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Sample records for adrenergic antagonists

  1. Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists.

    Science.gov (United States)

    Hong, Seoung-Soo; Bavadekar, Supriya A; Lee, Sang-Il; Patil, Popat N; Lalchandani, S G; Feller, Dennis R; Miller, Duane D

    2005-11-01

    The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.

  2. 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.

  3. Antagonism of apomorphine-enhanced startle by alpha 1-adrenergic antagonists.

    Science.gov (United States)

    Davis, M; Kehne, J H; Commissaris, R L

    1985-02-05

    The present study investigated the possible involvement of central noradrenergic neurons in mediating the excitatory effect of the dopamine agonist apomorphine on the acoustic startle response in rats. Experiment 1 assessed the effects of intraperitoneal (i.p.) administration of adrenergic antagonists on apomorphine-enhanced startle. The excitation of startle produced by apomorphine (1.0-3.0 mg/kg i.p.) was blocked by the alpha 1-adrenergic antagonists prazosin (0.03-1.0 mg/kg) and WB-4101 (1.0 mg/kg). Prazosin was very potent in this regard, having an ED50 of 0.03 mg/kg. Blockade of beta-adrenergic receptors with propranolol (20 mg/kg) or blockade of peripheral alpha-adrenergic receptors with phentolamine (10 mg/kg) failed to alter the effect of apomorphine. Prazosin did not block the enhancement of startle produced by other drugs (5-methoxy-N,N-dimethyltryptamine, strychnine), nor did it alter the entry of apomorphine into the brain. The alpha 1-adrenergic antagonists piperoxane (0.03 mg/kg), yohimbine (0.03 mg/kg) or RX781094 (0.07 mg/kg) markedly potentiated apomorphine excitation. These data indicated that specific blockade of central alpha 1-adrenergic receptors prevents apomorphine-enhanced startle. In contrast to the effects of alpha 1-adrenergic antagonists, Experiment 2 found that other drugs that produce an acute (clonidine, 0.040 mg/kg) or chronic (intraventricular 6-hydroxydopamine, 2 X 200 micrograms; DSP4, 50 mg/kg i.p.) disruption of noradrenergic transmission failed to affect apomorphine excitation. Thus, the ability of alpha 1-adrenergic antagonists to block apomorphine's excitation of startle cannot be explained by a simple dopamine-norepinephrine interaction. Alternative hypothesis are discussed.

  4. Impact of alpha 1-adrenergic antagonist use for benign prostatic hypertrophy on outcomes in patients with heart failure.

    Science.gov (United States)

    Dhaliwal, Amandeep S; Habib, Gabriel; Deswal, Anita; Verduzco, Melinda; Souchek, Julianne; Ramasubbu, Kumudha; Aguilar, David; Ma, Tony S; Jneid, Hani M; Bolos, Mariana; Bozkurt, Biykem

    2009-07-15

    Previous clinical trials have shown that alpha(1)-adrenergic antagonists are not effective in subjects with heart failure (HF) and might increase HF rates when used for hypertension. However, alpha(1)-adrenergic antagonists may be prescribed to subjects with HF who have symptomatic benign prostatic hyperplasia. We sought to determine any association between alpha(1)-adrenergic antagonist use, commonly prescribed for benign prostatic hyperplasia, and the clinical outcomes of subjects with HF receiving contemporary therapy. An existing database of 388 subjects with decompensated HF admissions from 2002 to 2004 at the Veterans Affairs Hospital was analyzed according to the use of alpha(1)-adrenergic antagonists at discharge. Covariate-adjusted Cox proportional hazard models were used to examine any association with future admissions for decompensated HF and total mortality. Alpha-1-adrenergic antagonist therapy was prescribed in 25% of our HF population, predominantly for benign prostatic hyperplasia, and was not associated with significant increases in the combined risk of all-cause mortality and rehospitalization for HF (hazard ratio 1.24, 95% confidence interval 0.93 to 1.65, p = 0.14), HF hospitalization (hazard ratio 1.20, 95% confidence interval 0.85 to 1.70, p = 0.31), or all-cause mortality (hazard ratio 1.10, 95% confidence interval 0.78 to 1.56, p = 0.57). In patients not receiving beta-blocker therapy, alpha(1)-adrenergic antagonist therapy was significantly associated with increased HF hospitalizations (hazard ratio 1.94, 95% confidence interval 1.14 to 3.32, p = 0.015). In conclusion, in patients with chronic HF, the use of alpha(1)-adrenergic antagonists was significantly associated with more HF hospitalizations when prescribed without concomitant beta blockade. Thus, background beta-blocker therapy appears to be protective against the potential harmful effects of alpha(1)-adrenergic antagonist therapy in patients with HF.

  5. Alpha-1 adrenergic antagonists in aircrew for the treatment of benign prostatic hypertrophy.

    Science.gov (United States)

    Matthies, Andrew K; Tachikawa, Nina J

    2013-01-01

    Benign prostatic hypertrophy (BPH) affects the majority of men later in life. Other than surgery, finasteride (Proscar) is currently the only pharmacologic option available for U.S. Air Force (USAF) aircrew. This article will evaluate the current literature regarding the treatment of benign prostatic hypertrophy with FDA approved tamsulosin (Flomax) and alfuzosin (Uroxatrol), third-generation alpha-1 adrenergic antagonists. Current literature supports the fact that some third-generation alpha blockers limit the side effects of hypotension when compared to other alpha blockers as a result of the specificity of subtype binding of the receptors and the sustained release formulation. Alpha blockers are currently used almost universally for the treatment of BPH; however, they are currently not approved for USAF aircrew. This article will review the aeromedical implications of the side effects of alpha-1 adrenergic antagonists (alfuzosin, tamsulosin), which affect aircrew while performing aeronautical duties, and examine whether alpha-1 adrenergic antagonists should be acceptable medications in certain situations depending on airframe and aeronautical duties.

  6. Postcountershock myocardial damage after pretreatment with adrenergic and calcium channel antagonists in halothane-anesthetized dogs

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    Gaba, D.M.; Metz, S.; Maze, M.

    1985-05-01

    Transthoracic electric countershock can cause necrotic myocardial lesions in humans as well as experimental animals. The authors investigated the effect on postcountershock myocardial damage of pretreatment with prazosin, an alpha-1 antagonist; L-metoprolol, a beta-1 antagonist, and verapamil, a calcium channel-blocking agent. Twenty dogs were anesthetized with halothane and given two transthoracic countershocks of 295 delivered joules each after drug or vehicle treatment. Myocardial injury was quantitated 24 h following countershock by measuring the uptake of technetium-99m pyrophosphate in the myocardium. Elevated technetium-99m pyrophosphate uptake occurred in visible lesions in most dogs regardless of drug treatment. For each of four parameters of myocardial damage there was no statistically significant difference between control animals and those treated with prazosin, metoprolol, or verapamil. These data suggest that adrenergic or calcium channel-mediated mechanisms are not involved in the pathogenesis of postcountershock myocardial damage.

  7. Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction.

    Science.gov (United States)

    Goldstein, I

    2000-03-01

    Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic receptor antagonist which has undergone clinical trials for erectile dysfunction treatment. Biochemical and physiological studies in human erectile tissue have revealed a high affinity of phentolamine for alpha-1 and alpha-2 adrenergic receptors. Based on pharmacokinetic studies, it is suggested that 30-40 min following oral ingestion of 40 or 80 mg of phentolamine (Vasomax), the mean plasma phentolamine concentrations are sufficient to occupy the alpha-1 and -2 adrenergic receptors in erectile tissue and thereby result in inhibition of adrenergic-mediated physiologic activity. In large multi-center, placebo-controlled pivotal phase III clinical trials, the mean change in the erectile function domain of the International Index of Erectile Function scores (Questions 1-5 and 15) from screening to the end of treatment was significantly higher following use of active drug (40 mg and 80 mg) compared to placebo. Three to four times as many patients receiving phentolamine reported being satisfied or very satisfied compared with those receiving placebo. At doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration with 51% and 53% achieving penetration on 75% of attempts. The correction of erectile dysfunction or improvement to a less severe category of dysfunction was experienced by 53% of men with the 80 mg dose and 40% with the 40 mg dose of phentolamine. All trends of response were the same regardless of any concomitant medication. There were no severe adverse events. At 40 mg, 7.7% experienced rhinitis and fewer than 3.1% experienced any other side effect of treatment. Phentolamine is safe, well tolerated and efficacious for the treatment of erectile dysfunction.

  8. The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder.

    Science.gov (United States)

    Taylor, Fletcher; Raskind, Murray A

    2002-02-01

    Heightened noradrenergic reactivity may be a contributing factor in the pathophysiology of posttraumatic stress disorder (PTSD). Prazosin is an alpha1-adrenoceptor antagonist commonly used as an antihypertensive agent. Because alpha1-adrenergic activity has been associated with fear and startle responses, a drug that blocks central alpha1-adrenergic activity may be useful in the treatment of PTSD symptoms. An outpatient who had been exposed to civilian trauma and had subsequent chronic refractory PTSD was thus prescribed prazosin. The marked reduction in PTSD symptoms, particularly sleep and nightmares, prompted the following open-label feasibility trial. Five outpatients with non-combat-related PTSD were consecutively identified and received prazosin in a 6-week open-label trial. In each case, the prazosin doses were slowly increased until optimal benefit was achieved. Change was assessed with the Clinician-Administered PTSD Scale for DSM-IV, One Week Symptom Version (CAPS-SX), the Clinical Global Impression of Change Scale (CGIC), and the Clinical Impression of Change-Nightmares (CIC-Nightmares) score. All five patients experienced moderate to marked improvement on the CGIC. The CAPS-SX PTSD nightmare and sleep PTSD categories showed at least a four-point reduction of those symptoms. All patients reported at least moderate improvement on the CIC-Nightmare score. Optimal doses of prazosin ranged from 1 to 4 mg/day. The drug was reasonably tolerated, and there were no drug discontinuations. These preliminary findings provide a rationale for blind placebo-controlled efficacy trials of the alpha 1 antagonist prazosin for PTSD.

  9. Effects of β2-Adrenergic Antagonist on Cytosolic Ca2+ in Ventricular Myocytes from Infarcted Rat Heart

    Institute of Scientific and Technical Information of China (English)

    Yang Hui; Wu Wei; Zeng Chong; Deng Chunyu; Fang Chang; Chen Shanming

    2006-01-01

    Objectives To investigate the effects of β2-adrenergic antagonist on cytosolic Ca2 +([Ca2+]i) in ventricular myocytes from infarcted rat heart. Methods A ligature was placed around left anterior descending coronary artery of rat hearts. Rats in the control group were sham-operated.Cardiomyocytes were dissociated at two, four, eight weeks after myocardial infarction (MI) and [Ca2+]i was measured via fura-2 fluorescence. The response of cardiomyocytes to isoproterenol in presence or absenceof beta1-adrenergic antagonist atenolol, beta2-adrenergic antagonist ICI118, 551 or non-selective β1,2- adrenergic antagonists propranolol was examined.Results The followings were found that ICI11 8, 551 had no significant effects on the rise of [Ca2+]i induced by isoproterenol in normal ventricular myocytes (P >0.05), ICI118, 551 only significantly attenuated the rise of [Ca2+]i induced by isoproterenol at four weeks and eight weeks after MI (24.5% ±5.7% vs 57.8% ±13.2%, P< 0.01; 12.2%±7.9% vs 44.6%±11.3%, P<0.01). Atenolol had suppressive effects only in the control group and the post-MI group of two weeks (P<0.05), and propranolol had suppressive effects in the control and all the three post-MI groups (P<0.01).Conclusions Beta2-adrenergic antagonist ICI118,551 may exert negative effects on Ca2+ overload initiated by sympathetic stimulation after MI.

  10. Effect Of α2-Adrenergic Agonists And Antagonists On Cytokine Release From Human Lung Macrophages Cultured In Vitro

    Science.gov (United States)

    Piazza, O.; Staiano, R.I.; De Robertis, E.; Conti, G.; Di Crescenzo, V.; Loffredo, S.; Marone, G.; Marinosci, G. Zito; Cataldi, M. M.

    2016-01-01

    The most trusted hypothesis to explain how α2-adrenergic agonists may preserve pulmonary functions in critically ill patients is that they directly act on macrophages by interfering with an autocrine/paracrine adrenergic system that controls cytokine release through locally synthetized noradrenaline and α1- and α2-adrenoreceptors. We tested this hypothesis in primary cultures of resident macrophages from human lung (HLMs). HLMs were isolated by centrifugation on percoll gradients from macroscopically healthy human lung tissue obtained from four different patients at the time of lung resection for cancer. HLMs from these patients showed a significant expression of α2A, α2B and α2C adrenoreceptors both at the mRNA and at the protein level. To evaluate whether α2 adrenoreceptors controlled cytokine release from HMLs, we measured IL-6, IL-8 and TNF-α concentrations in the culture medium in basal conditions and after preincubation with several α2-adrenergic agonists or antagonists. Neither the pretreatment with the α2-adrenergic agonists clonidine, medetomidine or dexdemetomidine or with the α2-adrenergic antagonist yohimbine caused significant changes in the response of any of these cytokines to LPS. These results show that, different from what reported in rodents, clonidine and dexdemetomidine do not directly suppress cytokine release from human pulmonary macrophages. This suggests that alternative mechanisms such as effects on immune cells activation or the modulation of autonomic neurotransmission could be responsible for the beneficial effects of these drugs on lung function in critical patients. PMID:27896229

  11. Interactions between an alpha2-adrenergic antagonist and a beta3-adrenergic agonist on the expression of UCP2 and UCP3 in rats.

    OpenAIRE

    2002-01-01

    This experimental trial was devised to assess whether selective β3-adrenergic receptor (AR) stimulation and simultaneous blockade of α2-AR would affect thermoregulation. With this purpose, the individual and combined administration of a β3-AR agonist, trecadrine, and an α2-AR antagonist, yohimbine, were evaluated. Yohimbine produced a marked decrease (p < 0.001) in body temperature one hour after administration (5 mg kg−1, i.p.) and blocked the thermogenic effect of trecadrine (1 mg kg−1, i.p...

  12. Blockade of catecholamine-induced growth by adrenergic and dopaminergic receptor antagonists in Escherichia coli O157:H7, Salmonella enterica and Yersinia enterocolitica

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    Lyte Mark

    2007-01-01

    Full Text Available Abstract Background The ability of catecholamines to stimulate bacterial growth was first demonstrated just over a decade ago. Little is still known however, concerning the nature of the putative bacterial adrenergic and/or dopaminergic receptor(s to which catecholamines (norepinephrine, epinephrine and dopamine may bind and exert their effects, or even whether the binding properties of such a receptor are similar between different species. Results Use of specific catecholamine receptor antagonists revealed that only α, and not β, adrenergic antagonists were capable of blocking norepinephrine and epinephrine-induced growth, while antagonism of dopamine-mediated growth was achieved with the use of a dopaminergic antagonist. Both adrenergic and dopaminergic antagonists were highly specific in their mechanism of action, which did not involve blockade of catecholamine-facilitated iron-acquisition. Use of radiolabeled norepinephrine suggested that the adrenergic antagonists could be acting by inhibiting catecholamine uptake. Conclusion The present data demonstrates that the ability of a specific pathogen to respond to a particular hormone is dependent upon the host anatomical region in which the pathogen causes disease as well as the neuroanatomical specificity to which production of the particular hormone is restricted; and that both are anatomically coincidental to each other. As such, the present report suggests that pathogens with a high degree of exclusivity to the gastrointestinal tract have evolved response systems to neuroendocrine hormones such as norepinephrine and dopamine, but not epinephrine, which are found with the enteric nervous system.

  13. Different affinity states of alpha-1 adrenergic receptors defined by agonists and antagonists in bovine aorta plasma membranes

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    Jagadeesh, G.; Deth, R.C.

    1987-11-01

    Evidence for a nonlinear relationship between alpha-1 adrenergic receptor occupancy and tissue responses, together with the finding of different affinity states for agonist binding, has raised the possibility of functional heterogeneity of alpha-1 adrenergic receptors. We have conducted studies to examine: 1) binding characteristics of (/sup 3/H)prazosin, 2) competition of antagonists at these sites and 3) different affinity states of the receptor for agonists and modulation of these states by 5'-guanylylimidodiphosphate (Gpp(NH)p). A plasma membrane-enriched vesicular fraction (F2; 15%/33% sucrose interphase) was prepared from the muscular medial layer of bovine thoracic aorta. (/sup 3/H)Prazosin binding was characterized by a monophasic saturation isotherm (KD = 0.116 nM, Bmax = 112 fmol/mg of protein). Antagonist displacement studies yielded a relative potency order of prazosin greater than or equal to WB4104 much greater than phentolamine greater than corynanthine greater than yohimbine greater than or equal to idazoxan greater than rauwolscine. Competition curves for unlabeled prazosin, WB4101 (2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4 benzodioxane) and phentolamine were shallow and were best modeled to two binding sites with picomolar and nanomolar KD values. Gpp(NH)p was without effect on antagonist affinity. Agonist (epinephrine, norepinephrine and phenylephrine) competition with (/sup 3/H)prazosin binding was biphasic with pseudo-Hill slopes less than 1.0. Binding was best described by a two-site model in which the average contribution of high affinity sites was 23% of total binding. KD values for the high affinity site ranged from 2.9 to 18 nM, and 3.9 to 5.0 microM for the low affinity site.

  14. The influence of adrenergic agonists and their antagonists on isolated salivary glands of ixodid ticks.

    Science.gov (United States)

    Kaufman, W R

    1977-09-01

    Various drugs elicit fluid secretion by isolated salivary glands of two species of ixodid ticks (Dermacentor andersoni Stiles and Amblyomma hebraeum Koch). Among catecholamines, the following order of potency was observed: dopamine, epinine, noradrenaline = adrenaline and isoprenaline. The following drugs, in order of potency, were also agonists on this preparation: ergonovine, ergotamine, 6-hydroxydopamine, apomorphine, phenylephrine, norphenylephrine, beta-phenylethylamine, tyramine, D, L-dopa and octopamine. Nialamide increased the response to near-threshold concentrations of dopamine but had no intrinsic activity. Dopamine-induced secretion was depressed by phenoxybenzamine, alpha-flupenthixol, phentolamine, propranolol and dichloroisoprenaline, but only at conce,trations 10- to 1000-fold that of the agonist. Pimozide and spiperone (10(-6) M) augmented the maximum response of dopamine. The tick salivary gland, thus appears to contain one or several receptors differing pharmacologically from mammalian alpha-adrenergic, beta-adrenergic and dopamine receptors.

  15. [Sleep disturbances in Smith-Magenis syndrome: treatment with melatonin and beta-adrenergic antagonists].

    Science.gov (United States)

    Van Thillo, A; Devriendt, K; Willekens, D

    2010-01-01

    Smith-Magenis syndrome is a generic disorder, characterised by physical, neurological and behavioural features and caused by a 17p11.2 deletion. Patients with this syndrome typically display an inversion of the sleep-wake cycle. In this article we describe clinical developments in a two-year-old girl with Smith-Magenis syndrome whose sleep problems were successfully treated with melatonin and beta-adrenergic blockers. We also mention relevant data obtained in our literature search.

  16. Molecular Modeling Study of Chiral Separation and Recognition Mechanism of β-Adrenergic Antagonists by Capillary Electrophoresis

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    Yifeng Chai

    2012-01-01

    Full Text Available Chiral separations of five β-adrenergic antagonists (propranolol, esmolol, atenolol, metoprolol, and bisoprolol were studied by capillary electrophoresis using six cyclodextrins (CDs as the chiral selectors. Carboxymethylated-β-cyclodextrin (CM-β-CD exhibited a higher enantioselectivity power compared to the other tested CDs. The influences of the concentration of CM-β-CD, buffer pH, buffer concentration, temperature, and applied voltage were investigated. The good chiral separation of five β-adrenergic antagonists was achieved using 50 mM Tris buffer at pH 4.0 containing 8 mM CM-β-CD with an applied voltage of 24 kV at 20 °C. In order to understand possible chiral recognition mechanisms of these racemates with CM-β-CD, host-guest binding procedures of CM-β-CD and these racemates were studied using the molecular docking software Autodock. The binding free energy was calculated using the Autodock semi-empirical binding free energy function. The results showed that the phenyl or naphthyl ring inserted in the hydrophobic cavity of CM-β-CD and the side chain was found to point out of the cyclodextrin rim. Hydrogen bonding between CM-β-CD and these racemates played an important role in the process of enantionseparation and a model of the hydrogen bonding interaction positions was constructed. The difference in hydrogen bonding formed with the –OH next to the chiral center of the analytes may help to increase chiral discrimination and gave rise to a bigger separation factor. In addition, the longer side chain in the hydrophobic phenyl ring of the enantiomer was not beneficial for enantioseparation and the chiral selectivity factor was found to correspond to the difference in binding free energy.

  17. 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...... in the rat. Spinal microdialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or without nicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptors were investigated. It was found that clonidine...

  18. Effects and mechanism of different adrenergic receptor antagonists on left ventricular hypertrophy subsequent to coarctation of abdominal aorta in rats

    Institute of Scientific and Technical Information of China (English)

    HU Qin; LI Long-gui; ZHANG Yun

    2004-01-01

    To study the changes of a collagen-binding protein (Colligin) and myosin heavy chain isoform (α/β-MHC) gene and protein in left ventricular hypertrophy subsequent to coarctation of abdominal aorta in rats and the ef-fects of three kinds of adrenergic receptor blockers: Carvedilol (CAR), Metoprolol (MET) and Terazosin (TER) on these changes, and to elucidate the effects and new mechanism of CAR on left ventricular hypearophy regression. Methods: A model of hypertrophy induced by coarctation of abdominal aorta(CAA) was used in this study. Thirty two male istar rats were divided randomly into four groups 4 weeks after CAA operation: CAA, CAR, MET and TER.emodynamics, ventric-ular remodeling parameters, expressions of Colligin and α/β-MHC mRNA, protein expressions of Collagen Ⅰ /Ⅲ and Colligin were investigated in the four groups and sham operation group. Results: Left ventricle hypertrophy was observed clearly 16 weeks after operation. The ratio of α/β-MHC mRNA decreased, while expressions of Collagen Ⅰ/Ⅲ proteins and Colligin mRNA/protein increased( P < 0.05). CAR could ameliorate left ventricle hypertrophy prior to MET and TER. CAR could also change the expressions of α/β-MHC, Collagen Ⅰ/Ⅲ and Colligin in both gene and protein levels ( P < 0.05), while MET and TER have no effect on them ( P > 0.05). Conclusion: The effects of CAR on extracellular matrix proteins and MHC isoform shift regression of left ventricle may be due to antiproliferative or antioxidative mechanism, which was indepen-dent of beta-adrenergic receptor antagonist.

  19. Immobility from administration of the alpha1-adrenergic antagonist, terazosin, in the IVth ventricle in rats.

    Science.gov (United States)

    Stone, Eric A; Lin, Yan; Quartermain, David

    2003-12-26

    Brain alpha1-adrenoceptors have been shown to be essential for motor activity and movement in mice using intraventricular injection of alpha1-antagonists. To facilitate subsequent neuroanatomical mapping of these receptors, the present study was undertaken to replicate these effects in the rat. Rats were administered the alpha1-antagonist, terazosin, in the absence and presence of the alpha1-agonist, phenylephrine, in the IVth ventricle and were tested for their motor activity responses to an environmental change. Terazosin was found to produce a dose-dependent, virtually complete cessation of behavioral activity that was reversed by coinfusion of phenylephrine. The results could not be explained by sedation. It is concluded that central alpha1-adrenoceptors are essential for behavioral activation in rats as in mice.

  20. Extractive spectrophotometric determination of some α-adrenergic-antagonists in pure forms and in pharmaceutical formulations

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    El Sheikh Ragaa

    2012-01-01

    Full Text Available A simple, rapid, and extractive spectrophotometric methods was developed for the determination of some postsynaptic α-1 adrenoreceptor antagonist; doxazosin mesylate (DOX, terazosin (TRZ and alfuzosine HCl (ALF in pure forms and pharmaceutical formulations. The developed methods are based on the formation of yellow colored chloroform ion-pair complexes between the basic nitrogen of the drugs and dyes, namely; bromocresol green (BCG, bromothymol blue (BTB, methyl orange (MO and alizarine red S (ARS, in acidic buffer of pH range (3.0-5.0. The formed complexes were extracted with chloroform or dichloromethane and measured at 418, 414, 425 and 426 nm for DOX and at 419, 415, 425 and 428 for TRZ and at 418, 412, 421 and 427 nm for ALF using BCG, BTB, MO and ARS, respectively. The analytical parameters and their effects on the reported systems are investigated. Beer’s law was obeyed in the range 1.0-130 μg mL−1 with correlation coefficient (n = 6 ≥ 0.9991. The molar absorpitivity, Sandell sensitivity, detection and quantification limits were also calculated. The composition of the ion associates was found 1:1 by Job’s method. The proposed methods have been applied successfully for the analysis of the studied drugs in pure forms and in pharmaceutical formulations with percentage recoveries ranges from 99.18-100.61. The results of analysis were validated statistically. The results were in good agreement and compared with those obtained with reported methods.

  1. β-Adrenergic receptor antagonists inhibit vasculogenesis of embryonic stem cells by downregulation of nitric oxide generation and interference with VEGF signalling.

    Science.gov (United States)

    Sharifpanah, Fatemeh; Saliu, Fatjon; Bekhite, Mohamed M; Wartenberg, Maria; Sauer, Heinrich

    2014-11-01

    The β-adrenoceptor antagonist Propranolol has been successfully used to treat infantile hemangioma. However, its mechanism of action is so far unknown. The hypothesis of this research was that β-adrenoceptor antagonists may interfere with endothelial cell differentiation of stem cells. Specifically, the effects of the non-specific β-adrenergic receptor (β-adrenoceptor) antagonist Propranolol, the β1-adrenoceptor-specific antagonist Atenolol and the β2-adrenoceptor-specific antagonist ICI118,551 on vasculogenesis of mouse embryonic stem (ES) cells were investigated. All three β-blockers dose-dependently downregulated formation of capillary structures in ES cell-derived embryoid bodies and decreased the expression of the vascular cell markers CD31 and VE-cadherin. Furthermore, β-blockers downregulated the expression of fibroblast growth factor-2 (FGF-2), hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor 165 (VEGF165), VEGF receptor 2 (VEGF-R2) and phospho VEGF-R2, as well as neuropilin 1 (NRP1) and plexin-B1 which are essential modulators of embryonic angiogenesis with additional roles in vessel remodelling and arteriogenesis. Under conditions of β-adrenoceptor inhibition, the endogenous generation of nitric oxide (NO) as well as the phosphorylation of endothelial nitric oxide synthase (eNOS) was decreased in embryoid bodies, whereas an increase in NO generation was observed with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP). Consequently, vasculogenesis of ES cells was restored upon treatment of differentiating ES cells with β-adrenoceptor antagonists in the presence of NO donor. In summary, our data suggest that β-blockers impair vasculogenesis of ES cells by interfering with NO generation which could be the explanation for their anti-angiogenic effects in infantile hemangioma.

  2. Acute Urinary Morbidity Following Stereotactic Body Radiation Therapy for Prostate Cancer with Prophylactic Alpha-Adrenergic Antagonist and Urethral Dose Reduction

    Directory of Open Access Journals (Sweden)

    Michael Charles Repka

    2016-05-01

    Full Text Available Background: Stereotactic body radiation therapy (SBRT delivers high doses of radiation to the prostate while minimizing radiation to adjacent critical organs. Large fraction sizes may increase urinary morbidity due to unavoidable treatment of the prostatic urethra. This study reports rates of acute urinary morbidity following SBRT for localized prostate cancer with prophylactic alpha-adrenergic antagonist utilization and urethral dose reduction (UDR.Methods: From April 2013 to September 2014, 102 patients with clinically localized prostate cancer were treated with robotic SBRT to a total dose of 35-36.25 Gy in 5 fractions. UDR was employed to limit the maximum point dose of the prostatic urethra to 40 Gy. Prophylactic alpha-adrenergic antagonists were initiated five days prior to SBRT and continued until resolution of urinary symptoms. Quality of life (QoL was assessed before and after treatment using the American Urological Association Symptom Score (AUA and the Expanded Prostate Cancer Index Composite-26 (EPIC-26. Clinical significance was assessed using a minimally important difference (MID of one half standard deviation change from baseline.Results: 102 patients underwent definitive prostate SBRT with UDR and were followed for 3 months. No patient experienced acute urinary retention requiring catheterization. A mean baseline AUA symptom score of 9.06 significantly increased to 11.83 one-week post-SBRT (p = 0.0024 and 11.84 one-month post-SBRT (p = 0.0023 but returned to baseline by 3 months. A mean baseline EPIC-26 irritative/obstructive score of 87.7 decreased to 74.1 one-week post-SBRT (p < 0.0001 and 77.8 one-month post-SBRT (p < 0.0001 but returned to baseline at 3 months. EPIC-26 irritative/obstructive score changes were clinically significant, exceeding the MID of 6.0. At baseline, 8.9% of men described their urinary function as a moderate to big problem, and that proportion increased to 37.6% one week following completion of SBRT

  3. Inhibition of Brain Swelling after Ischemia-Reperfusion by β-Adrenergic Antagonists: Correlation with Increased K+ and Decreased Ca2+ Concentrations in Extracellular Fluid

    Directory of Open Access Journals (Sweden)

    Dan Song

    2014-01-01

    Full Text Available Infarct size and brain edema following ischemia/reperfusion are reduced by inhibitors of the Na+, K+, 2Cl−, and water cotransporter NKCC1 and by β1-adrenoceptor antagonists. NKCC1 is a secondary active transporter, mainly localized in astrocytes, driven by transmembrane Na+/K+ gradients generated by the Na+,K+-ATPase. The astrocytic Na+,K+-ATPase is stimulated by small increases in extracellular K+ concentration and by the β-adrenergic agonist isoproterenol. Larger K+ increases, as occurring during ischemia, also stimulate NKCC1, creating cell swelling. This study showed no edema after 3 hr medial cerebral artery occlusion but pronounced edema after 8 hr reperfusion. The edema was abolished by inhibitors of specifically β1-adrenergic pathways, indicating failure of K+-mediated, but not β1-adrenoceptor-mediated, stimulation of Na+,K+-ATPase/NKCC1 transport during reoxygenation. Ninety percent reduction of extracellular Ca2+ concentration occurs in ischemia. Ca2+ omission abolished K+ uptake in normoxic cultures of astrocytes after addition of 5 mM KCl. A large decrease in ouabain potency on K+ uptake in cultured astrocytes was also demonstrated in Ca2+-depleted media, and endogenous ouabains are needed for astrocytic K+ uptake. Thus, among the ionic changes induced by ischemia, the decrease in extracellular Ca2+ causes failure of the high-K+-stimulated Na+,K+-ATPase/NKCC1 ion/water uptake, making β1-adrenergic activation the only stimulus and its inhibition effective against edema.

  4. Two distinct conformations of helix 6 observed in antagonist-bound structures of a β1-adrenergic receptor

    OpenAIRE

    2011-01-01

    The β1-adrenergic receptor (β1AR) is a G-protein-coupled receptor whose inactive state structure was determined using a thermostabilized mutant (β1AR–M23). However, it was not thought to be in a fully inactivated state because there was no salt bridge between Arg139 and Glu285 linking the cytoplasmic ends of transmembrane helices 3 and 6 (the R3.50 - D/E6.30 “ionic lock”). Here we compare eight new structures of β1AR–M23, determined from crystallographically independent molecules in four diff...

  5. Differential effects of adrenergic antagonists (Carvedilol vs Metoprolol on parasympathetic and sympathetic activity: a comparison of clinical results

    Directory of Open Access Journals (Sweden)

    Heather L. Bloom

    2014-08-01

    Full Text Available Background Cardiovascular autonomic neuropathy (CAN is recognized as a significant health risk, correlating with risk of heart disease, silent myocardial ischemia or sudden cardiac death. Beta-blockers are often prescribed to minimize risk. Objectives In this second of two articles, the effects on parasympathetic and sympathetic activity of the alpha/beta-adrenergic blocker, Carvedilol, are compared with those of the selective beta-adrenergic blocker, Metoprolol. Methods Retrospective, serial autonomic nervous system test data from 147 type 2 diabetes mellitus patients from eight ambulatory clinics were analyzed. Patients were grouped according to whether a beta-blocker was (1 introduced, (2 discontinued or (3 continued without adjustment. Group 3 served as the control. Results Introducing Carvedilol or Metoprolol decreased heart rate and blood pressure, and discontinuing them had the opposite effect. Parasympathetic activity increased with introducing Carvedilol. Sympathetic activity increased more after discontinuing Carvedilol, suggesting better sympathetic suppression. With ongoing treatment, resting parasympathetic activity decreased with Metoprolol but increased with Carvedilol. Conclusion Carvedilol has a more profound effect on sympathovagal balance than Metoprolol. While both suppress sympathetic activity, only Carvedilol increases parasympathetic activity. Increased parasympathetic activity may underlie the lower mortality risk with Carvedilol.

  6. Differential regulation of human cardiac β-adrenergic and muscarinic receptors by chronic β-adrenoceptor antagonist treatment

    OpenAIRE

    Motomura, S.; Deighton, N M; Zerkowski, H.-R.; Khamssi, M.; Brodde, O.-E.

    1990-01-01

    In patients undergoing coronary artery bypass grafting chronic β1-adrenoceptor antagonist treatment increased right atrial β1-adrenoceptor number, did not affect β2-adrenoceptor number and decreased muscarinic M2-receptor number. Concomitantly, the M2-receptor-mediated negative inotropic effect of carbachol was reduced, while the β1-adrenoceptor-mediated positive inotropic effect of noradrenaline was not altered. The β2-adrenoceptor mediated positive inotropic effect of procaterol, however, w...

  7. 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.

  8. Preventing the stress-induced shift from goal-directed to habit action with a β-adrenergic antagonist.

    Science.gov (United States)

    Schwabe, Lars; Höffken, Oliver; Tegenthoff, Martin; Wolf, Oliver T

    2011-11-23

    Stress modulates instrumental action in favor of habit processes that encode the association between a response and preceding stimuli and at the expense of goal-directed processes that learn the association between an action and the motivational value of the outcome. Here, we asked whether this stress-induced shift from goal-directed to habit action is dependent on noradrenergic activation and may therefore be blocked by a β-adrenoceptor antagonist. To this end, healthy men and women were administered a placebo or the β-adrenoceptor antagonist propranolol before they underwent a stress or a control procedure. Shortly after the stress or control procedure, participants were trained in two instrumental actions that led to two distinct food outcomes. After training, one of the food outcomes was selectively devalued by feeding participants to satiety with that food. A subsequent extinction test indicated whether instrumental behavior was goal-directed or habitual. As expected, stress after placebo rendered participants' behavior insensitive to the change in the value of the outcome and thus habitual. After propranolol intake, however, stressed participants behaved, same as controls, goal-directed, suggesting that propranolol blocked the stress-induced bias toward habit behavior. Our findings show that the shift from goal-directed to habitual control of instrumental action under stress necessitates noradrenergic activation and could have important clinical implications, particularly for addictive disorders.

  9. Evidence for activation of both adrenergic and cholinergic nervous pathways by yohimbine, an alpha 2-adrenoceptor antagonist.

    Science.gov (United States)

    Bagheri, H; Chale, J J; Guyen, L N; Tran, M A; Berlan, M; Montastruc, J L

    1995-01-01

    Adrenoceptors are involved in the control of the activity of the autonomic nervous system and especially the sympathetic nervous system. Activation of alpha 2-adrenoceptors decreases sympathetic tone whereas their blockade has an opposite effect. However, previous investigations have shown that yohimbine (a potent alpha 2-adrenoceptor antagonist) increases salivary secretion through activation of cholinergic pathways. The aim of the present experiment was to investigate the involvement of both the sympathetic and the parasympathetic system in several pharmacological effects of yohimbine. For this purpose, salivary secretion and various endocrino-metabolic parameters (noradrenaline and insulin secretions, lipomobilization) were evaluated in conscious fasting dogs before and after blockade of either the sympathetic (with the beta-adrenoceptor antagonist agent nadolol) or the parasympathetic (with the anticholinergic agent atropine) systems. Yohimbine alone (0.4 mg.kg-1, i.v.) increased within 5-15 minutes, plasma noradrenaline (600%), insulin levels (300%), free-fatty acids (79%) and salivary secretion (143%). Atropine (0.2 mg.kg-1, i.v.) suppressed yohimbine-induced salivary secretion (90%) but did not significantly modify the yohimbine induced changes in noradrenaline (312%), insulin (277%) and free-fatty acids (102%) plasma levels. Administration of nadolol (1 mg.kg-1, i.v.) did not change the magnitude of the increase in both noradrenaline plasma levels (550%) and salivary secretion (300%) induced by yohimbine. However, nadolol totally blunted the increase in insulin (15%) and free-fatty acids (4%) plasma levels. These results show that yohimbine-induced increase in salivary secretion is a cholinergic effect whereas the increase in insulin and free fatty acids can be explained by an increase in sympathetic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Effect of. cap alpha. -,. beta. -adrenergic receptor agonists and antagonists of the efflux of /sup 22/Na and uptake of /sup 42/K by rat brain cortical slices

    Energy Technology Data Exchange (ETDEWEB)

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

    1982-03-18

    The effects of norepinephrine on ion fluxes in rat brain cortical slices have now been ascertained. /sup 22/Na efflux and /sup 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 /sup 22/Na efflux is stereospecific as demonstrated by the very weak action of D-norepinephrine at 10/sup -5/ M concentration. Various ..cap alpha..-adrenergic and ..beta..-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.

  11. Adrenergic blockade in diabetic and uninephrectomized rats

    DEFF Research Database (Denmark)

    Thulesen, J; Poulsen, Steen Seier; Jørgensen, P E

    1999-01-01

    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......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...

  12. Mechanism of adrenergic stimulation of hepatic ketogenesis.

    Science.gov (United States)

    Kosugi, K; Harano, Y; Nakano, T; Suzuki, M; Kashiwagi, A; Shigeta, Y

    1983-11-01

    The effects of alpha- and beta-adrenergic stimulation on ketogenesis were examined in freshly isolated rat hepatocytes in order to determine which alpha- or beta-adrenergic stimulation is involved in the enhancement of ketogenesis. In the presence of 0.3 mmol/L (U-14C)-palmitate, epinephrine, norepinephrine, and phenylephrine at 500 ng/mL increased ketogenesis by 25% (16.0 +/- 0.17 v 12.8 +/- 0.13 nmol/mg protein per hour), 20% (15.3 +/- 0.28) and 20% (15.4 +/- 0.36), respectively. However, isoproterenol even at 1 microgram/mL did not stimulate ketogenesis. Phentolamine (5 micrograms/mL) almost completely abolished the effect of epinephrine on ketogenesis (13.7 +/- 0.30 v 16.0 +/- 0.17) but propranolol did not inhibit the stimulation by epinephrine (15.6 +/- 0.38 v 16.0 +/- 0.17). Trifluoperazine (10 mumol/L), presumably an inhibitor of calcium-dependent protein kinase, abolished the effect of epinephrine (13.6 +/- 0.22 v 16.0 +/- 0.17). These results indicate that catecholamines increase ketogenesis predominantly through the alpha-adrenergic system independent of cyclic AMP, and calcium-dependent protein kinase is thought to be involved in the activation of ketogenesis. On the other hand, glucagon stimulated ketogenesis with an increase of cyclic AMP, which was not inhibited by alpha- and beta-adrenergic antagonists. Alpha-adrenergic stimulation increased hepatic glycogenolysis much more at much lower concentrations when compared with ketogenesis. Stimulation of ketogenesis by catecholamines seemed to be less sensitive and responsive compared with hepatic glycogenolysis.

