Kropp, Bradley P; Lin, Hsueh-Kung

    2014-03-05

    Neuroendocrine (NE) differentiation has been attributed to the progression of castration-resistant prostate cancer (CRPC). Growth factor pathways including the epidermal growth factor receptor (EGFR) signaling have been implicated in the development of NE features and progression to a castration-resistant phenotype. However, upstream molecules that regulate the growth factor pathway remain largely unknown. Using androgen-insensitive bone metastasis PC-3 cells and androgen-sensitive lymph node metastasis LNCaP cells derived from human prostate cancer (PCa) patients, we demonstrated that γ-aminobutyric acid A receptor (GABA(A)R) ligand (GABA) and agonist (isoguvacine) stimulate cell proliferation, enhance EGF family members expression, and activate EGFR and a downstream signaling molecule, Src, in both PC-3 and LNCaP cells. Inclusion of a GABA(A)R antagonist, picrotoxin, or an EGFR tyrosine kinase inhibitor, Gefitinib (ZD1839 or Iressa), blocked isoguvacine and GABA-stimulated cell growth, trans-phospohorylation of EGFR, and tyrosyl phosphorylation of Src in both PCa cell lines. Spatial distributions of GABAAR α₁ and phosphorylated Src (Tyr416) were studied in human prostate tissues by immunohistochemistry. In contrast to extremely low or absence of GABA(A)R α₁-positive immunoreactivity in normal prostate epithelium, elevated GABA(A)R α₁ immunoreactivity was detected in prostate carcinomatous glands. Similarly, immunoreactivity of phospho-Src (Tyr416) was specifically localized and limited to the nucleoli of all invasive prostate carcinoma cells, but negative in normal tissues. Strong GABAAR α₁ immunoreactivity was spatially adjacent to the neoplastic glands where strong phospho-Src (Tyr416)-positive immunoreactivity was demonstrated, but not in adjacent to normal glands. These results suggest that the GABA signaling is linked to the EGFR pathway and may work through autocrine or paracine mechanism to promote CRPC progression. Copyright © 2013 Elsevier

  10. PET measures of pre- and post-synaptic cardiac beta adrenergic function

    Energy Technology Data Exchange (ETDEWEB)

    Link, Jeanne M.; Stratton, John R.; Levy, Wayne; Poole, Jeanne E.; Shoner, Steven C.; Stuetzle, Werner; Caldwell, James H. E-mail: jcald@u.washington.edu

    2003-11-01

    Positron Emission Tomography was used to measure global and regional cardiac {beta}-adrenergic function in 19 normal subjects and 9 congestive heart failure patients. [{sup 11}C]-meta-hydroxyephedrine was used to image norepinephrine transporter function as an indicator of pre-synaptic function and [{sup 11}C]-CGP12177 was used to measure cell surface {beta}-receptor density as an indicator of post-synaptic function. Pre-synaptic, but not post-synaptic, function was significantly different between normals and CHF patients. Pre-synaptic function was well matched to post-synaptic function in the normal hearts but significantly different and poorly matched in the CHF patients studied. This imaging technique can help us understand regional sympathetic function in cardiac disease.

  11. Nebivolol protects against myocardial infarction injury via stimulation of beta 3-adrenergic receptors and nitric oxide signaling.

    Directory of Open Access Journals (Sweden)

    Zheng Zhang

    Full Text Available Nebivolol, third-generation β-blocker, may activate β3-adrenergic receptor (AR, which has been emerged as a novel and potential therapeutic targets for cardiovascular diseases. However, it is not known whether nebivolol administration plays a cardioprotective effect against myocardial infarction (MI injury. Therefore, the present study was designed to clarify the effects of nebivolol on MI injury and to elucidate the underlying mechanism. MI model was constructed by left anterior descending (LAD artery ligation. Nebivolol, β3-AR antagonist (SR59230A, Nitro-L-arginine methylester (L-NAME or vehicle was administered for 4 weeks after MI operation. Cardiac function was monitored by echocardiography. Moreover, the fibrosis and the apoptosis of myocardium were assessed by Masson's trichrome stain and TUNEL assay respectively 4 weeks after MI. Nebivolol administration reduced scar area by 68% compared with MI group (p<0.05. Meanwhile, nebivolol also decreased the myocardial apoptosis and improved the heart function after MI (p<0.05 vs. MI. These effects were associated with increased β3-AR expression. Moreover, nebivolol treatment significantly increased the phosphorylation of endothelial NOS (eNOS and the expression of neuronal NOS (nNOS. Conversely, the cardiac protective effects of nebivolol were abolished by SR and L-NAME. These results indicate that nebivolol protects against MI injury. Furthermore, the cardioprotective effects of nebivolol may be mediated by β3-AR-eNOS/nNOS pathway.