  13. Adrenergic Metabolic and Hemodynamic Effects of Octopamine in the Liver

    Directory of Open Access Journals (Sweden)

    Adelar Bracht

    2013-11-01

    Full Text Available The fruit extracts of Citrus aurantium (bitter orange are traditionally used as weight-loss products and as appetite suppressants. A component of these extracts is octopamine, which is an adrenergic agent. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of octopamine on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways and hemodynamics. Octopamine increased glycogenolysis, glycolysis, oxygen uptake, gluconeogenesis and the portal perfusion pressure. Octopamine also accelerated the oxidation of exogenous fatty acids (octanoate and oleate, as revealed by the increase in 14CO2 production derived from 14C labeled precursors. The changes in glycogenolysis, oxygen uptake and perfusion pressure were almost completely abolished by α1-adrenergic antagonists. The same changes were partly sensitive to the β-adrenergic antagonist propranolol. It can be concluded that octopamine accelerates both catabolic and anabolic processes in the liver via adrenergic stimulation. Acceleration of oxygen uptake under substrate-free perfusion conditions also means acceleration of the oxidation of endogenous fatty acids, which are derived from lipolysis. All these effects are compatible with an overall stimulating effect of octopamine on metabolism, which is compatible with its reported weight-loss effects in experimental animals.

  14. beta-Adrenergic agonist activity of a monoclonal anti-idiotypic antibody.

    Science.gov (United States)

    Guillet, J G; Kaveri, S V; Durieu, O; Delavier, C; Hoebeke, J; Strosberg, A D

    1985-03-01

    Hybridoma cells bearing monoclonal antibody against the beta-adrenergic ligand alprenolol were used as an immunogen to raise monoclonal anti-idiotypic antibodies. Of six anti-idiotypic antibodies, which inhibit ligand binding, three were able to recognize beta-adrenergic receptors. One of them, mAb2B4, an IgM that could be amplified into ascites, binds to the beta-adrenergic catecholamine receptors of intact epidermoid A431 cells and precipitates receptors solubilized from plasma membranes by digitonin. This antibody identifies the beta 2-adrenergic receptor of A431 cells as a single 55-kDa protein and stimulates adenylate cyclase activity. This stimulation is inhibited by the beta-adrenergic antagonist propranolol.

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

    OpenAIRE

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

    2015-01-01

    Objective: 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. Methods: 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 pr...

  16. 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...

  17. 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

    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...... to diabetic autonomic neuropathy. Regardless of the mechanism of adrenergic denervation hypersensitivity in such patients, these data provide further evidence that measurements of cellular adrenergic receptors (and adenylate cyclase) in vitro are a fallible index of sensitivity to catecholamines in vivo....

  18. Phosphoinositide metabolism and adrenergic receptors in astrocytes

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-03-01

    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/sup + +/ mobilization. Using purified astrocyte cultures from neonatal rat brain, the effects of adrenergic agonists and antagonists at 10/sup -5/ M were measured on PI breakdown. Astrocytes grown in culture were prelabeled with (/sup 3/H)inositol, and basal (/sup 3/H) inositol phosphate (IP/sub 1/) accumulation was measured in the presence of Li/sup +/. Epinephrine > norepinephrine (NE) were the most active stimulants of IP/sub 1/ production. The ..cap alpha../sub 1/ adrenoreceptor blockers, phentolamine and phenoxybenzamine, added alone had no effect on IP/sub 1/ production was reduced below basal levels. Propranolol partially blocked the effects of NE. Clonidine and isoproterenol, separately added, reduced IP/sub 1/ below basal levels and when added together diminished IP/sub 1/ accumulation even further. The role of adrenergic stimulation in the production of c-AMP.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1984-11-01

    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 /sup 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 /sup 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 /sup 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).

  20. Adrenergic receptor subtypes in the cerebral circulation of newborn piglets

    Energy Technology Data Exchange (ETDEWEB)

    Wagerle, L.C.; Delivoria-Papadopoulos, M.

    1987-06-01

    The purpose of this study was to identify the ..cap alpha..-adrenergic receptor subtype mediating cerebral vasoconstriction during sympathetic nerve stimulation in the newborn piglet. The effect of ..cap alpha../sub 1/- and ..cap alpha../sub 2/-antagonists prazosin and yohimbine on the cerebrovascular response to unilateral electrical stimulation (15 Hz, 15 V) of the superior cervical sympathetic trunk was studied in 25 newborn piglets. Regional cerebral blood flow was measured with tracer microspheres. Sympathetic stimulation decreased blood flow to the ipsilateral cerebrum hippocampus, choroid plexus, and masseter muscle. ..cap alpha../sub 1/-Adrenergic receptor blockade with prazosin inhibited the sympathetic vasoconstriction in the cerebrum, hippocampus, and masseter muscle and abolished it in the choroid plexus. ..cap alpha../sub s/-Adrenergic receptor blockade with yohimbine had no effect. Following the higher dose of yohimbine, however, blood flow to all brain regions was increased by approximately two-fold, possibly due to enhanced cerebral metabolism. These data demonstrate that vascular ..cap alpha../sub 1/-adrenergic receptors mediate vasoconstriction to neuroadrenergic stimulation in cerebral resistance vessels in the newborn piglet.

  1. 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 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...

  2. DNA synthesis in mouse brown adipose tissue is under. beta. -adrenergic control

    Energy Technology Data Exchange (ETDEWEB)

    Rehnmark, S.; Nedergaard, J. (Univ. of Stockholm (Sweden))

    1989-02-01

    The rate of DNA synthesis in mouse brown adipose tissue was followed with injections of ({sup 3}H)thymidine. Cold exposure led to a large increase in the rate of ({sup 3}H)thymidine incorporation, reaching a maximum after 8 days, after which the activity abruptly ceased. A series of norepinephrine injections was in itself able to increase ({sup 3}H)thymidine incorporation. When norepinephrine was injected in combination with the {alpha}-adrenergic antagonist phentolamine or with the {beta}-adrenergic antagonist propranolol, the stimulation was fully blocked by propranolol. It is suggested that stimulation of DNA synthesis in brown adipose tissue is a {beta}-adrenergically mediated process and that the tissue is an interesting model for studies of physiological control of DNA synthesis.

  3. 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.

  4. 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.......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 binding...... from sarcolemma of soleus muscle (phentolamine greater than phenylephrine greater than idazoxan greater than yohimbine) suggested that the receptors were alpha 1. Binding sites for dihydroalprenolol (beta antagonist) were also more concentrated on red than white muscle and outnumbered prazosin sites...

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

    Energy Technology Data Exchange (ETDEWEB)

    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 (/sup 3/H)yohimbine, whereas (/sup 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, (/sup 3/H) clonidine and (/sup 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 (/sup 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.

  6. β-Adrenergic receptor agonist increases voltage-gated Na(+) currents in medial prefrontal cortex pyramidal neurons.

    Science.gov (United States)

    Szulczyk, Bartlomiej

    2015-05-19

    The prefrontal cortex does not function properly in neuropsychiatric diseases and during chronic stress. The aim of this study was to test the effects of isoproterenol, a β-adrenergic receptor agonist, on the voltage-dependent fast-inactivating Na(+) currents in medial prefrontal cortex (mPFC) pyramidal neurons obtained from young rats. The recordings were performed in the cell-attached configuration. Isoproterenol (2μM) did not change the peak Na(+) current amplitude but shifted the IV curve of the Na(+) currents toward hyperpolarization. Pretreatment of the cells with the β-adrenergic antagonists propranolol and metoprolol abolished the effect of isoproterenol on the Na(+) currents, suggesting the involvement of β1-adrenergic receptors. The effect of β-adrenergic receptor stimulation on the sodium currents was dependent on kinase A and kinase C; the effect was diminished in the presence of the kinase A antagonist H-89 and the kinase C antagonist chelerythrine and abolished when the antagonists were coapplied. Moreover, isoproterenol depolarized the membrane potential recorded using the perforated-patch method, and this depolarization was abolished by cesium ions. Thus, in mPFC pyramidal neurons, stimulation of β-adrenergic receptors up-regulates the fast-inactivating voltage-gated Na(+) currents evoked by suprathreshold depolarizations.

  7. Adrenergic blockade does not abolish elevated glucose turnover during bacterial infection

    Energy Technology Data Exchange (ETDEWEB)

    Hargrove, D.M.; Bagby, G.J.; Lang, C.H.; Spitzer, J.J. (Louisiana State Univ., New Orleans (USA))

    1988-01-01

    Infusions of adrenergic antagonists were used to investigate the role of catecholamines in infection-induced elevations of glucose kinetics. Infection was produced in conscious catheterized rats by repeated subcutaneous injections of live Escherichia coli over 24 h. Glucose kinetics were measured by the constant intravenous infusion of (6-{sup 3}H)- and (U-{sup 14}C)glucose. Compared with noninfected rats, infected animals were hyperthermic and showed increased rates of glucose appearance, clearance, and recycling as well as mild hyperlacticacidemia. Plasma catecholamine concentrations were increased by 50-70% in the infected rats, but there were no differences in plasma glucagon, corticosterone, and insulin levels. Adrenergic blockade was produced by primed constant infusion of both propranolol ({beta}-blocker) and phentolamine ({alpha}-blocker). A 2-h administration of adrenergic antagonists did not attenuate the elevated glucose kinetics or plasma lactate concentration in the infected rats, although it abolished the hyperthermia. In a second experiment, animals were infused with propranolol and phentolamine beginning 1 h before the first injection of E. coli and throughout the course of infection. Continuous adrenergic blockade failed to attenuate infection-induced elevations in glucose kinetics and plasma lactate. These results indicate that the adrenergic system does not mediate the elevated glucose metabolism observed in this mild model of infection.

  8. Effects of Adrenergic Blockade on Postpartum Adaptive Responses Induced by Labor Contractions

    Science.gov (United States)

    Ronca, April E.; Mills, N. A.; Lam, K. P.; Hayes, L. E.; Bowley, Susan M. (Technical Monitor)

    2000-01-01

    Prenatal exposure to labor contractions augments the expression of postnatal adaptive responses in newborn rats. Near-term rat fetuses exposed prenatally to simulated labor contractions and delivered by cesarean section breath and attach to nipples at greater frequencies than non-stimulated fetuses. Plasma NE (norepinephrine) and EPI (epinephrine) was significantly elevated in newborn rats exposed to vaginal birth or simulated labor contractions (compressions) with cesarean delivery as compared to non-compressed fetuses. In the present study, we investigated adrenergic mechanisms underlying labor-induced postnatal adaptive responses. Following spinal transection of late pregnant rat dams, fetuses were administered neurogenic or non-neurogenic adrenergic blockade: 1) bretylium (10 mg/kg sc) to prevent sympathetic neuronal release, 2) hexamethonium (30 mg/kg) to produce ganglionic blockade, 3) phenoxybenzanune (10mg/kg sc), an a- adrenergic receptor antagonist, 4) ICI-118551, 10 mg/kg sc), a b receptor antagonist, or 5) vehicle alone. Fetuses were either compressed (C) or non-compressed (NC) prior to cesarean delivery. a- and b- adrenergic antagonists reduced respiration and nipple attachment rates while sympathetic and vehicle alone did not. These results provide additional support for the hypothesis that adaptive neonatal effects of labor contractions are mediated by adrenal and extra-adrenal catecholamines.

  9. α1A-adrenergic receptor mediated pressor response to phenylephrine in anesthetized rat

    Institute of Scientific and Technical Information of China (English)

    XU Qi; ZHU Weizhong; L(U) Zhizhen; ZHANG Youyi; HAN Qide

    2004-01-01

    To determine which subtype of α1A-adrenergic receptors plays a role in the regulation of blood pressure, with α1A-adrenergic receptor-mediated vasoconstriction in perfused hindlimb as a control, we compared the inhibitory effects of various α1A-adrenergic receptor selective antagonists on the vasopressure responses to phenylephrine between the mean arterial pressure and hindlimb perfusion pressure in anesthetized rats. In Normotensive Wistar rats, the results showed that the inhibitory effects (dose ratios of ED50, Dr) of α1A-adrenoceptor selective antagonist (prazosin, Dr 13.5 ± 3.6 vs.15.1 ± 4.3, n = 11), α1A-adrenoceptor selective antagonist (5- methyl-urapidil, Dr 2.4 ± 0.9 vs. 3.7 ± 2.3, n = 12; RS-17053, Dr 3.2 ± 1.6 vs. 4.4 ± 3.3, n =12) and α1D- adrenoceptor selective antagonist (BMY7378, Dr 1.9 ± 0.9 vs. 2.2 ± 0.8, n = 8) on phenylephrine- induced increases of perfusion pressure in the autoperfused femoral beds were the same as that in the mean arterial blood pressure in normotensive Wistar rats. The inhibitory effects of antagonists (RS-17053, Dr 3.4 ± 0.6 vs. 4.3 ± 0.9, n = 5; BMY7378, Dr 1.7±0.5 vs. 1.7 ± 0.5, n = 8) in spontaneous hypertensive rats were similar with the Wistar rats. These results suggest that the mean arterial pressure induced by phenylephrine was mainly mediated by α1A-adrenergic receptor in both the anesthetized Wistar rats and spontaneous hypertensive rats.

  10. Characterization of beta-adrenergic receptors in dispersed rat testicular interstitial cells

    Energy Technology Data Exchange (ETDEWEB)

    Poyet, P.; Labrie, F.

    1987-01-01

    Recent studies have shown that beta-adrenergic agents stimulate steroidogenesis and cyclic AMP formation in mouse Leydig cells in culture. To obtain information about the possible presence and the characteristics of a beta-adrenergic receptor in rat testicular interstitial cells, the potent beta-adrenergic antagonist (/sup 125/I)cyanopindolol (CYP) was used as ligand. Interstitial cells prepared by collagenase dispersion from rat testis were incubated with the ligand for 2 h at room temperature. (/sup 125/I)cyanopindolol binds to a single class of high affinity sites at an apparent KD value of 15 pM. A number of sites of 6,600 sites/cell is measured when 0.1 microM (-) propranolol is used to determine non-specific binding. The order of potency of a series of agonists competing for (/sup 125/I)cyanopindolol binding is consistent with the interaction of a beta 2-subtype receptor: zinterol greater than (-) isoproterenol greater than (-) epinephrine = salbutamol much greater than (-) norepinephrine. In addition, it was observed that the potency of a large series of specific beta 1 and beta 2 synthetic compounds for displacing (/sup 125/I)cyanopindolol in rat interstitial cells is similar to the potency observed for these compounds in a typical beta 2-adrenergic tissue, the rat lung. For example, the potency of zinterol, a specific beta 2-adrenergic agonist, is 10 times higher in interstitial cells and lung than in rat heart, a typical beta 1-adrenergic tissue. Inversely, practolol, a typical beta 1-antagonist, is about 50 times more potent in rat heart than in interstitial cells and lung.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-06-01

    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 (/sup 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, /sup 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). /sup 125/I-rau-AMPC was quantitatively converted to the photolabile arylazide derivative 17 alpha-hydroxy-20 alpha-yohimban-16 beta-(N-4-azido-3-(/sup 125/I)iodophenyl) carboxamide (/sup 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 /sup 125/I-rau-AMPC and the photolabile arylazide derivative, /sup 125/I-rau-AZPC, should prove useful as molecular probes for the structural and biochemical characterization of alpha 2-adrenergic receptors.

  12. Altered adrenergic response and specificity of the receptors in rat ascites hepatoma AH130.

    Science.gov (United States)

    Sanae, F; Miyamoto, K; Koshiura, R

    1989-11-15

    Adenylate cyclase activation through adrenergic receptors in rat ascites hepatoma (AH) 130 cells in response to adrenergic drugs was studied, and receptor binding and displacement were compared with those of normal rat hepatocytes. Epinephrine (Epi) and norepinephrine (NE) activated AH130 adenylate cyclase about half as much as isoproterenol (IPN) but equaled IPN after treatment with the alpha-antagonist phentolamine or islet-activating protein (IAP). The three catecholamines in hepatocytes were similar regardless of phentolamine or IAP. These catecholamines activated adenylate cyclase in order of IPN greater than NE greater than Epi in AH130 cells but IPN greater than Epi greater than NE in hepatocytes. We then used the alpha 1-selective ligand [3H]prazosin, the alpha 2-selective ligand [3H]clonidine, and the beta-ligand [125I]iodocyanopindolol [( 125I]ICYP), and found that AH130 cells had few prazosin-binding sites, about eight times as many clonidine-binding sites with high affinity, and many more ICYP-binding sites than in hepatocytes. The dissociation constant (Ki) of the beta 1-selective drug metoprolol by Hofstee plots for AH130 cells was lower than that for hepatocytes. The inhibition of specific ICYP binding by the beta 2-selective agonist salbutamol for AH130 cells gave only one Ki value which was much higher than both high and low Ki values of the drug for hepatocytes. These findings indicate that the alpha- and beta-adrenergic receptors in hepatocytes are predominantly alpha 1-type and beta 2-type, but that those in AH130 cells are predominantly alpha 2-type and beta 1-type, and the low adrenergic response of AH130 cells is due to the dominant appearance of alpha 2-adrenergic receptors, linked with the inhibitory guanine-nucleotide binding regulatory protein, instead of alpha 1-adrenergic receptors, and beta 1-adrenergic receptors with low affinity for the hormone.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-06-01

    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.

  14. GABAB antagonists

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Hansen, J J; Krogsgaard-Larsen, P

    1994-01-01

    Phaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)-3-(4-chlorophenyl)-4-aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral chroma...

  15. β-Adrenergic Regulation of Cardiac Progenitor Cell Death Versus Survival and Proliferation

    Science.gov (United States)

    Khan, Mohsin; Mohsin, Sadia; Avitabile, Daniele; Siddiqi, Sailay; Nguyen, Jonathan; Wallach, Kathleen; Quijada, Pearl; McGregor, Michael; Gude, Natalie; Alvarez, Roberto; Tilley, Douglas G.; Koch, Walter J.; Sussman, Mark A.

    2013-01-01

    Rationale Short-term β-adrenergic stimulation promotes contractility in response to stress but is ultimately detrimental in the failing heart because of accrual of cardiomyocyte death. Endogenous cardiac progenitor cell (CPC) activation may partially offset cardiomyocyte losses, but consequences of long-term β-adrenergic drive on CPC survival and proliferation are unknown. Objective We sought to determine the relationship between β-adrenergic activity and regulation of CPC function. Methods and Results Mouse and human CPCs express only β2 adrenergic receptor (β2-AR) in conjunction with stem cell marker c-kit. Activation of β2-AR signaling promotes proliferation associated with increased AKT, extracellular signal-regulated kinase 1/2, and endothelial NO synthase phosphorylation, upregulation of cyclin D1, and decreased levels of G protein–coupled receptor kinase 2. Conversely, silencing of β2-AR expression or treatment with β2-antagonist ICI 118, 551 impairs CPC proliferation and survival. β1-AR expression in CPC is induced by differentiation stimuli, sensitizing CPC to isoproterenol-induced cell death that is abrogated by metoprolol. Efficacy of β1-AR blockade by metoprolol to increase CPC survival and proliferation was confirmed in vivo by adoptive transfer of CPC into failing mouse myocardium. Conclusions β-adrenergic stimulation promotes expansion and survival of CPCs through β2-AR, but acquisition of β1-AR on commitment to the myocyte lineage results in loss of CPCs and early myocyte precursors. PMID:23243208

  16. 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.

  17. 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

    2015-01-01

    Objective: 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. Methods: 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. Results: 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 < 0.05). Blood pressure suffered no significant decrease following administration of the 0.8 mg dose of tamsulosin. Conclusion: 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. PMID:26543414

  18. Involvement of adrenergic and serotonergic receptors in antidepressant-like effect of urocortin 3 in a modified forced swimming test in mice.

    Science.gov (United States)

    Tanaka, Masaru; Telegdy, Gyula

    2008-11-25

    Most of the evidence suggests that peptides in the corticotropin-releasing factor (CRF) family act on CRF receptors and are involved in depressive disorders. Urocortin 3 (Ucn 3) is specific for CRF type 2 (CRF(2)) receptors and mediates anxiolytic-like action. Little is known about the roles of Ucn 3 and CRH(2) receptors on depressive disorders. The previous study revealed that Ucn 3 elicits the antidepressant-like action by shortening the immobility time and increasing both the climbing time and the swimming time. The involvement of the adrenergic and serotonergic receptors in the antidepressant-like effect of Ucn 3 (0.5μg/2μl, i.c.v.) was studied in a modified forced swimming test (FST) in mice. Mice were pretreated with a non-selective α-adrenergic receptor antagonist, phenoxybenzamine, an α(1)/α(2β)-adrenergic receptor antagonist, prazosin, an α(2)-adrenergic receptor antagonist, yohimbine, a mixed 5-HT(1)/5-HT(2) serotonergic receptor antagonist, methysergide, a non-selective 5-HT(2) serotonergic receptor antagonist, cyproheptadine or a β-adrenergic receptor antagonist, propranolol. Phenoxybenzamine prevented the effects of Ucn 3 on the immobility time. Prazosin prevented the effects of Ucn 3 on the climbing time. Yohimbine prevented the effects of Ucn 3 on the immobility, climbing and swimming times. Methysergide prevented the effects of Ucn 3 on the immobility and climbing time. Cyproheptadine prevented the effects of Ucn 3 on the swimming time. Propranolol did not change the effects of Ucn 3. The results demonstrated that the antidepressant-like effect of Ucn 3 is mediated, at least in part, by an interaction of the α-adrenergic and serotonergic receptors in a modified mouse FST.

  19. Identification of alpha 2-adrenergic receptor sites in human retinoblastoma (Y-79) and neuroblastoma (SH-SY5Y) cells

    Energy Technology Data Exchange (ETDEWEB)

    Kazmi, S.M.; Mishra, R.K.

    1989-02-15

    The existence of specific alpha 2-adrenergic receptor sites has been shown in human retinoblastoma (Y-79) and neuroblastoma (SH-SH5Y) cells using direct radioligand binding. (/sup 3/H)Rauwolscine, a selective alpha 2-adrenergic receptor antagonist, exhibited high affinity, saturable binding to both Y-79 and SH-SY5Y cell membranes. The binding of alpha 1 specific antagonist, (/sup 3/H)Prazocine, was not detectable in either cell type. Competition studies with antagonists yielded pharmacological characteristics typical of alpha 2-adrenergic receptors: rauwolscine greater than yohimbine greater than phentolamine greater than prazocine. Based on the affinity constants of prazocine and oxymetazoline, it appears that Y-79 cells contain alpha 2A receptor, whereas SH-SY5Y cells probably represent a mixture of alpha 2A and alpha 2B receptors. alpha 2-agonists clonidine and (-)epinephrine inhibition curves yielded high and low affinity states of the receptor in SH-SY5Y cells. Gpp(NH)p and sodium ions reduced the proportion of high affinity sites of alpha 2 receptors. These two neuronal cell lines of human origin would prove useful in elucidating the action and regulation of human alpha 2-adrenergic receptors and their interaction with other receptor systems.

  20. Biochemical and pharmacological studies of the hepatic alpha sub 1 -adrenergic receptor

    Energy Technology Data Exchange (ETDEWEB)

    Tchakarov, L.E.

    1988-01-01

    The structure and the regulation of the hepatic {alpha}{sub 1}-adrenergic receptors have been studied in the rat. The in vitro incubation of isolated liver cells in a serum-free buffer for 4 hr leads to the conversion of the adrenergic activation of glycogen phosphorylase from an {alpha}{sub 1}- to a {beta}-adrenoceptor-mediated event. This change is associated with no change in the glycogenolytic response to vasopressin and a reduction of the glycogenolytic response to glucagon. The time-dependent shift in the adrenergic control of glycogenolysis does not influence the density or the affinity of ({sup 3}H)prazosin-labeled {alpha}{sub 1}-receptors and ({sup 3}H)CGP-12177-labeled {beta}-receptors. The change in the adrenergic control of glycogenolysis is reversed by a 30-min incubation with 50 nM lipomodulin, whereas in freshly isolated cells lipomodulin doesn't affect the predominant {alpha}-receptor response. Conversely, exposure of freshly isolated cells to a monoclonal antibody to lipomodulin in the presence of 10 {mu}M phenylephrine, or to 2 {mu}g/ml mellitin, results in a shift in the adrenergic control of glycogenolysis from {alpha}{sub 1}- to {beta}-type within 30 min. The mechanism of activation of the Ca{sup 2+}-linked receptors for vasopressin and adrenaline was studied in isolated liver cells. A novel irreversible antagonist for the {alpha}{sub 1}-adrenergic receptors, I-phenyoxybenzamine (I-POB) has been synthesized and pharmacologically characterized.

  1. Ghrelin secretion stimulated by β1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice

    Science.gov (United States)

    Zhao, Tong-Jin; Sakata, Ichiro; Liang, Guosheng; Richardson, James A.; Brown, Michael S.; Goldstein, Joseph L.; Zigman, Jeffrey M.

    2010-01-01

    Ghrelin, an octanoylated peptide hormone produced in the stomach, rises dramatically in mouse plasma during chronic severe calorie deprivation, an event that is essential to maintain life. The mechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene. We found that the ghrelin-secreting cells express high levels of mRNA encoding β1-adrenergic receptors. Addition of norepinephrine or epinephrine to the culture medium stimulated ghrelin secretion, and this effect was blocked by atenolol, a selective β1-adrenergic antagonist. When WT mice were treated with reserpine to deplete adrenergic neurotransmitters from sympathetic neurons, the fasting-induced increase in plasma ghrelin was blocked. Inhibition was also seen following atenolol administration. We conclude that ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons and acting directly on β1 receptors on the ghrelin-secreting cells of the stomach. PMID:20713709

  2. Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice.

    Science.gov (United States)

    Zhao, Tong-Jin; Sakata, Ichiro; Li, Robert Lin; Liang, Guosheng; Richardson, James A; Brown, Michael S; Goldstein, Joseph L; Zigman, Jeffrey M

    2010-09-07

    Ghrelin, an octanoylated peptide hormone produced in the stomach, rises dramatically in mouse plasma during chronic severe calorie deprivation, an event that is essential to maintain life. The mechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene. We found that the ghrelin-secreting cells express high levels of mRNA encoding beta(1)-adrenergic receptors. Addition of norepinephrine or epinephrine to the culture medium stimulated ghrelin secretion, and this effect was blocked by atenolol, a selective beta(1)-adrenergic antagonist. When WT mice were treated with reserpine to deplete adrenergic neurotransmitters from sympathetic neurons, the fasting-induced increase in plasma ghrelin was blocked. Inhibition was also seen following atenolol administration. We conclude that ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons and acting directly on beta(1) receptors on the ghrelin-secreting cells of the stomach.

  3. Alpha-1 adrenergic receptor: Binding and phosphoinositide breakdown in human myometrium

    Energy Technology Data Exchange (ETDEWEB)

    Breuiller-Fouche, M.; Doualla-Bell Kotto Maka, F.; Geny, B.; Ferre, F. (INSERM U.166 Groupe de recherches sur l' Endocrinologie de la Reproduction, Maternite Baudelocque, Paris (France))

    1991-07-01

    Alpha-1 adrenergic receptors were examined in both inner and outer layers of human pregnant myometrium using radioligand binding of (3H)prazosin. (3H)prazosin bound rapidly and reversibly to a single class of high affinity binding sites in myometrial membrane preparations. Scatchard analysis gave similar values of equilibrium dissociation constants in both myometrial layers. In contrast, more alpha-1 adrenergic receptors were detected in the outer layer than in the inner layer. Antagonist inhibited (3H)prazosin binding with an order of potency of prazosin greater than phentolamine greater than idazoxan. Competition experiments have also revealed that a stable guanine nucleotide decreases the apparent affinity of norepinephrine for myometrial (3H)prazosin binding sites. The functional status of these alpha-1 adrenergic receptors was also assessed by measuring the norepinephrine-induced accumulation of inositol phosphates in myometrial tissue. Norepinephrine produced a concentration-dependent accumulation of inositol phosphates in both myometrial layers. However, norepinephrine-induced increases in inositol 1,4,5-triphosphate were only observed in the outer layer. These results indicate that alpha-1 adrenergic receptors in human myometrium at the end of pregnancy are linked to phosphoinositide hydrolysis and that this response occurs mainly in the outer layer.

  4. Modulation of nicotinic receptor channels by adrenergic stimulation in rat pinealocytes

    Science.gov (United States)

    Yoon, Jin-Young; Jung, Seung-Ryoung; Hille, Bertil

    2014-01-01

    Melatonin secretion from the pineal gland is triggered by norepinephrine released from sympathetic terminals at night. In contrast, cholinergic and parasympathetic inputs, by activating nicotinic cholinergic receptors (nAChR), have been suggested to counterbalance the noradrenergic input. Here we investigated whether adrenergic signaling regulates nAChR channels in rat pinealocytes. Acetylcholine or the selective nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) activated large nAChR currents in whole cell patch-clamp experiments. Norepinephrine (NE) reduced the nAChR currents, an effect partially mimicked by a β-adrenergic receptor agonist, isoproterenol, and blocked by a β-adrenergic receptor antagonist, propranolol. Increasing intracellular cAMP levels using membrane-permeable 8-bromoadenosine (8-Br)-cAMP or 5,6-dichlorobenzimidazole riboside-3′,5′-cyclic monophosphorothioate (cBIMPS) also reduced nAChR activity, mimicking the effects of NE and isoproterenol. Further, removal of ATP from the intracellular pipette solution blocked the reduction of nAChR currents, suggesting involvement of protein kinases. Indeed protein kinase A inhibitors, H-89 and Rp-cAMPS, blocked the modulation of nAChR by adrenergic stimulation. After the downmodulation by NE, nAChR channels mediated a smaller Ca2+ influx and less membrane depolarization from the resting potential. Together these results suggest that NE released from sympathetic terminals at night attenuates nicotinic cholinergic signaling. PMID:24553185

  5. Characterization and regulation of. beta. /sub 2/-adrenergic receptors in rat vas deferens

    Energy Technology Data Exchange (ETDEWEB)

    May, J.M.

    1985-01-01

    ..beta../sub 2/-Adrenergic receptors in rat vas deferens were examined by measuring the binding of /sup 125/I-pindolol (/sup 125/IPIN) to membrane preparations and the inhibition of evoked contractions in intact tissues. /sup 125/IPIN labeled a single class of binding sites with mass action kinetics. Affinity constants for ..beta..-adrenergic receptor antagonists calculated from both binding and functional experiments agreed well, suggesting that /sup 125/IPIN labels the functional ..beta../sub 2/-adrenergic receptor. n-Bromoacetylalprenololmenthane (BAAM) was used to decrease receptor density so that agonist affinity constants could be determined functionally. Treatment of tissues with BAAM decreased the functional potencies of agonists. Higher concentrations of BAAM decreased the maximum tissue response. Affinity constants for agonists calculated after BAAM treatment were compared to affinity constants determined from binding studies done under conditions designed to promote high or low affinity agonist binding. Functional affinity constants for isoproterenol and salbutamol agreed with the low affinity binding constants, suggesting that the low affinity form of the receptor initiates the functional response. Because acute denervation of vasa deferentia did not alter the density of /sup 125/IPIN binding sites, the sites are probably post-junctional. Chronic infusion of isoproterenol reduced the potency of isoproterenol, the maximum tissue response, and the receptor density. These results suggest that ..beta..-adrenergic receptor density and responsiveness in rat vas deferens are not affected by removing catecholamine sources, but receptor density and responsiveness can be decreased by increasing agonist concentration at the receptor.

  6. Changing face of β2-adrenergic and muscarinic receptor therapies in asthma.

    Science.gov (United States)

    Wasilewski, Nastasia V; Lougheed, M Diane; Fisher, John T

    2014-06-01

    Despite current available treatment options, a significant proportion of patients with asthma remain uncontrolled and asthma pharmacotherapy continues to evolve. β2-Adrenergic receptor agonists play a major role as bronchodilators in asthma therapy, although new perspectives reflect the potential for bias G-protein coupled receptor signaling pathways. Due to the success of muscarinic antagonists in chronic obstructive pulmonary disease, and the elucidation that muscarinic receptors play a role in airway remodeling, muscarinic receptors represent an attractive therapeutic target in asthma. Although short-acting muscarinic antagonists are currently limited to their use in acute asthma and as alternative bronchodilators in individuals who experience side effects with β2-agonists, recent clinical trials indicate that the long-acting muscarinic antagonist, tiotropium, deserves consideration as a potential therapeutic agent for select populations. The continued evolution of anticholinergic therapy in asthma will require appropriately designed studies to assess mechanisms, efficacy and safety in asthma.

  7. Role of alpha 1- and alpha 2-adrenergic receptors in the growth hormone and prolactin response to insulin-induced hypoglycemia in man.

    Science.gov (United States)

    Tatár, P; Vigas, M

    1984-09-01

    The effects of intravenous infusion of the nonselective alpha-adrenergic antagonist phentolamine or of the selective alpha 2-adrenergic antagonist yohimbine on growth hormone (GH), prolactin (PRL) and cortisol secretion during insulin-induced hypoglycemia were studied in 11 healthy young men. The GH response was blunted following each antagonist used, PRL secretion was higher after yohimbine and diminished after phentolamine when compared to controls. The plasma cortisol response was not influenced by either compound. In another series of experiments no effect of an oral administration of prazosin, a selective alpha 1-adrenergic antagonist, on the secretion of GH, PRL and cortisol was found in any of 7 subjects. Prazosin inhibited blood pressure increase during hypoglycemia and induced slight drowsiness and fatigue in the subjects. It is concluded that in man alpha-adrenergic stimulation of GH secretion during hypoglycemia is transmitted via alpha 2-receptors, PRL secretion is mediated via alpha 1-receptors, whereas inhibition of PRL release is mediated via alpha 2-receptors. In this experiment no effect of alpha 1- or alpha 2-blockade on cortisol response to hypoglycemia was seen.

  8. Binding of (3H)dihydroergocryptine to an alpha-adrenergic site in the stalk median eminence of the steer

    Energy Technology Data Exchange (ETDEWEB)

    Chen, H.T.; Roberts, J.M.; Weiner, R.I.

    1981-12-01

    Dihydroergocryptine (DHE), a potent dopamine agonist and alpha-adrenergic antagonist, has been used as a radioligand to characterize both dopamine and alpha-adrenergic receptors. In the present study, the binding of (3H)DHE to particulate fractions of the steer stalk median eminence was characterized using a filtration assay. Specific binding was defined by the presence of 10 microM phentolamine or by an iterative nonlinear hyperbolic curve-fitting program. Scatchard analysis of equilibrium isotherms of specific binding defined a single high affinity (Kd . 1.78 +/- 0.22 nM), saturable (maximum binding, 481 +/- 39 fmol/mg protein), stereoselective binding site. The Kd, calculated from the ratio of the rate constants k2 and k1, was 2.8 +/- 0.14 nM. The rank order of potency of agonists to compete for (3H)DHE binding (l-epinephrine greater than l-norepinephrine greater than dopamine greater than l-isoproterenol) was consistent with interactions at an alpha-adrenergic site. The rank order of potency of alpha-antagonists (phentolamine greater than yohimbine greater than prazosin) suggested that this was an alpha 2-adrenergic receptor. The affinity of dopamine agonists for the (3H)DHE-binding site was 10-fold lower relative to their potency at known dopamine receptors, while the affinity of dopaminergic antagonists was 100-fold lower. Furthermore, Scatchard analysis of specific (3H)DHE binding in the presence of a concentration of spiperone which should saturate dopamine receptors, only decreased the number of binding sites by 9%. These data demonstrate the presence of large numbers of alpha-adrenergic receptors in the stalk median eminence of the steer. Only a small number of dopaminergic binding sites for (3H)DHE appeared to be present.

  9. 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''.

  10. Acute exposure to long-chain fatty acids impairs {alpha}2-adrenergic receptor-mediated antilipolysis in human adipose tissue.

    Science.gov (United States)

    Polak, Jan; Moro, Cédric; Bessière, David; Hejnova, Jindra; Marquès, Marie A; Bajzova, Magda; Lafontan, Max; Crampes, Francois; Berlan, Michel; Stich, Vladimir

    2007-10-01

    The acute in vitro and in vivo effects of long-chain fatty acids (LCFAs) on the regulation of adrenergic lipolysis were investigated in human adipose tissue. The effect of a 2 h incubation, without or with LCFA (200 mumol/l), on basal and hormonally induced lipolysis was tested in vitro on isolated fat cells. The lipolytic response to epinephrine was enhanced by suppression of the antilipolytic alpha(2)-adrenergic effect. Then, healthy lean and obese male subjects performed a 45 min exercise bout at 50% of their heart rate reserve either after an overnight fast or 3 h after a high-fat meal (HFM: 95% fat, 5% carbohydrates). Subcutaneous adipose tissue lipolysis was measured by microdialysis in the presence or absence of an alpha-antagonist (phentolamine). In vivo, a HFM increased plasma levels of nonesterified fatty acids in lean and obese subjects. In both groups, the HFM did not alter hormonal responses to exercise. Under fasting conditions, the alpha(2)-adrenergic antilipolytic effect was more pronounced in obese than in lean subjects. The HFM totally suppressed the alpha(2)-adrenergic antilipolytic effect in lean and obese subjects during exercise. LCFAs per se, in vitro as well as in vivo, suppress alpha(2)-adrenergic-mediated antilipolysis in adipose tissue. LCFA-mediated suppression of antilipolytic pathways represents another mechanism whereby a high fat content in the diet might increase adipose tissue lipolysis.

  11. 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.

  12. Hypocaloric diet reduces exercise-induced alpha 2-adrenergic antilipolytic effect and alpha 2-adrenergic receptor mRNA levels in adipose tissue of obese women.

    Science.gov (United States)

    Stich, V; Marion-Latard, F; Hejnova, J; Viguerie, N; Lefort, C; Suljkovicova, H; Langin, D; Lafontan, M; Berlan, M

    2002-03-01

    Previous investigations have shown that alpha 2-adrenoceptor (alpha 2-AR) stimulation blunts lipid mobilization during physiological activation of the sympathetic nervous system promoted by exercise in sc abdominal adipose tissue (SCAAT) in obese men. To investigate the effect of a low calorie diet (LCD) on the alpha 2-adrenergic responsiveness and on the expression of alpha 2-AR and beta 2-adrenoceptor (beta 2-AR) in SCAAT, 11 obese women (weight: 99.1 +/- 4.6 kg; body mass index: 34.3 +/- 1.1 kg/m(2)) received a 12-wk diet providing 500 kcal/d less than their usual diet. The exercise-induced alpha 2-adrenergic antilipolytic effect was investigated in SCAAT before and at the end of LCD. Changes in extracellular glycerol concentration and local blood flow were measured in SCAAT during a 45-min exercise bout (50% of heart rate reserve) using a control microdialysis probe and a probe supplemented with the alpha2-AR antagonist phentolamine. SCAAT biopsies were performed for determination of mRNA levels using RT-competitive PCR. Plasma catecholamine responses to exercise bout were not different before and at the end of LCD. Before LCD, the exercise-induced increase in extracellular glycerol concentration was potentiated by phentolamine supplementation, while this potentiating effect of the alpha-antagonist was not observed at the end of LCD. No changes were observed for beta 2-AR and hormone-sensitive lipase mRNA levels, while alpha 2-AR mRNA level was significantly decreased in adipose tissue during LCD. These findings show that alpha 2-AR-mediated antilipolytic action is reduced by a moderate hypocaloric diet and that down-regulation of alpha 2-AR mRNA levels may participate in the decrease of the alpha 2-adrenergic effect revealed by microdialysis.

  13. The use of alpha-1 adrenergic blockers in children with distal ureterolithiasis: a systematic review and meta-analysis

    Science.gov (United States)

    Glina, F.P.; Castro, P.M.V.; Monteiro, G.G.R.; Guerra, G.C. Del; Glina, S.; Mazzurana, M.; Bernardo, W.M.

    2015-01-01

    ABSTRACT Introduction: Urinary lithiasis is the main urologic cause of emergency treatment in adult patient. In the past years, the incidence in children population has increased. However, literature about the use of alpha-1 adrenergic blockers in pediatric population with distal ureterolithiasis is still scarce. The drug acts by decreasing ureter contractions, especially in the distal portion, facilitating calculus expulsion. Objective: This review has the objective to evaluate the use of alpha-1 adrenergic blockers as medical expulsive treatment in children with distal ureterolithiasis. Evidence Acquisition: An electronic literature search was performed using the MEDLINE, COCHRANE, and LILACS databases. We further searched manually the references of the primary studies. Searches were concluded on October 4th, 2014. Articles were selected, independently and in pairs, by the respective titles and summaries. Any divergence was resolved by consensus. Evidence Synthesis: Alpha-1 adrenergic antagonists increased the probability of calculus expulsion by 27% (NNT=4). Calculi smaller than 5mm, increased by 33% (NNT=3). Larger than 5mm, increased by 34% (NNT=3). Conclusion: Alpha-1 adrenergic blocker use is related with a greater incidence of expulsion of ureteral calculi, smaller or greater than 5mm, and fewer episodes of pain when compared to ibuprofen. However it is necessary larger samples to enhance the power analysis of the expulsion of ureteral calculi larger than 5mm and the episodes of pain. Patient Summary: This review analyzed the outcome of alpha adrenergic antagonist in children with ureteral calculi. We conclude that it is the best medicine for use, since it helps the expulsion of the stone. PMID:26717117

  14. The use of alpha-1 adrenergic blockers in children with distal ureterolithiasis: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    F.P. Glina

    2015-12-01

    Full Text Available Introduction: Urinary lithiasis is the main urologic cause of emergency treatment in adult patient. In the past years, the incidence in children population has increased. However, literature about the use of alpha-1 adrenergic blockers in pediatric population with distal ureterolithiasis is still scarce. The drug acts by decreasing ureter contractions, especially in the distal portion, facilitating calculus expulsion. Objective: This review has the objective to evaluate the use of alpha-1 adrenergic blockers as medical expulsive treatment in children with distal ureterolithiasis. Evidence Acquisition: An electronic literature search was performed using the MEDLINE, COCHRANE, and LILACS databases. We further searched manually the references of the primary studies. Searches were concluded on October 4th, 2014. Articles were selected, independently and in pairs, by the respective titles and summaries. Any divergence was resolved by consensus. Evidence Synthesis: Alpha-1 adrenergic antagonists increased the probability of calculus expulsion by 27% (NNT=4. Calculi smaller than 5mm, increased by 33% (NNT=3. Larger than 5mm, increased by 34% (NNT=3. Conclusion: Alpha-1 adrenergic blocker use is related with a greater incidence of expulsion of ureteral calculi, smaller or greater than 5mm, and fewer episodes of pain when compared to ibuprofen. However it is necessary larger samples to enhance the power analysis of the expulsion of ureteral calculi larger than 5mm and the episodes of pain. Patient Summary: This review analyzed the outcome of alpha adrenergic antagonist in children with ureteral calculi. We conclude that it is the best medicine for use, since it helps the expulsion of the stone.

  15. Adrenergic β2-receptors mediates visceral hypersensitivity induced by heterotypic intermittent stress in rats.

    Directory of Open Access Journals (Sweden)

    Chunhua Zhang

    Full Text Available Chronic visceral pain in patients with irritable bowel syndrome (IBS has been difficult to treat effectively partially because its pathophysiology is not fully understood. Recent studies show that norepinephrine (NE plays an important role in the development of visceral hypersensitivity. In this study, we designed to investigate the role of adrenergic signaling in visceral hypersensitivity induced by heterotypical intermittent stress (HIS. Abdominal withdrawal reflex scores (AWRs used as visceral sensitivity were determined by measuring the visceromoter responses to colorectal distension. Colon-specific dorsal root ganglia neurons (DRGs were labeled by injection of DiI into the colon wall and were acutely dissociated for whole-cell patch-clamp recordings. Blood plasma level of NE was measured using radioimmunoassay kits. The expression of β2-adrenoceptors was measured by western blotting. We showed that HIS-induced visceral hypersensitivity was attenuated by systemic administration of a β-adrenoceptor antagonist propranolol, in a dose-dependent manner, but not by a α-adrenoceptor antagonist phentolamine. Using specific β-adrenoceptor antagonists, HIS-induced visceral hypersensitivity was alleviated by β2 adrenoceptor antagonist but not by β1- or β3-adrenoceptor antagonist. Administration of a selective β2-adrenoceptor antagonist also normalized hyperexcitability of colon-innervating DRG neurons of HIS rats. Furthermore, administration of β-adrenoceptor antagonist suppressed sustained potassium current density (IK without any alteration of fast-inactivating potassium current density (IA. Conversely, administration of NE enhanced the neuronal excitability and produced visceral hypersensitivity in healthy control rats, and blocked by β2-adrenoceptor antagonists. In addition, HIS significantly enhanced the NE concentration in the blood plasma but did not change the expression of β2-adrenoceptor in DRGs and the muscularis externa of the

  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. NORADRENERGIC AND ADRENERGIC FUNCTIONING IN AUTISM

    NARCIS (Netherlands)

    MINDERAA, RB; ANDERSON, GM; VOLKMAR, FR; AKKERHUIS, GW; COHEN, DJ

    1994-01-01

    A neurochemical assessment of noradrenergic and adrenergic functioning was carried out with autistic patients and normal control individuals. Norepinephrine and related compounds were measured in autistic (n = 17 unmedicated, 23 medicated; age range 9-29 years old) and normal controls (n = 27; age r

  18. -Adrenergic receptors on rat ventricular myocytes: characteristics and linkage to cAMP metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Buxton, I.L.O.; Brunton, L.L.

    1986-08-01

    When incubated with purified cardiomyocytes from adult rat ventricle, the 1-antagonist (TH)prazosin binds to a single class of sites with high affinity. Competition for (TH)prazosin binding by the 2-selective antagonist yohimbine and the nonselective -antagonist phentolamine demonstrates that these receptors are of the 1-subtype. In addition, incubation of myocyte membranes with (TH)yohimbine results in no measurable specific binding. Agonist competition for (TH)prazosin binding to membranes prepared from purified myocytes demonstrates the presence of two components of binding: 28% of 1-receptors interact with norepinephrine with high affinity (K/sub D/ = 36 nM), whereas the majority of receptors (72%) have a low affinity for agonist (K/sub D/ = 2.2 M). After addition of 10 M GTP, norepinephrine competes for (TH)prazosin binding to a single class of sites with lower affinity (K/sub D/ = 2.2 M). Incubation of intact myocytes for 2 min with 1 M norepinephrine leads to significantly less cyclic AMP (cAMP) accumulation than stimulation with either norepinephrine plus prazosin or isoproterenol. Likewise, incubation of intact myocytes with 10 W M norepinephrine leads to significantly less activation of cAMP-dependent protein kinase than when myocytes are stimulated by both norepinephrine and the 1-adrenergic antagonist, prazosin or the US -adrenergic agonist, isoproterenol. They conclude that the cardiomyocyte 1 receptor is coupled to a guanine nucleotide-binding protein, that 1-receptors are functionally linked to decreased intracellular cAMP content, and that this change in cellular cAMP is expressed as described activation of cAMP-dependent protein kinase.

  19. Alpha-Adrenergic receptors in cerebral microvessels of normotensive and spontaneously hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, H.; Wada, A.; Izumi, F.; Magnoni, M.S.; Trabucchi, M.

    1985-03-01

    In rat cerebral microvessels, we characterized alpha 1- and alpha 2-adrenergic receptors, using (/sup 3/H)prazosin and (/sup 3/H)-p-amino-clonidine as radioligands. (/sup 3/H)Prazosin binding to the cerebral microvessels was saturable and of high affinity (dissociation constant of 78 pM), with a maximum binding of 48 fmol/mg protein. (/sup 3/H)Prazosin binding reached equilibrium within 15 minutes and was dissociated by the addition of 10 microM phentolamine. The inhibitory effects of isomers of norepinephrine and epinephrine on the binding showed that l-isomers were over 10 times more potent than d-isomers. (/sup 3/H)-p-Amino-clonidine binding to the cerebral microvessels was saturable and of high affinity (K/sub D/ . 0.61 nM) with a B/sub max/ of 73 fmol/mg protein. The binding reached equilibrium within 30 minutes, and was dissociated by the addition of 100 microM l-norepinephrine. l-Isomers of norepinephrine and epinephrine were over 10 times more potent than d-isomers in displacing the binding. Thus, both (/sup 3/H)prazosin and (/sup 3/H)-p-amino-clonidine bindings to the cerebral microvessels were characterized by saturability, high affinity, reversibility, and stereo-specificity. Furthermore, the specificity of both binding sites was pharmacologically evaluated by the inhibitory effects of various adrenergic agonists and antagonists on the bindings. These data indicate the existence of alpha-adrenergic receptors in the cerebral microvessels and are consistent with the hypothesis that the cerebral microcirculation is regulated by adrenergic innervation. Furthermore, the receptors were measured in cerebral microvessels of spontaneously hypertensive rats and Wistar-Kyoto controls.

  20. Alpha-Amylase Activity in Blood Increases after Pharmacological, But Not Psychological, Activation of the Adrenergic System

    Science.gov (United States)

    Nater, Urs M.; La Marca, Roberto; Erni, Katja; Ehlert, Ulrike

    2015-01-01

    Background & Aim 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. Methods 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 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. Conclusions 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. PMID:26110636

  1. Beta-adrenergic signals regulate cardiac differentiation of mouse embryonic stem cells via mitogen-activated protein kinase pathways.

    Science.gov (United States)

    Yan, Lihui; Jia, Zhuqing; Cui, Jingjing; Yang, Hongtao; Yang, Huangtian; Zhang, Yongzhen; Zhou, Chunyan

    2011-08-01

    As embryonic stem cell-derived cardiomyocytes (ESC-CMs) have the potential to be used in cell replacement therapy, an understanding of the signaling mechanisms that regulate their terminal differentiation is imperative. In previous studies, we discovered the presence of adrenergic and muscarinic receptors in mouse embryonic stem cells (ESCs). However, little is known about the role of these receptors in cardiac differentiation and development, which is critically important in cardiac physiology and pharmacology. Here, we demonstrated that a β-adrenergic receptor (β-AR) agonist significantly enhanced cardiac differentiation as indicated by a higher percentage of beating embryoid bodies and a higher expression level of cardiac markers. Application of β1-AR and β2-AR antagonists partly abolished the effect of the β-AR agonist. In addition, by administering selective inhibitors we found that the effect of β-AR was driven via p38 mitogen-activated protein kinase and extracellular-signal regulated kinase pathway. These findings suggest that ESCs are also a target for β-adrenergic regulation and β-adrenergic signaling plays a role in ESC cardiac differentiation.

  2. 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.

  3. Recent progress in α1-adrenergic receptor research

    Institute of Scientific and Technical Information of China (English)

    Zhong-jian CHEN; Kenneth P MINNEMAN

    2005-01-01

    α1-Adrenergic receptors (AR) play an important role in the regulation of physiological responses mediated by norepinephrine and epinephrine, particularly in the cardiovascular system. The three cloned α1-AR subtypes (α1A, α1B, and α1D)are G protein-coupled receptors that signal through the Gq/11 signaling pathway,each showing distinct pharmacological properties and tissue distributions.However, due to the lack of highly subtype-selective drugs, the functional rolesof individual subtypes are still not clear. Development of new subtype-specific drugs will greatly facilitate the identification of the functions of each subtype.Conopeptide ρ-TIA has been found to be a new α1B-AR selective antagonist withdifferent modes of inhibition at α1-AR subtypes. In addition, recent studies using genetically engineered mice have shed some light on α1-AR functions in vivo,especially in the cardiovascular system and brain. Several proteins have been shown to interact directly with particular α1-AR, and may be important in regulating receptor function. Receptor heterodimerization has been shown to be important for cell surface expression, signaling and internalization. These new observations are likely to help elucidate the functional roles of individual α1-AR subtypes.

  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. The potential of metabolomic analysis techniques for the characterisation of α1-adrenergic receptors in cultured N1E-115 mouse neuroblastoma cells.

    Science.gov (United States)

    Wenner, Maria I; Maker, Garth L; Dawson, Linda F; Drummond, Peter D; Mullaney, Ian

    2016-08-01

    Several studies of neuropathic pain have linked abnormal adrenergic signalling to the development and maintenance of pain, although the mechanisms underlying this are not yet fully understood. Metabolomic analysis is a technique that can be used to give a snapshot of biochemical status, and can aid in the identification of the mechanisms behind pathological changes identified in cells, tissues and biological fluids. This study aimed to use gas chromatography-mass spectrometry-based metabolomic profiling in combination with reverse transcriptase-polymerase chain reaction and immunocytochemistry to identify functional α1-adrenergic receptors on cultured N1E-115 mouse neuroblastoma cells. The study was able to confirm the presence of mRNA for the α1D subtype, as well as protein expression of the α1-adrenergic receptor. Furthermore, metabolomic data revealed changes to the metabolite profile of cells when exposed to adrenergic pharmacological intervention. Agonist treatment with phenylephrine hydrochloride (10 µM) resulted in altered levels of several metabolites including myo-inositol, glucose, fructose, alanine, leucine, phenylalanine, valine, and n-acetylglutamic acid. Many of the changes observed in N1E-115 cells by agonist treatment were modulated by additional antagonist treatment (prazosin hydrochloride, 100 µM). A number of these changes reflected what is known about the biochemistry of α1-adrenergic receptor activation. This preliminary study therefore demonstrates the potential of metabolomic profiling to confirm the presence of functional receptors on cultured cells.

  6. Adrenergic Receptors From Molecular Structure to in vivo function.

    Science.gov (United States)

    Hein, L; Kobilka, B K

    1997-07-01

    Adrenergic receptors form the interface between the sympathetic nervous system and the cardiovascular system as well as many endocrine and parenchymal tissues. Although several hundred G-protein-coupled receptors have been identified, adrenergic receptors, along with the visual pigment rhodopsin, have been among the most extensively studied members of this family of receptors. This review focuses on recent advances in understanding the molecular structure, function, and regulation of adrenergic receptors using in vitro systems and integrates recent transgenic animal models that were generated to study the adrenergic system in vivo. (Trends Cardiovasc Med 1997;7:137-145). © 1997, Elsevier Science Inc.

  7. Regulatory volume increase in astrocytes exposed to hypertonic medium requires β1 -adrenergic Na(+) /K(+) -ATPase stimulation and glycogenolysis.

    Science.gov (United States)

    Song, Dan; Xu, Junnan; Hertz, Leif; Peng, Liang

    2015-01-01

    The cotransporter of Na(+) , K(+) , 2Cl(-) , and water, NKKC1, is activated under two conditions in the brain, exposure to highly elevated extracellular K(+) concentrations, causing astrocytic swelling, and regulatory volume increase in cells shrunk in response to exposure to hypertonic medium. NKCC1-mediated transport occurs as secondary active transport driven by Na(+) /K(+) -ATPase activity, which establishes a favorable ratio for NKCC1 operation between extracellular and intracellular products of the concentrations of Na(+) , K(+) , and Cl(-) × Cl(-) . In the adult brain, astrocytes are the main target for NKCC1 stimulation, and their Na(+) /K(+) -ATPase activity is stimulated by elevated K(+) or the β-adrenergic agonist isoproterenol. Extracellular K(+) concentration is normal during regulatory volume increase, so this study investigated whether the volume increase occurred faster in the presence of isoproterenol. Measurement of cell volume via live cell microscopic imaging fluorescence to record fluorescence intensity of calcein showed that this was the case at isoproterenol concentrations of ≥1 µM in well-differentiated mouse astrocyte cultures incubated in isotonic medium with 100 mM sucrose added. This stimulation was abolished by the β1 -adrenergic antagonist betaxolol, but not by ICI118551, a β2 -adrenergic antagonist. A large part of the β1 -adrenergic signaling pathway in astrocytes is known. Inhibitors of this pathway as well as the glycogenolysis inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol hydrochloride and the NKCC1 inhibitors bumetanide and furosemide abolished stimulation by isoproterenol, and it was weakened by the Na(+) /K(+) -ATPase inhibitor ouabain. These observations are of physiological relevance because extracellular hypertonicity occurs during intense neuronal activity. This might trigger a regulatory volume increase, associated with the post-excitatory undershoot.

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    Shogo Sato

    2011-01-01

    Full Text Available 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 by the downregulation of the receptor. Endurance training improves oxidative performance partly by increasing β2-adrenergic receptor density in exercise-recruited slow-twitch muscles. However, excessive stimulation of β2-adrenergic receptors negates their beneficial effects. Although the preventive effects of β2-adrenergic receptor stimulation on atrophy induced by muscle disuse and catabolic hormones or drugs are observed, these catabolic conditions decrease β2-adrenergic receptor expression in slow-twitch muscles. These findings present evidence against the use of β2-adrenergic agonists in therapy for muscle wasting and weakness. Thus, β2-adrenergic receptors in the skeletal muscles play an important physiological role in the regulation of protein and energy balance.

  10. Human fat cell alpha-2 adrenoceptors. I. Functional exploration and pharmacological definition with selected alpha-2 agonists and antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Galitzky, J.; Mauriege, P.; Berlan, M.; Lafontan, M.

    1989-05-01

    This study was undertaken to investigate more fully the pharmacological characteristics of the human fat cell alpha-2 adrenoceptor. Biological assays were performed on intact isolated fat cells while radioligand binding studies were carried out with (/sup 3/H)yohimbine in membranes. These pharmacological studies brought: (1) a critical definition of the limits of the experimental conditions required for the exploration of alpha-2 adrenergic responsiveness on human fat cells and membranes; (2) an improvement in the pharmacological definition of the human fat cell postsynaptic alpha-2 adrenoceptor. Among alpha-2 agonists, UK-14,304 was the most potent and the relative order of potency was: UK-14,304 greater than p-aminoclonidine greater than clonidine = B-HT 920 greater than rilmenidine. For alpha-2 antagonists, the potency order was: yohimbine greater than idazoxan greater than SK F-86,466 much greater than benextramine; (3) a description of the impact of benextramine (irreversible alpha-1/alpha-2 antagonist) on human fat cell alpha-2 adrenergic receptors and on human fat cell function; the drug inactivates the alpha-2 adrenergic receptors with a minor impact on beta adrenergic receptors and without noticeable alterations of fat cell function as assessed by preservation of beta adrenergic and Al-adenosine receptor-mediated lipolytic responses; and (4) a definition of the relationship existing between alpha-2 adrenergic receptor occupancy, inhibition of adenylate cyclase activity and antilipolysis with full and partial agonists. The existence of a receptor reserve must be taken into account when evaluating alpha-2 adrenergic receptor distribution and regulation of human fat cells.

  11. [Mivazerol and other benzylimidazoles with alpha-2 adrenergic properties].

    Science.gov (United States)

    Cossement, E; Geerts, J P; Michel, P; Motte, G; Noyer, M

    1994-01-01

    4-Benzyl-imidazole compounds derived from Salbutanol are evaluated for potential adrenergic activities. The prevalent property of a series of new bioisosteres of catecholamines either of the saligenol-(ucb LO61) or benzamide-(Mivazerol) type is a selective alpha-adrenergic agonism, at the presynaptic level. The present study stresses the structural features responsible for the alpha-2-agonistic property.

  12. Data on Arc and Zif268 expression in the brain of the α-2A adrenergic receptor knockout mouse

    Directory of Open Access Journals (Sweden)

    Jeff Sanders

    2016-06-01

    Full Text Available The α2-adrenergic receptor (α2-AR is widely distributed in the brain with distinct roles for α2-AR subtypes (A, B and C. In this article, data are provided on Activity Regulated Cytoskeleton Associated Protein (Arc and Zif268 expression in the brain of the α2A-AR knockout (α2A-AR KO mouse. These data are supplemental to an original research article examining Arc and Zif268 expression in rats injected with the α2-AR antagonist, RX821002 (http://dx.doi.org/10.1016/j.neulet.2015.12.002. [1].

  13. [Adrenergic innervation and norepinephrine content in postnatal rat uterus].

    Science.gov (United States)

    Itoh, M

    1983-03-01

    Using fluorescent histochemical method and high performance liquid chromatography with electrochemical detector, we investigated adrenergic innervation and norepinephrine content in the rat uterus in the process of the growth. The adrenergic nerve terminals in the rat uterus developed with age and reached to adult level at 7 weeks of age after birth, although the short adrenergic ganglionic cells and small intense fluorescent cells were present even at birth. Norepinephrine content per organ also increased with age and reached to adult level at 10 weeks of age after birth, while NE content per gram wet tissue weight had a peak in 3-day-old rat uterus. These morphological and biochemical data revealed that the sympathetic nervous system in rat uterus matures in 7 to 10 weeks after birth, while the short adrenergic nervous system is accomplished in earlier stage. The maturation of adrenergic innervation in the uterus was considerably later than in the other organs of rat and developed with the sexual maturation.

  14. Adrenergic urticaria: review of the literature and proposed mechanism.

    Science.gov (United States)

    Hogan, Sara R; Mandrell, Joshua; Eilers, David

    2014-04-01

    Adrenergic urticaria is a rare type of stress-induced physical urticaria characterized by transient outbreaks of red papules surrounded by halos of hypopigmented, vasoconstricted skin. First described in 1985, there are 10 reported cases of adrenergic urticaria in the English-language medical literature. Episodes are caused by various triggers, including emotional upset, coffee, and chocolate, during which serum catecholamines and IgE are elevated, whereas histamine and serotonin levels remain within normal limits. The precise mechanisms leading to the pathogenesis of adrenergic urticaria have yet to be elucidated. Diagnosis can be made by intradermal injection of epinephrine or norepinephrine, which reproduces the characteristic rash, or by clinical observation. Trigger avoidance and oral propranolol are currently the best known treatments for adrenergic urticaria. Nonspecific therapies, including tranquilizers and antihistamines, may also ease symptoms. This article explores the pathophysiology of adrenergic urticaria and proposes a mechanism by which propranolol treats the condition.

  15. 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.

  16. The role of adrenergic agonists on glycogenolysis in rat hepatocyte cultures and possible involvement of NO.

    Science.gov (United States)

    Hodis, J; Kutinová-Canová, N; Potmesil, P; Kameníková, L; Kmonícková, E; Zídek, Z; Farghali, H

    2007-01-01

    Certain liver metabolic diseases point to the presence of disturbances in glycogen deposition. Epinephrine raises the cAMP level that activates protein kinase A leading to the activation of phosphorylase and glycogen breakdown. In the present report, we sought to investigate whether NO is produced during adrenoceptor agonist-induced glycogenolysis in rat hepatocytes in cultures. Isolated glycogen rich rat hepatocytes in cultures were used. NO production (NO(2)(-)) was assessed under the effect of adrenergic agonists and adrenergic agonist/antagonist pairs, dibutyryl cyclic AMP sodium-potassium salt (db-cAMP), NO synthase (NOS) inhibitors N(omega)-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG) and the NO donor S-nitroso-N-acetyl penicillamine (SNAP). The inducible NO synthase (iNOS) mRNA was examined by the reverse transcription-polymerase chain reaction (RT-PCR). Glycogenolysis was quantified by glucose levels released into medium. The amount of glucose and NO(2)(-) released by hepatocytes was increased as a result of epinephrine, phenylephrine or db-cAMP treatments. The increase in glucose and NO(2)(-) released by epinephrine or phenylephrine was blocked or reduced by prazosin pretreatment and by NOS inhibitors aminoguanidine and L-NAME. iNOS gene expression was up-regulated by epinephrine. It can be concluded that glycogenolysis occurs through -adrenoceptor stimulation and a signaling cascade may involve NO production.

  17. Beta-adrenergic Blockade at Memory Encoding, but Not Retrieval, Decreases the Subjective Sense of Recollection.

    Science.gov (United States)

    Rimmele, Ulrike; Lackovic, Sandra F; Tobe, Russell H; Leventhal, Bennett L; Phelps, Elizabeth A

    2016-06-01

    Humans remember emotional events not only better but also exhibit a qualitatively distinct recollective experience-that is, emotion intensifies the subjective vividness of the memory, the sense of reliving the event, and confidence in the accuracy of the memory [Phelps, E. A., & Sharot, T. How (and why) emotion enhances the subjective sense of recollection. Current Directions in Psychological Science, 17, 147-152, 2008]. Although it has been demonstrated that activation of the beta-adrenergic system, linked to increases in stress hormone levels and physiological arousal, mediates enhanced emotional memory accuracy, the mechanism underlying the increased subjective sense of recollection is unknown. Behavioral evidence suggests that increased arousal associated with emotional events, either at encoding or retrieval, underlies their increased subjective sense of recollection. Using a double-blind, placebo-controlled, within-subject design, we showed that reducing arousal at encoding through oral intake of 80-mg of the beta-adrenergic receptor antagonist propranolol decreases the subjective sense of recollection for both negative and neutral stimuli 24 hr later. In contrast, administration of propranolol before memory retrieval did not alter the subjective sense of recollection. These results suggest that the neurohormonal changes underlying increased arousal at the time of memory formation, rather than the time of memory retrieval, modulate the subjective sense of recollection.

  18. Lack of alpha(2)-adrenergic antilipolytic effect during exercise in subcutaneous adipose tissue of trained men.

    Science.gov (United States)

    De Glisezinski, I; Marion-Latard, F; Crampes, F; Berlan, M; Hejnova, J; Cottet-Emard, J M; Stich, V; Rivière, D

    2001-10-01

    The aim of this study was to investigate the involvement of the antilipolytic alpha(2)-adrenergic receptor pathway in the regulation of lipolysis during exercise in subcutaneous abdominal adipose tissue (SCAAT). Seven trained men and 15 untrained men were studied. With the use of microdialysis, the extracellular glycerol concentration was measured in SCAAT at rest and during 60 min of exercise at 50% of maximal oxygen consumption. One microdialysis probe was perfused with Ringer solution; the other was supplemented with phentolamine (alpha(2)-adrenergic receptor antagonist). No differences in baseline extracellular or plasma glycerol concentrations were found between the two groups. The exercise-induced extracellular and plasma glycerol increase was higher in trained compared with untrained subjects (P < 0.05). Addition of phentolamine to the perfusate enhanced the exercise-induced response of extracellular glycerol in untrained subjects but not in trained subjects. The exercise-induced increase in plasma norepinephrine and epinephrine concentrations and the decrease in plasma insulin were not different in the two groups. These in vivo findings demonstrate higher exercise-induced lipolysis in trained compared with untrained subjects and show that, in trained subjects, the alpha(2)-mediated antilipolytic action is not involved in the regulation of lipolysis in SCAAT during exercise.

  19. Locus Coeruleus Stimulation Facilitates Long-Term Depression in the Dentate Gyrus That Requires Activation of β-Adrenergic Receptors

    Science.gov (United States)

    Hansen, Niels; Manahan-Vaughan, Denise

    2015-01-01

    Synaptic plasticity comprises a cellular mechanism through which the hippocampus most likely enables memory formation. Neuromodulation, related to arousal, is a key aspect in information storage. The activation of locus coeruleus (LC) neurons by novel experience leads to noradrenaline release in the hippocampus at the level of the dentate gyrus (DG). We explored whether synaptic plasticity in the DG is influenced by activation of the LC via electrical stimulation. Coupling of test-pulses that evoked stable basal synaptic transmission in the DG with stimulation of the LC induced β-adrenoreceptor-dependent long-term depression (LTD) at perforant path–DG synapses in adult rats. Furthermore, persistent LTD (>24 h) induced by perforant path stimulation also required activation of β-adrenergic receptors: Whereas a β-adrenergic receptor antagonist (propranolol) prevented, an agonist (isoproterenol) strengthened the persistence of LTD for over 24 h. These findings support the hypothesis that persistent LTD in the DG is modulated by β-adrenergic receptors. Furthermore, LC activation potently facilitates DG LTD. This suggests in turn that synaptic plasticity in the DG is tightly regulated by activity in the noradrenergic system. This may reflect the role of the LC in selecting salient information for subsequent synaptic processing in the hippocampus. PMID:24464942

  20. Trafficking of α1B-adrenergic receptor mediated by inverse agonist in living cells

    Institute of Scientific and Technical Information of China (English)

    MingXU; Ying-huaGUAN; NingXU; Zhang-yiLIANG; Shu-yiWang; YaoSONG; Chi-deHAN; Xin-shengZHAO; You-yiZHANG

    2005-01-01

    AIM The project is aimed at understanding the action of inverse agonist at single molecule level and capturing the real time picture of molecular behavior of α1B-adrenergic receptor (AR) mediated by inverse agonist in living cells by single molecule detection (SMD). METHODS The location and distribution of α1B-AR was detected by laser confocal and whole cell 3H-prazosin binding assay. Dynamic imaging of BODIPY-FL-labeled prazosin (Praz), specific antagonist of (1-AR, was observed in α1B-AR stably expressed human embryonic kidney 293 (HEK293) living cells. The detection of real-time dynamic behaviors of AR was achieved by using fluorescence-labeled AR and its ligand combined with SMD techniques. RESULTS α1B-AR was predominantly distributed on the cell surface and 8.2% of the total receptors were located in cytosol.

  1. Cholinergic and adrenergic influence on the teleost heart in vivo.

    Science.gov (United States)

    Axelsson, M; Ehrenström, F; Nilsson, S

    1987-01-01

    The tonical cholinergic and adrenergic influence on the heart rate was investigated in vivo in seven species of marine teleosts (pollack, Pollachius pollachius; cuckoo wrasse, Labrus mixtus; ballan wrasse, Labrus berggylta; five-bearded rockling, Ciliata mustela; tadpole fish, Raniceps raninus; eel-pout, Zoarces viviparus and short-spined sea scorpion, Myoxocephalus scor pius) during rest and, in two of the species (P. pollachius and L. mixtus), also during moderate swimming exercise in a Blazka-type swim tunnel. Ventral aortic blood pressure and heart rate were recorded via a catheter implanted in an afferent branchial artery, and the influence of the cholinergic and adrenergic tonus on the heart rate was assessed by injection of atropine and sotalol respectively. During rest the adrenergic tonus was higher than the cholinergic tonus in all species except L. berggylta, where the reverse was true. In P. pollachius and L. mixtus, exercise appeared to produce a lowering of the cholinergic tonus on the heart and, possibly, a slight increase of the adrenergic tonus. The nature of the adrenergic tonus (humoral or neural) is not clear, but the low plasma concentrations of catecholamines both during rest and exercise could be interpreted in favour of a mainly neural adrenergic tonus on the teleost heart. These experiments are compatible with the view that both a cholinergic inhibitory tonus and an adrenergic excitatory tonus are general features in the control of the teleost heart in vivo, both at rest and during moderate swimming exercise.

  2. Comparison of alpha-2 adrenergic receptors and their regulation in rodent and porcine species

    Energy Technology Data Exchange (ETDEWEB)

    Feller, D.J.; Bylund, D.B.

    1984-02-01

    The alpha-2 adrenergic antagonist (/sup 3/H)yohimbine (YOH) and the alpha-2 agonist (/sup 3/H)p-aminoclonidine (PAC) saturably label high-affinity binding sites in the submandibular gland from 3-week-old rats and 5-week-old pigs and in the lung from neonatal rats and 5-week-old pigs. (/sup 3/H)YOH had KD values of 5.5, 1.8, 0.45 and 0.22 nM in the rat gland and lung and porcine gland and lung, respectively. KD values of 2.4, 5.3 and 1.3 nM were found for (/sup 3/H)PAC in rodent and pig submandibular gland and pig lung, respectively. Both /sup 3/H-ligands labeled approximately the same density of sites within each tissue except in the rat lung in which (/sup 3/H)PAC binding was too low to reliably estimate. In all cases the pharmacologic profile was indicative of an alpha-2 adrenergic receptor site. However, the Ki of yohimbine vs. (/sup 3/H)PAC was 30- to 140-fold higher for the rodent relative to the porcine species. GTP decreased the affinity of (-)-epinephrine and PAC at (/sup 3/H)YOH-labeled sites in the pig gland and lung, but did not shift the affinity of epinephrine in the rat gland. These results suggest the possibility of subtype or species differences for the alpha-2 receptor. The Ki values of the antagonists YOH and phentolamine were different at (/sup 3/H)PAC and (/sup 3/H)YOH sites. GTP caused a dose-dependent reduction in (/sup 3/H)PAC binding in the porcine submandibular gland and lung. At 10 microM GTP, this loss was due to a decrease in /sup 3/H-agonist affinity, but not density.

  3. 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.

  4. Alpha/sub 2/-adrenergic receptors on a platelet precursor cell line, HEL

    Energy Technology Data Exchange (ETDEWEB)

    McKernan, R.M.; Motulsky, H.J.; Rozansky, D.; Insel, P.A.

    1986-03-01

    The authors have identified ..cap alpha../sub 2/-adrenergic receptors on human erythroleukemia HEL cells, a suspension-growing, bone-marrow-derived cell line related to human platelets. Intact HEL cells were studied using radioligand binding and cAMP accumulation assays. The authors identified saturable specific binding of the ..cap alpha../sub 2/-antagonist (/sup 3/H)yohimbine (yoh) in cells incubated at 37/sup 0/C for 1 hr (B/sub max/ 5900 +/- 2100 sites/cell, K/sub d/ 3.6 +/- 0.9 nM, n = 7). Competition for (/sup 3/H)yoh binding sites with antagonists confirmed that these sites were similar to human ..cap alpha../sub 2/-adrenoceptors from platelets and other resources, as typified by their high affinity for WY-26392, yohimbine and idazoxan, and very low affinity for prazosin. Studies at 37/sup 0/C revealed a low affinity of these sites for catecholamines (K/sub i/ for (-)-epinephrine, 21 ..mu..M; (-)-norepinephrine, 45 ..mu..M, (+)-epinephrine, 80 ..mu..M). When experiments were conducted at 4 /sup 0/C, (-)-epinephrine was able to compete for only 50-60% of the sites specifically labelled by (/sup 3/H)yoh at 37/sup 0/, but (-)-epinephrine had an approximately 10-fold greater affinity for these sites (K/sub i/ at 4 /sup 0/C = 2.4 ..mu..M). In addition, epinephrine inhibited cAMP accumulation stimulated by forskolin and PGE/sub 1/ in HEL cells; this response was inhibited by pertussis toxin. The authors conclude that HEL cells possess ..cap alpha../sub 2/-adrenergic receptors linked to G/sub i/ and thus should serve as a useful model to explore metabolism and regulation of these receptors in human cells.

  5. Activation of antilipolytic alpha(2)-adrenergic receptors by epinephrine during exercise in human adipose tissue.

    Science.gov (United States)

    Stich, V; de Glisezinski, I; Crampes, F; Suljkovicova, H; Galitzky, J; Riviere, D; Hejnova, J; Lafontan, M; Berlan, M

    1999-10-01

    The involvement of the antilipolytic alpha(2)-adrenergic pathway and the specific role of epinephrine in the control of lipolysis during exercise in adipose tissue (AT) were investigated in healthy male subjects (age: 24.1 +/- 2.2 yr; body mass index: 23.0 +/- 1.6). An in vitro study carried out on isolated adipocytes showed that the weak lipolytic effect of epinephrine was potentiated after blockade of alpha(2)-adrenergic receptor (AR) by an alpha(2)-AR antagonist and reached that of isoproterenol, a beta-AR agonist. The effect of the nonselective alpha(2)-AR antagonist phentolamine on the response of the extracellular glycerol concentration (EGC) in AT during two successive bouts of aerobic exercise (50% maximum O(2) uptake, 60 min duration) was evaluated using the microdialysis method. The metabolic responses measured in perfused probes with Ringer solution were compared with those obtained in perfused probes with Ringer plus 0.1 mmol/l phentolamine. Plasma norepinephrine level was not different during the two exercise bouts, whereas that of epinephrine was 2.5-fold higher during the second exercise. EGC in AT was twofold higher in the second compared with the first exercise, and the same response pattern was found for plasma glycerol. The exercise-induced increase in EGC was higher in the probe perfused with phentolamine compared with the control probe in both bouts of exercise. However, the potentiating effect of phentolamine on EGC was significant during the second exercise bout but did not reach a significant level during the first. These results suggest that epinephrine is involved in the control of lipid mobilization through activation of antilipolytic alpha(2)-AR in human subcutaneous AT during exercise.

  6. Effects of alpha-1 adrenergic receptor antagonist, terazosin, on cardiovascular functions in anaesthetised dogs.

    Science.gov (United States)

    Sharma, R; Ahuja, V M; Fahim, M

    2004-12-01

    Initially a dose-response curve of phenylephrine was constructed at dose strengths of 1-16 microg/kg in a cumulative manner. Phenylephrine caused a significant rise in the mean arterial pressure, left ventricular systolic pressure, left ventricular contractility, stroke volume and a significant decline in the heart rate. Terazosin was administered in three selected doses of 10, 100 and 300 microg/kg. Following each dose of terazosin, dose-response curve of phenylephrine was constructed. Terazosin, per se, decreased the basal mean arterial pressure, left ventricular systolic pressure, left ventricular contractility and stroke volume significantly in a dose dependent manner with an increase in the heart rate with no significant change in the cardiac output. The baroreflex sensitivity at all the three doses remained unchanged. In conclusion, the present findings support the view that terazosin reduces the blood pressure in a physiologically more favorable manner by maintaining the neural integrity of the cardiovascular system.

  7. Synthesis of heteroaromatic potential beta-adrenergic antagonists by the glycidol route.

    Science.gov (United States)

    Antonio, Y; Camargo, C; Galeazzi, E; Iriarte, J; Guzman, M; Muchowski, J M; Gerrity, K; Liu, F; Miller, L M; Strosberg, M M

    1978-01-01

    The synthesis of several 3-alkylamino-2-hydroxypropyl heteroaryl ethers (13-15, 17, and 18) is described. These compounds were prepared by the alkylamination of the corresponding glycidyl ethers (6-8, 10, and 11), which in turn were obtained from the requisite heteroaryl halides and the sodium salt of glycidol. The above basic ethers exhibited beta-blocking activity, but the potency of the tested compounds was considerably less than that of propanolol. Only 3-tert-butylamino-2-hydroxyl-1-(1,2,4-thiadiazol-5-yl) propyl ether (13) showed some selective myocardial beta-blocking activity.

  8. Severe hyperkalemia as a complication of timolol, a topically applied beta-adrenergic antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Swenson, E.R.

    1986-06-01

    Severe hyperkalemia occurred in a patient with radiation pneumonitis and glaucoma shortly after beginning prednisone therapy. There was no evidence of renal failure, diabetes, acidosis, increased potassium intake, or significant tissue trauma. Medications having adverse effects on potassium metabolism were considered, and the patient's use of timolol maleate eyedrops was discontinued. His serum potassium level normalized despite continuation of the prednisone therapy. He became hyperkalemic on rechallenge with timolol and normokalemic following its withdrawal. This case indicates that the potential for beta-blocker-induced hyperkalemia exists even with topical appreciation.