  12. Changes in serotoninergic receptors 1A and 2A in the piglet brainstem after intermittent hypercapnic hypoxia (IHH) and nicotine.

    Science.gov (United States)

    Say, Meichien; Machaalani, Rita; Waters, Karen A

    2007-06-04

    We studied the effects of intermittent hypercapnic hypoxia (IHH) and/or nicotine on the immunoreactivity of serotoninergic (5-HT) receptors 1A and 2A in the piglet brainstem. These exposures were developed to mimic two common risk factors for Sudden Infant Death Syndrome (SIDS); prone sleeping (IHH) and cigarette smoke exposure (nicotine). Immunoreactivity for 5-HT(1A)R and 5-HT(2A)R were studied in four nuclei of the caudal medulla. Three exposure groups were compared to controls (n=14): IHH (n=10), nicotine (n=14), and nicotine+IHH (n=14). In control piglets, the immunoreactivity of 5-HT(1A)R was highest in the hypoglossal nucleus (XII), followed by inferior olivary nucleus (ION), nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus (DMNV), whereas for 5-HT(2A)R, the immunoreactivity was highest in DMNV/NTS and then ION. Compared to controls, IHH reduced 5-HT(1A)R immunoreactivity in all studied nuclei (pIHH reduced 5-HT(1A)R in DMNV, ION and NTS (pIHH and/or nicotine can reduce 5-HT receptor immunoreactivity within functionally important nuclei of the piglet medulla. The findings support our hypothesis that 5-HT receptor abnormalities may be caused by postnatal exposures to clinically-relevant stimuli such as cigarette smoke exposure and/or prone sleeping.

  13. Attenuation of alpha2A-adrenergic receptor expression in neonatal rat brain by RNA interference or antisense oligonucleotide reduced anxiety in adulthood.

    Science.gov (United States)

    Shishkina, G T; Kalinina, T S; Dygalo, N N

    2004-01-01

    Brain alpha2-adrenergic receptors (alpha2-ARs) have been implicated in the regulation of anxiety, which is associated with stress. Environmental treatments during neonatal development could modulate the level of brain alpha2-AR expression and alter anxiety in adults, suggesting possible involvement of these receptors in early-life programming of anxiety state. The present study was undertaken to determine whether the reduction of the expression of A subtype of these receptors most abundant in the neonatal brain affects anxiety-related behavior in adulthood. We attenuated the expression of alpha2A-ARs during neonatal life by two different sequence specific approaches, antisense technology and RNA interference. Treatment of rats with the antisense oligodeoxynucleotide or short interfering RNA (siRNA) against alpha2A-ARs on the days 2-4 of their life, produced a marked acute decrease in the levels of both alpha2A-AR mRNA and [3H]RX821002 binding sites in the brainstem into which drugs were injected. The decrease of alpha2A-AR expression in the neonatal brainstem influenced the development of this receptor system in the brain regions as evidenced by the increased number of [3H]RX821002 binding sites in the hypothalamus of adult animals with both neonatal alpha2A-AR knockdown treatments; also in the frontal cortex of antisense-treated, and in the hippocampus of siRNA-treated adult rats. These adult animals also demonstrated a decreased anxiety in the elevated plus-maze as evidenced by an increased number of the open arm entries, greater proportion of time spent in the open arms, and more than a two-fold increase in the number of exploratory head dips. The results provide the first evidence that the reduction in the brain expression of a gene encoding for alpha2A-AR during neonatal life led to the long-term neurochemical and behavioral alterations. The data suggests that alterations in the expression of the receptor-specific gene during critical periods of brain

  14. FMRFamide-like immunoreactivity in the nervous system of Hydra

    DEFF Research Database (Denmark)

    Grimmelikhuijzen, C J; Dockray, G J; Schot, L P

    1982-01-01

    FMRFamide-like immunoreactivity has been localized in different parts of the hydra nervous system. Immunoreactivity occurs in nerve perikarya and processes in the ectoderm of the lower peduncle region near the basal disk, in the ectoderm of the hypostome and in the ectoderm of the tentacles...