  9. Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with β-adrenergic activity

    Science.gov (United States)

    Careaga, Mariella B. L.; Tiba, Paula A.; Ota, Simone M.; Suchecki, Deborah

    2015-01-01

    Cognitive processes, such as learning and memory, are essential for our adaptation to environmental changes and consequently for survival. Numerous studies indicate that hormones secreted during stressful situations, such as glucocorticoids (GCs), adrenaline and noradrenaline, regulate memory functions, modulating aversive memory consolidation and retrieval, in an interactive and complementary way. Thus, the facilitatory effects of GCs on memory consolidation as well as their suppressive effects on retrieval are substantially explained by this interaction. On the other hand, low levels of GCs are also associated with negative effects on memory consolidation and retrieval and the mechanisms involved are not well understood. The present study sought to investigate the consequences of blocking the rise of GCs on fear memory retrieval in multiple tests, assessing the participation of β-adrenergic signaling on this effect. Metyrapone (GCs synthesis inhibitor; 75 mg/kg), administered 90 min before the first test of contextual or tone fear conditioning (TFC), negatively affected animals’ performances, but this effect did not persist on a subsequent test, when the conditioned response was again expressed. This result suggested that the treatment impaired fear memory retrieval during the first evaluation. The administration immediately after the first test did not affect the animals’ performances in contextual fear conditioning (CFC), suggesting that the drug did not interfere with processes triggered by memory reactivation. Moreover, metyrapone effects were independent of β-adrenergic signaling, since concurrent administration with propranolol (2 mg/kg), a β-adrenergic antagonist, did not modify the effects induced by metyrapone alone. These results demonstrate that pre-test metyrapone administration led to negative effects on fear memory retrieval and this action was independent of a β-adrenergic signaling. PMID:25784866

  10. Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with β-adrenergic activity

    Directory of Open Access Journals (Sweden)

    Mariella B.L. Careaga

    2015-03-01

    Full Text Available Cognitive processes, such as learning and memory, are essential for our adaptation to environmental changes and consequently for survival. Numerous studies indicate that hormones secreted during stressful situations, such as glucocorticoids (GCs, adrenaline and noradrenaline, regulate memory functions, modulating aversive memory consolidation and retrieval, in an interactive and complementary way. Thus, the facilitatory effects of GCs on memory consolidation as well as their suppressive effects on retrieval are substantially explained by this interaction. On the other hand, low levels of GCs are also associated with negative effects on memory consolidation and retrieval and the mechanisms involved are not well understood. The present study sought to investigate the consequences of blocking the rise of GCs on fear memory retrieval in multiple tests, assessing the participation of β-adrenergic signaling on this effect. Metyrapone (GCs synthesis inhibitor, administered 90 min before the first test of contextual or auditory fear conditioning, negatively affected animals’ performances, but this effect did not persist on a subsequent test, when the conditioned response was again expressed. This result suggested that the treatment impaired fear memory retrieval during the first evaluation. The administration immediately after the first test did not affect the animals’ performances in contextual fear conditioning, suggesting that the drug did not interfere with processes triggered by memory reactivation. Moreover, metyrapone effects were independent of β-adrenergic signaling, since concurrent administration with propranolol, a β-adrenergic antagonist, did not modify the effects induced by metyrapone alone. These results demonstrate that pre-test metyrapone administration led to negative effects on fear memory retrieval and this action was independent of a β-adrenergic signaling.

  11. Pharmacologic specificity of alpha-2 adrenergic receptor subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Petrash, A.; Bylund, D.

    1986-03-01

    The authors have defined alpha-2 adrenergic receptor subtypes in human and rat tissues using prazosin as a subtype selective drug. Prazosin has a lower affinity (250 nM) at alpha-2A receptor and a higher affinity (5 nM) at alpha-2B receptors. In order to determine if other adrenergic drugs are selective for one or the other subtypes, the authors performed (/sup 3/H)yohimbine inhibition experiments with various adrenergic drugs in tissues containing alpha-2A, alpha-2B or both subtypes. Oxymetazoline, WB4101 and yohimbine were found to be 80-, 20- and 10-fold more potent at alpha-2A receptors than at alpha-2B receptors. Phentolamine, adazoxan, (+)- and (-)-mianserin, clonidine, (+)-butaclamol, (-)- and (+)-norepinephrine, epinephrine, dopamine and thioridazine were found to have equal affinities for the two subtypes. These results further validate the subdivision of alpha-2 adrenergic receptors into alpha-2A and alpha-2B subtypes.

  12. Roles of adrenergic α1 and dopamine D1 and D2 receptors in the mediation of the desynchronization effects of modafinil in a mouse EEG synchronization model.

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    Chang-Rui Chen

    Full Text Available BACKGROUND: Synchronized electroencephalogram (EEG activity is observed in pathological stages of cognitive impairment and epilepsy. Modafinil, known to increase the release of catecholamines, is a potent wake-promoting agent, and has shown some abilities to desynchronize EEG,but its receptor mechanisms by which modafinil induces desynchoronization remain to be elucidated. Here we used a pharmacological EEG synchronization model to investigate the involvement of adrenergic α1 receptors (R, α1R and dopamine (DA D1 and D2 receptors (D1Rs and D2Rs on modafinil-induced desynchronization in mice. METHODOLOGY/PRINCIPAL FINDINGS: Mice were treated with cholinergic receptor antagonist scopolamine and monoamine depletor reserpine to produce experimental EEG synchronization characterized by continuous large-amplitude synchronized activity, with prominent increased delta and decreased theta, alpha, and beta power density. The results showed that modafinil produced an EEG desynchronization in the model. This was characterized by a general decrease in amplitude of all the frequency bands between 0 and 20 Hz, a prominent reduction in delta power density, and an increase in theta power density. Adrenergic α1R antagonist terazosin (1 mg/kg, i.p. completely antagonized the EEG desynchronization effects of modafinil at 90 mg/kg. However, DA D1R and D2R blockers partially attenuated the effects of modafinil. The modafinil-induced decrease in the amplitudes of the delta, theta, alpha, and beta waves and in delta power density were completely abolished by pretreatment with a combination of the D1R antagonist SCH 23390 (30 µg/kg and the D2R antagonist raclopride (2 mg/kg, i.p.. CONCLUSIONS/SIGNIFICANCE: These results suggest that modafinil-mediated desynchronization may be attributed to the activation of adrenergic α1R, and dopaminergic D1R and D2R in a model of EEG synchronization.

  13. Adrenergic receptor control mechanism for growth hormone secretion.

    Science.gov (United States)

    Blackard, W G; Heidingsfelder, S A

    1968-06-01

    The influence of catecholamines on growth hormone secretion has been difficult to establish previously, possibly because of the suppressive effect of the induced hyperglycemia on growth hormone concentrations. In this study, an adrenergic receptor control mechanism for human growth hormone (HGH) secretion was uncovered by studying the effects of alpha and beta receptor blockade on insulin-induced growth hormone elevations in volunteer subjects. Alpha adrenergic blockade with phentolamine during insulin hypoglycemia, 0.1 U/kg, inhibited growth hormon elevations to 30-50% of values in the same subjects during insulin hypoglycemia without adrenergic blockade. More complete inhibition by phentolamine could not be demonstrated at a lower dose of insulin (0.05 U/kg). Beta adrenergic blockade with propranolol during insulin hypoglycemia significantly enhanced HGH concentrations in paired experiments. The inhibiting effect of alpha adrenergic receptor blockade on HGH concentrations could not be attributed to differences in blood glucose or free fatty acid values; however, more prolonged hypoglycemia and lower plasma free fatty acid values may have been a factor in the greater HGH concentrations observed during beta blockade. In the absence of insulin induced hypoglycemia, neither alpha nor beta adrenergic receptor blockade had a detectable effect on HGH concentrations. Theophylline, an inhibitor of cyclic 3'5'-AMP phosphodiesterase activity, also failed to alter plasma HGH concentrations. These studies demonstrate a stimulatory effect of alpha receptors and a possible inhibitory effect of beta receptors on growth hormone secretion.

  14. Opioid Antagonist Impedes Exposure.

    Science.gov (United States)

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  15. Higenamine 4'-O-β-d-glucoside in the lotus plumule induces glucose uptake of L6 cells through β2-adrenergic receptor.

    Science.gov (United States)

    Kato, Eisuke; Inagaki, Yosuke; Kawabata, Jun

    2015-07-01

    Hypoglycemic effect is an efficient means to modulate elevated blood glucose levels in patients with diabetes. We found that the extract of lotus plumule (the germ of Nelumbo nucifera Gaertn. seed) showed potent glucose uptake enhancement activity against L6 myotubes, which results in a hypoglycemic effect. This activity was further investigated, and an active constituent was identified as a single bioactive compound, higenamine 4'-O-β-d-glucoside. Mechanistic studies employing phosphatidylinositol 3-kinase (PI3K) inhibitor, AMP-activated protein kinase (AMPK) inhibitor, or adrenergic receptor antagonist showed that the compound induced its activity through β2-adrenergic receptor. Patients with type II diabetes mellitus frequently develop insulin resistance. Owing to the differences between the mechanism of action of insulin and of the isolated compound, the compound or lotus plumule itself may have the possibility of modulating blood glucose levels in insulin-resistant patients effectively.

  16. Role of descending noradrenergic system and spinal alpha2-adrenergic receptors in the effects of gabapentin on thermal and mechanical nociception after partial nerve injury in the mouse.

    Science.gov (United States)

    Tanabe, Mitsuo; Takasu, Keiko; Kasuya, Noriyo; Shimizu, Shinobu; Honda, Motoko; Ono, Hideki

    2005-03-01

    1. To gain further insight into the mechanisms underlying the antihyperalgesic and antiallodynic actions of gabapentin, a chronic pain model was prepared by partially ligating the sciatic nerve in mice. The mice then received systemic or local injections of gabapentin combined with either central noradrenaline (NA) depletion by 6-hydroxydopamine (6-OHDA) or alpha-adrenergic receptor blockade. 2. Intraperitoneally (i.p.) administered gabapentin produced antihyperalgesic and antiallodynic effects that were manifested by elevation of the withdrawal threshold to a thermal (plantar test) or mechanical (von Frey test) stimulus, respectively. 3. Similar effects were obtained in both the plantar and von Frey tests when gabapentin was injected intracerebroventricularly (i.c.v.) or intrathecally (i.t.), suggesting that it acts at both supraspinal and spinal loci. This novel supraspinal analgesic action of gabapentin was only obtained in ligated neuropathic mice, and gabapentin (i.p. and i.c.v.) did not affect acute thermal and mechanical nociception. 4. In mice in which central NA levels were depleted by 6-OHDA, the antihyperalgesic and antiallodynic effects of i.p. and i.c.v. gabapentin were strongly suppressed. 5. The antihyperalgesic and antiallodynic effects of systemic gabapentin were reduced by both systemic and i.t. administration of yohimbine, an alpha2-adrenergic receptor antagonist. By contrast, prazosin (i.p. or i.t.), an alpha1-adrenergic receptor antagonist, did not alter the effects of gabapentin. 6. It was concluded that the antihyperalgesic and antiallodynic effects of gabapentin are mediated substantially by the descending noradrenergic system, resulting in the activation of spinal alpha2-adrenergic receptors.

  17. [Antifibrillatory activity of dipeptide antagonist of nerve growth factor].

    Science.gov (United States)

    Kryzhanovskiĭ, S A; Stoliarchuk, V N; Vititnova, M B; Tsorin, I B; Pekel'dina, E S; Gudasheva, T A

    2012-01-01

    In experiments on anesthetized rats were assessed antifibrillatoty action of dipeptide GK-1. This compound is the fragment of fourth loop of nerve growth factor (NGF) and manifests antagonistic activity in respect to TrkA receptor, that specified for NGF. It is shown that this compound is able to significantly increase the threshold of electrical fibrillation of the heart and its effectiveness is not inferior to the reference antiarrhythmics I and III class on Vaughan Williams classification. However, unlike the latter, antifibrillatory action of dipeptide GK-1 was delayed and realized within 40-60 minutes after its administration. It is discussed possible mechanisms underlying antifibrillatory action of dipeptide GK-1, that, to some extent, may be associated with its ability to change the reactivity of beta-adrenergic structures of the heart.

  18. Adrenergic Receptors and Metabolism: Role in development of cardiovascular disease

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    Michele eCiccarelli

    2013-10-01

    Full Text Available Activation of the adrenergic system has a profound effects on metabolism. Increased circulating catecholamine and activation of the different adrenergic receptors deployed in the various organs produce important metabolic responses which include: 1 increased lipolysis and elevated levels of fatty acids in plasma, 2 increased gluconeogenesis by the liver to provide substrate for the brain and 3 moderate inhibition of insulin release by the pancreas to conserve glucose and to shift fuel metabolism of muscle in the direction of fatty acid oxidation. These physiological responses, typical of the stress conditions, are demonstrated to be detrimental for the functioning of different organs like the cardiac muscle when they become chronic. Indeed, a common feature of many pathological conditions involving over-activation of the adrenergic system is the development of metabolic alterations which can include insulin resistance, altered glucose and lipid metabolism and mitochondrial dysfunction. These patterns are involved with a variably extent among the different pathologies , however they are in general strictly correlated to the level of activation of the adrenergic system. Here we will review the effects of the different adrenergic receptors subtypes on the metabolic variation observed in important disease like Heart Failure.

  19. Solubilization of a guanyl nucleotide-sensitive alpha/sub 1/ adrenergic receptor from liver membranes

    Energy Technology Data Exchange (ETDEWEB)

    Harris, S.I.; Moss, J.

    1987-05-01

    Rat liver membranes incubated with norepinephrine before solubilization with digitonin yielded a soluble hormone-receptor complex from which the release of tightly bound norepinephrine was facilitated by guanyl nucleotides. Binding of the alpha/sub 1/-adrenergic receptor antagonist, (/sup 3/H)-prazosin, to the soluble preparation was utilized as a gauge of guanyl nucleotide-induced release of receptor-bound agonist. The following potency series was obtained with regard to the ability of guanyl nucleotides to facilitate (/sup 3/H)-prazosin binding to the solubilized preparation: guanosine 5'-0-(3-thiotriphosphate)(K/sub 1/2/ = 2.5 nM), guanylyl-imidodiphosphate (K/sub 1/2/ = 10 nM), guanosine triphosphate (K/sub 1/2/ = 34 nM) and adenylyl-imidodiphosphate (K/sub 1/2/ > 1 mM). In the presence of guanylyl-imidodiphosphate (0.4 mM), the receptor population displayed monotonic binding parameters with a K/sub d/ for (/sup 3/H)-prazosin of 1.16 nM by Scatchard analysis. Competition curves against (/sup 3/H)-prazosin with the antagonists phentolamine and yohimbine revealed respective K/sub i/'s of .089 ..mu..M and 1.8 ..mu..M; curves with the agonists norepinephrine and isoproterenol yielded respective K/sub i/'s of 6.2..mu..M and 360 ..mu..M. Competition curves performed in the absence of guanyl nucleotide were complex demonstrating an apparent increase in affinity for agonists and an apparent decrease in affinity for antagonists. These curve shifts are consistent with the conversion of receptor to and from the guanyl nucleotide-sensitive state as a function of competing ligand concentration.

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

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    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.

  1. Changes of lymphocyte beta-adrenergic receptors after surgical stress.

    Science.gov (United States)

    Eandi, M; Buraglio, M; Arduino, C; Viano, I; Sansalvadore, G; Arbinolo, M A

    1984-01-01

    In this study the authors' purpose was to observe the effects of surgical stress on the number of lymphocyte beta-adrenergic receptors in hypertensive and normotensive subjects. It was noticed that after surgery a significant reduction occurred in the number of binding sites of lymphocytes of both hypertensive and normotensive subjects. The time course of recovery to the pre-operative values of binding sites varied between the two groups, being slower in normotensive than in hypertensive patients. This might suggest a different pattern of regulation of the beta-adrenergic receptor between hypertensive and normotensive subjects.

  2. [The sources of the adrenergic innervation of the rat uterus].

    Science.gov (United States)

    Proĭmina, F I; Rakitskaia, V V

    1990-09-01

    Complete disappearance of adrenergic fibers in the rat uterus is only possible after complete removal of ovaries along with ovarian plexus, transection of the uterus-vaginal connexion and removal of a portion of sympathetic nervous trunk. "Long" adrenergic neurons situated in spinal sympathetic ganglia, seem not to be the only source of sympathetic innervation of the myometrium's vessels. A part of nervous fibers of vascular plexuses and all muscle nerves are represented by "short" neurons starting from the ganglionic structures of the uterus-vaginal connexion.

  3. Tetrahydroindolizinone NK1 antagonists.

    Science.gov (United States)

    Bao, Jianming; Lu, Huagang; Morriello, Gregori J; Carlson, Emma J; Wheeldon, Alan; Chicchi, Gary G; Kurtz, Marc M; Tsao, Kwei-Lan C; Zheng, Song; Tong, Xinchun; Mills, Sander G; DeVita, Robert J

    2010-04-01

    A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.

  4. p-( sup 125 I)iodoclonidine, a novel radiolabeled agonist for studying central alpha 2-adrenergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Baron, B.M.; Siegel, B.W. (Merrell Dow Research Institute, Cincinnati, OH (USA))

    1990-09-01

    Unlabeled p-iodoclonidine was efficacious in attenuating forskolin-stimulated cAMP accumulation in SK-N-SH neuroblastoma cells. Maximal attenuation was 76 +/- 3%, with an EC50 of 347 +/- 60 nM. Comparable values of epinephrine were 72 +/- 3% and 122 +/- 22 nM. Responses to both agonists were abolished by 10 microM phentolamine. Therefore, p-iodoclonidine is an agonist in a cell culture model system of the neuronal alpha 2-adrenergic receptor. p-(125I)Iodoclonidine binding to membranes were measured using various regions of the rat brain. The agonist labeled a single population of sites present on cerebral cortical membranes, which was saturable (Bmax = 230 fmol/mg of protein) and possessed high affinity for the ligand (Kd = 0.6 nM). Binding was largely specific (93% at 0.6 nM). A variety of alpha 2-adrenergic agonists and antagonists were shown to compete for the binding of the radioligand. The binding of p-(125I)iodoclonidine was much less sensitive to agents that interact with alpha 1-adrenergic, serotonergic, and dopaminergic receptors. Approximately 65% of the binding was sensitive to guanine nucleotides. Association kinetics using 0.4 nM radioligand were biphasic (37% associate rapidly, with kobs = 0.96 min-1, with the remainder binding more slowly, with kobs = 0.031 min-1) and reached a plateau by 90 min at 25 degrees. Dissociation kinetics were also biphasic, with 30% of the binding dissociating rapidly (k1 = 0.32 min-1) and the remainder dissociating 50-fold more slowly (k2 = 0.006 min-1). Agonist binding is, therefore, uniquely complex and probably reflects the conformational changes that accompany receptor activation.

  5. Adrenergic pathways in dopamine modulation of K+ transport in cortex slices after low dose X-Rays

    Energy Technology Data Exchange (ETDEWEB)

    Kulikova, I.A.; Dvoretsky, A.I. [Laboratoire of Radiobiology et Radioecology, Science Research Institute of Biology, Dnipropetrovsk State University (Ukraine)

    1997-03-01

    Using the method of surviving brain cortex slices it has been shown that prolonged whole body acute or chronic 25 cGy X-irradiation (1 cGy/day at dose rate of 2.22 mGy/min) essentially modified dopamine (DA) modulating influence upon Na, K-pump in nervous tissue. Obtained results pointed to that normally DA had the defined biphasic effect upon active K{sup +} transport with lower level activation (by 24.0 %) and higher level inhibition (by 42.1 %). The patterns of the Na,K-pump reaction to DA was not changed after irradiation, but percentage of the total DA suppression was increased by 15.1 % in average after single X-ray exposure and by 34.5 % after chronic one. The decisive role of {beta}-adrenergic mechanisms in realization of postirradiation interaction between systems of catecholamine and active K{sup +} transfer across neuronal membrane has been determined. Experimental data obtained with the use of 10 {mu}M phentolamine and 10 {mu}M propranolol, respectively {alpha}- and {beta}-adrenergic antagonists, supported that metabolic DA effect was mediated via {alpha}-AR normally, and via {beta}-AR after low dose-rate irradiation. (authors)

  6. Use of ß-adrenergic agonists in hybrid catfish

    Science.gov (United States)

    Ractopamine hydrochloride (RH) is a potent ß-adrenergic agonist that has been used in some species of fish to improve growth performance and dress out characteristics. While this metabolic modifier has been shown to have positive effects on growth of fish, little research has focused on the mechani...

  7. Beta adrenergic blockade reduces utilitarian judgement.

    Science.gov (United States)

    Terbeck, Sylvia; Sylvia, Terbeck; Kahane, Guy; Guy, Kahane; McTavish, Sarah; Sarah, McTavish; Savulescu, Julian; Julian, Savulescu; Levy, Neil; Neil, Levy; Hewstone, Miles; Miles, Hewstone; Cowen, Philip J

    2013-02-01

    Noradrenergic pathways are involved in mediating the central and peripheral effects of physiological arousal. The aim of the present study was to investigate the role of noradrenergic transmission in moral decision-making. We studied the effects in healthy volunteers of propranolol (a noradrenergic beta-adrenoceptor antagonist) on moral judgement in a set of moral dilemmas pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person) in a double-blind, placebo-controlled, parallel group design. Propranolol (40 mg orally) significantly reduced heart rate, but had no effect on self-reported mood. Importantly, propranolol made participants more likely to judge harmful actions as morally unacceptable, but only in dilemmas where harms were 'up close and personal'. In addition, longer response times for such personal dilemmas were only found for the placebo group. Finally, judgments in personal dilemmas by the propranolol group were more decisive. These findings indicate that noradrenergic pathways play a role in responses to moral dilemmas, in line with recent work implicating emotion in moral decision-making. However, contrary to current theorising, these findings also suggest that aversion to harming is not driven by emotional arousal. Our findings are also of significant practical interest given that propranolol is a widely used drug in different settings, and is currently being considered as a potential treatment for post-traumatic stress disorder in military and rescue service personnel.

  8. Characterization of a β-adrenergic-like octopamine receptor from the rice stem borer (Chilo suppressalis).

    Science.gov (United States)

    Wu, Shun-Fan; Yao, Yao; Huang, Jia; Ye, Gong-Yin

    2012-08-01

    Octopamine, the invertebrate counterpart of adrenaline and noradrenaline, plays a key role in regulation of many physiological and behavioral processes in insects. It modulates these functions through binding to specific octopamine receptors, which are typical rhodopsin-like G-protein coupled receptors. A cDNA encoding a seven-transmembrane receptor was cloned from the nerve cord of the rice stem borer, Chilo suppressalis, viz. CsOA2B2, which shares high sequence similarity to CG6989, a Drosophila β-adrenergic-like octopamine receptor (DmOctβ2R). We generated an HEK-293 cell line that stably expresses CsOA2B2 in order to examine the functional and pharmacological properties of this receptor. Activation of CsOA2B2 by octopamine increased the production of cAMP in a dose-dependent manner (EC(50)=2.33 nmol l(-1)), with a maximum response at 100 nmol l(-1). Tyramine also activated the receptor but with much less potency than octopamine. Dopamine and serotonin had marginal effects on cAMP production. Using a series of known agonists and antagonists for octopamine receptors, we observed a rather unique pharmacological profile for CsOA2B2 through measurements of cAMP. The rank order of potency of the agonists was naphazoline > clonidine. The activated effect of octopamine is abolished by co-incubation with phentolamine, mianserin or chlorpromazine. Using in vivo pharmacology, CsOA2B2 antagonists mianserin and phentolamine impaired the motor ability of individual rice stem borers. The results of the present study are important for a better functional understanding of this receptor as well as for practical applications in the development of environmentally sustainable pesticides.

  9. The rush to adrenaline: drugs in sport acting on the beta-adrenergic system.

    Science.gov (United States)

    Davis, E; Loiacono, R; Summers, R J

    2008-06-01

    Athletes attempt to improve performance with drugs that act on the beta-adrenergic system directly or indirectly. Of three beta-adrenoceptor (AR) subtypes, the beta(2)-AR is the main target in sport; they have bronchodilator and anabolic actions and enhance anti-inflammatory actions of corticosteroids. Although demonstrable in animal experiments and humans, there is little evidence that these properties can significantly improve performance in trained athletes. Their actions may also be compromised by receptor desensitization and by common, naturally occurring receptor mutations (polymorphisms) that can influence receptor signalling and desensitization properties in individuals. Indirectly acting agents affect release and reuptake of noradrenaline and adrenaline, thereby influencing all AR subtypes including the three beta-ARs. These agents can have potent psychostimulant effects that provide an illusion of better performance that does not usually translate into improvement in practice. Amphetamines and cocaine also have considerable potential for cardiac damage. beta-AR antagonists (beta-blockers) are used in sports that require steadiness and accuracy, such as archery and shooting, where their ability to reduce heart rate and muscle tremor may improve performance. They have a deleterious effect in endurance sports because they reduce physical performance and maximum exercise load. Recent studies have identified that many beta-AR antagonists not only block the actions of agonists but also activate other (mitogen-activated PK) signalling pathways influencing cell growth and fate. The concept that many compounds previously regarded as 'blockers' may express their own spectrum of pharmacological properties has potentially far-reaching consequences for the use of drugs both therapeutically and illicitly.

  10. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-mediated Calcium Signaling and Arrhythmias in the Heart Evoked by β-Adrenergic Stimulation*♦

    Science.gov (United States)

    Nebel, Merle; Schwoerer, Alexander P.; Warszta, Dominik; Siebrands, Cornelia C.; Limbrock, Ann-Christin; Swarbrick, Joanna M.; Fliegert, Ralf; Weber, Karin; Bruhn, Sören; Hohenegger, Martin; Geisler, Anne; Herich, Lena; Schlegel, Susan; Carrier, Lucie; Eschenhagen, Thomas; Potter, Barry V. L.; Ehmke, Heimo; Guse, Andreas H.

    2013-01-01

    Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+-releasing second messenger known to date. Here, we report a new role for NAADP in arrhythmogenic Ca2+ release in cardiac myocytes evoked by β-adrenergic stimulation. Infusion of NAADP into intact cardiac myocytes induced global Ca2+ signals sensitive to inhibitors of both acidic Ca2+ stores and ryanodine receptors and to NAADP antagonist BZ194. Furthermore, in electrically paced cardiac myocytes BZ194 blocked spontaneous diastolic Ca2+ transients caused by high concentrations of the β-adrenergic agonist isoproterenol. Ca2+ transients were recorded both as increases of the free cytosolic Ca2+ concentration and as decreases of the sarcoplasmic luminal Ca2+ concentration. Importantly, NAADP antagonist BZ194 largely ameliorated isoproterenol-induced arrhythmias in awake mice. We provide strong evidence that NAADP-mediated modulation of couplon activity plays a role for triggering spontaneous diastolic Ca2+ transients in isolated cardiac myocytes and arrhythmias in the intact animal. Thus, NAADP signaling appears an attractive novel target for antiarrhythmic therapy. PMID:23564460

  11. Effect of endurance training on adrenergic control of lipolysis in adipose tissue of obese women.

    Science.gov (United States)

    Richterova, B; Stich, V; Moro, C; Polak, J; Klimcakova, E; Majercik, M; Harant, I; Viguerie, N; Crampes, F; Langin, D; Lafontan, M; Berlan, M

    2004-03-01

    The effect of a 12-wk training program on sc abdominal adipose tissue (SCAAT) was studied in 11 obese women. Before and after the training, biopsies of SCAAT were performed for mRNA levels determination. Using the microdialysis method, involvement of alpha(2)- and beta-adrenergic receptor (ARs) in the control of lipolysis in SCAAT was studied using local perfusion of epinephrine alone or supplemented with phentolamine, an alpha(2)-AR antagonist. In addition, the variation in dialysate glycerol concentrations during exercise (50% peak oxygen consumption at 40 min) in a probe perfused with Ringer's solution was compared with that obtained in a probe perfused with Ringer's solution plus phentolamine. Training did not promote changes in the expression of key genes of the lipolytic pathway. The epinephrine-induced rise in the dialysate glycerol concentration was identical before and after training and was similarly potentiated by phentolamine. During exercise, the potentiating effect of phentolamine on the glycerol response was apparent before, but not after, training. The exercise-induced increase in plasma norepinephrine was lower after training (P = 0.04). In conclusion, training did not modify either the expression of genes involved in the control of lipolysis or alpha(2)- and beta-ARs in situ sensitivity to epinephrine in SCAAT. Training reduced the antilipolytic action of catecholamines mediated by alpha(2)-ARs during exercise, probably due to a reduction of exercise-induced catecholamine increase.

  12. Activation of alpha(2)-adrenergic receptors impairs exercise-induced lipolysis in SCAT of obese subjects.

    Science.gov (United States)

    Stich, V; De Glisezinski, I; Crampes, F; Hejnova, J; Cottet-Emard, J M; Galitzky, J; Lafontan, M; Rivière, D; Berlan, M

    2000-08-01

    With the use of the microdialysis method, exercise-induced lipolysis was investigated in subcutaneous adipose tissue (SCAT) in obese subjects and compared with lean ones, and the effect of blockade of alpha(2)-adrenergic receptors (ARs) on lipolysis during exercise was explored. Changes in extracellular glycerol concentrations and blood flow were measured in SCAT in a control microdialysis probe at rest and during 60-min exercise bouts (50% of heart rate reserve) and in a probe supplemented with the alpha(2)-AR antagonist phentolamine. At rest and during exercise, plasma norepinephrine and epinephrine concentrations were not different in obese compared with lean men. In the basal state, plasma and extracellular glycerol concentrations were higher, whereas blood flow was lower in SCAT of obese subjects. During exercise, the increase of plasma glycerol was higher in obese subjects (115 +/- 35 vs. 65 +/- 21 micromol/l). Oppositely, the exercise-induced increase in extracellular glycerol concentrations in SCAT was five- to sixfold lower in obese than in lean subjects (50 +/- 14 vs. 318 +/- 53 micromol/l). The exercise-induced increase in extracellular glycerol concentration was not significantly modified by phentolamine infusion in lean subjects but was strongly enhanced in the obese subjects and reached the concentrations found in lean sujects (297 +/- 46 micromol/l). These findings demonstrate that the physiological stimulation of SCAT adipocyte alpha(2)-ARs during exercice-induced sympathetic nervous system activation contributes to the blunted lipolysis noted in obese men.

  13. Beta 1- and beta 2-adrenergic /sup 125/I-pindolol binding sites in the interpeduncular nucleus of the rat: Normal distribution and the effects of deafferentation

    Energy Technology Data Exchange (ETDEWEB)

    Battisti, W.P.; Artymyshyn, R.P.; Murray, M.

    1989-07-01

    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.

  14. Vaninolol: a new selective beta 1-adrenoceptor antagonist derived from vanillin.

    Science.gov (United States)

    Wu, B N; Hwang, T L; Liao, C F; Chen, I J

    1994-07-05

    The beta-adrenoceptor blocking properties of vaninolol ((+/-)4-[4'-(2-hydroxy-3-tert-butyl-aminopropoxy)-3'-methoxyphenyl]- 3-buten-2-one), derived from vanillin, were first investigated under in vivo and in vitro conditions. Vaninolol (0.1, 0.5, 1.0 mg/kg, i.v.), as well as propranolol, produced a dose-dependent bradycardia response and a sustained pressor action in urethane-anesthetized normotensive rats. Vaninolol inhibited the tachycardia effects induced by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by phenylephrine. These findings suggested that vaninolol possessed beta-adrenergic blocking activity, but was without alpha-adrenergic blocking activity. In isolated guinea-pig tissues, vaninolol antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that vaninolol was a beta-adrenoceptor competitive antagonist. The effect of vaninolol was more potent on the atria than on tracheal tissues, indicating it had some beta 1-adrenoceptor selectivity. On the other hand, the order of the hydrophilicity was atenolol > vaninolol > propranolol. In addition, vaninolol had a mild direct cardiac depression at high concentrations and was without intrinsic sympathomimetic activity (ISA). Furthermore, binding characteristics of vaninolol and other beta-adrenoceptor antagonists were evaluated in [3H]dihydroalprenolol binding to guinea-pig ventricular membranes. The order of potency of beta-adrenoceptor antagonists in competing for the binding sites was (-)propranolol > vaninolol > or = atenolol. In conclusion, vaninolol was found to be a selective beta 1-adrenoceptor antagonist with relatively low lipophilicity in comparison with propranolol, devoid of ISA, and had a mild myocardial depressant effect.

  15. 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 of vagot...

  16. The roles of beta-adrenergic receptors in tumorigenesis and the possible use of beta-adrenergic blockers for cancer treatment: possible genetic and cell-signaling mechanisms

    Directory of Open Access Journals (Sweden)

    Luong KV

    2012-12-01

    Full Text Available Khanh vinh quốc Lương, Lan Thi Hoàng NguyễnVietnamese American Medical Research Foundation, Westminster, California, USAAbstract: Cancer is the leading cause of death in the USA, and the incidence of cancer increases dramatically with age. Beta-adrenergic blockers appear to have a beneficial clinical effect in cancer patients. In this paper, we review the evidence of an association between β-adrenergic blockade and cancer. Genetic studies have provided the opportunity to determine which proteins link β-adrenergic blockade to cancer pathology. In particular, this link involves the major histocompatibility complex class II molecules, the renin–angiotensin system, transcription factor nuclear factor-kappa-light-chain-enhancer of activated B cells, poly(ADP-ribose polymerase-1, vascular endothelial growth factor, and the reduced form of nicotinamide adenine dinucleotide phosphate oxidase. Beta-adrenergic blockers also exert anticancer effects through non-genomic factors, including matrix metalloproteinase, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase-2, oxidative stress, and nitric oxide synthase. In conclusion, β-adrenergic blockade may play a beneficial role in cancer treatment. Additional investigations that examine β-adrenergic blockers as cancer therapeutics are required to further elucidate this role.Keywords: β-adrenergic blocker, neoplasm, β-adrenergic antagonism, non-genomic factor

  17. Possible Mechanisms for Functional Antagonistic Effect of Ferula assafoetida on Muscarinic Receptors in Tracheal Smooth Muscle

    Science.gov (United States)

    Kiyanmehr, Majid; Boskabady, Mohammad Hossein; Khazdair, Mohammad Reza; Hashemzehi, Milad

    2016-01-01

    Background The contribution of histamine (H1) receptors inhibitory and/or β-adrenoceptors stimulatory mechanisms in the relaxant property of Ferula assa-foetida. (F. asafoetida) was examined in the present study. Methods We evaluated the effect of three concentrations of F. asafoetida extract (2.5, 5, and 10 mg/mL), a muscarinic receptors antagonist, and saline on methacholine concentration-response curve in tracheal smooth muscles incubated with β-adrenergic and histamine (H1) (group 1), and only β-adrenergic (group 2) receptors antagonists. Results EC50 values in the presence of atropine, extract (5 and 10 mg/mL) and maximum responses to methacholine due to the 10 mg/mL extract in both groups and 5 mg/mL extract in group 1 were higher than saline (P < 0.0001, P = 0.0477, and P = 0.0008 in group 1 and P < 0.0001, P = 0.0438, and P = 0.0107 in group 2 for atropine, 5 and 10 mg/mL extract, respectively). Values of concentration ratio minus one (CR-1), in the presence of extracts were lower than atropine in both groups (P = 0.0339 for high extract concentration in group 1 and P < 0.0001 for other extract concentrations in both groups). Conclusion Histamine (H1) receptor blockade affects muscarinic receptors inhibitory property of F. asafoetida in tracheal smooth muscle PMID:27540324

  18. 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.

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

    OpenAIRE

    Patricia C. Brum; Rolim, Natale P. L.; BACURAU, Aline V. N.; Alessandra Medeiros

    2006-01-01

    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 cardia...

  20. Pregnancy modifies the alpha2-beta-adrenergic receptor functional balance in rabbit fat cells.

    Science.gov (United States)

    Bousquet-Mélou, A; Muñoz, C; Galitzky, J; Berlan, M; Lafontan, M

    1999-02-01

    The sympathetic nervous system controls lipolysis in fat by activation of four adrenergic receptors: beta1, beta2, beta3, and alpha2. During pregnancy, maternal metabolism presents anabolic and catabolic phases, characterized by modifications of fat responsiveness to catecholamines. The contributions of the four adrenergic receptors to adipocyte responsiveness during pregnancy have never been studied. Our aim was to evaluate the influence of pregnancy on adrenergic receptor-mediated lipolysis in rabbit white adipocytes. Functional studies were performed using subtype-selective and non-selective adrenergic receptor agonists. Overall adrenergic responsiveness was measured with the physiological agonist epinephrine. Non-adrenergic agents were used to evaluate different steps of the lipolytic cascade. The alpha2- and beta1/beta2-adrenergic receptor numbers were determined with selective radioligands. Non-adrenergic agents revealed that pregnancy induced an intracytoplasmic modification of the lipolytic cascade in inguinal but not in retroperitoneal adipocytes. Pregnancy induced an increase in beta1- and specially beta3-mediated lipolysis. The amounts of adipocyte beta1/beta2- and alpha2-adrenergic receptors were increased in pregnant rabbits. Epinephrine effects revealed an increased contribution of alpha2-adrenergic receptor-mediated antilipolysis in adipocytes from pregnant rabbits. These results indicate that pregnancy regulates adipocyte responsiveness to catecholamines mainly via the alpha2- and beta3-adrenergic pathways. Pregnancy induces an intracytoplasmic modification of the lipolytic cascade, probably via hormone-sensitive lipase, with differences according to fat location.-Bousquet-Mélou, A., C. Muñoz, J. Galitzky, M. Berlan, and M. Lafontan. Pregnancy modifies the alpha2-beta-adrenergic receptor functional balance in rabbit fat cells.

  1. Experimental study on alteration of adrenergic receptors activity in neuronal membranes protein of cerebral cortex following brain trauma in rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xin-wei; XU Ru-xiang; QI Yi-long; CHEN Chang-cai

    2001-01-01

    Objective: To define the course of changes taken by α1 and β adrenergic receptors (AR) activity after traumatic brain injury (TBI) and explore the approach for secondary brain injury (SBI) management. Methods: The neuronal membrane protein of cortex were extracted from the rats subject to traumatic brain injury, and the changes of α1- and β-AR activities in the neuronal membranes were examined by radio ligand binding assay (RLBA). Results: α1- and β-AR activities underwent obvious changes, reaching their peak values at 24 h after TBI. α1-AR binding density (Bmax) reduced by 22.6%while the ligand affinity increased by 66.7%, and for β-AR, however, Bmax increased by 116.9% and the ligand affinity reduced by 50.7%. Their antagonists could counteract the changes ofα1- and β-AR activity. Conclusion: The patterns of changes varies between α1- and β-AR activity after TBI, suggesting their different roles in the neuronal membranes after brain trauma, and timely administration of AR antagonists is potentially beneficial in TBI management.

  2. Activation of α2A-adrenergic signal transduction in chondrocytes promotes degenerative remodelling of temporomandibular joint

    Science.gov (United States)

    Jiao, Kai; Zeng, Guang; Niu, Li-Na; Yang, Hong-xu; Ren, Gao-tong; Xu, Xin-yue; Li, Fei-fei; Tay, Franklin R.; Wang, Mei-qing

    2016-01-01

    This study tested whether activation of adrenoreceptors in chondrocytes has roles in degenerative remodelling of temporomandibular joint (TMJ) and to determine associated mechanisms. Unilateral anterior crossbite (UAC) was established to induce TMJ degeneration in rats. Saline vehicle, α2- and β-adrenoreceptor antagonists or agonists were injected locally into the TMJ area of UAC rats. Cartilage degeneration, subchondral bone microarchitecture and the expression of adrenoreceptors, aggrecans, matrix metalloproteinases (MMPs) and RANKL by chondrocytes were evaluated. Chondrocytes were stimulated by norepinephrine to investigate signal transduction of adrenoreceptors. Increased α2A-adrenoreceptor expression was observed in condylar cartilage of UAC rats, together with cartilage degeneration and subchondral bone loss. Norepinephrine depresses aggrecans expression but stimulates MMP-3, MMP-13 and RANKL production by chondrocytes through ERK1/2 and PKA pathway; these effects were abolished by an α2A-adrenoreceptor antagonist. Furthermore, inhibition of α2A-adrenoreceptor attenuated degenerative remodelling in the condylar cartilage and subchondral bone, as revealed by increased cartilage thickness, proteoglycans and aggrecan expression, and decreased MMP-3, MMP-13 and RANKL expressions in cartilage, increased BMD, BV/TV, and decreased Tb.Sp in subchondral bone. Conversely, activation of α2A-adrenoreceptor intensified aforementioned degenerative changes in UAC rats. It is concluded that activation of α2A-adrenergic signal in chondrocytes promotes TMJ degenerative remodelling by chondrocyte-mediated pro-catabolic activities. PMID:27452863

  3. Characterization of a panel of six β2-adrenergic receptor antibodies by indirect immunofluorescence microscopy

    Science.gov (United States)

    Koryakina, Yulia A; Fowler, Tristan W; Jones, Stacie M; Schnackenberg, Bradley J; Cornett, Lawrence E; Kurten, Richard C

    2008-01-01

    Background The β2-adrenergic receptor (β2AR) is a primary target for medications used to treat asthma. Due to the low abundance of β2AR, very few studies have reported its localization in tissues. However, the intracellular location of β2AR in lung tissue, especially in airway smooth muscle cells, is very likely to have a significant impact on how the airways respond to β-agonist medications. Thus, a method for visualizing β2AR in tissues would be of utility. The purpose of this study was to develop an immunofluorescent labeling technique for localizing native and recombinant β2AR in primary cell cultures. Methods A panel of six different antibodies were evaluated in indirect immunofluorescence assays for their ability to recognize human and rat β2AR expressed in HEK 293 cells. Antibodies capable of recognizing rat β2AR were identified and used to localize native β2AR in primary cultures of rat airway smooth muscle and epithelial cells. β2AR expression was confirmed by performing ligand binding assays using the β-adrenergic antagonist [3H] dihydroalprenolol ([3H]DHA). Results Among the six antibodies tested, we identified three of interest. An antibody developed against the C-terminal 15 amino acids of the human β2AR (Ab-Bethyl) specifically recognized human but not rat β2AR. An antibody developed against the C-terminal domain of the mouse β2AR (Ab-sc570) specifically recognized rat but not human β2AR. An antibody developed against 78 amino acids of the C-terminus of the human β2AR (Ab-13989) was capable of recognizing both rat and human β2ARs. In HEK 293 cells, the receptors were predominantly localized to the cell surface. By contrast, about half of the native rat β2AR that we visualized in primary cultures of rat airway epithelial and smooth muscle cells using Ab-sc570 and Ab-13989 was found inside cells rather than on their surface. Conclusion Antibodies have been identified that recognize human β2AR, rat β2AR or both rat and human β2AR

  4. Characterization of a panel of six β2-adrenergic receptor antibodies by indirect immunofluorescence microscopy

    Directory of Open Access Journals (Sweden)

    Jones Stacie M

    2008-04-01

    Full Text Available Abstract Background The β2-adrenergic receptor (β2AR is a primary target for medications used to treat asthma. Due to the low abundance of β2AR, very few studies have reported its localization in tissues. However, the intracellular location of β2AR in lung tissue, especially in airway smooth muscle cells, is very likely to have a significant impact on how the airways respond to β-agonist medications. Thus, a method for visualizing β2AR in tissues would be of utility. The purpose of this study was to develop an immunofluorescent labeling technique for localizing native and recombinant β2AR in primary cell cultures. Methods A panel of six different antibodies were evaluated in indirect immunofluorescence assays for their ability to recognize human and rat β2AR expressed in HEK 293 cells. Antibodies capable of recognizing rat β2AR were identified and used to localize native β2AR in primary cultures of rat airway smooth muscle and epithelial cells. β2AR expression was confirmed by performing ligand binding assays using the β-adrenergic antagonist [3H] dihydroalprenolol ([3H]DHA. Results Among the six antibodies tested, we identified three of interest. An antibody developed against the C-terminal 15 amino acids of the human β2AR (Ab-Bethyl specifically recognized human but not rat β2AR. An antibody developed against the C-terminal domain of the mouse β2AR (Ab-sc570 specifically recognized rat but not human β2AR. An antibody developed against 78 amino acids of the C-terminus of the human β2AR (Ab-13989 was capable of recognizing both rat and human β2ARs. In HEK 293 cells, the receptors were predominantly localized to the cell surface. By contrast, about half of the native rat β2AR that we visualized in primary cultures of rat airway epithelial and smooth muscle cells using Ab-sc570 and Ab-13989 was found inside cells rather than on their surface. Conclusion Antibodies have been identified that recognize human β2AR, rat β2AR or

  5. Cardiovascular effects of the novel histamine H2 receptor agonist amthamine: interaction with the adrenergic system.

    Science.gov (United States)

    Coruzzi, G; Gambarelli, E; Bertaccini, G; Timmerman, H

    1996-03-01

    The cardiovascular effects of the new histamine H2 receptor agonist amthamine were studied in the anaesthetized rat, with particular reference to a possible interaction with the adrenergic system. Amthamine (0.03-3 mumol/kg i.v.) caused vasodepressor responses which were antagonized by famotidine (3 mumol/kg i.v.). At higher doses (30-100 mumol/kg i.v.), amthamine induced a modest increase in the mean arterial pressure, which was significantly enhanced by the blockade of H2 receptors and significantly reduced by the alpha 2 adrenoceptor antagonist yohimbine (1 mumol/kg i.v.). The vasopressor response to amthamine was not modified in rats pre-treated with reserpine or 6-hydroxydopamine, and was only minimally modified in adrenalectomized animals, thus suggesting a predominant interaction with postjunctional alpha 2 adrenoceptors in the vascular muscle. The H2 receptor agonist dimaprit (0.3-100 mumol/kg i.v.) caused a reduction in arterial pressure, which was antagonized by famotidine, no pressor response being unmasked. Dimaprit (0.1-30 mumol/kg i.v.) did not modify heart rate but caused a modest bradycardia at 100 mumol/kg i.v. Amthamine (1-100 mumol/kg i.v.) induced a dose-dependent tachycardia, which was only partially (approximately 20%) reduced by famotidine and was totally blocked by propranolol (0.3 mg/kg i.v.). This effect was significantly reduced in rats pre-treated with reserpine or 6-hydroxydopamine and was further reduced by cocaine, thus suggesting a tyramine-like action of amthamine. In conclusion, these data demonstrate that the H2 receptor agonist amthamine can also interact with the adrenergic system when used at doses higher than those necessary to activate H2 receptors. Whereas the increase in blood pressure induced by amthamine seems to be mainly mediated by a direct activation of postjunctional alpha 2 adrenoceptors, the increase in heart rate is predominantly due to neuronal release of catecholamines. These effects should be considered when

  6. Infusions of alpha-2 noradrenergic agonists and antagonists into the amygdala: effects on kindling.

    Science.gov (United States)

    Pelletier, M R; Corcoran, M E

    1993-12-31

    We reported previously that activation of alpha-2 adrenoceptors with infusions of clonidine into the amygdala/pyriform region is sufficient to retard kindling. To characterize further the involvement in kindling of alpha-2 receptors in the amygdala/pyriform, we exposed rats to unilateral intraamygdaloid infusions of a variety of noradrenergic drugs followed by either low-frequency stimulation of the amygdala, to induce rapid kindling, or conventional high-frequency stimulation. Infusions and electrical stimulation were administered once every 48 h. The prophylactic effects of clonidine were blocked by simultaneous infusion of idazoxan, an alpha-2 adrenergic antagonist, which suggests strongly that these effects were produced at an alpha-2 receptor. Intraamygdaloid infusions of xylazine, another alpha-2 agonist, also significantly retarded low-frequency kindling. Unexpectedly, intraamygdaloid infusions of the alpha-2 antagonists idazoxan, yohimbine, and SK&F 104856 failed to accelerate kindling. Infusion of the alpha-1 antagonist corynanthine also failed to affect kindling. We propose that the alpha-2 adrenoceptors in the amygdala/pyriform region contribute to the prophylactic effects of systemically administered clonidine and that the facilitation of kindling observed after systemic administration of alpha-2 antagonists may be due to blockade of alpha-2 adrenoceptors outside of the amygdala/pyriform region.

  7. Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD.

    Science.gov (United States)

    Moulton, Bart C; Fryer, Allison D

    2011-05-01

    In the lungs, parasympathetic nerves provide the dominant control of airway smooth muscle with release of acetylcholine onto M3 muscarinic receptors. Treatment of airway disease with anticholinergic drugs that block muscarinic receptors began over 2000 years ago. Pharmacologic data all indicated that antimuscarinic drugs should be highly effective in asthma but clinical results were mixed. Thus, with the discovery of effective β-adrenergic receptor agonists the use of muscarinic antagonists declined. Lack of effectiveness of muscarinic antagonists is due to a variety of factors including unwanted side effects (ranging from dry mouth to coma) and the discovery of additional muscarinic receptor subtypes in the lungs with sometimes competing effects. Perhaps the most important problem is ineffective dosing due to poorly understood differences between routes of administration and no effective way of testing whether antagonists block receptors stimulated physiologically by acetylcholine. Newer muscarinic receptor antagonists are being developed that address the problems of side effects and receptor selectivity that appear to be quite promising in the treatment of asthma and chronic obstructive pulmonary disease.

  8. Contribution of α- and β-Adrenergic Mechanisms to the Development of Pulmonary Edema

    Directory of Open Access Journals (Sweden)

    Beate Rassler

    2012-01-01

    Full Text Available Endogenous or exogenous catecholamines can induce pulmonary edema (PE. This may occur in human pathologic conditions such as in pheochromocytoma or in neurogenic pulmonary edema (NPE but can also be provoked after experimental administration of adrenergic agonists. PE can result from stimulation with different types of adrenergic stimulation. With -adrenergic treatment, it develops more rapidly, is more severe with abundant protein-rich fluid in the alveolar space, and is accompanied by strong generalized inflammation in the lung. Similar detrimental effects of -adrenergic stimulation have repeatedly been described and are considered to play a pivotal role in NPE or in PE in patients with pheochromocytoma. Although -adrenergic agonists have often been reported to prevent or attenuate PE by enhancing alveolar fluid clearance, PE may also be induced by -adrenergic treatment as can be observed in tocolysis. In experimental models, infusion of -adrenergic agonists induces less severe PE than -adrenergic stimulation. The present paper addresses the current understanding of the possible contribution of - and -adrenergic pathways to the development of PE.

  9. 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

  10. Epinephrine effects on mitochondrial Krebs cycle are not mediated by typical adrenergic receptors in isolated rat hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Mohan, C.; Memon, R.A.; Bessman, S.P. (Univ. of Southern California, Los Angeles (United States))

    1990-02-26

    Oxidation of 2,3-{sup 14}C succinate (suc) carbons in the intra-mitochondrial Krebs cycle was used as a probe to investigate the effects of epinephrine (epi) on isolated rat hepatocytes. Hepatocytes were incubated at 30{degrees}C in Krebs-Henseleit bicarbonate buffer, pH 7.4, with 0.5 mM concentration of each of the 20 natural amino acids, 0.5 mm concentration of each of the 20 natural amino acids, 2,3-{sup 14}C suc and epi (10 uM), phenylephrine (pheni) (10uM) or isoproterenol (10 uM). Epi and phepi caused a significant increase in {sup 14}CO{sub 2} formation from 2,3-{sup 14}C suc, however, phentolamine, an {infinity}-antagonist, failed to inhibit this increased oxidation of suc carbons. Isoproterenol had no effect on hepatocyte metabolism and propranolol, a {beta}-antagonist, failed to cause any reduction in basal or epi stimulated oxidation of 2,3-{sup 14}C carbons. Unlike insulin, neither epi nor phepi had any significant effect on the anabolic utilization of suc carbons for protein or lipid synthesis. Anabolic channeling of Krebs cycle intermediates into amino acids was reduced by epi treatment of hepatocytes. Although epi treatment can enhance the oxidation of substrate through the Krebs cycle reactions, only insulin is capable of channeling these substrates into anabolic reactions. Data presented also suggest that epi effects on mitochondrial Krebs cycle oxidation are mediated through an atypical {infinity}-adrenergic receptor which is unresponsive to inhibition by non-selective {infinity}-antagonists.

  11. Modeling of ligand binding to G protein coupled receptors: cannabinoid CB1, CB2 and adrenergic β 2 AR.

    Science.gov (United States)

    Latek, Dorota; Kolinski, Michal; Ghoshdastider, Umesh; Debinski, Aleksander; Bombolewski, Rafal; Plazinska, Anita; Jozwiak, Krzysztof; Filipek, Slawomir

    2011-09-01

    Cannabinoid and adrenergic receptors belong to the class A (similar to rhodopsin) G protein coupled receptors. Docking of agonists and antagonists to CB(1) and CB(2) cannabinoid receptors revealed the importance of a centrally located rotamer toggle switch and its possible participation in the mechanism of agonist/antagonist recognition. The switch is composed of two residues, F3.36 and W6.48, located on opposite transmembrane helices TM3 and TM6 in the central part of the membranous domain of cannabinoid receptors. The CB(1) and CB(2) receptor models were constructed based on the adenosine A(2A) receptor template. The two best scored conformations of each receptor were used for the docking procedure. In all poses (ligand-receptor conformations) characterized by the lowest ligand-receptor intermolecular energy and free energy of binding the ligand type matched the state of the rotamer toggle switch: antagonists maintained an inactive state of the switch, whereas agonists changed it. In case of agonists of β(2)AR, the (R,R) and (S,S) stereoisomers of fenoterol, the molecular dynamics simulations provided evidence of different binding modes while preserving the same average position of ligands in the binding site. The (S,S) isomer was much more labile in the binding site and only one stable hydrogen bond was created. Such dynamical binding modes may also be valid for ligands of cannabinoid receptors because of the hydrophobic nature of their ligand-receptor interactions. However, only very long molecular dynamics simulations could verify the validity of such binding modes and how they affect the process of activation.

  12. Receptor subtype involved in α1-adrenergic receptor-mediated Ca2+ sig-naling in cardiomyocytes

    Institute of Scientific and Technical Information of China (English)

    Da-li LUO; Jian GAO; Lin-lin FAN; Yu TANG; You-yi ZHANG; Qi-de HAN

    2007-01-01

    Aim: The enhancement of intracellular Ca2+ signaling in response to α1-adrener-gic receptor (α1-AR) stimulation is an essential signal transduction event in the regulation of cardiac functions, such as cardiac growth, cardiac contraction, and cardiac adaptation to various situations. The present study was intended to determine the role(s) of the α1-AR subtype(s) in mediating this response. Methods: We evaluated the effects of subtype-specific agonists and antagonists of the α1- AR on the intracellular Ca2+ signaling of neonatal rat ventricular myocytes using a confocal microscope. Results: After being cultured for 48 h, the myocytes exhibited spontaneous local Ca2+ release, sparks, and global Ca2+ transients. The activation of the α1-AR with phenylephrine, a selective agonist of the α1-AR, dose-dependently increased the frequency of Ca2+ transients with an EC50 value of 2.3 μmol/L. Blocking the α1A-AR subtype with 5-methyhirapidil (5-Mu) inhi-bited the stimulatory effect of phenylephrine with an IC50 value of 6.7 nmol/L. In contrast, blockade of the α1B-AR and α1D-AR subtypes with chloroethylclonidine and BMY 7378, respectively, did not affect the phenylephrine effect. Similarly, the local Ca2+ spark numbers were also increased by the activation of theα1-AR, and this effect could be abolished selectively by 5-Mu. More importantly, A61603, a novel selective α1A-AR agonist, mimicked the effects of phenylephrine, but with more potency (EC50 value =6.9 nmol/L) in the potentiation of Ca2+ transients, and blockade of the α1A-AR by 5-Mu caused abolishment of its effects. Conclusion: These results indicate that α1-adrenergic stimulation of intracellular Ca2+ activity is mediated selectively by the α1A-AR.

  13. Differential regulation of atrial natriuretic peptide- and adrenergic receptor-dependent lipolytic pathways in human adipose tissue.

    Science.gov (United States)

    Moro, Cédric; Polak, Jan; Richterova, Blanka; Sengenès, Coralie; Pelikanova, Terezie; Galitzky, Jean; Stich, Vladimir; Lafontan, Max; Berlan, Michel

    2005-01-01

    The aim of the study was to investigate the regulation affecting the recently described atrial natriuretic peptide (ANP)-dependent lipolytic pathway in comparison with the adrenergic lipolytic cascade. We studied in vivo the effect of a euglycemic-hyperinsulinemic clamp on the changes occurring in the extracellular glycerol concentration (EGC) of subcutaneous adipose tissue (SCAT) during ANP or epinephrine perfusion in a microdialysis probe. Homologous desensitization and the incidence of hyperinsulinemia on the ANP- and catecholaminergic-dependent control of lipolysis were also investigated in vitro on fat cells from SCAT. When perfused in SCAT, epinephrine and ANP promoted an increase in EGC; the EGC increase was significantly lower during the clamp. The reduction of epinephrine-induced lipolysis was limited (18%) when phentolamine (an alpha(2)-adrenergic receptor [AR] antagonist) was perfused together with epinephrine. Unlike the effect of epinephrine, the response to ANP observed during the second perfusion was reduced by 32%. The increase in extracellular guanosine 3',5' -cyclic monophosphate concentration, which reflects ANP activity, was also reduced during the second perfusion. Desensitization of the lipolytic effects of ANP was observed in vitro after a 2-hour period of recovery, while the effects of alpha(2)-AR agonist or of epinephrine were unchanged. Insulin was without any effect on ANP-induced lipolysis and alpha(2)-AR-mediated antilipolysis, while it reduced beta-AR-induced lipolysis. The ANP-dependent lipolytic pathway undergoes desensitization in vitro and in situ. Insulin had no inhibitory effect on either ANP- or alpha(2)-AR-dependent pathways, while it counteracted the beta-AR pathway.

  14. Adrenergic deficiency leads to impaired electrical conduction and increased arrhythmic potential in the embryonic mouse heart.

    Science.gov (United States)

    Baker, Candice; Taylor, David G; Osuala, Kingsley; Natarajan, Anupama; Molnar, Peter J; Hickman, James; Alam, Sabikha; Moscato, Brittany; Weinshenker, David; Ebert, Steven N

    2012-07-01

    To determine if adrenergic hormones play a critical role in the functional development of the cardiac pacemaking and conduction system, we employed a mouse model where adrenergic hormone production was blocked due to targeted disruption of the dopamine β-hydroxylase (Dbh) gene. Immunofluorescent histochemical evaluation of the major gap junction protein, connexin 43, revealed that its expression was substantially decreased in adrenergic-deficient (Dbh-/-) relative to adrenergic-competent (Dbh+/+ and Dbh+/-) mouse hearts at embryonic day 10.5 (E10.5), whereas pacemaker and structural protein staining appeared similar. To evaluate cardiac electrical conduction in these hearts, we cultured them on microelectrode arrays (8×8, 200 μm apart). Our results show a significant slowing of atrioventricular conduction in adrenergic-deficient hearts compared to controls (31.4±6.4 vs. 15.4±1.7 ms, respectively, pheart rate and rhythm, mouse hearts from adrenergic-competent and deficient embryos were cultured ex vivo at E10.5, and heart rates were measured before and after challenge with the β-adrenergic receptor agonist, isoproterenol (0.5 μM). On average, all hearts showed increased heart rate responses following isoproterenol challenge, but a significant (phearts. These results show that adrenergic hormones may influence heart development by stimulating connexin 43 expression, facilitating atrioventricular conduction, and helping to maintain cardiac rhythm during a critical phase of embryonic development.

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

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba

    1985-01-01

    , 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...

  16. Autoantibodies against α1 adrenergic receptor related with cardiac remodeling in hypertensive patients by clinical observation

    Institute of Scientific and Technical Information of China (English)

    李正在

    2006-01-01

    Objective To investigate the effects of autoantibodies against a adrenergic receptor on cardiac remodeling in patients with hypertension. Methods Five hundred and fifty three patients with hypertension in our hospital were selected. The autoantibodies againstα1 adrenergic receptor in sera of donor were detected by ELISA, and the Results of echocardiography were recorded. By

  17. Interaction between muscarinic and β-adrenergic receptors

    Institute of Scientific and Technical Information of China (English)

    Martin C. Michel

    2012-01-01

    In many tissues the parasympathetic and sympathetic nervous system regulate smooth musc tone via their transmitters aeetylcholine and noradrenaline, respectively. Direct smooth musc e e effects of acetylcholine via muscarinic receptors always promote contraction, but non-neuronal sources can importantly contribute to such stimulation. Direct smooth muscle effects of noradren- aline can promote contraction via al- and sometimes also α2-adrenoceptors but can promote re- laxation and inhibit contraction via β-adrenoceptors. I will focus on the interaction between sub- types of muscarinic and β-adrenergic receptors, largely using the urinary bladder as an exam- ple.

  18. 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...... of alpha-adrenergic receptors and had a positive inotropic effect during contractions which was abolished by alpha- as well as by beta-adrenergic blockade. The results indicate that epinephrine has profound effects on contracting muscle, and that these effects are elicited through different combinations...

  19. Prognostic significance of β2-adrenergic receptor expression in malignant melanoma.

    Science.gov (United States)

    Shimizu, Akira; Kaira, Kyoichi; Mori, Keita; Kato, Madoka; Shimizu, Kimihiro; Yasuda, Masahito; Takahashi, Ayumi; Oyama, Tetsunari; Asao, Takayuki; Ishikawa, Osamu

    2016-05-01

    Recent studies cite β2-adrenergic receptor (β2AR) antagonists as novel therapeutic agents for melanoma, as they may reduce the disease progression. The β2AR has shown to be expressed in malignant melanoma. However, it remains unclear whether the β2AR expression has a clinical and pathological significance in patients with cutaneous malignant melanoma. We herein conducted a clinicopathological study to investigate the protein expression of β2AR in malignant melanoma of the skin and its prognostic significance. One hundred thirty-three patients with surgically resected cutaneous malignant melanoma were evaluated. Tumor sections were stained by immunohistochemistry for β2AR, Ki-67, the microvessel density (MVD) determined by CD34, and p53. β2AR was highly expressed in 44.4 % (59 out of 133) of the patients. The expression of β2AR was significantly associated with the tumor thickness, ulceration, T factor, N factor, disease stage, tumor size, cell proliferation (Ki-67), and MVD (CD34). Using Spearman's rank test, the β2AR expression was correlated with Ki-67 (r = 0.278; 95 % CI, 0.108 to 0.432; P = 0.001), CD34 (r = 0.445; 95 %CI, 0.293 to 0.575; P melanoma of the skin. β2AR can serve as a promising prognostic factor for predicting a worse outcome after surgical treatment and may play an important role in the development and aggressiveness of malignant melanoma.

  20. Beta-adrenergic modulation of tremor and corticomuscular coherence in humans.

    Directory of Open Access Journals (Sweden)

    Mark R Baker

    Full Text Available Coherence between the bioelectric activity of sensorimotor cortex and contralateral muscles can be observed around 20 Hz. By contrast, physiological tremor has a dominant frequency around 10 Hz. Although tremor has multiple sources, it is partly central in origin, reflecting a component of motoneuron discharge at this frequency. The motoneuron response to ~20 Hz descending input could be altered by non-linear interactions with ~10 Hz motoneuron firing. We investigated this further in eight healthy human subjects by testing the effects of the beta-adrenergic agents propranolol (non-selective β-antagonist and salbutamol (β(2-agonist, which are known to alter the size of physiological tremor. Corticomuscular coherence was assessed during an auxotonic precision grip task; tremor was quantified using accelerometry during index finger extension. Experiments with propranolol used a double-blind, placebo-controlled crossover design. A single oral dose of propranolol (40 mg significantly increased beta band (15.3-32.2 Hz corticomuscular coherence compared with placebo, but reduced tremor in the 6.2-11.9 Hz range. Salbutamol (2.5 mg was administered by inhalation. Whilst salbutamol significantly increased tremor amplitude as expected, it did not change corticomuscular coherence. The opposite direction of the effects of propranolol on corticomuscular coherence and tremor, and the fact that salbutamol enhances tremor but does not affect coherence, implies that the magnitude of corticomuscular coherence is little influenced by non-linear interactions with 10 Hz oscillations in motoneurons or the periphery. Instead, we suggest that propranolol and salbutamol may affect both tremor and corticomuscular coherence partly via a central site of action.

  1. Heart rate control with adrenergic blockade: Clinical outcomes in cardiovascular medicine

    Directory of Open Access Journals (Sweden)

    David Feldman

    2010-05-01

    conditions, and vasodilating β-blocker efficacy may aid in accomplishing improved outcomes.Keywords: adrenergic beta-antagonists, heart failure, hypertension, myocardial infarction

  2. The β3-adrenergic receptor is dispensable for browning of adipose tissues.

    Science.gov (United States)

    de Jong, Jasper M A; Wouters, René T F; Boulet, Nathalie; Cannon, Barbara; Nedergaard, Jan; Petrovic, Natasa

    2017-02-21

    Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with β3-adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the β3-adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the β3-adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and β3-adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression (Ucp1, Pgc1a, Dio2 and Cidea) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the β3-adrenergic receptor. Experiments with the β3-adrenergic receptor agonist CL-316,243 verified the functional absence of β3-adrenergic signaling in these knockout mice. The β3-adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus, our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the β3-adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells. This should be taken into account in the increasing number of studies on the induction of browning and their extrapolation to human physiology.

  3. Site-specific O-glycosylation by Polypeptide GalNAc-transferase T2 Co-regulates Beta1-adrenergic Receptor N-terminal Cleavage.

    Science.gov (United States)

    Goth, Christoffer K; Tuhkanen, Hanna E; Khan, Hamayun; Lackman, Jarkko J; Wang, Shengjun; Narimatsu, Yoshiki; Holst Hansen, Lasse; Overall, Christopher; Clausen, Henrik; Schjoldager, Katrine T; Petäjä-Repo, Ulla E

    2017-02-06

    The β1-adrenergic receptor (β1AR) is a G protein-coupled receptor (GPCR) and the predominant adrenergic receptor subtype in the heart, where it mediates cardiac contractility and the force of contraction. Although it is the most important target for β-adrenergic antagonists, such as beta-blockers, relatively little is still known about its regulation. We have previously shown that β1AR undergoes constitutive and regulated N-terminal cleavage participating in receptor down-regulation, and moreover that the receptor is modified by O-glycosylation. Here we demonstrate that the polypeptide GalNAc-transferase 2 (GalNAc-T2) specifically O-glycosylates β1AR at five residues in the extracellular N-terminus, including the Ser49 residue at a location of the common Ser49Gly single-nucleotide polymorphism. Using in vitro O-glycosylation and proteolytic cleavage assays, a cell line deficient in O-glycosylation, GalNAc-T edited cell line model systems, and a GalNAc-T2 knockout rat model, we show that GalNAc-T2 co-regulates the metalloproteinase-mediated limited proteolysis of β1AR. Furthermore, we demonstrate that impaired O-glycosylation and enhanced proteolysis leads to attenuated receptor signaling, as the maximal response elicited by the βAR agonist isoproterenol and it potency in a cAMP accumulation assay was decreased in HEK293 cells lacking GalNAc-T2. Our findings reveal, for the first time, a GPCR as a target for co-regulatory functions of site-specific O-glycosylation mediated by a unique GalNAc-T isoform. The results provide a new level of β1AR regulation that may open up possibilities for new therapeutic strategies for cardiovascular diseases.

  4. Mivazerol, a novel compound with high specificity for alpha 2 adrenergic receptors: binding studies on different human and rat membrane preparations.

    Science.gov (United States)

    Noyer, M; de Laveleye, F; Vauquelin, G; Gobert, J; Wülfert, E

    1994-03-01

    Mivazerol, 3-[1(H-imidazol-4-yl)methyl]-2-hydroxybenzamide hydrochloride, a new potential anti-ischemic drug designed by UCB S.A. Pharma Sector, has been studied in binding experiments on adrenergic, dopaminergic, serotoninergic, muscarinic and idazoxan binding sites. Our results indicate that this compound displays high affinity and marked specificity for alpha 2 adrenoceptors. Mivazerol displaced the binding of the alpha 2 adrenoceptor antagonist [3H]RX 821002 to the alpha 2A adrenoceptors in human frontal cortex membranes with an apparent Ki value of 37 nM. The competition curve was shallow (nH = 0.55), suggesting that this compound acts as an alpha 2 adrenergic agonist. Mivazerol was also a potent competitor for [3H]RX 821002 binding to human platelet membranes (containing alpha 2A adrenoceptors) and rat kidney membranes (75% of the alpha 2 adrenoceptors of the alpha 2B subtype), indicating that this compound is not alpha 2 adrenoceptor subtype selective. Equilibrium dissociation constants for alpha 1 adrenoceptors (displacement of [3H]prazosin) and 5-HT1A receptors (displacement of [3H]rauwolscine) were respectively about 120 times (Ki = 4.4 microM) and 14 times (Ki = 530 nM) higher than that for the alpha 2 adrenoceptors. Equilibrium dissociation constants were approximately 1000 times higher for all other receptors tested in this study; namely beta 1 and beta 2 adrenoceptors, D1- and D2-dopamine receptors, M1-, M2- and M3-muscarinic receptors, 5-HT2 receptors and non-adrenergic idazoxan binding sites.

  5. Activation of alpha2-adrenergic receptors blunts epinephrine-induced lipolysis in subcutaneous adipose tissue during a hyperinsulinemic euglycemic clamp in men.

    Science.gov (United States)

    Stich, Vladimir; Pelikanova, Tereza; Wohl, Petr; Sengenès, Coralie; Zakaroff-Girard, Alexia; Lafontan, Max; Berlan, Michel

    2003-09-01

    The aim of this study was to investigate whether hyperinsulinemia modifies adrenergic control of lipolysis, with particular attention paid to the involvement of antilipolytic alpha2-adrenergic receptors (AR). Eight healthy male subjects (age: 23.9 +/- 0.9 yr; body mass index: 23.8 +/- 1.9) were investigated during a 6-h euglycemichyperinsulinemic clamp and in control conditions. Before and during the clamp, the effect of graded perfusions of isoproterenol (0.1 and 1 microM) or epinephrine (1 and 10 microM) on the extracellular glycerol concentration in subcutaneous abdominal adipose tissue was evaluated by using the microdialysis method. Both isoproterenol and epinephrine induced a dose-dependent increase in extracellular glycerol concentration when infused for 60 min through the microdialysis probes before and during hours 3 and 6 of the clamp. The catecholamine-induced increase was significantly lower during the clamp than before it, with the inhibition being more pronounced in hour 6 of the clamp. Isoproterenol (1 microM)-induced lipolysis was reduced by 28 and 44% during hours 3 and 6 of the clamp, respectively, whereas the reduction of epinephrine (100 microM)-induced lipolysis was significantly greater (by 63 and 70%, P < 0.01 and P < 0.04, respectively) during the same time intervals. When epinephrine was infused in combination with 100 microM phentolamine (a nonselective alpha-AR antagonist), the inhibition of epinephrine (10 microM)-induced lipolysis was only of 19 and 40% during hours 3 and 6 of the clamp, respectively. The results demonstrate that, in situ, insulin counteracts the epinephrine-induced lipolysis in adipose tissue. The effect involves 1) reduction of lipolysis stimulation mediated by the beta-adrenergic pathway and 2) the antilipolytic component of epinephrine action mediated by alpha2-ARs.

  6. Synthesis of potential mescaline antagonists.

    Science.gov (United States)

    DeSantis, F; Nieforth, K A

    1976-10-01

    1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-3-pyrroline, 2-(3,4,5-trimethoxybenzyl)-1,2,3,6-tetrahydropyridine, N-n-propylmescaline, N-cyclopropylmethylmescaline, and N-allylmescaline were synthesized as potential mescaline antagonists. The ability of these compounds to antagonize mescaline-induced disruption of swim behavior is also given.

  7. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1997-01-01

    We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation......)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments......, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation...

  8. DEVELOPMENT OF NEW LHRH ANTAGONISTS

    Institute of Scientific and Technical Information of China (English)

    PENGDun-Ren; XIAOShao-Bo

    1989-01-01

    An ideal antagonist of LHRH is one which can act on the pitutary to inhibit LHRH-stimulatod LH / FSH secretion by competitive occupying the LHRH receptor in the pitutary gland. Its action should be very specific, fast and highly effective, the durations

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

    Energy Technology Data Exchange (ETDEWEB)

    Mechler, F.; Mastaglia, F.L.

    1981-02-01

    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.

  10. β-adrenergic modulation of in vivo long-term potentiation in area CA1 and its role in spatial learning in rats

    Institute of Scientific and Technical Information of China (English)

    JI; Jinzhao; (季今朝); ZHANG; Xuehan; (张雪寒); LI; Baoming; (李葆明)

    2003-01-01

    Activation of β-adrenoceptors in area CA1 of the hippocampus facilitates in vitro long-term potentiation (LTP) in this region. However, it is unclear if in vivo LTP in area CA1 and hippocampus-dependent learning are subjected to β-adrenergic regulation. To address this question, we investigated the effects of the β-adrenergic agonist L-isoproterenol or antagonist DL-propranolol on in vivo LTP of area CA1 and the spatial learning in Morris water maze. In the presence of L-isoproterenol (through local infusion into area CA1), the theta-pulse stimulation with the parameter of 10 Hz, 150 pulses/train, 1 train, a frequency weakly modifying synaptic strength, induced a robust LTP, and this effect was blocked when DL-propranolol was co-administered. By contrast, the theta-pulse stimulation with the parameter of 5 Hz, 150 pulses/train, 3 trains, a frequency strongly modifying synaptic strength, induced a significantly smaller LTP when DL-propranolol was administered into area CA1. Accordingly, DL-propranolol impaired the spatial learning in the water maze when infused into area CA1 20 min pretraining. Compared with control rats, the DL-propranolol-treated rats showed significantly slower learning in the water maze and subsequently exhibited poor memory retention at 24-h test. These results suggest that β-adrenoceptors in area CA1 are involved in regulating in vivo synaptic plasticity of this area and are important for spatial learning.

  11. Lack of delayed effects of amphetamine, methoxamine, and prazosin (adrenergic drugs) on behavioral outcome after lateral fluid percussion brain injury in the rat.

    Science.gov (United States)

    Dose, J M; Dhillon, H S; Maki, A; Kraemer, P J; Prasad, R M

    1997-05-01

    This study examined the delayed effects of the administration of d-amphetamine, methoxamine (an alpha1-adrenergic receptor agonist), and prazosin (an alpha1-adrenergic receptor antagonist) on the behavioral outcome of lateral fluid-percussion (FP) brain injury. Rats trained to perform a beam-walking task were subjected to brain injury of moderate severity (2.1 to 2.2 atm). Twenty-four hours after injury, rats were treated with amphetamine, methoxamine, or prazosin at two or three different dose levels. Amphetamine-treated animals displayed no significant improvement in beam-walking ability either during or after drug intoxication (from days 3 to 5 after brain injury). Similarly, neither methoxamine nor prazosin significantly affected beam-walking ability during or after drug intoxication. Neither amphetamine treatment at three different doses nor treatment with methoxamine or prazosin at two different doses affected the spatial learning disabilities of brain-injured animals. These results suggest that (1) unlike amphetamine administration after sensorimotor cortex (SMC) ablation or contusion brain injury models, amphetamine administration at 24 h after concussive FP brain injury does not improve beam-walking performance; (2) unlike amphetamine administration 10 min after concussive FP brain injury amphetamine administration 24 h after injury does not improve cognitive function; and (3) unlike prazosin administration after SMC ablation brain injury, prazosin administration 24 h after concussive FP brain injury does not effect beam-walking performance.

  12. Involvement of serotoninergic 5-HT1A/2A, alpha-adrenergic and dopaminergic D1 receptors in St. John's wort-induced prepulse inhibition deficit: a possible role of hyperforin.

    Science.gov (United States)

    Tadros, Mariane G; Mohamed, Mohamed R; Youssef, Amal M; Sabry, Gilane M; Sabry, Nagwa A; Khalifa, Amani E

    2009-05-16

    Prepulse inhibition (PPI) of acoustic startle response is a valuable paradigm for sensorimotor gating processes. Previous research showed that acute administration of St. John's wort extract (500 mg/kg, p.o.) to rats caused significant disruption of PPI while elevating monoamines levels in some brain areas. The cause-effect relationship between extract-induced PPI disruption and augmented monoaminergic transmission was studied using different serotoninergic, adrenergic and dopaminergic antagonists. The effects of hypericin and hyperforin, as the main active constituents of the extract, on PPI response were also tested. PPI disruption was prevented after blocking the serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors. Results also demonstrated a significant PPI deficit after acute treatment of rats with hyperforin, and not hypericin. In some conditions manifesting disrupted PPI response, apoptosis coexists. Electrophoresis of DNA isolated from brains of hyperforin-treated animals revealed absence of any abnormal DNA fragmentation patterns. It is concluded that serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors are involved in the disruptive effect of St. John's wort extract on PPI response in rats. We can also conclude that hyperforin, and not hypericin, is one of the active ingredients responsible for St. John's wort-induced PPI disruption with no relation to apoptotic processes.

  13. Purification and reconstitution of the human platelet. cap alpha. /sub 2/-adrenergic receptor

    Energy Technology Data Exchange (ETDEWEB)

    Regan, J.W.; Cerione, R.A.; Nakata, H.; Benovic, J.L.; DeMarinis, R.M.; Caron, M.G.; Lefkowitz, R.J.

    1986-05-01

    Human platelet ..cap alpha../sub 2/-adrenergic receptors have been purified approx.80,000 fold to apparent homogeneity by a five step chromatographic procedure. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of radioiodinated protein from purified receptor preparations shows a single major band of M/sub r/ 64,000. The competitive binding of ligands to the purified receptor protein shows the proper ..cap alpha../sub 2/-adrenergic specificity. The ..cap alpha../sub 2/-adrenergic receptor contains an essential sulfhydryl residues. Thus, exposure of the purified receptor to the sulfhydryl specific reagent, phenylmercuric chloride (PMC), resulted in a 80% loss of binding activity. This loss of binding activity was prevented when exposure to PMC was done in the presence of ..cap alpha../sub 2/-adrenergic ligands and it was reversed by subsequent exposure to dithiothreitol. Partial proteolysis of purified ..cap alpha../sub 2/-adrenergic receptors was obtained with S. aureus V-8 protease, ..cap alpha..-chymotrypsin and papain. In a comparison with purified ..beta../sub 2/-adrenergic receptors no common partial proteolytic products were found. Partially purified preparations of the ..cap alpha../sub 2/-adrenergic receptor were successfully reconstituted into phospholipid vesicles with the inhibitory guanyl nucleotide-binding regulatory protein, N/sub i/. In these reconstituted preparations, epinephrine could stimulate, and phentolamine could block, the GTPase activity of N/sub i/.

  14. Phospholemman and beta-adrenergic stimulation in the heart.

    Science.gov (United States)

    Wang, JuFang; Gao, Erhe; Song, Jianliang; Zhang, Xue-Qian; Li, Jifen; Koch, Walter J; Tucker, Amy L; Philipson, Kenneth D; Chan, Tung O; Feldman, Arthur M; Cheung, Joseph Y

    2010-03-01

    Phosphorylation at serine 68 of phospholemman (PLM) in response to beta-adrenergic stimulation results in simultaneous inhibition of cardiac Na(+)/Ca(2+) exchanger NCX1 and relief of inhibition of Na(+)-K(+)-ATPase. The role of PLM in mediating beta-adrenergic effects on in vivo cardiac function was investigated with congenic PLM-knockout (KO) mice. Echocardiography showed similar ejection fraction between wild-type (WT) and PLM-KO hearts. Cardiac catheterization demonstrated higher baseline contractility (+dP/dt) but similar relaxation (-dP/dt) in PLM-KO mice. In response to isoproterenol (Iso), maximal +dP/dt was similar but maximal -dP/dt was reduced in PLM-KO mice. Dose-response curves to Iso (0.5-25 ng) for WT and PLM-KO hearts were superimposable. Maximal +dP/dt was reached 1-2 min after Iso addition and declined with time in WT but not PLM-KO hearts. In isolated myocytes paced at 2 Hz. contraction and intracellular Ca(2+) concentration ([Ca(2+)](i)) transient amplitudes and [Na(+)](i) reached maximum 2-4 min after Iso addition, followed by decline in WT but not PLM-KO myocytes. Reducing pacing frequency to 0.5 Hz resulted in much smaller increases in [Na(+)](i) and no decline in contraction and [Ca(2+)](i) transient amplitudes with time in Iso-stimulated WT and PLM-KO myocytes. Although baseline Na(+)-K(+)-ATPase current was 41% higher in PLM-KO myocytes because of increased alpha(1)- but not alpha(2)-subunit activity, resting [Na(+)](i) was similar between quiescent WT and PLM-KO myocytes. Iso increased alpha(1)-subunit current (I(alpha1)) by 73% in WT but had no effect in PLM-KO myocytes. Iso did not affect alpha(2)-subunit current (I(alpha2)) in WT and PLM-KO myocytes. In both WT and NCX1-KO hearts, PLM coimmunoprecipitated with Na(+)-K(+)-ATPase alpha(1)- and alpha(2)-subunits, indicating that association of PLM with Na(+)-K(+)-ATPase did not require NCX1. We conclude that under stressful conditions in which [Na(+)](i) was high, beta-adrenergic agonist

  15. Alpha adrenoceptor antagonists in the year 2000: is there anything new?

    Science.gov (United States)

    Chapple, C R

    2001-01-01

    Selective alpha1-adrenergic blockade is now a well accepted and widely used therapeutic treatment for patients presenting with symptomatic bladder outlet obstruction thought to be associated with benign prostatic hyperplasia. This review summarizes the recent developments in this field relating to the subject of receptor subtype selectivity and the potential relevance of this to clinical usefulness of existing drug therapy. Whilst a number of unanswered questions remain as to the exact mechanisms of both drug action and side-effect profile, nevertheless it is clear that existing clinically available alpha1-antagonists provide a safe, effective and generally well tolerated therapy for patients with lower urinary tract symptoms thought to be associated with benign prostatic obstruction. The implications of the ALLHAT study are discussed.