  15. Localization of Brain Natriuretic Peptide Immunoreactivity in Rat Spinal Cord

    Directory of Open Access Journals (Sweden)

    Essam M Abdelalim

    2016-12-01

    Full Text Available Brain natriuretic peptide (BNP exerts its functions through natriuretic peptide receptors. Recently, BNP has been shown to be involved in a wide range of functions. Previous studies reported BNP expression in the sensory afferent fibers in the dorsal horn of the spinal cord. However, BNP expression and function in the neurons of the central nervous system are still controversial. Therefore, in this study, we investigated BNP expression in the rat spinal cord in detail using RT-PCR and immunohistochemistry. RT-PCR analysis showed that BNP mRNA was present in the spinal cord and DRG. BNP immunoreactivity was observed in different structures of the spinal cord, including the neuronal cell bodies and neuronal processes. BNP immunoreactivity was observed in the dorsal horn of the spinal cord and in the neurons of the intermediate column and ventral horn. Double-immunolabeling showed a high level of BNP expression in the afferent fibers (laminae I-II labeled with calcitonin gene-related peptide (CGRP, suggesting BNP involvement in sensory function. In addition, BNP was co-localized with CGRP and choline acetyltransferase in the motor neurons of the ventral horn. Together, these results indicate that BNP is expressed in sensory and motor systems of the spinal cord, suggesting its involvement in several biological actions on sensory and motor neurons via its binding to NPR-A and/or NPR-B in the DRG and spinal cord.

  16. Inhibition of protein synthesis but not β-adrenergic receptors blocks reconsolidation of a cocaine-associated cue memory.

    Science.gov (United States)

    Dunbar, Amber B; Taylor, Jane R

    2016-08-01

    Previously consolidated memories have the potential to enter a state of lability upon memory recall, during which time the memory can be altered before undergoing an additional consolidation-like process and being stored again as a long-term memory. Blocking reconsolidation of aberrant memories has been proposed as a potential treatment for psychiatric disorders including addiction. Here we investigated of the effect of systemically administering the protein synthesis inhibitor cycloheximide or the β-adrenergic antagonist propranolol on reconsolidation. Rats were trained to self-administer cocaine, during which each lever press resulted in the presentation of a cue paired with an intravenous infusion of cocaine. After undergoing lever press extinction to reduce operant responding, the cue memory was reactivated and rats were administered systemic injections of propranolol, cycloheximide, or vehicle. Post-reactivation cycloheximide, but not propranolol, resulted in a reactivation-dependent decrease in cue-induced reinstatement, indicative of reconsolidation blockade by protein synthesis inhibition. The present data indicate that systemically targeting protein synthesis as opposed to the β-adrenergic system may more effectively attenuate the reconsolidation of a drug-related memory and decrease drug-seeking behavior. © 2016 Dunbar and Taylor; Published by Cold Spring Harbor Laboratory Press.

  17. Nitric oxide-dependent activation of CaMKII increases diastolic sarcoplasmic reticulum calcium release in cardiac myocytes in response to adrenergic stimulation.

    Science.gov (United States)

    Curran, Jerry; Tang, Lifei; Roof, Steve R; Velmurugan, Sathya; Millard, Ashley; Shonts, Stephen; Wang, Honglan; Santiago, Demetrio; Ahmad, Usama; Perryman, Matthew; Bers, Donald M; Mohler, Peter J; Ziolo, Mark T; Shannon, Thomas R