  16. [Involvement of adrenergic mechanisms in developing the nervous syndrome of high pressure and nitrogen narcosis].

    Science.gov (United States)

    Sledkov, A I; Bernarskii, K V; Shilina, M N

    1996-01-01

    Involvement of the adrenergic mediator system in central mechanisms of hyperbaric nitrogen narcosis or the high pressure nervous syndrome (NSHP) produced by nitrogen or heliox gas mixtures under increased pressure was studied in mice and rabbit experiments with the use of pharmacological substances-analyzers. Accumulated data are indicative of lack of a significant role of the adrenergic system in the NSHP genesis and a protective effect of activation of the central but not peripheric adrenergic mediation in development of the behavioural and electrophysiological symptomatics of nitrogen narcosis. Mechanisms of NSHP and nitrogen narcosis and possible principles of pharmacological correction are under discussion.

  17. Glutamate antagonists limit tumor growth

    OpenAIRE

    2001-01-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N...

  18. Pharmacological targeting of β-adrenergic receptor functions abrogates NF-κB signaling and MMP-9 secretion in medulloblastoma cells

    Directory of Open Access Journals (Sweden)

    Borhane Annabi

    2010-11-01

    Full Text Available Borhane Annabi1,*, Eric Vaillancourt-Jean1,*, Alexander G Weil3, Richard Béliveau2,31Laboratoire d’Oncologie Moléculaire, Département de Chimie, Centre de Recherche BioMED, 2Laboratory of Molecular Medicine, Université du Québec à Montréal, Quebec, Canada; 3Department of Neurosurgery, CHUM Notre Dame, Montreal, Quebec, Canada; *These authors contributed equally to this workAbstract: Targeting of the vascular endothelium compartment explains, in part, the therapeutic efficacy of the nonselective β-adrenergic antagonist propranolol against common endothelial tumors such as hemangiomas. In vitro, the antiangiogenic biological activity of propranolol was shown to inhibit human brain microvascular endothelial cell tubulogenesis. However, possible interference of propranolol with cell signaling associated with the tumoral compartment remains unexplored. We therefore assessed the potency of propranolol against a pediatric brain tumor-derived DAOY medulloblastoma cell model. Gene expression of β1-, β2-, and β3-adrenergic receptors was confirmed in DAOY cells by semiquantitative RT-PCR. We next found that propranolol dose-dependently inhibited induction of the key extracellular matrix-degrading and blood–brain barrier disrupting enzyme matrix metalloproteinase-9 (MMP-9 by phorbol 12-myristate 13-acetate (PMA. Propranolol not only inhibited PMA-induced phosphorylation of the extracellular signal-regulated kinase (Erk, but also that of IkappaB (IκB, preventing the IκB phosphorylation which is a prerequisite for IκB degradation. Propranolol inhibition of IκB phosphorylation was shown to occur with optimal efficacy at 30 µM. Although propranolol, at up to 100 µM, did not affect cell viability, it potentiated PMA-mediated signaling that ultimately led to diminished phosphorylation of Akt. The anti-Erk and anti-Akt phosphorylation effects are both suggestive of antiproliferative and antisurvival signaling, respectively. Our data are

  19. EEG differences between the opioid and adrenergic psyhoneuroendocrine rat types

    DEFF Research Database (Denmark)

    Cristea, A; Moldovan, M; Munteanu, A M

    2000-01-01

    Our work is based on the hypothesis of the existence of an opioid psychoneuroendocrine type named "O" type (Cristea, 1993), opposed to the well known adrenergic "A" type described by Roseman and Friedman in 1980. In the present study we tested the differences between the background EEG activity...... adult (140 g) male Wistar population using the distribution of the tail retraction time (TRT) during a tail-flick test. The epidural EEG activity, was quantified within the 1-30 Hz band by six numerical parameters: root mean square (RMS), mean spectral frequency (MSF), spectral edge frequency at 95...... theta RSP asymmetry both during consciousness and ether anesthesia while no such theta gradient could be shown for the "O" type. The differences between the "A" and "O" types are enhanced under light Ether anesthesia to which the "A" type is more resistant. The EEG complementarity between the "A" and "O...

  20. 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...

  1. Comparison of relaxation responses of cavernous and trigonal smooth muscles from rabbits by alpha1-adrenoceptor antagonists; prazosin, terazosin, doxazosin, and tamsulosin.

    Science.gov (United States)

    Seo, K. K.; Lee, M. Y.; Lim, S. W.; Kim, S. C.

    1999-01-01

    Alpha1a-adrenergic receptor (AR) primarily mediates the contraction of the prostatic and cavernous smooth muscles. Among clinically available alpha1-AR antagonists for the medical management of benign prostatic hyperplasia (BPH), tamsulosin has a modest selectivity for alpha1A- and alpha1D- over alpha1B-ARs. To compare the effects of various alpha1-AR antagonists on relaxation responses of cavernous and trigonal smooth muscles, isometric tension studies with relatively selective (tamsulosin) and non-selective (prazosin, doxazosin, and terazosin) alpha1A-AR antagonists, were conducted in the cavernous and trigonal muscle strips of rabbits (n=10 each). Tamsulosin had the strongest inhibitory effect on contraction of trigonal smooth muscle among the various alpha1-AR antagonists, and the inhibitory activities of prazosin, doxazosin, and terazosin were not statistically different. All alpha1-AR antagonists caused concentration-dependent relaxation of the cavernous muscle strips. Tamsulosin was shown to have greater potency than prazosin (more than 100-fold), doxazosin (more than 1000-fold), and terazosin (more than 1000-fold), in relaxation of cavernous smooth muscle. In conclusion, tamsulosin might be the most effective drug among the four commonly used alpha1-AR antagonists for the medical management of BPH. Tamsulosin might be a potential substitute for phentolamine in combination with vasoactive agents as an intracavernous injection therapy for patients with erectile dysfunction. PMID:10102527

  2. 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.

  3. 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.

  4. Discovery of high affinity ligands for β2-adrenergic receptor through pharmacophore-based high-throughput virtual screening and docking.

    Science.gov (United States)

    Yakar, Ruya; Akten, Ebru Demet

    2014-09-01

    Novel high affinity compounds for human β2-adrenergic receptor (β2-AR) were searched among the clean drug-like subset of ZINC database consisting of 9,928,465 molecules that satisfy the Lipinski's rule of five. The screening protocol consisted of a high-throughput pharmacophore screening followed by an extensive amount of docking and rescoring. The pharmacophore model was composed of key features shared by all five inactive states of β2-AR in complex with inverse agonists and antagonists. To test the discriminatory power of the pharmacophore model, a small-scale screening was initially performed on a database consisting of 117 compounds of which 53 antagonists were taken as active inhibitors and 64 agonists as inactive inhibitors. Accordingly, 7.3% of the ZINC database subset (729,413 compounds) satisfied the pharmacophore requirements, along with 44 antagonists and 17 agonists. Afterwards, all these hit compounds were docked to the inactive apo form of the receptor using various docking and scoring protocols. Following each docking experiment, the best pose was further evaluated based on the existence of key residues for antagonist binding in its vicinity. After final evaluations based on the human intestinal absorption (HIA) and the blood brain barrier (BBB) penetration properties, 62 hit compounds have been clustered based on their structural similarity and as a result four scaffolds were revealed. Two of these scaffolds were also observed in three high affinity compounds with experimentally known Ki values. Moreover, novel chemical compounds with distinct structures have been determined as potential β2-AR drug candidates.

  5. Alpha 2 adrenergic receptors in hyperplastic human prostate: identification and characterization using (/sup 3/H) rauwolscine

    Energy Technology Data Exchange (ETDEWEB)

    Shapiro, E.; Lepor, H.

    1986-05-01

    (/sup 3/H)Rauwolscine ((/sup 3/H)Ra), a selective ligand for the alpha 2 adrenergic receptor, was used to identify and characterize alpha 2 adrenergic receptors in prostate glands of men with benign prostatic hyperplasia. Specific binding of (/sup 3/H)Ra to prostatic tissue homogenates was rapid and readily reversible by addition of excess unlabelled phentolamine. Scatchard analysis of saturation experiments demonstrates a single, saturable class of high affinity binding sites (Bmax = 0.31 +/- 0.04 fmol./microgram. DNA, Kd = 0.9 +/- 0.11 nM.). The relative potency of alpha adrenergic drugs (clonidine, alpha-methylnorepinephrine and prazosin) in competing for (/sup 3/H)Ra binding sites was consistent with the order predicted for an alpha 2 subtype. The role of alpha 2 adrenergic receptors in normal prostatic function and in men with bladder outlet obstruction secondary to BPH requires further investigation.

  6. Differential Regulation of Two Palmitoylation Sites in the Cytoplasmic Tail of the β1-Adrenergic Receptor*

    OpenAIRE

    2011-01-01

    S-Palmitoylation of G protein-coupled receptors (GPCRs) is a prevalent modification, contributing to the regulation of receptor function. Despite its importance, the palmitoylation status of the β1-adrenergic receptor, a GPCR critical for heart function, has never been determined. We report here that the β1-adrenergic receptor is palmitoylated on three cysteine residues at two sites in the C-terminal tail. One site (proximal) is adjacent to the seventh transmembrane domain and is a consensus ...

  7. [Modifying effect of incorporated 137Cs on the mechanism of adrenergic control of myocardial contraction].

    Science.gov (United States)

    Lobanok, L M; Bulanova, K Ia; Gerasimovich, N V; Sineleva, M V; Miliutin, A A

    1994-01-01

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

  8. 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....

  9. Analysis of adrenergic regulation of melatonin synthesis in Siberian hamster pineal emphasizes the role of HIOMT.

    Science.gov (United States)

    Ceinos, R M; Chansard, M; Revel, F; Calgari, C; Míguez, J M; Simonneaux, V

    2004-01-01

    Seasonal variations of environmental factors are translated into annual fluctuations in synthesis and release of melatonin, which in turn acts as a neuroendocrine messenger for the synchronization of annual functions. So far, most studies performed to understand the regulation of melatonin synthesis have used the non seasonal laboratory rat. It was demonstrated that nocturnal melatonin synthesis depends on alpha- and beta-adrenergic activation of the enzyme arylalkylamine N-acetyltransferase (AA-NAT). In this study, we investigated the mechanisms of melatonin synthesis in the Siberian hamster, a seasonal species with marked photoperiodic variation in melatonin peak duration and amplitude. A beta-adrenergic receptor agonist alone markedly stimulated AA-NAT activity and melatonin synthesis and release. An alpha-adrenergic receptor agonist, while having no effect per se, potentiated the beta-adrenergic stimulation of AA-NAT activity both in vitro and in vivo. Strikingly, the potentiation of AA-NAT activity did not result in a potentiation of melatonin synthesis, suggesting that the rate of melatonin production is limited downstream in the metabolic pathway, most probably at the level of hydroxyindole-O-methyltransferase (HIOMT). HIOMT presented a constitutively high activity that was not acutely (within hours) stimulated by beta-adrenergic agonist, but was rather up-regulated by chronic application of the agonist. This long-term beta-adrenergic regulation may explain the reported large photoperiodic variation of HIOMT activity that drives the photoperiodic variation in melatonin peak.

  10. Immunoanalogue of vertebrate beta-adrenergic receptor in the unicellular eukaryote Paramecium.

    Science.gov (United States)

    Wiejak, Jolanta; Surmacz, Liliana; Wyroba, Elzbieta

    2002-01-01

    Cell fractionation, SDS-PAGE, quantitative Western blot, confocal immunolocalization and immunogold labelling were performed to find an interpretation of the physiological response of the unicellular eukaryote Paramecium to beta-adrenergic ligands. The 69 kDa polypeptide separated by SDS-PAGE in S2 and P2 Paramecium subcellular fractions cross-reacted with antibody directed against human beta2-adrenergic receptor. This was detected by Western blotting followed by chemiluminescent detection. Quantitative image analysis showed that beta-selective adrenergic agonist (-)-isoproterenol--previously shown to enhance phagocytic activity--evoked redistribution of the adrenergic receptor analogue from membraneous (P2) to cytosolic (S2) fraction. The relative increase in immunoreactive band intensity in S2 reached 80% and was paralleled by a 59% decrease in P2 fraction. Confocal immunofluorescence revealed beta2-adrenergic receptor sites on the cell surface and at the ridge of the cytopharynx--where nascent phagosomes are formed. This localization was confirmed by immunoelectron microscopy. These results indicate that the 69 kDa Paramecium polypeptide immunorelated to vertebrate beta2-adrenergic receptor appeared in this evolutionary ancient cell as a nutrient receptor.

  11. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly

    2001-02-01

    Full Text Available A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes. Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

  12. p-( sup 125 I)iodoclonidine is a partial agonist at the alpha 2-adrenergic receptor

    Energy Technology Data Exchange (ETDEWEB)

    Gerhardt, M.A.; Wade, S.M.; Neubig, R.R. (Univ. of Michigan Medical School, Ann Arbor (USA))

    1990-08-01

    The binding properties of p-(125I)iodoclonidine (( 125I)PIC) to human platelet membranes and the functional characteristics of PIC are reported. (125I)PIC bound rapidly and reversibly to platelet membranes, with a first-order association rate constant (kon) at room temperature of 8.0 +/- 2.7 x 10(6) M-1 sec-1 and a dissociation rate constant (koff) of 2.0 +/- 0.8 x 10(-3) sec-1. Scatchard plots of specific (125I)PIC binding (0.1-5 nM) were linear, with a Kd of 1.2 +/- 0.1 nM. (125I)PIC bound to the same number of high affinity sites as the alpha 2-adrenergic receptor (alpha 2-AR) full agonist (3H) bromoxidine (UK14,304), which represented approximately 40% of the sites bound by the antagonist (3H)yohimbine. Guanosine 5'-(beta, gamma-imido)triphosphate greatly reduced the amount of (125I)PIC bound (greater than 80%), without changing the Kd of the residual binding. In competition experiments, the alpha 2-AR-selective ligands yohimbine, bromoxidine, oxymetazoline, clonidine, p-aminoclonidine, (-)-epinephrine, and idazoxan all had Ki values in the low nanomolar range, whereas prazosin, propranolol, and serotonin yielded Ki values in the micromolar range. Epinephrine competition for (125I)PIC binding was stereoselective. Competition for (3H)bromoxidine binding by PIC gave a Ki of 1.0 nM (nH = 1.0), whereas competition for (3H)yohimbine could be resolved into high and low affinity components, with Ki values of 3.7 and 84 nM, respectively. PIC had minimal agonist activity in inhibiting adenylate cyclase in platelet membranes, but it potentiated platelet aggregation induced by ADP with an EC50 of 1.5 microM. PIC also inhibited epinephrine-induced aggregation, with an IC50 of 5.1 microM. Thus, PIC behaves as a partial agonist in a human platelet aggregation assay. (125I)PIC binds to the alpha 2B-AR in NG-10815 cell membranes with a Kd of 0.5 +/- 0.1 nM.

  13. Postnatal development of adrenergic responsiveness in the rabbit heart.

    Science.gov (United States)

    Feng, Z P; Dryden, W F; Gordon, T

    1989-08-01

    It is uncertain how changes in the beta-adrenoceptor population influence the contractility of developing heart. To resolve this we have examined postnatal developmental changes in the adrenergic responsiveness of the rabbit heart. The inotropic effect of isoproterenol on isolated left ventricular papillary muscles from rabbits aged 3, 21, and 90 days was compared with the relative number of beta-adrenoceptors at each age measured using [3H]dihydroalprenolol ([3H]DHA) as the specific ligand. The maximum tension developed in response to isoproterenol increases from 37 +/- 7 to 175 +/- 33% above control twitch tension between 3 and 21 days of age; this is followed by a decrease to 68 +/- 12% in the young adult. During this period of development, there is a decline in EC50 towards increased sensitivity. These differences are partially accounted for by an increase in the numbers of specific [3H]DHA binding sites from 17.3 +/- 2.3 to 56.6 +/- 9.9 fmol/mg wet tissue weight from 3 to 21 days, and a subsequent decrease to 32 +/- 4.5 fmol/mg tissue in the young adult. The proportionally larger increase in contractility compared with the number of beta-adrenoceptor binding sites during the first 3 weeks of life is discussed in terms of the developmental changes in the efficacy of coupling between receptor occupancy and contraction.

  14. The α1 Antagonist Doxazosin Alters the Behavioral Effects of Cocaine in Rats

    Directory of Open Access Journals (Sweden)

    Colin N. Haile

    2012-11-01

    Full Text Available Medications that target norepinephrine (NE neurotransmission alter the behavioral effects of cocaine and may be beneficial for stimulant-use disorders. We showed previously that the short-acting, α1-adrenergic antagonist, prazosin, blocked drug-induced reinstatement of cocaine-seeking in rats and doxazosin (DOX, a longer-acting α1 antagonist blocked cocaine’s subjective effects in cocaine-dependent volunteers. To further characterize DOX as a possible pharmacotherapy for cocaine dependence, we assessed its impact on the development and expression of cocaine-induced locomotor sensitization in rats. Rats (n = 6–8 were administered saline, cocaine (COC, 10 mg/kg or DOX (0.3 or 1.0 mg/kg alone or in combination for 5 consecutive days (development. Following 10-days of drug withdrawal, all rats were administered COC and locomotor activity was again assessed (expression. COC increased locomotor activity across days indicative of sensitization. The high dose (1.0 mg/kg, but not the low dose (0.3 mg/kg of DOX significantly decreased the development and expression of COC sensitization. DOX alone did not differ from saline. These results are consistent with studies showing that α1 receptors are essential for the development and expression of cocaine’s behavioral effects. Results also suggest that blockade of both the development and expression of locomotor sensitization may be important characteristics of possible pharmacotherapies for cocaine dependence in humans.

  15. New antagonist agents of neuropeptide y receptors

    Directory of Open Access Journals (Sweden)

    Ignacio Aldana

    2000-12-01

    Full Text Available In the CNS, NPY has been implicated in obesity and feeding, endocrine function and metabolism. Potent and selective rNPY antagonists will be able to probe the merits of this approach for the treatment of obesity. We report the synthesis and preliminary evaluation of some hydrazide derivatives as antagonists of rNPY.

  16. Social crowding stress diminishes the pituitary-adrenocortical and hypothalamic histamine response to adrenergic stimulation.

    Science.gov (United States)

    Bugajski, J; Gadek-Michalska, A; Borycz, J

    1993-12-01

    Social stress of crowding almost totally reduced the rise in serum corticosterone elicited by intracerebroventricular administration of isoprenaline, a beta-adrenergic receptor agonist, after 3 and 7 day of crowding and substantially diminished that response after 14 and 21 days. Crowding stress totally abolished the increase in hypothalamic histamine induced by isoprenaline in control rats. Crowding also significantly diminished the increase in serum corticosterone evoked by clonidine, an alpha 2-adrenergic agonist, and abolished the clonidine-induced elevation in hypothalamic histamine levels. The stimulatory effect of phenylephrine, an alpha 1-adrenergic agonist, on corticosterone secretion was only moderately diminished in crowded rats. Neither phenylephrine nor crowding stress changed significantly the hypothalamic histamine levels. These results indicate that social stress of crowding considerably impairs the hypothalamic-pituitary-adrenocortical responsiveness to central beta- and alpha 2-adrenergic receptor stimulation. Crowding also abolishes the rise in hypothalamic histamine induced by beta- and alpha 2-adrenergic agonist, suggesting a role of hypothalamic histamine in the HPA adaptation to the social stress of crowding.

  17. 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.

  18. 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

    2017-01-01

    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. PMID:28198454

  19. A single bout of exercise induces beta-adrenergic desensitization in human adipose tissue.

    Science.gov (United States)

    Marion-Latard, F; De Glisezinski, I; Crampes, F; Berlan, M; Galitzky, J; Suljkovicova, H; Riviere, D; Stich, V

    2001-01-01

    This study was designed to assess whether physiological activation of the sympathetic nervous system induced by exercise changes adipose tissue responsiveness to catecholamines in humans. Lipid mobilization in abdominal subcutaneous adipose tissue was studied with the use of a microdialysis method in 11 nontrained men (age: 22. 3 +/- 1.5 yr; body mass index: 23.0 +/- 1.6). Adipose tissue adrenergic sensitivity was explored with norepinephrine, dobutamine (beta(1)-agonist), or terbutaline (beta(2)-agonist) perfused during 30 min through probes before and after 60-min exercise (50% of the maximal aerobic power). The increase in extracellular glycerol concentration during infusion was significantly lower after the exercise when compared with the increase observed before the exercise (P < 0.05, P < 0.02, and P < 0.01, respectively, for norepinephrine, dobutamine, and terbutaline). In a control experiment realized without exercise, no difference in norepinephrine-induced glycerol increase between the two infusions was observed. To assess the involvement of catecholamines in the blunted beta-adrenergic-induced lipolytic response after exercise, adipose tissue adrenergic sensitivity was explored with two 60-min infusions of norepinephrine or epinephrine separated by a 60-min interval. With both catecholamines, the increase in glycerol was significantly lower during the second infusion (P < 0.05). The findings suggest that aerobic exercise, which increased adrenergic activity, induces a desensitization in beta(1)- and beta(2)-adrenergic lipolytic pathways in human subcutaneous adipose tissue.

  20. 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.

  1. Sexual dimorphism in adrenergic regulation of hepatic glycogenolysis

    Energy Technology Data Exchange (ETDEWEB)

    Studer, R.K.

    1987-04-01

    The total phosphorylase a plus b of hepatocytes isolated from females and incubated in the absence or presence of estradiol and progesterone at concentrations found in vivo does not vary during the estrous cycle. However, there is a slight but significant influence of the estrous cycle on basal and epinephrine-stimulated phosphorylase a activity, with a nadir being seen on diestrus. The relative contributions of the ..cap alpha..- and ..beta..-mediated pathways to phosphorylase a activation do not vary with the estrous cycle but are constant at 75 and 56%, respectively, of the response to 5 x 10/sup -8/ M epinephrine. When the epinephrine-stimulated glucose release from glycogen stores in cells from females and males is compared, the release from the female is greater than that from the male, while the ..cap alpha..-receptor-mediated stimulation in the female is comparable with that in the male. The epinephrine-stimulated increase in cytostolic free calcium (Ca/sub i/) is greater in the male than the female at 10/sup -6/ M but greater in the female than the male at 5 x 10/sup -9/ M. The changes in Ca/sub i/ are equivalent at intermediate epinephrine concentrations. When considered with the prior analysis of /sup 45/Ca efflux after adrenergic stimulation, this suggests there may be a sexual dimorphism in hepatocyte calcium transport systems. The glucose release for a given increase in Ca/sub i/ is greater in the female than the male probably due to the concomitant action of the ..beta..-mediated increase in cAMP and the ..cap alpha..-mediated increase in Ca/sub i/. This supports the conclusion that the ..beta..-mediated component does make a significant contribution to the catecholamine regulation of glycogenolysis in hepatocytes from adult female rats.

  2. Cerebral aterial spasm. I. Adrenergic mechanism in experimental cerebral vasospasm.

    Directory of Open Access Journals (Sweden)

    Morooka,Hiroshi

    1978-04-01

    Full Text Available This study demonstrates that an adrenergic mechanism plays an important role in producing the delayed cerebral vasospasm which follows subarachnoid hemorrhage. Results were as follows: 1. Experimental subarachnoid hemorrhage (SAH was produced by injection of fresh arterial blood into the cisterna magna in cats. The cerebral vasospasm was shown angiographically to be biphasic in nature: immediate constriction lasting 1 h and marked prolonged spasm occurring between the 3rd and 5th day after SAH. The amount of noradrenaline (NA and dopamine-beta-hydroxylase (DBH activity decreased over a period of 24 h both within the wall of the basilar artery and in the locus ceruleus and then gradually increased, reaching a maximum on the 3rd day after SAH. 2. Topical application of spasmogenic substances (NA and blood produced a marked constriction of the hypersensitive basilar artery on the 3rd day after SAH. 3. 6-Hydroxydopamine (6-OHDA injection into the cisterna magna produced prolonged vasocilatation. The dilated vessel responded with mild transient constriction after the topical application of NA or fresh blood. DBH activity and NA concentration in the vessels, locus ceruleus and medial hypothalamus decreased markedly on the 3rd day after the cisternal injection of 6-OHDA. 4. Various spasmogenic substances (i.e. serotonin, NA, prostaglandins and methemoglobin were measured in a mixture of equal volume of CSF and blood in cats. ONly the serotonin in the mixed fluid produced vasoconstriction. Spasmogenic substances decreased markedly in the mixed fluid incubated for 3 days at 37 degrees C, and none of these substances apart from methemoglobin was present in a concentration sufficient to produce constriction of vessels. 5. These results suggest that early spasm is induced by serotonin around the arteries of the cranial base, and delayed spasm might be caused by hyperreaction of cerebral vessels to spasmogenic substances such as methemoglobin, during the

  3. Cardiovascular effects of selective agonists and antagonists of histamine H3 receptors in the anaesthetized rat.

    Science.gov (United States)

    Coruzzi, G; Gambarelli, E; Bertaccini, G; Timmerman, H

    1995-06-01

    The cardiovascular responses to a series of selective histamine H3 receptor agonists, (R) alpha-methylhistamine, imetit and immepip and selective antagonists, thioperamide, clobenpropit and clophenpropit, were studied in anaesthetized rats. At 0.003-1 mumol/kg i.v. doses, H3 agonists failed to produce any significant change in the basal blood pressure and heart rate. Larger doses of (R) alpha-methylhistamine increased the blood pressure and heart rate and higher doses of imetit caused vasodepressor responses and reduced heart rate, whereas immepip proved virtually inactive. While (R) alpha-methylhistamine-induced effects were not blocked by histamine H1-, H2- and H3-receptor antagonists, they were however reduced by idazoxan and propranolol, which indicates that the mechanisms involved are adrenergic. The effects induced by imetit are not related to histamine H3 receptors but are mediated by indirect (via 5HT3 receptors) cholinergic mechanisms, since these effects were prevented by 1 mg/kg i.v. atropine and by 0.1 mg/kg i.v. ondansetron. Similarly, the H3 antagonists per se failed to change basal cardiovascular function up to 10 mumol/kg i.v. and only at 30 mumol/kg i.v. were marked decreases observed in the blood pressure and heart rate with a significant reduction in the effects of noradrenaline. These data indicate that in anaesthetized rats, histamine H3 receptor activation or blockade has no effect on basal cardiovascular function. The effects recorded after the administration of large doses of (R) alpha-methylhistamine and imetit are clearly unrelated to histamine H3 receptors and should be taken into account when using these compounds as H3 ligands for "in vivo" experiments.

  4. The acute modulation of norepinephrine on immune responses and genes expressions via adrenergic receptors in the giant freshwater prawn, Macrobrachium rosenbergii.

    Science.gov (United States)

    Chang, Chin-Chyuan; Tsai, Wan-Lin; Jiang, Jia-Rong; Cheng, Winton

    2015-10-01

    Norepinephrine (NE), immunocompetent parameters (total haemocyte count (THC), phenoloxidase (PO) activity, respiratory burst (RB), superoxide dismutase (SOD) activity, phagocytic activity and clearance efficiency to Lactococcus garvieae), and prophenoloxidase (proPO) system-related genes (lipopolysaccharide- and β-1,3-glucan-binding protein, LGBP; prophenoloxidase, proPO; peroxinectin, PE; α2-macroglobulin, α2-M) expressions were investigated in Macrobrachium rosenbergii received NE through injection at 50 pmol/prawn after 0, 30, 60, and 120 min. Furthermore, the PO activity, RB, SOD activity, phagocytic activity and proPO system-related genes expressions were determined in haemocytes incubated with cacodylate buffer (CAC), NE, and NE co-treated with various adrenergic receptor (AR) antagonists in vitro. Results showed that NE, THC, granular cells, PO activity, SOD activity, proPO system-related genes expressions, and phagocytic activity and clearance efficiency to L. garvieae increased; PO activity per granulocyte and RB per haemocyte decreased from 30 to 120 min; semigranular cells and RB increased in the initial 30 min, and then decreased at 120 min when the prawns received NE by injection. In vitro studies, all the determined immune parameters and genes expressions were significantly decreased in haemocytes incubated with NE after 30 min. The negative effects of NE were prevented on the PO activity and phagocytic activity by the β-AR antagonist of metoprolol (Met), on the SOD activity by the β-AR antagonist of propranolol (Pro), on the RB by the β-AR antagonist of Met and prazosin (Pra), and on the proPO system-related genes expressions by α-AR antagonist of Pra. These results show that NE modulates prawn haemocytes proPO system-related genes expressions via α1-AR, PO activity and phagocytosis via β1-AR, respiratory burst via α1-and β1-ARs, and SOD activity via β2-AR. It is concluded that NE stimulates the regulation of immunocompetence parameters

  5. Prenatal exposure to methylmercury alters development of adrenergic receptor binding sites in peripheral sympathetic target tissues

    Energy Technology Data Exchange (ETDEWEB)

    Slotkin, T.A.; Orband, L.; Cowdery, T.; Kavlock, R.J.; Bartolome, J.

    1987-01-01

    In order to assess the impact of prenatal exposure to methylmercury on sympathetic neurotransmission, effects on development of adrenergic receptor binding sites in peripheral tissues was evaluated. In the liver, methylmercury produced a dose-dependent increase in alpha/sub 1/, alpha/sub 2/, and beta-receptor binding of radioliganda throughout the first 5 weeks of postnatal life. Similarly, renal alpha-receptor subtypes showed increased binding capabilities, but binding to alpha-receptor sites was reduced. At least some of the changes in receptors appear to be of functional significance, as physiological reactivity to adrenergic stimulation is altered in the same directions in these two tissues. The actions of methylmercury displayed tissue specificity in that the same receptor populations were largely unaffected in other tissues (lung, heart). These results suggest that methylmercury exposure in utero alters adrenergic responses through targeted effects on postsynaptic receptor populations in specific tissues.

  6. The role of adrenergic receptors in the motility of duodenum and choledochoduodenal junction in the pig.

    Science.gov (United States)

    Blichowski, A; Andrzejewski, W; Gaszyński, W; Kozulski, W

    1977-01-01

    The role of adenergic receptors in the motility of duodenum and choledochoduodenal junction in the pig. Acta Physiol. Pol., 1977, 28 (6): 521-528. The choldeochoduodenal junction in the Vietnamese pig is functionally and anatomically a part of duodenal wall. In view of this, investigations were carried out for establishing the role of adrenergic receptors in the development of motor function of this part of the intestinal tract. The experiments were performed on domestic Vietnamese pigs (Sus scrofa domestica) and they showed that after stimulation of alpha and beta adrenergic receptors the motor activity of the duodenal muscular coat and the choledochoduodenal junction is inhibited. The obtained results suggest similar reactions of the adrenergic receptors in both examined parts of the intestinal tract in the pig.

  7. Adrenergic effects on secretion of epidermal growth factor from Brunner's glands

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier

    1985-01-01

    The influence of the sympathetic nervous system and adrenergic agonists on flow rate and secretion of epidermal growth factor (EGF) from Brunner's glands has been investigated in the rat. Chemical sympathectomy by administration of 6-hydroxydopamine increased volume secretion and output of EGF from...... Brunner's glands but depleted the glands of EGF. Infusion of noradrenaline, an alpha-adrenergic agonist, inhibited basal and vasoactive intestinal polypeptide (VIP) stimulated flow rate and output of EGF from Brunner's glands and increased the amount of EGF in the tissue. Vasoactive intestinal polypeptide...... also increased the amount of EGF in Brunner's gland tissue and this was unchanged after simultaneous infusion of VIP and noradrenaline as well as VIP and isoproterenol, a beta-adrenergic agonist. Isoproterenol had no effect on basal and VIP stimulated secretion of EGF from Brunner's glands...

  8. Distribution of adrenergic receptors in the enteric nervous system of the guinea pig, mouse, and rat.

    Science.gov (United States)

    Nasser, Yasmin; Ho, Winnie; Sharkey, Keith A

    2006-04-10

    Adrenergic receptors in the enteric nervous system (ENS) are important in control of the gastrointestinal tract. Here we describe the distribution of adrenergic receptors in the ENS of the ileum and colon of the guinea pig, rat, and mouse by using single- and double-labelling immunohistochemistry. In the myenteric plexus (MP) of the rat and mouse, alpha2a-adrenergic receptors (alpha2a-AR) were widely distributed on neurons and enteric glial cells. alpha2a-AR mainly colocalized with calretinin in the MP, whereas submucosal alpha2a-AR neurons colocalized with vasoactive intestinal polypeptide (VIP), neuropeptide Y, and calretinin in both species. In the guinea pig ileum, we observed widespread alpha2a-AR immunoreactivity on nerve fibers in the MP and on VIP neurons in the submucosal plexus (SMP). We observed extensive beta1-adrenergic receptor (beta1-AR) expression on neurons and nerve fibers in both the MP and the SMP of all species. Similarly, the beta2-adrenergic receptor (beta2-AR) was expressed on neurons and nerve fibers in the SMP of all species, as well as in the MP of the mouse. In the MP, beta1- and beta2-AR immunoreactivity was localized to several neuronal populations, including calretinin and nitrergic neurons. In the SMP of the guinea pig, beta1- and beta2-AR mainly colocalized with VIP, whereas, in the rat and mouse, beta1- and beta2-AR were distributed among the VIP and calretinin populations. Adrenergic receptors were widely localized on specific neuronal populations in all species studied. The role of glial alpha2a-AR is unknown. These results suggest that sympathetic innervation of the ENS is directed toward both enteric neurons and enteric glia.

  9. Distinctive left-sided distribution of adrenergic-derived cells in the adult mouse heart.

    Directory of Open Access Journals (Sweden)

    Kingsley Osuala

    Full Text Available Adrenaline and noradrenaline are produced within the heart from neuronal and non-neuronal sources. These adrenergic hormones have profound effects on cardiovascular development and function, yet relatively little information is available about the specific tissue distribution of adrenergic cells within the adult heart. The purpose of the present study was to define the anatomical localization of cells derived from an adrenergic lineage within the adult heart. To accomplish this, we performed genetic fate-mapping experiments where mice with the cre-recombinase (Cre gene inserted into the phenylethanolamine-n-methyltransferase (Pnmt locus were cross-mated with homozygous Rosa26 reporter (R26R mice. Because Pnmt serves as a marker gene for adrenergic cells, offspring from these matings express the β-galactosidase (βGAL reporter gene in cells of an adrenergic lineage. βGAL expression was found throughout the adult mouse heart, but was predominantly (89% located in the left atrium (LA and ventricle (LV (p<0.001 compared to RA and RV, where many of these cells appeared to have cardiomyocyte-like morphological and structural characteristics. The staining pattern in the LA was diffuse, but the LV free wall displayed intermittent non-random staining that extended from the apex to the base of the heart, including heavy staining of the anterior papillary muscle along its perimeter. Three-dimensional computer-aided reconstruction of XGAL+ staining revealed distribution throughout the LA and LV, with specific finger-like projections apparent near the mid and apical regions of the LV free wall. These data indicate that adrenergic-derived cells display distinctive left-sided distribution patterns in the adult mouse heart.

  10. The QseC adrenergic signaling cascade in Enterohemorrhagic E. coli (EHEC.

    Directory of Open Access Journals (Sweden)

    David T Hughes

    2009-08-01

    Full Text Available The ability to respond to stress is at the core of an organism's survival. The hormones epinephrine and norepinephrine play a central role in stress responses in mammals, which require the synchronized interaction of the whole neuroendocrine system. Mammalian adrenergic receptors are G-coupled protein receptors (GPCRs; bacteria, however, sense these hormones through histidine sensor kinases (HKs. HKs autophosphorylate in response to signals and transfer this phosphate to response regulators (RRs. Two bacterial adrenergic receptors have been identified in EHEC, QseC and QseE, with QseE being downstream of QseC in this signaling cascade. Here we mapped the QseC signaling cascade in the deadly pathogen enterohemorrhagic E. coli (EHEC, which exploits this signaling system to promote disease. Through QseC, EHEC activates expression of metabolic, virulence and stress response genes, synchronizing the cell response to these stress hormones. Coordination of these responses is achieved by QseC phosphorylating three of the thirty-two EHEC RRs. The QseB RR, which is QseC's cognate RR, activates the flagella regulon which controls bacteria motility and chemotaxis. The QseF RR, which is also phosphorylated by the QseE adrenergic sensor, coordinates expression of virulence genes involved in formation of lesions in the intestinal epithelia by EHEC, and the bacterial SOS stress response. The third RR, KdpE, controls potassium uptake, osmolarity, and also the formation of lesions in the intestine. Adrenergic regulation of bacterial gene expression shares several parallels with mammalian adrenergic signaling having profound effects in the whole organism. Understanding adrenergic regulation of a bacterial cell is a powerful approach for studying the underlying mechanisms of stress and cellular survival.

  11. 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.

  12. Affinity chromatography of alpha/sub 2/-adrenergic receptors (. cap alpha. /sub 2/AR) from pig cerebral cortex

    Energy Technology Data Exchange (ETDEWEB)

    Repaske, M.G.; Limbird, L.E.

    1986-03-01

    A high capacity, ..cap alpha../sub 2/AR-selective affinity resin (YOH. ag) has been prepared by coupling yohimbinic acid to diaminodipropylamine agarose with 1,3 dicyclohexylcarbodiimide. Unreacted amino groups on the agarose matrix are blocked subsequently by acetylation. One volume of YOH. ag adsorbs 75% of the ..cap alpha../sub 2/AR from 50 volumes of digitonin-solubilized preparation containing 0.2 pmol ..cap alpha../sub 2/AR/mg protein. Digitonin-solubilized preparations are derived from cholate extracts of porcine cerebral cortex containing approx. 0.075 pmol ..cap alpha../sub 2/AR/mg protein. Adsorption of ..cap alpha../sub 2/AR to YOH. ag is selective and thus is blocked by the ..cap alpha..-adrenergic antagonist phentolamine. Adsorbed ..cap alpha../sub 2/AR are eluted with 10 ..mu..M phentolamine (20% yield) after removal of non-related proteins with NaCl gradients. Following hydroxylapatite chromatography to concentrate ..cap alpha..''AR and to remove phentolamine, the ..cap alpha..AR is present at 200-400 pmol/mg protein, assayed using sub-saturating concentrations of (/sup 3/H)-yohimbine. (It is estimated that the specific activity of a homogeneous ..cap alpha../sub 2/AR preparation would be 12,000-16,000 pmol/mg protein.) The availability of large quantities of cortical ..cap alpha../sub 2/AR and a resin easily prepared from commercially-supplied reagents suggests that purification of quantities of ..cap alpha../sub 2/AR sufficient for subsequent biochemical studies is feasible.

  13. Inhibition of α-adrenergic tone disturbs the distribution of blood flow in the exercising human limb.

    Science.gov (United States)

    Heinonen, Ilkka; Wendelin-Saarenhovi, Maria; Kaskinoro, Kimmo; Knuuti, Juhani; Scheinin, Mika; Kalliokoski, Kari K

    2013-07-15

    The role of neuronal regulation of human cardiovascular function remains incompletely elucidated, especially during exercise. Here we, by positron emission tomography, monitored tissue-specific blood flow (BF) changes in nine healthy young men during femoral arterial infusions of norepinephrine (NE) and phentolamine. At rest, the α-adrenoceptor agonist NE reduced BF by ~40%, similarly in muscles (from 3.2 ± 1.9 to 1.4 ± 0.3 ml·min(-1)·100 g(-1) in quadriceps femoris muscle), bone (from 1.1 ± 0.4 to 0.5 ± 0.2 ml·min(-1)·100 g(-1)) and adipose tissue (AT) (from 1.2 ± 0.7 to 0.7 ± 0.3 ml·min(-1)·100 g(-1)). During exercise, NE reduced exercising muscle BF by ~16%. BF in AT was reduced similarly as rest. The α-adrenoceptor antagonist phentolamine increased BF similarly in the different muscles and other tissues of the limb at rest. During exercise, BF in inactive muscle was increased 3.4-fold by phentolamine compared with exercise without drug, but BF in exercising muscles was not influenced. Bone and AT (P = 0.055) BF were also increased by phentolamine in the exercise condition. NE increased and phentolamine decreased oxygen extraction in the limb during exercise. We conclude that inhibition of α-adrenergic tone markedly disturbs the distribution of BF and oxygen extraction in the exercising human limb by increasing BF especially around inactive muscle fibers. Moreover, although marked functional sympatholysis also occurs during exercise, the arterial NE infusion that mimics the exaggerated sympathetic nerve activity commonly seen in patients with cardiovascular disease was still capable of directly limiting BF in the exercising leg muscles.

  14. Characterization of a β-Adrenergic-Like Octopamine Receptor in the Oriental Fruit Fly, Bactrocera dorsalis (Hendel)

    Science.gov (United States)

    Li, Hui-Min; Jiang, Hong-Bo; Gui, Shun-Hua; Liu, Xiao-Qiang; Liu, Hong; Lu, Xue-Ping; Smagghe, Guy; Wang, Jin-Jun

    2016-01-01

    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. PMID:27669213

  15. Stimulation of α1a adrenergic receptors induces cellular proliferation or antiproliferative hypertrophy dependent solely on agonist concentration.

    Directory of Open Access Journals (Sweden)

    Beilei Lei

    Full Text Available Stimulation of α1aAdrenergic Receptors (ARs is known to have anti-proliferative and hypertrophic effects; however, some studies also suggests this receptor can increase cell proliferation. Surprisingly, we find the α1aAR expressed in rat-1 fibroblasts can produce either phenotype, depending exclusively on agonist concentration. Stimulation of the α1aAR by high dose phenylephrine (>10(-7 M induces an antiproliferative, hypertrophic response accompanied by robust and extended p38 activation. Inhibition of p38 with SB203580 prevented the antiproliferative response, while inhibition of Erk or Jnk had no effect. In stark contrast, stimulation of the α1aAR with low dose phenylephrine (∼10(-8 M induced an Erk-dependent increase in cellular proliferation. Agonist-induced Erk phosphorylation was preceded by rapid FGFR and EGFR transactivation; however, only EGFR inhibition blocked Erk activation and proliferation. The general matrix metalloprotease inhibitor, GM6001, blocked agonist induced Erk activation within seconds, strongly suggesting EGFR activation involved extracellular triple membrane pass signaling. Erk activation required little Ca(2+ release and was blocked by PLCβ or PKC inhibition but not by intracellular Ca(2+ chelation, suggesting Ca(2+ independent activation of novel PKC isoforms. In contrast, Ca(2+ release was essential for PI3K/Akt activation, which was acutely maximal at non-proliferative doses of agonist. Remarkably, our data suggests EGFR transactivation leading to Erk induced proliferation has the lowest activation threshold of any α1aAR response. The ability of α1aARs to induce proliferation are discussed in light of evidence suggesting antagonistic growth responses reflect native α1aAR function.

  16. Indices of brain beta-adrenergic receptor signal transduction in the learned helplessness animal model of depression.

    Science.gov (United States)

    Gurguis, G N; Kramer, G; Petty, F

    1996-01-01

    Both stress response and antidepressant drug action may be mediated by beta-adrenergic receptors (beta AR). Since learned helplessness is a stress-induced animal model of depression, beta AR are relevant to investigate in this model. To date, studies have measured changes in total receptor density (RT), but have not examined more detailed aspects of signal transduction mechanisms such as coupling of the receptor to GS protein. We have investigated brain beta AR coupling in the frontal cortex, hippocampus and hypothalamus of rats exposed to inescapable shock and then tested for learned helplessness, and in both tested and naive controls using [125I]-iodocyanopindolol (ICYP) as the ligand. Both antagonist-saturation and agonist-displacement experiments were conducted, and the specificity for the beta AR was optimized by excluding ICYP binding to 5HT1B receptors. The percentage receptor density in the high-conformational state (%RH) and the ratio of agonist (isoproterenol) dissociation constant from the receptor in the low-/high-conformational states (KL/KH) were used as indices of coupling to GS protein. No significant differences were found between rats developing learned helplessness and non-helpless rats after inescapable stress in any parameter measured in any brain region. In the frontal cortex, exposure to inescapable shock induced beta AR uncoupling from GS protein as suggested by a low KL/KH ratio both in helpless and non-helpless rats but not in either control group. In the hypothalamus, there were trends for higher RL, RT and KL/KH ratio in helpless rats and stressed controls compared to naive controls. These findings suggest that beta AR binding parameters in frontal cortex, hippocampus or hypothalamus did not differentiate between helpless and non-helpless rats. Changes in beta AR coupling observed in these brain regions may reflect effects of stress, which appeared to be region-specific, rather than stress-induced behavioral depression.

  17. The beta-adrenergic blocker carvedilol restores L-type calcium current in a myocardial infarction model of rabbit

    Institute of Scientific and Technical Information of China (English)

    LI Xia; HUANG Cong-xin; JIANG Hong; CAO Feng; WANG Teng

    2005-01-01

    Background Carvedilol, an antagonist of α1- and β-adrenergic receptors, has shown efficacy in reducing all-cause death and arrhythmia death for ischemic heart disease and congestive heart failure in several large-scale trials. It has been found to prevent ventricular remodeling, and recently was reported to reverse down-regulation of Na+ channel in a chronic heart failure model. This study was conducted to investigate whether carvedilol could reverse the ion remodeling in a myocardial infarction model of rabbit.Methods After the procedure of coronary ligation, animals were randomized to placebo or carvedilol treatment (5 mg/kg). Action potentials, L-type calcium current (Ica L) and the effect of isoproterenol stimulation on Ica L were measured using whole-cell patch method. Evaluation of the expression of calcium channel subunits was carried out by RT-PCR and Western blot. Results The results indicate that mean peak Ica L densities (pA/pF) at +10 mV was reduced in postinfarction myocytes (5.33±0.45, n=25) compared to sham myocytes (6.52±0.21, n=20). Treatment of myocardial infarction rabbits with carvedilol could restore it partially (5.91±0.39, n=20, P<0.05). However, steady-state activation parameters were similar in three groups. With stimulation by isoproterenol (1 μmol/L) Ica L increased in all three groups, but the increase was smaller in postinfarction myocytes. mRNA levels of calcium channel subunit CaA1 gene was decreased but CaB2a, CaB2b and CaB3 mRNA levels did not change after MI. Corresponding change in CaA1 protein was also observed. Conclusions The results demonstrate that carvedilol restores Ica L density and reverse the downregulation of CaA1 postinfarction.

  18. Antagonists of the kappa opioid receptor.

    Science.gov (United States)

    Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward

    2014-05-01

    The research community has increasingly focused on the development of OPRK antagonists as pharmacotherapies for the treatment of depression, anxiety, addictive disorders and other psychiatric conditions produced or exacerbated by stress. Short-acting OPRK antagonists have been recently developed as a potential improvement over long-acting prototypic ligands including nor-BNI and JDTic. Remarkably the short-acting LY2456302 is undergoing phase II clinical trials for the augmentation of the antidepressant therapy in treatment-resistant depression. This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists.

  19. Antagonistic formation motion of cooperative agents

    Institute of Scientific and Technical Information of China (English)

    卢婉婷; 代明香; 薛方正

    2015-01-01

    This paper investigates a new formation motion problem of a class of first-order multi-agent systems with antagonis-tic interactions. A distributed formation control algorithm is proposed for each agent to realize the antagonistic formation motion. A sufficient condition is derived to ensure that all agents make an antagonistic formation motion in a distributed manner. It is shown that all agents can be spontaneously divided into several groups, and agents in the same group collab-orate while agents in different groups compete. Finally, a numerical simulation is included to demonstrate our theoretical results.

  20. Adrenergic regulation of cellular plasticity in brown, beige/brite and white adipose tissues.

    Science.gov (United States)

    Ramseyer, Vanesa D; Granneman, James G

    2016-01-01

    The discovery of brown adipose tissue in adult humans along with the recognition of adipocyte heterogeneity and plasticity of white fat depots has renewed the interest in targeting adipose tissue for therapeutic benefit. Adrenergic activation is a well-established means of recruiting catabolic adipocyte phenotypes in brown and white adipose tissues. In this article, we review mechanisms of brown adipocyte recruitment by the sympathetic nervous system and by direct β-adrenergic receptor activation. We highlight the distinct modes of brown adipocyte recruitment in brown, beige/brite, and white adipose tissues, UCP1-independent thermogenesis, and potential non-thermogenic, metabolically beneficial effects of brown adipocytes.

  1. Beta-adrenergic stimulation of phagocytosis in the unicellular eukaryote Paramecium aurelia.

    Science.gov (United States)

    Wyroba, E

    1989-08-01

    Bete-adrenergic agonists isoproterenol and norepinephrine enhanced phagocytosis in Paramecium. Stimulation was stereospecific, dose-dependent and inhibited by the beta-agonists propranolol and alprenolol. Phorbol ester and forskolin potentiated the stimulatory effect of catecholamines on Paramecium phagocytosis. The dansyl analogue of propranolol (DAPN) was used for fluorescent visualization of the beta-adrenergic receptor sites in Paramecium which have been found to be localized at the cell membrane and within the membrane of the nascent digestive vacuoles. The appearance of the characteristic fluorescent pattern has been blocked by 1-propranolol.

  2. Inhaled adrenergics and anticholinergics in obstructive lung disease: do they enhance mucociliary clearance?

    Science.gov (United States)

    Restrepo, Ruben D

    2007-09-01

    Pulmonary mucociliary clearance is an essential defense mechanism against bacteria and particulate matter. Mucociliary dysfunction is an important feature of obstructive lung diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, and bronchiectasis. This dysfunction in airway clearance is associated with accelerated loss of lung function in patients with obstructive lung disease. The involvement of the cholinergic and adrenergic neural pathways in the pathophysiology of mucus hypersecretion suggests the potential therapeutic role of bronchodilators as mucoactive agents. Although anticholinergics and adrenergic agonist bronchodilators have been routinely used, alone or in combination, to enhance mucociliary clearance in patients with obstructive lung disease, the existing evidence does not consistently show clinical effectiveness.

  3. Inflammation and exercise: Inhibition of monocytic intracellular TNF production by acute exercise via β2-adrenergic activation.

    Science.gov (United States)

    Dimitrov, Stoyan; Hulteng, Elaine; Hong, Suzi

    2017-03-01

    Regular exercise is shown to exert anti-inflammatory effects, yet the effects of acute exercise on cellular inflammatory responses and its mechanisms remain unclear. We tested the hypothesis that sympathoadrenergic activation during a single bout of exercise has a suppressive effect on monocytic cytokine production mediated by β2 adrenergic receptors (AR). We investigated the effects of 20-min moderate (65-70% VO2 peak) exercise-induced catecholamine production on LPS-stimulated TNF production by monocytes in 47 healthy volunteers and determined AR subtypes involved. We also examined the effects of β-agonist isoproterenol and endogenous β- and α-agonists epinephrine and norepinephrine, and receptor-subtype-specific β- and α-antagonists on TNF production in a series of in vitro investigations. LPS-stimulated TNF production by peripheral blood monocytes was determined intracellularly by flow cytometry, using an intracellular protein transport inhibitor. Percent TNF-producing monocytes and per-cell TNF production with and without LPS was suppressed by exercise with moderate to large effects, which was reversed by a β2-AR antagonist in spite that plasma TNF levels did not change. This inhibitory response in TNF production by exercise was mirrored by β-AR agonists in an agonist-specific and dose-dependent manner in vitro: similar isoproterenol (EC50=2.1-4.7×10(-10)M) and epinephrine (EC50=4.4-10×10(-10)M) potency and higher norepinephrine concentrations (EC50=2.6-4.3×10(-8)M) needed for the effects. Importantly, epinephrine levels observed during acute exercise in vivo significantly inhibited TNF production in vitro. The inhibitory effect of the AR agonists was abolished by β2-, but not by β1- or α-AR blockers. We conclude that the downregulation of monocytic TNF production during acute exercise is mediated by elevated epinephrine levels through β2-ARs. Decreased inflammatory responses during acute exercise may protect against chronic conditions with low

  4. Changes in postnatal norepinephrine alter alpha-2 adrenergic receptor development.

    Science.gov (United States)

    Sanders, J D; Happe, H K; Bylund, D B; Murrin, L C

    2011-09-29

    Alpha-2 adrenergic receptors (A2AR) regulate multiple brain functions and are enriched in developing brain. Studies demonstrate norepinephrine (NE) plays a role in regulating brain maturation, suggesting it is important in A2AR development. To investigate this we employed models of NE absence and excess during brain development. For decreases in NE we used N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4), a specific noradrenergic neurotoxin. Increased noradrenergic terminal density was produced by methylazoxymethanol acetate (MAM) treatment. A2AR density was assayed with [(3)H]RX821002 autoradiography. DSP4 lesions on postnatal day (PND) 3 produce A2AR decreases in many regions by PND 5. A2AR recover to control levels by PND 15 and 25 and there is no further change in total receptor density. We also assayed A2AR in brains lesioned with DSP4 on PND 13, 23, 33 and 43 and harvested 22 days post-lesion. A2AR levels remain similar to control at each of these time points. We examined A2AR functionality and high affinity state with epinephrine-stimulated [(35)S]GTPγS and [(125)I]p-iodoclonidine autoradiography, respectively. On PND 25, control animals and animals lesioned with DSP4 on PND 3 have similar levels of [(35)S]GTPγS incorporation and no change in high affinity state. This is in contrast to increases in A2AR high affinity state produced by DSP4 lesions of mature brain. We next investigated A2AR response to increases in norepinephrine levels produced by MAM. In contrast to DSP4 lesions, increasing NE results in a large increase in A2AR. Animals treated with MAM on gestational day 14 had cortical [(3)H]RX821002 binding 100-200% greater than controls on PND 25, 35, 45, 55 and 65. These data indicate that NE regulation of A2AR differs in developing and mature brain and support the idea that NE regulates A2AR development and this has long term effects on A2AR function.

  5. Benzodiazepine receptor antagonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy....

  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...

  7. β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus.

    Science.gov (United States)

    O'Dell, Thomas J; Connor, Steven A; Guglietta, Ryan; Nguyen, Peter V

    2015-09-01

    Encoding new information in the brain requires changes in synaptic strength. Neuromodulatory transmitters can facilitate synaptic plasticity by modifying the actions and expression of specific signaling cascades, transmitter receptors and their associated signaling complexes, genes, and effector proteins. One critical neuromodulator in the mammalian brain is norepinephrine (NE), which regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express β-adrenergic receptors, which are known to play important roles in gating the induction of long-lasting forms of synaptic potentiation. These forms of long-term potentiation (LTP) are believed to importantly contribute to long-term storage of spatial and contextual memories in the brain. In this review, we highlight the contributions of noradrenergic signaling in general and β-adrenergic receptors in particular, toward modulating hippocampal LTP. We focus on the roles of NE and β-adrenergic receptors in altering the efficacies of specific signaling molecules such as NMDA and AMPA receptors, protein phosphatases, and translation initiation factors. Also, the roles of β-adrenergic receptors in regulating synaptic "tagging" and "capture" of LTP within synaptic networks of the hippocampus are reviewed. Understanding the molecular and cellular bases of noradrenergic signaling will enrich our grasp of how the brain makes new, enduring memories, and may shed light on credible strategies for improving mental health through treatment of specific disorders linked to perturbed memory processing and dysfunctional noradrenergic synaptic transmission.

  8. Preserved alpha-adrenergic tone in the leg vascular bed of spinal cord-injured individuals.

    NARCIS (Netherlands)

    Kooijman, H.M.; Rongen, G.A.P.J.M.; Smits, P.; Hopman, M.T.E.

    2003-01-01

    BACKGROUND: Supraspinal sympathetic control of leg vascular tone is lost in spinal cord-injured individuals, but this does not result in a reduced leg vascular tone: Leg vascular resistance is even increased. The aim of this study was to assess the alpha-adrenergic contribution to the increased vasc

  9. The role of the alpha-adrenergic receptor in the leg vasoconstrictor response to orthostatic stress.

    NARCIS (Netherlands)

    Kooijman, M.; Rongen, G.A.P.J.M.; Smits, P.; Kuppevelt, H.J.M. van; Hopman, M.T.E.

    2009-01-01

    AIM: The prompt increase in peripheral vascular resistance, mediated by sympathetic alpha-adrenergic stimulation, is believed to be the key event in blood pressure control during postural stress. However, despite the absence of central sympathetic control of the leg vasculature, postural leg vasocon

  10. β3-Adrenergic receptor gene polymorphism and type 2 diabetes in a Caucasian population

    NARCIS (Netherlands)

    Oeveren van-Dybicz, A.M.; Vonkeman, H.E.; Bon, M.A.M.; Bergh, van den F.A.J.T.M.; Vermes, I.

    2008-01-01

    Aim: The β3-adrenergic receptor (β3-AR) is suspected to play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. A mutation in the β3-AR gene (Trp64Arg) has been associated with the capacity of weight gain and with early onset of noninsulin dependent diabetes me

  11. 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.

  12. Tailoring therapy for heart failure: the pharmacogenomics of adrenergic receptor signaling

    Directory of Open Access Journals (Sweden)

    Femminella GD

    2014-09-01

    Full Text Available Grazia Daniela Femminella,1 Vincenzo Barrese,2,3 Nicola Ferrara,1,4 Giuseppe Rengo4 1Department of Translational Medical Sciences, Federico II University, Naples, Italy; 2Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy; 3Division of Biomedical Sciences, St George’s University of London, London, UK; 4”Salvatore Maugeri” Foundation – IRCCS – Scientific Institute of Telese Terme, Telese Terme, Benevento, Italy Abstract: Heart failure is one of the leading causes of mortality in Western countries, and β-blockers are a cornerstone of its treatment. However, the response to these drugs is variable among individuals, which might be explained, at least in part, by genetic differences. Pharmacogenomics is the study of genetic contributions to drug response variability in order to provide evidence for a tailored therapy in an individual patient. Several studies have investigated the pharmacogenomics of the adrenergic receptor system and its role in the context of the use of β-blockers in treating heart failure. In this review, we will focus on the most significant polymorphisms described in the literature involving adrenergic receptors and adrenergic receptor-related proteins, as well as genetic variations influencing β-blocker metabolism. Keywords: adrenergic system, polymorphisms, β-blockers, functional recovery

  13. 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 exerci...

  14. Vasoconstriction induced by ouabain in the canine coronary artery: contribution of adrenergic and nonadrenergic responses.

    Science.gov (United States)

    Cooke, J P; Shepherd, J T; Vanhoutte, P M

    1988-07-01

    Ouabain, when applied to rings of the left circumflex coronary artery of the dog (which contains both alpha 1-adrenoceptors leading to contraction and beta 1-adrenoceptors leading to relaxation) caused an initial contraction which peaked within 15 minutes and a later secondary increase in tension which peaked within 60 minutes. These contractions were prevented by Ca2+ removal or by verapamil. Adrenergic denervation with 6-hydroxydopamine did not affect the initial contraction. Thus it is due to a nonadrenergic effect of the glycoside. Since the secondary increase in tension was prevented by adrenergic denervation and prazosin, it is likely to be due to norepinephrine released from adrenergic nerves acting on alpha-adrenoceptors. This interpretation was confirmed by the finding that ouabain, after a latent period of about 35 minutes, augmented the output of 3H-norepinephrine from helical strips of the artery previously incubated with tritiated transmitter. In rings contracted with prostaglandin F2 alpha, ouabain reduced beta-adrenergic relaxations caused by isoproterenol or exogenous norepinephrine, but not those caused by sodium nitroprusside. Thus, in this artery, ouabain depresses the responses of the beta-adrenoceptors to the norepinephrine which it releases, thereby permitting the neurotransmitter to cause contraction by activating postjunctional alpha 1-adrenoceptors.

  15. [Adrenergic innervation of the uterus of the rat in various phases of the estrous cycle].

    Science.gov (United States)

    Rakitskaia, V V; Proimina, F I; Chudinov, Iu V

    1986-07-01

    Adrenergic innervation of the rat uterus is connected chiefly with vessel innervation. The highest density of fibers and the highest intensity of specific fluorescence is shown in the stage of dioestrus, the least those--in oestrus. These indices correlated with the estradiol and progesterone level in the plasma.

  16. Methylphenidate amplifies long-term potentiation in rat hippocampus CA1 area involving the insertion of AMPA receptors by activation of β-adrenergic and D1/D5 receptors.

    Science.gov (United States)

    Rozas, C; Carvallo, C; Contreras, D; Carreño, M; Ugarte, G; Delgado, R; Zeise, M L; Morales, B

    2015-12-01

    Methylphenidate (MPH, Ritalin©) is widely used in the treatment of Attention Deficit Hyperactivity Disorder and recently as a drug of abuse. Although the effect of MPH has been studied in brain regions such as striatum and prefrontal cortex (PFC), the hippocampus has received relatively little attention. It is known that MPH increases the TBS-dependent Long Term Potentiation (LTP) in the CA1 area. However, the cellular and molecular mechanisms involved in this process are still unknown. Using field potential recordings and western blot analysis in rat hippocampal slices of young rats, we found that acute application of MPH enhances LTP in CA3-CA1 synapses in a dose-dependent manner with an EC50 of 73.44±6.32 nM. Using specific antagonists and paired-pulse facilitation protocols, we observed that the MPH-dependent increase of LTP involves not only β-adrenergic receptors activation but also post-synaptic D1/D5 dopamine receptors. The inhibition of PKA with PKI, suppressed the facilitation of LTP induced by MPH consistent with an involvement of the adenyl cyclase-cAMP-PKA dependent cascade downstream of the activation of D1/D5 receptors. In addition, samples of CA1 areas taken from slices potentiated with MPH presented an increase in the phosphorylation of the Ser845 residue of the GluA1 subunit of AMPA receptors compared to control slices. This effect was reverted by SCH23390, antagonist of D1/D5 receptors, and PKI. Moreover, we found an increase of surface-associated functional AMPA receptors. We propose that MPH increases TBS-dependent LTP in CA3-CA1 synapses through a polysynaptic mechanism involving activation of β-adrenergic and D1/D5 dopaminergic receptors and promoting the trafficking and insertion of functional AMPA receptors to the plasma membrane.

  17. Alpha-adrenergic receptor blockade by phentolamine increases the efficacy of vasodilators in penile corpus cavernosum.

    Science.gov (United States)

    Kim, N N; Goldstein, I; Moreland, R B; Traish, A M

    2000-03-01

    Penile trabecular smooth muscle tone, a major determinant of erectile function, is highly regulated by numerous inter- and intracellular pathways. The interaction between pathways mediating contraction and relaxation has not been studied in detail. To this end, we investigated the functional effects of alpha adrenergic receptor blockade with phentolamine and its interaction with vasodilators (sildenafil, vasoactive intestinal polypeptide (VIP) and PGE1) that elevate cyclic nucleotides on penile cavernosal smooth muscle contractility. In organ bath preparations of cavernosal tissue strips contracted with phenylephrine, phentolamine significantly enhanced relaxation induced by sildenafil, VIP and PGE1. Sildenafil, VIP or PGE1 also significantly enhanced relaxation induced by phentolamine in cavernosal tissue strips contracted with phenylephrine. To study the effects of alpha adrenergic receptor blockade and modification of cyclic nucleotide metabolism during active neurogenic input, cavernosal tissue strips in organ bath preparations were contracted with the non-adrenergic agonist endothelin-1 and subjected to electrical field stimulation (EFS) in the absence or presence of phentolamine and/or sildenafil. EFS (5-40Hz) typically caused biphasic relaxation and contraction responses. Phentolamine alone enhanced relaxation and reduced or prevented contraction to EFS. Sildenafil enhanced relaxation to EFS at lower frequencies (phentolamine and sildenafil enhanced EFS-induced relaxation at all frequencies tested. EFS, in the presence of 10 nM phentolamine and 30 nM sildenafil, produced enhanced relaxation responses which were quantitatively similar to those obtained in the presence of 50 nM sildenafil alone. Thus, blockade of alpha-adrenergic receptors with phentolamine increases the efficacy of cyclic nucleotide-dependent vasodilators. Furthermore, phentolamine potentiates relaxation and attenuates contraction in response to endogenous neurotransmitters which are released

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

    Science.gov (United States)

    Jensen, Cathy Joanna; Demol, Frauke; Bauwens, Romy; Kooijman, Ron; Massie, Ann; Villers, Agnès; 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 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. PMID:27776147

  19. Beta-adrenergic stimulation reverses the IKr–IKs dominant pattern during cardiac action potential

    Science.gov (United States)

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T.; Chen-Izu, Ye

    2014-01-01

    β-adrenergic stimulation differentially modulates different K+ channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of IKs, IKr, and IK1 current in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K+ current to the total repolarization reserve. In this study we used an innovative AP-clamp Sequential Dissection technique to directly record the dynamic –IKs, IKr, IK1– currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of IKs, IKr, IK1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca2+ homeostasis. We found that isoproterenol treatment significantly enhanced IKs, moderately increased IK1, but slightly decreased IKr in a dose-dependent manner. The dominance pattern of the K+ currents was IKr>IK1>IKs at the control condition, but reversed to IKradrenergic stimulation. We systematically determined the changes in the relative contribution of IKs, IKr, IK1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K+ currents in a dose-dependent manner. This Knowledge is important for designing anti-arrhythmic drug strategies to treat the hearts exposed to various sympathetic tones. PMID:24535581

  20. Catechol-O-methlytransferase inhibition alters pain and anxiety-related volitional behaviors through activation of β-adrenergic receptors in the rat

    Science.gov (United States)

    Kline, R. H.; Exposto, F. G.; O’Buckley, S. C.; Westlund, K. N.; Nackley, A. G.

    2015-01-01

    Reduced catechol-O-methyltransferase (COMT) activity resulting from genetic variation or pharmacological depletion results in enhanced pain perception in humans and nociceptive behaviors in animals. Using phasic mechanical and thermal reflex tests (e.g. von Frey, Hargreaves), recent studies show that acute COMT-dependent pain in rats is mediated by β-adrenergic receptors (βARs). In order to more closely mimic the characteristics of human chronic pain conditions associated with prolonged reductions in COMT, the present study sought to determine volitional pain-related and anxiety-like behavioral responses following sustained as well as acute COMT inhibition using an operant 10–45°C thermal place preference task and a light/dark preference test. In addition, we sought to evaluate the effects of sustained COMT inhibition on generalized body pain by measuring tactile sensory thresholds of the abdominal region. Results demonstrated that acute and sustained administration of the COMT inhibitor OR486 increased pain behavior in response to thermal heat. Further, sustained administration of OR486 increased anxiety behavior in response to bright light, as well as abdominal mechanosensation. Finally, all pain-related behaviors were blocked by the non-selective βAR antagonist propranolol. Collectively, these findings provide the first evidence that stimulation of ARs following acute or chronic COMT inhibition drives cognitive-affective behaviors associated with heightened pain that affects multiple body sites. PMID:25659347

  1. Catechol-O-methyltransferase inhibition alters pain and anxiety-related volitional behaviors through activation of β-adrenergic receptors in the rat.

    Science.gov (United States)

    Kline, R H; Exposto, F G; O'Buckley, S C; Westlund, K N; Nackley, A G

    2015-04-02

    Reduced catechol-O-methyltransferase (COMT) activity resulting from genetic variation or pharmacological depletion results in enhanced pain perception in humans and nociceptive behaviors in animals. Using phasic mechanical and thermal reflex tests (e.g. von Frey, Hargreaves), recent studies show that acute COMT-dependent pain in rats is mediated by β-adrenergic receptors (βARs). In order to more closely mimic the characteristics of human chronic pain conditions associated with prolonged reductions in COMT, the present study sought to determine volitional pain-related and anxiety-like behavioral responses following sustained as well as acute COMT inhibition using an operant 10-45°C thermal place preference task and a light/dark preference test. In addition, we sought to evaluate the effects of sustained COMT inhibition on generalized body pain by measuring tactile sensory thresholds of the abdominal region. Results demonstrated that acute and sustained administration of the COMT inhibitor OR486 increased pain behavior in response to thermal heat. Further, sustained administration of OR486 increased anxiety behavior in response to bright light, as well as abdominal mechanosensation. Finally, all pain-related behaviors were blocked by the non-selective βAR antagonist propranolol. Collectively, these findings provide the first evidence that stimulation of βARs following acute or chronic COMT inhibition drives cognitive-affective behaviors associated with heightened pain that affects multiple body sites.

  2. In vitro and in vivo impairment of alpha2-adrenergic receptor-dependent antilipolysis by fatty acids in human adipose tissue.

    Science.gov (United States)

    Gesta, S; Hejnova, J; Berlan, M; Daviaud, D; Crampes, F; Stich, V; Valet, P; Saulnier-Blache, J S

    2001-12-01

    The aim of the present study was to study the influence of fatty acids on the adrenergic control of lipolysis both in vitro and in vivo. Human subcutaneous adipose tissue explants were cultured for 48 h in the presence of 100 microM bromopalmitate (BrPal), and lipolysis was measured in isolated adipocytes. In control conditions, beta-AR-dependent activation of lipolysis by epinephrine was almost undetectable, and could be fully restored by pharmacological blockade of alpha2-AR-dependent antilipolysis. After BrPal treatment, epinephrine became fully lipolytic and was no longer influenced by alpha2-AR-blockade. Radioligand binding analysis revealed that BrPal treatment led to a significant reduction in the coupling of alpha2-AR to G proteins. In parallel, a chronic and significant increase in plasma fatty acids resulting from a 4-day high-fat diet (HFD) was accompanied by an impairment of the amplifying effect of the alpha2-AR antagonist phentolamine on exercise-induced lipolysis (measured in the subcutaneous adipose tissue with the use of a microdialysis probe) normally observed after a low-fat diet. In conclusion, in vitro and in vivo studies showed that fatty acids impair alpha2-AR-dependent antilipolysis.

  3. Auxin-Oxylipin Crosstalk: Relationship of Antagonists

    Institute of Scientific and Technical Information of China (English)

    Maik Hoffmann; Mathias Hentrich; Stephan Pollmann

    2011-01-01

    Phytohormones regulate a wide array of developmental processes throughout the life cycle of plants. Herein, the various plant hormones may interact additively, synergistically, or antagonistically. By their cooperation they create a delicate regulatory network whose net output largely depends on the action of specific phytohormone combinations rather than on the independent activities of separate hormones. While most classical studies of plant hormonal control have focused mainly on the action of single hormones or on the synergistic interaction of hormones in regulating various developmental processes, recent work is beginning to shed light on the crosstalk of nominally antagonistic plant hormones, such as gibberellins and auxins with oxylipins or abscisic acid. In this review, we summarize our current understanding of how two of the first sight antagonistic plant hormones, i.e. auxins and oxylipins,interact in controlling plant responses and development.

  4. Effects of α-adrenoreceptor antagonists on apoptosis and proliferation of pancreatic cancer cells in vitro

    Institute of Scientific and Technical Information of China (English)

    Su-Gang Shen; Dong Zhang; Heng-Tong Hu; Jun-Hui Li; Zheng Wang; Qing-Yong Ma

    2008-01-01

    AIM: To discuss the expression of α-adrenoreceptors in pancreatic cancer cell lines PC-2 and PC-3 and the effects of α1- and α2-adrenoreceptor antagonists, yohimbine and urapidil hydrochloride, on the cell lines in vitro.METHODS: We cultured the human ductal pancreatic adenocarcinoma cell lines PC-2 and PC-3 and analyzed the mRNA expression of α1- and α2-adrenergic receptors by reverse transcription polymerase chain reaction (RT-PCR).The effects of yohimbine and urapidil hydrochloride on cell proliferation were assessed by 3-(4,5-dimethylthiasol-2-yl)2,4,-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected using the terminal deoxyribonucleoticlyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) assay and flow cytometry (FCM).RESULTS: PC-2 expressed rnRNA in α1- and α2-adrenoreceptors. MTT assays showed that urapidil hydrochloride had no effect on PC-3 cell lines. However,exposure to urapidil hydrochloride increased DNA synthesis in PC-2 cell lines as compared to the control group. PC-2 cell lines were sensitive to both drugs. The proliferation of the 2 cell lines was inhibited by yohimbine.Cell proliferation was inhibited by yohimbine via apoptosis induction.CONCLUSION: The expression of α1-and α2-adrenoreceptors is different in PC-2 and PC-3 cell lines,which might be indicative of their different functions. Theα2-adrenoceptor antagonist, yohimbine, can inhibit the proliferation of both cell lines and induce their apoptosis,suggesting that yohimbine can be used as an anticancer drug for apoptosis of PC-2 and PC-3 cells.

  5. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies.

    Science.gov (United States)

    Graudins, Andis; Lee, Hwee Min; Druda, Dino

    2016-03-01

    Management of cardiovascular instability resulting from calcium channel antagonist (CCB) or beta-adrenergic receptor antagonist (BB) poisoning follows similar principles. Significant myocardial depression, bradycardia and hypotension result in both cases. CCBs can also produce vasodilatory shock. Additionally, CCBs, such as verapamil and diltiazem, are commonly ingested in sustained-release formulations. This can also be the case for some BBs. Peak toxicity can be delayed by several hours. Provision of early gastrointestinal decontamination with activated charcoal and whole-bowel irrigation might mitigate this. Treatment of shock requires a multimodal approach to inotropic therapy that can be guided by echocardiographic or invasive haemodynamic assessment of myocardial function. High-dose insulin euglycaemia is commonly recommended as a first-line treatment in these poisonings, to improve myocardial contractility, and should be instituted early when myocardial dysfunction is suspected. Catecholamine infusions are complementary to this therapy for both inotropic and chronotropic support. Catecholamine vasopressors and vasopressin are used in the treatment of vasodilatory shock. Optimizing serum calcium concentration can confer some benefit to improving myocardial function and vascular tone after CCB poisoning. High-dose glucagon infusions have provided moderate chronotropic and inotropic benefits in BB poisoning. Phosphodiesterase inhibitors and levosimendan have positive inotropic effects but also produce peripheral vasodilation, which can limit blood pressure improvement. In cases of severe cardiogenic shock and/or cardiac arrest post-poisoning, extracorporeal cardiac assist devices have resulted in successful recovery. Other treatments used in refractory hypotension include intravenous lipid emulsion for lipophilic CCB and BB poisoning and methylene blue for refractory vasodilatory shock.

  6. Assessment of myocardial adrenergic innervation in patients with sick sinus syndrome: effect of asynchronous ventricular activation from ventricular apical stimulation

    OpenAIRE

    Marketou, M E; Simantirakis, E N; Prassopoulos, V K; Chrysostomakis, S I; Velidaki, A A; Karkavitsas, N S; Vardas, P.E.

    2002-01-01

    Objective: To investigate ventricular sympathetic innervation in patients with sick sinus syndrome and to detect regional deterioration of adrenergic innervation caused by asynchronous ventricular activation from right ventricular pacing.

  7. Docking-based virtual screening of potential human P2Y12 receptor antagonists

    Institute of Scientific and Technical Information of China (English)

    Hua Chen; Xianchi Dong; Minyun Zhou; Haiming Shi; Xinping Luo

    2011-01-01

    Platelet plays essential roles in hemostasis and its dysregulation can lead to arterial thrombosis. P2Y12 is an important platelet membrane adenosine diphosphate receptor,and its antagonists have been widely developed as anticoagulation agents. The current P2Y12 inhibitors available in clinical practice have not fully achieved saOsfactory antithrombotic effects, leaving room for further improvement To identify new chemical compounds as potential anticoagulation inhibitors, we constructed a three-dimensional structure model of human P2Y12 by homology modeling based on the recently reported G-protein coupled receptor Meleagris gallopavo βl adrenergic receptor. Virtual screening of the modeled P2Y12 against three subsets of small molecules from the ZINC database, namely lead-like, fragment-like, and drug-like, identified a number of compounds tbat might have high binding affinity to P2Y12.Detailed analyses of the top three compounds from each subset with the highest scores indicated that all of these compounds beard a hydrophobic bulk supplemented with a few polar atoms which bound at the ligand binding site via largely hydrophobic interactions with the receptor. This study not only provides a structure model of P2Y12 for rational design of anti-platelet inhibitors, but also identifies some potential chemicals for further development.

  8. cAMP-synthesis in a medullary thyroid carcinoma cell line: response to adrenergic agents and prostaglandines.

    Science.gov (United States)

    Mertens, P R; Goretzki, P E; Keck, E

    1999-01-01

    Calcitonin secretion by C-cells is mediated through intracellular 3'5'-cyclic adenosine monophosphate (cAMP) and calcium signaling. Calcitonin release stimulation tests may take advantage of both signaling cascades in screening for medullary thyroid carcinomas (MTC). To elucidate the regulation of the adenylyl cyclase system we have determined cAMP levels of a calcitonin-expressing MTC cell line (RG) after exposure to adrenergic agents and prostaglandines. In early passages (20-30) cAMP concentrations were significantly elevated in RG cells after exposure to beta-adrenergic agents and prostaglandines E1 and E2. In advanced passages (60-80) the beta-adrenergic response was no longer detectable and adrenergic receptors were uncoupled from the adenylyl cyclase complex; while the effect of prostaglandines E1 and E2 remained unaffected. Preincubation with dexamethasone, in a process requiring protein new synthesis, re-established the adrenergic response in later passages, indicating that RG cells dedifferentiated in culture over time. Our in vitro findings suggest that MTC cell dedifferentiation may be accompanied by adrenergic receptor-uncoupling from the adenylate cyclase system and that this process may be reversed by dexamethasone incubation.

  9. Altered beta-adrenergic receptor-stimulated cAMP formation in cultured skin fibroblasts from Alzheimer donors.

    Science.gov (United States)

    Huang, H M; Gibson, G E

    1993-07-15

    An alteration in signal transduction systems in Alzheimer's disease would likely be of pathophysiological significance, because these steps are critical to normal brain function. Since dynamic processes are difficult to study in autopsied brain, the current studies utilized cultured skin fibroblasts. The beta-adrenergic-stimulated increase in cAMP was reduced approximately 80% in fibroblasts from Alzheimer's disease compared with age-matched controls. The deficit in Alzheimer fibroblasts in response to various adrenergic agonists paralleled their beta-adrenergic potency, and enhancement of cAMP accumulation by a non-adrenergic agonist, such as prostaglandin E1, was similar in Alzheimer and control fibroblasts. Diminished adenylate cyclase activity did not underlie these abnormalities, since direct stimulation of adenylate cyclase by forskolin elevated cAMP production equally in Alzheimer and control fibroblasts. Cholera toxin equally stimulated cAMP formation in Alzheimer and control fibroblasts. Moreover, cholera toxin partially reduced isoproterenol-induced cAMP deficit in Alzheimer fibroblasts. Pertussis toxin, on the other hand, did not alter the Alzheimer deficits. The results suggest either that the coupling of the GTP-binding protein(s) to the beta-adrenergic receptor is abnormal or that the sensitivity of receptor is altered with Alzheimer's disease. Further, any hypothesis about Alzheimer's disease must explain why a reduced beta-adrenergic-stimulated cAMP formation persists in tissue culture.