    2014-01-01

    Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca(2+) leak) through ryanodine receptors. Beta-adrenergic (β-AR) tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII) and the subsequent phosphorylation of the ryanodine receptor. When β-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent evidence has indicated that CaMKII activation can be regulated by cellular oxidizing agents, such as reactive oxygen species. Here, we investigate how the cellular second messenger, nitric oxide, mediates CaMKII activity downstream of the adrenergic signaling cascade and promotes the generation of arrhythmogenic spontaneous Ca(2+) waves in intact cardiomyocytes. Both SCaWs and SR Ca(2+) leak were measured in intact rabbit and mouse ventricular myocytes loaded with the Ca-dependent fluorescent dye, fluo-4. CaMKII activity in vitro and immunoblotting for phosphorylated residues on CaMKII, nitric oxide synthase, and Akt were measured to confirm activity of these enzymes as part of the adrenergic cascade. We demonstrate that stimulation of the β-AR pathway by isoproterenol increased the CaMKII-dependent SR Ca(2+) leak. This increased leak was prevented by inhibition of nitric oxide synthase 1 but not nitric oxide synthase 3. In ventricular myocytes isolated from wild-type mice, isoproterenol stimulation also increased the CaMKII-dependent leak. Critically, in myocytes isolated from nitric oxide synthase 1 knock-out mice this effect is ablated. We show that isoproterenol stimulation leads to an increase in nitric oxide production, and nitric oxide alone is sufficient to activate CaMKII and increase SR Ca(2+) leak. Mechanistically, our data links Akt to nitric oxide synthase 1 activation downstream of β-AR stimulation. Collectively, this evidence supports the hypothesis that CaMKII is

  18. Serotonin Immunoreactive Cells and Nerve Fibers in the Mucosa of ...

    African Journals Online (AJOL)

    hydroxytryptamine) immunoreactivity in the pyloric mucosa of the rat stomach. The immunoreactive elements included the endocrine cells, mast cells and mucosal nerve fibers in the lamina propria. The immunopositive endocrine cells were oval in ...

  19. β-adrenergic relaxation of smooth muscle: differences between cells and tissues

    International Nuclear Information System (INIS)

    Scheid, C.R.

    1987-01-01

    The present studies were carried out in an attempt to resolve the controversy about the Na + dependence of β-adrenergic relaxation in smooth muscle. Previous studies on isolated smooth muscle cells from the toad stomach had suggested that at least some of the actions of β-adrenergic agents, including a stimulatory effect on 45 Ca efflux, were dependent on the presence of a normal transmembrane Na + gradient. Studies by other investigators using tissues derived from mammalian sources had suggested that the relaxing effect of β-adrenergic agents was Na + independent. Uncertainty remained as to whether these discrepancies reflected differences between cells and tissues or differences between species. Thus, in the present studies, the authors utilized both tissues and cells from the same source, the stomach muscle of the toad Bufo marinus, and assessed the Na + dependence of β-adrenergic relaxation. They found that elimination of a normal Na + gradient abolished β-adrenergic relaxation of isolated cells. In tissues, however, similar manipulations had no effect on relaxation. The reasons for this discrepancy are unclear but do not appear to be attributable to changes in smooth muscle function following enzymatic dispersion. Thus the controversy concerning the mechanisms of β-adrenergic relaxation may reflect inherent differences between tissues and cells

  20. Mechanism of action of cysteamine in depleting prolactin immunoreactivity

    International Nuclear Information System (INIS)

    Sagar, S.M.; Millard, W.J.; Martin, J.B.; Murchison, S.C.

    1985-01-01

    The thiol reagent cysteamine (CSH) depletes anterior pituitary cells of immunoreactive PRL both in vivo and in vitro. The authors examined the hypothesis that CSH affects either the solubility or immunoreactivity of PRL through a mechanism involving thiol-disulfide exchange. Adult female rats were treated with either CSH (300 mg/kg, sc) or an equimolar dose of ethanolamine as a control. Anterior pituitary glands were extracted in 0.1 M sodium borate buffer, pH 9.0. Treatment of pituitary extracts with beta-mercaptoethanol (BME) destroys the immunoreactivity of PRL. However, extraction in the presence of reduced glutathione or CSH of pituitaries of rats treated with CSH restores immunoreactive PRL to control levels. Extracts were also subjected to polyacrylamide gel electrophoresis (PAGE). On gels of pituitary extracts of CSH-treated rats, the band that comigrates with purified PRL is diminished compared to that in ethanolamine-treated controls. However, extraction of the pituitaries in sodium dodecyl sulfate-containing buffer followed by chemical reduction with BME restores the PRL band. Therefore, CSH acts on PRL through a thiol-related mechanism to yield a product that is poorly soluble in aqueous buffer at pH 9 and is poorly immunoreactive. Dispersed anterior pituitary cells in tissue culture were incubated with L-[ 35 S]methionine to radiolabel newly synthesized peptides. PAGE followed by autoradiography confirmed the above results obtained in vivo