  10. The Effects of Inhaled β-Adrenergic Agonists in Transient Tachypnea of the Newborn

    Directory of Open Access Journals (Sweden)

    Esengul Keleş MD

    2016-05-01

    Full Text Available Aim. To investigate the efficacy of an inhaled β-adrenergic agonists in transient tachypnea of the newborn (TTN. Method. We retrospectively analyzed a cohort of 51 term infants (Group 1 and 37 term infants (Group 2 monitored in the newborn intensive care unit diagnosed with TTN. Infants in Group 1 received humidified oxygen alone, and infants in Group 2 were administered the inhaled β-2 agonist plus humidified oxygen. Results. TTN clinical respiratory assessment, respiratory rate, oxygen saturation values, need for supplemental oxygen therapy, blood gas PH, PO2, and duration of hospitalization were significantly improved in infants in Group 2 as compared with infants in Group 1 (P .05. Conclusion. Inhaled β-adrenergic agonist added to humidified oxygen was found to improve clinical and laboratory parameters. We believe that further studies should be conducted with larger groups to demonstrate the efficacy of β-2 agonists in TTN patients.

  11. 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

    Albumin excretion marks early glomerular injury in hypertension. This study investigated heritability of albumin excretion in twin pairs and its genetic determination by adrenergic pathway polymorphism. Genetic associations used single nucleotide polymorphisms at adrenergic pathway loci spanning...... 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...

  12. Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth

    Science.gov (United States)

    Armaiz-Pena, Guillermo N.; Gonzalez-Villasana, Vianey; Nagaraja, Archana S.; Rodriguez-Aguayo, Cristian; Sadaoui, Nouara C.; Stone, Rebecca L.; Matsuo, Koji; Dalton, Heather J.; Previs, Rebecca A.; Jennings, Nicholas B.; Dorniak, Piotr; Hansen, Jean M.; Arevalo, Jesusa M.G.; Cole, Steve W.; Lutgendorf, Susan K.; Sood, Anil K.; Lopez-Berestein, Gabriel

    2015-01-01

    Increased adrenergic signaling facilitates tumor progression, but the underlying mechanisms remain poorly understood. We examined factors responsible for stress-mediated effects on monocyte/macrophage recruitment into the tumor microenvironment, and the resultant effects on tumor growth. In vitro, MCP1 was significantly increased after catecholamine exposure, which was mediated by cAMP and PKA. Tumor samples from mice subjected to daily restraint stress had elevated MCP1 gene and protein levels, increased CD14+ cells, and increased infiltration of CD68+ cells. hMCP1 siRNA-DOPC nanoparticles significantly abrogated daily restraint stress-induced tumor growth and inhibited infiltration of CD68+ and F4/80+ cells. In ovarian cancer patients, elevated peripheral blood monocytes and tumoral macrophages were associated with worse overall survival. Collectively, we demonstrate that increased adrenergic signaling is associated with macrophage infiltration and mediated by tumor cell-derived MCP1 production. PMID:25738355

  13. Expression of hippocampal adrenergic receptor mRNA in a rat model of depression

    Institute of Scientific and Technical Information of China (English)

    Jianbin Zhang; Lingling Wang; Xinjun Wang; Jingfeng Jiang; Xiaoren Xiang; Tianjun Wang

    2011-01-01

    Adrenergic receptor dysfunction is suggested as a potential cause of hippocampal vulnerability to stress-related pathology. We examined mRNA expression of adrenergic receptor (AR) subtypes α1-AR, α2-AR, and β1-AR in hippocampal subregions (CA1, CA3, dentate gyrus) using in situ hybridization in a depression model induced by chronic unpredictable mild stress and social isolation. α1-AR mRNA expression was significantly increased in the CA3 and dentate gyrus, β1-AR mRNA was significantly increased in the CA1, and α2-AR mRNA remained unchanged in all regions of depression rats compared with controls. Thus, different AR subtypes exhibit a differing pattern of mRNA expression in various hippocampal subregions following depression.

  14. β2 Adrenergic receptor on T lymphocytes and its clinical implications

    Institute of Scientific and Technical Information of China (English)

    Xuelai Fan; Yuedan Wang

    2009-01-01

    Sustained complex cross-talk between the immune system and the nervous system plays a vital role in retaining homeostasis in a healthy individual.One of the central regulatory mechanisms involved is the existence and functions of β2-adrenergic receptors (β2AR) on T lymphocytes.This article reviews research progress made recently,including the expression of adrenergic receptors on Tlymphocytes,the structure and intracellular pathways of β2AR,the activation of I32AR by either endogenous or exogenous agonists,and the effect of β2AR stimulation on T cells which alters T cell proliferation,differentiation,cytokine production and T-helper-mediated antibody production.Furthermore,we discuss the roles of β2AR played in the pathogenesis and treatment of autoimmune diseases.

  15. Genetic factors influencing pyrimidine-antagonist chemotherapy

    NARCIS (Netherlands)

    Maring, JG; Groen, HJM; Wachters, FM; Uges, DRA; de Vries, EGE

    2005-01-01

    Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of

  16. Why are mineralocorticoid receptor antagonists cardioprotective?

    NARCIS (Netherlands)

    W. Chai (Wenxia); A.H.J. Danser (Jan)

    2006-01-01

    textabstractTwo clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effe

  17. Beta2-adrenergic signaling affects the phenotype of human cardiac progenitor cells through EMT modulation.

    Science.gov (United States)

    Pagano, Francesca; Angelini, Francesco; Siciliano, Camilla; Tasciotti, Julia; Mangino, Giorgio; De Falco, Elena; Carnevale, Roberto; Sciarretta, Sebastiano; Frati, Giacomo; Chimenti, Isotta

    2017-01-15

    Human cardiac progenitor cells (CPCs) offer great promises to cardiac cell therapy for heart failure. Many in vivo studies have shown their therapeutic benefits, paving the way for clinical translation. The 3D model of cardiospheres (CSs) represents a unique niche-like in vitro microenvironment, which includes CPCs and supporting cells. CSs have been shown to form through a process mediated by epithelial-to-mesenchymal transition (EMT). β2-Adrenergic signaling significantly affects stem/progenitor cells activation and mobilization in multiple tissues, and crosstalk between β2-adrenergic signaling and EMT processes has been reported. In the present study, we aimed at investigating the biological response of CSs to β2-adrenergic stimuli, focusing on EMT modulation in the 3D culture system of CSs. We treated human CSs and CS-derived cells (CDCs) with the β2-blocker butoxamine (BUT), using either untreated or β2 agonist (clenbuterol) treated CDCs as control. BUT-treated CS-forming cells displayed increased migration capacity and a significant increase in their CS-forming ability, consistently associated with increased expression of EMT-related genes, such as Snai1. Moreover, long-term BUT-treated CDCs contained a lower percentage of CD90+ cells, and this feature has been previously correlated with higher cardiogenic and therapeutic potential of the CDCs population. In addition, long-term BUT-treated CDCs had an increased ratio of collagen-III/collagen-I gene expression levels, and showed decreased release of inflammatory cytokines, overall supporting a less fibrosis-prone phenotype. In conclusion, β2 adrenergic receptor block positively affected the stemness vs commitment balance within CSs through the modulation of type1-EMT (so called "developmental"). These results further highlight type-1 EMT to be a key process affecting the features of resident cardiac progenitor cells, and mediating their response to the microenvironment.

  18. 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.

  19. Adrenergic signaling elements in the bladder wall of the adult rat.

    Science.gov (United States)

    Persyn, Sara; Eastham, Jane; De Wachter, Stefan; Gillespie, James

    2016-12-01

    A growing body of work is describing the absence of a significant sympathetic innervation of the detrusor implying little sympathetic regulation of bladder contractility. However, low doses of adrenergic agonists are capable of relaxing the bladder smooth muscle. If these effects underpin a physiological response then the cellular nature and operation of this system are currently unknown. The present immunohistochemistry study was done to explore the existence of alternative adrenergic signaling elements in the rat bladder wall. Using antibodies to tyrosine hydroxylase (TH) and vesicular mono-amine transporter (vmat), few adrenergic nerves were found in the detrusor although TH immunoreactive (IR) nerves were apparent in the bladder neck. TH-IR and vmat-IR nerves were however abundant surrounding blood vessels. A population of vmat-IR cells was found within the network of interstitial cells that surround the detrusor muscle bundles. These vmat-IR cells were not or only weakly TH-IR. This suggests that these interstitial cells have the capacity to store and release catecholamines that may involve noradrenaline. Cells expressing the β1-adrenoceptor (β1AR-IR) were also detected within the interstitial cell network. Double staining with antibodies to β1AR and vmat suggests that the majority of vmat-IR interstitial cells show β1AR-IR indicative of an autocrine signaling system. In conclusion, a population of interstitial cells has the machinery to store, release and respond to catecholamines. Thus, there might exist a non-neuronal β-adrenergic system operating in the bladder wall possibly linked to one component of motor activity, micro-contractions, a system that may be involved in mechanisms underpinning bladder sensation.

  20. β2 adrenergic agonists in acute lung injury? The heart of the matter

    OpenAIRE

    Lee, Jae W

    2009-01-01

    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of β2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to in...

  1. [The adrenergic innervation of the normal rat uterus and during pregnancy].

    Science.gov (United States)

    Rakitskaia, V V; Chudinov, Iu V; Shaliapina, V G

    1990-09-01

    Histochemical analysis revealed that, normally, the main amount of adrenergic fibers in the rat uterus is connected with vascular innervation. The amount of neural elements projecting to the muscle cells in insignificant. In pregnancy, the amount of fibers with the specific fluorescence decreases and they completely disappear from the myometrium in parturient rats. Biochemical analysis corroborated the finding that the noradrenaline level is considerably decreased at the time in sympathetic neurons innervating the uterus thus leading to a physiological "desympathization" of the organ.

  2. Minimum Alveolar Concentration for Blunting Adrenergic Responses (MAC-BAR) of Sevoflurane in Dogs

    OpenAIRE

    YAMASHITA, Kazuto; FURUKAWA, Erika; ITAMI, Takaharu; ISHIZUKA, Tomohito; TAMURA, Jun; MIYOSHI, Kenjirou

    2012-01-01

    It is well known that heart rate or arterial blood pressure may increase in response to surgical stimulation despite the absence of a purposeful movement. However, there is limited information regarding anesthetic requirement for blunting adrenergic response in dogs. This study was designed to compare the minimum alveolar concentrations of sevoflurane required to prevent autonomic response (MAC-BAR) and purposeful movement (MAC) in dogs. Sevoflurane MAC-BAR and MAC were determined in 5 beagle...

  3. 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.

  4. Alpha adrenergic modulation of the Na/sup +/ pump of canine vascular smooth muscle

    Energy Technology Data Exchange (ETDEWEB)

    Navran, S.S.; Adair, S.E.; Allen, J.C.; Seidel, C.L.

    1986-03-01

    Some vasoactive agents, eg. beta adrenergic agonists and forskolin, stimulate the Na/sup 7/ pump by a cAMP- dependent mechanism. The authors have now demonstrated that phenylephrine (PE) stimulates the Na/sup 7/ pump in intact blood vessels as quantitated by an increased ouabain-sensitive /sup 86/Rb uptake. The stimulation is dose-dependent (ED/sub 50/, 3 x 10/sup -6/M) and blocked by phentolamine (I/sub 50/, 10/sup -7/M), prazosin (I/sub 50/, 10/sup -8/M) yohimbine (I/sub 50/, 10/sup -6/M) or elevated intracellular Na/sup +/. These data suggest that the Na/sup +/ pump stimulation is mediated through alpha/sub 1/ receptors which produce an influx of extracellular Na/sup +/. In vascular smooth muscle cell cultures PE stimulates the Na/sup +/ pump, but only when cells have been deprived of fetal calf serum (FCS). Since FCS is known to stimulate Na/sup +/influx, in the continuous presence of FCS, these cells may already be Na/sup +/-loaded and therefore refractory to further stimulation by alpha-adrenergic agents. Unlike those vasorelaxants whose mechanism involves stimulation of the Na/sup +/ pump, alpha adrenergic agents are vasoconstrictors and therefore the role of Na/sup +/ pump stimulation in this case may be as a mechanism of feedback inhibition of contractility.

  5. Brain beta-adrenergic receptor binding in rats with obesity induced by a beef tallow diet.

    Science.gov (United States)

    Matsuo, T; Suzuki, M

    1997-01-01

    We have previously reported that compared with safflower oil diet, feeding a beef tallow diet leads to a greater accumulation of body fat by reducing sympathetic activities. The present study examined the effects of dietary fats consisting of different fatty acids on alpha1- and beta-adrenergic receptor binding in the hypothalamus and cerebral cortex. Male Sprague-Dawley rats were meal-fed isoenergetic diets based on safflower oil (rich in n-6 polyunsaturated fatty acids) or beef tallow (rich in saturated fatty acids) for 8 weeks. Binding affinities of the beta-adrenergic receptor in the hypothalamus and cortex were significantly lower in the beef tallow diet group, but those of the alpha1-receptor did not differ between the two groups. The polyunsaturated to saturated fatty acid (P/S) ratio and fluidities of plasma membranes in the hypothalamus and cortex were lower in the beef tallow diet group than in the safflower oil diet group. These results suggest that the beef tallow diet decreases membrane fluidity by altering the fatty acid composition of plasma membranes in the hypothalamus and cerebral cortex of rat. Consequently, beta-adrenergic receptor binding affinities in the brain were lower in rats fed the beef tallow diet than in rats fed the safflower oil diet. We recognized that there is possible link between the membrane fluidity and the changes in affinity of beta-adrenoceptors in rat brain.

  6. Adrenergic mechanism responsible for pathological alteration in gastric mucosal blood flow in rats with ulcer bleeding

    Science.gov (United States)

    Semyachkina-Glushkovskaya, O. V.; Pavlov, A. N.; Semyachkin-Glushkovskiy, I. A.; Gekalyuk, A. S.; Ulanova, M. V.; Lychagov, V. V.; Tuchin, V. V.

    2014-09-01

    The adrenergic system plays an important role in regulation of central and peripheral circulation in normal state and during hemorrhage. Because the impaired gastric mucosal blood flow (GMBF) is the major cause of gastroduodenal lesions, including ulcer bleeding (UB), we studied the adrenergic mechanism responsible for regulation of GMBF in rats with a model of stress-induced UB (SUB) using the laser Doppler flowmetry (LDF). First, we examined the effect of adrenaline on GMBF in rats under normal state and during UB. In all healthy animals the submucosal adrenaline injection caused a decrease in local GMBF. During UB the submucosal injection of adrenaline was accompanied by less pronounced GMBF suppression in 30,3% rats with SUB vs. healthy ones. In 69,7% rats with SUB we observed the increase in local GMBF after submucosal injection of adrenaline. Second, we studied the sensitivity of gastric β2-adrenoreceptors and the activity of two factors which are involved in β2-adrenomediated vasorelaxation-KATP -channels and NO. The effects of submucosal injection of isoproterenol, ICI118551 and glybenclamide on GMBF as well as NO levels in gastric tissue were significantly elevated in rats with SUB vs. healthy rats. Thus, our results indicate that high activation of gastric β2-adrenoreceptors associated with the increased vascular KATP -channels activity and elevated NO production is the important adrenergic mechanism implicated in the pathogenesis of UB.

  7. GENETIC VARIATION IN THE ALPHA1B - ADRENERGIC RECEPTOR AND VASCULAR RESPONSE

    Science.gov (United States)

    Adefurin, Abiodun; Ghimire, Laxmi V.; Kohli, Utkarsh; Muszkat, Mordechai; Sofowora, Gbenga G.; Li, Chun; Levinson, Rebecca T.; Paranjape, Sachin Y.; Stein, C. Michael; Kurnik, Daniel

    2016-01-01

    α1B- adrenergic receptors contribute to vasoconstriction in humans. We tested the hypothesis that variation in the ADRA1B gene contributes to interindividual variability and ethnic differences in adrenergic vasoconstriction. We measured dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 41 African-Americans and genotyped 34 ADRA1B variants. We validated findings in another model of catecholamine-induced vasoconstriction, the increase in mean arterial pressure (ΔMAP) during a cold pressor test (CPT). One ADRA1B variant, rs10070745, present in 14 African-American heterozygotes but not in Caucasians, was associated with a lower phenylephrine ED50 (geometric mean [95% CI], 144 [69–299] ng/ml) compared to 27 African-American non-carriers (208 [130–334] ng/ml; P=0.015) and contributed to the ethnic differences in ED50. The same variant was also associated with a greater ΔMAP during CPT (P=0.008). In conclusion, ADRA1B rs10070745 was significantly associated with vasoconstrictor responses after adrenergic stimulation and contributed to the ethnic difference in phenylephrine sensitivity. PMID:27089938

  8. Cholesterol modulates the dimer interface of the β₂-adrenergic receptor via cholesterol occupancy sites.

    Science.gov (United States)

    Prasanna, Xavier; Chattopadhyay, Amitabha; Sengupta, Durba

    2014-03-18

    The β2-adrenergic receptor is an important member of the G-protein-coupled receptor (GPCR) superfamily, whose stability and function are modulated by membrane cholesterol. The recent high-resolution crystal structure of the β2-adrenergic receptor revealed the presence of possible cholesterol-binding sites in the receptor. However, the functional relevance of cholesterol binding to the receptor remains unexplored. We used MARTINI coarse-grained molecular-dynamics simulations to explore dimerization of the β2-adrenergic receptor in lipid bilayers containing cholesterol. A novel (to our knowledge) aspect of our results is that receptor dimerization is modulated by membrane cholesterol. We show that cholesterol binds to transmembrane helix IV, and cholesterol occupancy at this site restricts its involvement at the dimer interface. With increasing cholesterol concentration, an increased presence of transmembrane helices I and II, but a reduced presence of transmembrane helix IV, is observed at the dimer interface. To our knowledge, this study is one of the first to explore the correlation between cholesterol occupancy and GPCR organization. Our results indicate that dimer plasticity is relevant not just as an organizational principle but also as a subtle regulatory principle for GPCR function. We believe these results constitute an important step toward designing better drugs for GPCR dimer targets.

  9. Beta-adrenergic receptors support attention to extinction learning that occurs in the absence, but not the presence, of a context change

    Directory of Open Access Journals (Sweden)

    Marion Emma André

    2015-05-01

    Full Text Available The noradrenergic (NA-system is an important regulator of cognitive function. It contributes to extinction learning(EL, and in disorders where EL is impaired NA-dysfunction has been postulated. We explored whether NA acting on beta-adrenergic-receptors (β-AR, regulates EL that depends on context, but is not fear-associated. We assessed behaviour in an ‘AAA’ or ‘ABA’ paradigm: rats were trained for 3 days in a T-maze(context-A to learn that a reward is consistently found in the goal arm, despite low reward probability. This was followed on day 4 by EL(unrewarded, whereby in the ABA-paradigm, EL was reinforced by a context change (B, and in the AAA-paradigm, no context change occurred. On day 5, re-exposure to the A-context (unrewarded occurred. Typically, in control ‘AAA’ animals EL occurred on day 4 that progressed further on day 5. In control ‘ABA’ animals, EL also occurred on day 4, followed by renewal of the previously learned (A behavior on day 5, that was followed (in day 5 by extinction of this behavior, as the animals realised that no food reward would be given.Treatment with the β-AR-antagonist, propranolol, prior to EL on day 4, impaired EL in the AAA-paradigm. In the ‘ABA’ paradigm, antagonist treatment on day 4, had no effect on extinction that was reinforced by a context change (B. Furthermore, β-AR-antagonism prior to renewal testing (on day 5 in the ABA-paradigm, resulted in normal renewal behavior, although subsequent extinction of responses during day 5 was prevented by the antagonist. Thus, under both treatment conditions, β-AR-antagonism prevented extinction of the behavior learned in the ‘A’ context.β-AR-blockade during an overt context change did not prevent EL, whereas β-AR were required for EL in an unchanging context. These data suggest that β-AR may support EL by reinforcing attention towards relevant changes in the previously learned experience, and that this process supports extinction

  10. Beta-adrenergic receptors support attention to extinction learning that occurs in the absence, but not the presence, of a context change

    Science.gov (United States)

    André, Marion Agnès Emma; Wolf, Oliver T.; Manahan-Vaughan, Denise

    2015-01-01

    The noradrenergic (NA)-system is an important regulator of cognitive function. It contributes to extinction learning (EL), and in disorders where EL is impaired NA-dysfunction has been postulated. We explored whether NA acting on beta-adrenergic-receptors (β-AR), regulates EL that depends on context, but is not fear-associated. We assessed behavior in an “AAA” or “ABA” paradigm: rats were trained for 3 days in a T-maze (context-A) to learn that a reward is consistently found in the goal arm, despite low reward probability. This was followed on day 4 by EL (unrewarded), whereby in the ABA-paradigm, EL was reinforced by a context change (B), and in the AAA-paradigm, no context change occurred. On day 5, re-exposure to the A-context (unrewarded) occurred. Typically, in control “AAA” animals EL occurred on day 4 that progressed further on day 5. In control “ABA” animals, EL also occurred on day 4, followed by renewal of the previously learned (A) behavior on day 5, that was succeeded (on day 5) by extinction of this behavior, as the animals realised that no food reward would be given. Treatment with the β-AR-antagonist, propranolol, prior to EL on day 4, impaired EL in the AAA-paradigm. In the “ABA” paradigm, antagonist treatment on day 4, had no effect on extinction that was reinforced by a context change (B). Furthermore, β-AR-antagonism prior to renewal testing (on day 5) in the ABA-paradigm, resulted in normal renewal behavior, although subsequent extinction of responses during day 5 was prevented by the antagonist. Thus, under both treatment conditions, β-AR-antagonism prevented extinction of the behavior learned in the “A” context. β-AR-blockade during an overt context change did not prevent EL, whereas β-AR were required for EL in an unchanging context. These data suggest that β-AR may support EL by reinforcing attention towards relevant changes in the previously learned experience, and that this process supports extinction

  11. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit+ bosentan group and Nit+ losartan group. Nitroglycerin tolerance was induced by 2-day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg- 1· d- 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg- 1· d- 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit+ losartan group and Nit+ bosentan group compared with Nit group [(31.95± 4.45 ) % vs (21.00± 3.69 ) % , P Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance .

  12. 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

  13. Mineralocorticoid and glucocorticoid receptor antagonists in animal models of anxiety

    NARCIS (Netherlands)

    Korte, SM; KorteBouws, GAH; Koob, GF; DeKloet, ER; Bohus, B

    1996-01-01

    The behavioral effects of intracerebroventricular (ICV) administration of a specific mineralocorticoid receptor (MR) antagonist [RU28318 (10-50 ng/2 mu l)], a glucocorticoid receptor (GR) antagonist [RU38486 (1-50 ng/2 mu l)], or both antagonists (50 ng/2 mu l), were studied in two different animal

  14. High affinity retinoic acid receptor antagonists: analogs of AGN 193109.

    Science.gov (United States)

    Johnson, A T; Wang, L; Gillett, S J; Chandraratna, R A

    1999-02-22

    A series of high affinity retinoic acid receptor (RAR) antagonists were prepared based upon the known antagonist AGN 193109 (2). Introduction of various phenyl groups revealed a preference for substitution at the para-position relative to the meta-site. Antagonists with the highest affinities for the RARs possessed hydrophobic groups, however, the presence of polar functionality was also well tolerated.

  15. Novel benzimidazole-based MCH R1 antagonists.

    Science.gov (United States)

    Carpenter, Andrew J; Al-Barazanji, Kamal A; Barvian, Kevin K; Bishop, Michael J; Britt, Christy S; Cooper, Joel P; Goetz, Aaron S; Grizzle, Mary K; Hertzog, Donald L; Ignar, Diane M; Morgan, Ronda O; Peckham, Gregory E; Speake, Jason D; Swain, Will R

    2006-10-01

    The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.

  16. Ischemia- and agonist-induced changes in. alpha. - and. beta. -adrenergic receptor traffic in guinea pig hearts

    Energy Technology Data Exchange (ETDEWEB)

    Maisel, A.S.; Motulsky, H.J.; Ziegler, M.G.; Insel, P.A. (Univ. of California, La Jolla (USA))

    1987-11-01

    The authors have used radioligand binding techniques and subcellular fraction to assess whether changes in expression of myocardial {alpha}{sub 1}- and {beta}-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 {alpha}{sub 1}-adrenergic receptors (({sup 3}H)prazosin binding) in light vesicles was only 25% of the total {alpha}{sub 1}-receptor density found in sarcolemmal and light vesicle fractions as compared with 50% for {beta}-adrenergic receptors (({sup 125}I)iodocyanopindolol binding sites). Although ischemia was associated with a 53% decrease in the number of light vesicle {beta}-adrenergic receptors and a 42% increase in the number of sarcolemma {beta}-receptors there was no change in the number of light vesicle {alpha}{sub 1}-receptors, even though the number of sarcolemmal {alpha}{sub 1}-receptors increased 34%. Epinephrine treatment promoted internalization of {beta}-adrenergic receptors. These results indicate that {alpha}{sub 1} and {beta}{sub 1}-adrenergic receptors may undergo a different cellular itinerary in guinea pig myocardium. Agonist and ischemia-induced changes in surface {beta}-receptors, but not {alpha}{sub 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 {alpha}{sub 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.

  17. [Cutaneous adverse effects of TNFalpha antagonists].

    Science.gov (United States)

    Failla, V; Sabatiello, M; Lebas, E; de Schaetzen, V; Dezfoulian, B; Nikkels, A F

    2012-01-01

    The TNFalpha antagonists, including adalimumab, etanercept and infliximab, represent a class of anti-inflammatory and immunosuppressive drugs. Although cutaneous adverse effects are uncommon, they are varied. There is no particular risk profile to develop cutaneous adverse effects. The principal acute side effects are injection site reactions and pruritus. The major long term cutaneous side effects are infectious and inflammatory conditions. Neoplastic skin diseases are exceptional. The association with other immunosuppressive agents can increase the risk of developing cutaneous adverse effects. Some adverse effects, such as lupus erythematosus, require immediate withdrawal of the biological treatment, while in other cases temporary withdrawal is sufficient. The majority of the other cutaneous adverse effects can be dealt without interrupting biologic treatment. Preclinical and clinical investigations revealed that the new biologics, aiming IL12/23, IL23 and IL17, present a similar profile of cutaneous adverse effects, although inflammatory skin reactions may be less often encountered compared to TNFalpha antagonists.

  18. 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.

  19. Aminopyrimidine derivatives as adenosine antagonists / Janke Kleynhans

    OpenAIRE

    Kleynhans, Janke

    2013-01-01

    Aims of this project - The aim of this study was to design and synthesise novel 2-aminopyrimidine derivatives as potential adenosine A1 and A2A receptor antagonists. Background and rationale - Parkinson’s disease is the second most common neurodegenerative disorder (after Alzheimer’s disease) and is characterised by the selective death of the dopaminergic neurons of the nigro-striatal pathway. Distinctive motor symptoms include bradykinesia, muscle rigidity and tremor, while non-m...

  20. The Justification of Antagonistic Response to Wrongdoing

    OpenAIRE

    Goldman, David Michael

    2012-01-01

    There is a strong Western tradition of opposing angry, hostile, or antagonistic reactions to wrongdoing. In the twentieth century, leaders like Mahatma Gandhi and Dr. Martin Luther King, Jr. counseled responding to wrongdoing with forgiveness and love rather than anger, hate, or vindictiveness.This ideal has taken on an exalted status in Western culture. Gandhi and King are widely regarded as moral saints. And yet sometimes antagonism seems deeply appropriate. Consider a very serious wrong: s...

  1. Antagonistic parent-offspring co-adaptation.

    Directory of Open Access Journals (Sweden)

    Mathias Kölliker

    Full Text Available BACKGROUND: In species across taxa, offspring have means to influence parental investment (PI. PI thus evolves as an interacting phenotype and indirect genetic effects may strongly affect the co-evolutionary dynamics of offspring and parental behaviors. Evolutionary theory focused on explaining how exaggerated offspring solicitation can be understood as resolution of parent-offspring conflict, but the evolutionary origin and diversification of different forms of family interactions remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In contrast to previous theory that largely uses a static approach to predict how "offspring individuals" and "parental individuals" should interact given conflict over PI, we present a dynamic theoretical framework of antagonistic selection on the PI individuals obtain/take as offspring and the PI they provide as parents to maximize individual lifetime reproductive success; we analyze a deterministic and a stochastic version of this dynamic framework. We show that a zone for equivalent co-adaptation outcomes exists in which stable levels of PI can evolve and be maintained despite fast strategy transitions and ongoing co-evolutionary dynamics. Under antagonistic co-adaptation, cost-free solicitation can evolve as an adaptation to emerging preferences in parents. CONCLUSIONS/SIGNIFICANCE: We show that antagonistic selection across the offspring and parental life-stage of individuals favors co-adapted offspring and parental behavior within a zone of equivalent outcomes. This antagonistic parent-offspring co-adaptation does not require solicitation to be costly, allows for rapid divergence and evolutionary novelty and potentially explains the origin and diversification of the observed provisioning forms in family life.

  2. Electrical Stimulation Decreases Coupling Efficiency Between Beta-Adrenergic Receptors and Cyclic AMP Production in Cultured Muscle Cells

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.

    1999-01-01

    Electrical stimulation of skeletal muscle cells in culture is an effective way to simulate the effects of muscle contraction and its effects on gene expression in muscle cells. Expression of the beta-adrenergic receptor and its coupling to cyclic AMP synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this project was to determine if electrical stimulation altered the beta-adrenergic response in muscle cells. Chicken skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. At the end of this two-day stimulation period, beta-adrenergic receptor population was measured by the binding of tritium-labeled CGP-12177 to muscle cells, and coupling to cAMP synthesis was measured by Radioimmunoassay (RIA) after treating the cells for 10 min with the potent (beta)AR agonist, isoproterenol. The number of beta adrenergic receptors and the basal levels of intracellular cyclic AMP were not affected by electrical stimulation. However, the ability of these cells to synthesize cyclic AMP was reduced by approximately 50%. Thus, an enhanced level of contraction reduces the coupling efficiency of beta-adrenergic receptors for cyclic AMP production.

  3. From the Cover: Glutamate antagonists limit tumor growth

    Science.gov (United States)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  4. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    张建梅; 陈永红; 王晓红; 唐朝枢

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n =6, each): Control group, Nitroglycerin (Nit) group, Nit + bosentan group and Nit + losartan group. Nitroglycerin tolerance was induced by 2-day treatment ofnitroglycerin patch (0. 05mg/h). Angiotensin I1 receptor antagonist losartan (10mg ·kg-1·d-1) and endothe-lin receptor antagonist bosentan ( 100 mg·kg-1· d-1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group. The effec-tive percentages of hypotensive response to SNP were increased in both Nit + losartan group and Nit + bosentangroup compared with Nit group [(31.95±4.45) % vs (21.00±3.69) %, P <0.01and (33. 18±6. 16)% vs (21.00±3.69 ) %, P < 0. 01 , respectivelyl. The maximal vessel relaxation induced by SNP was thesame in 4 different groups but the highest EC50 (concentration which produces 50% of the maximal response toSNP) was found in tolerant group[ (34 ±10) nmol/L, P < 0. 01 ]. The ET-1 amounts in plasma and vasculartissue were markedly increased by 54% and 60% in Nit group compared with those in control group( P<0. 01). The ET-1 amounts in plasma and vascular tissue were decreased by 30% and 37% in Nit + losartangroup compared with those in Nit group ( P < 0.01 ). Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance.

  5. Cyclic Adenosine Monophosphate Accumulation and beta-Adrenergic Binding in Unweighted and Denervated Rat Soleus Muscle

    Science.gov (United States)

    Kirby, Christopher R.; Woodman, Christopher R.; Woolridge, Dale; Tischler, Marc E.

    1992-01-01

    Unweighting, but not denervation, of muscle reportedly "spares" insulin receptors, increasing insulin sensitivity. Unweighting also increases beta-adrenergic responses of carbohydrate metabolism. These differential characteristics were studied further by comparing cyclic adenosine monophosphate (cAMP) accumulation and beta-adrenergic binding in normal and 3-day unweighted or denervated soleus muscle. Submaximal amounts of isoproterenol, a p-agonist, increased cAMP accumulation in vitro and in vivo (by intramuscular (IM) injection) to a greater degree (P less than .05) in unweighted muscles. Forskolin or maximal isoproterenol had similar in vitro effects in all muscles, suggesting increased beta-adrenergic sensitivity following unweighting. Increased sensitivity was confirmed by a greater receptor density (B(sub max)) for iodo-125(-)-pindolol in particulate preparations of unweighted (420 x 10(exp -18) mol/mg muscle) than of control or denervated muscles (285 x 10(exp-18) mol/mg muscle). The three dissociation constant (Kd) values were similar (20.3 to 25.8 pmol/L). Total binding capacity (11.4 fmol/muscle) did not change during 3 days of unweighting, but diminished by 30% with denervation. This result illustrates the "sparing" and loss of receptors, respectively, in these two atrophy models. In diabetic animals, IM injection of insulin diminished CAMP accumulation in the presence of theophylline in unweighted muscle (-66% +/- 2%) more than in controls (-42% +'- 6%, P less than .001). These results show that insulin affects CAMP formation in muscle, and support a greater in vivo insulin response following unweighting atrophy. These various data support a role for lysosomal proteolysis in denervation, but not in unweighting, atrophy.

  6. An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice

    Science.gov (United States)

    Montgomery, Megan D.; Chan, Trevor; Swigart, Philip M.; Myagmar, Bat-erdene; Dash, Rajesh; Simpson, Paul C.

    2017-01-01

    Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35–40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies. PMID:28081170

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-03-05

    The authors used previously established methods to determine the presence of alpha adrenergic receptors in different sizes of dog coronary arteries using autoradiography of /sup 3/H-prazosin (PRAZ) and /sup 125/I-BE 2254 (HEAT) to label alpha/sub 1/ adrenergic receptors and /sup 3/H-rauwolscine (RAUW) to label alpha/sub 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/sup -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 < 0.016), but no significant difference between total and nonspecific binding in the LAD (p < 0.19) or in the arterioles (p < 0.68). In the experiments with HEAT, similar results were obtained. With RAUW, there was significant labeling of arterioles (p < 0.004), but not over the LAD (p < 0.11) or the LMA (p < 0.49). The results suggest that the number of coronary alpha/sub 1/ receptors decreases as vessel size decreases, while the number of alpha/sub 2/ receptors increases as vessel size decreases.

  8. MiRNA-1/133a clusters regulate adrenergic control of cardiac repolarization.

    Directory of Open Access Journals (Sweden)

    Johannes Besser

    Full Text Available The electrical properties of the heart are primarily determined by the activity of ion channels and the activity of these molecules is permanently modulated and adjusted to the physiological needs by adrenergic signaling. miRNAs are known to control the expression of many proteins and to fulfill distinct functions in the mammalian heart, though the in vivo effects of miRNAs on the electrical activity of the heart are poorly characterized. The miRNAs miR-1 and miR-133a are the most abundant miRNAs of the heart and are expressed from two miR-1/133a genomic clusters. Genetic modulation of miR-1/133a cluster expression without concomitant severe disturbance of general cardiomyocyte physiology revealed that these miRNA clusters govern cardiac muscle repolarization. Reduction of miR-1/133a dosage induced a longQT phenotype in mice especially at low heart rates. Longer action potentials in cardiomyocytes are caused by modulation of the impact of β-adrenergic signaling on the activity of the depolarizing L-type calcium channel. Pharmacological intervention to attenuate β-adrenergic signaling or L-type calcium channel activity in vivo abrogated the longQT phenotype that is caused by modulation of miR-1/133a activity. Thus, we identify the miR-1/133a miRNA clusters to be important to prevent a longQT-phenotype in the mammalian heart.

  9. Beta-adrenergic stimulation of skeletal muscle HSL can be overridden by AMPK signaling.

    Science.gov (United States)

    Watt, Matthew J; Steinberg, Gregory R; Chan, Stanley; Garnham, Andrew; Kemp, Bruce E; Febbraio, Mark A

    2004-09-01

    Hormone-sensitive lipase (HSL), an important regulatory enzyme for triacylglycerol hydrolysis within skeletal muscle, is controlled by beta-adrenergic signaling as well as intrinsic factors related to contraction and energy turnover. In the current study, we tested the capacity of 5'AMP-activated protein kinase (AMPK) to suppress beta-adrenergic stimulation of HSL activity. Eight male subjects completed 60 min of cycle exercise at 70% VO2 peak on two occasions: either with normal (CON) or low (LG) pre-exercise muscle glycogen content, which is known to enhance exercise-induced AMPK activity. Muscle samples were obtained before and immediately after exercise. Pre-exercise glycogen averaged 375 +/- 35 and 163 +/- 27 mmol x kg(-1) dm for CON and LG, respectively. AMPK alpha-2 was not different between trials at rest and was increased (3.7-fold, PHSL activity did not differ between trials at rest and increased (0 min: 1.67 +/- 0.13; 60 min: 2.60 +/- 0.26 mmol x min(-1) x kg(-1) dm) in CON. The exercise-induced increase in HSL activity was attenuated by AMPK alpha-2 activation in LG. The attenuated HSL activity during LG occurred despite higher plasma epinephrine levels (60 min: CON, 1.96 +/- 0.29 vs LG, 4.25 +/- 0.60 nM, PHSL activity in LG, IMTG was decreased by exercise (0 min: 27.1 +/- 2.0; 60 min: 22.5 +/- 2.0 mmol x kg(-1) dm, PHSL activity, we performed experiments in muscle cell culture. The epineprine-induced increase in HSL activity was totally attenuated (PHSL activity that can override beta-adrenergic stimulation. However, the increased IMTG degradation in LG suggests factors other than HSL activity are important for IMTG degradation.

  10. Beta(3)-adrenergic signaling acutely down regulates adipose triglyceride lipase in brown adipocytes.

    Science.gov (United States)

    Deiuliis, Jeffrey A; Liu, Li-Fen; Belury, Martha A; Rim, Jong S; Shin, Sangsu; Lee, Kichoon

    2010-06-01

    Mice exposed to cold rely upon brown adipose tissue (BAT)-mediated nonshivering thermogenesis to generate body heat using dietary glucose and lipids from the liver and white adipose tissue. In this report, we investigate how cold exposure affects the PI3 K/Akt signaling cascade and the expression of genes involved in lipid metabolism and trafficking in BAT. Cold exposure at an early time point led to the activation of the PI3 K/Akt, insulin-like signaling cascade followed by a transient decrease in adipose triglyceride lipase (ATGL) gene and protein expression in BAT. To further investigate how cold exposure-induced signaling altered ATGL expression, cultured primary brown adipocytes were treated with the beta(3)-adrenergic receptor (beta(3)AR) agonist CL 316,243 (CL) resulting in activation of PI3 K/Akt, ERK 1/2, and p38 signaling pathways and significantly decreased ATGL protein levels. ATGL protein levels decreased significantly 30 min post CL treatment suggesting protein degradation. Inhibition of PKA signaling by H89 rescued ATGL levels. The effects of PKA signaling on ATGL were shown to be independent of relevant pathways downstream of PKA such as PI3 K/Akt, ERK 1/2, and p38. However, CL treatment in 3T3-L1 adipocytes did not decrease ATGL protein and mRNA expression, suggesting a distinct response in WAT to beta3-adrenergic agonism. Transitory effects, possibly attributed to acute Akt activation during the early recruitment phase, were noted as well as stable changes in gene expression which may be attributed to beta3-adrenergic signaling in BAT.

  11. A compartmentalized mathematical model of the β1-adrenergic signaling system in mouse ventricular myocytes.

    Directory of Open Access Journals (Sweden)

    Vladimir E Bondarenko

    Full Text Available The β1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca(2+]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of β1-adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is developed, which includes major subcellular functional compartments (caveolae, extracaveolae, and cytosol. The model describes biochemical reactions that occur during stimulation of β1-adrenoceptors, changes in ionic currents, and modifications of Ca(2+ handling system. Simulations describe the dynamics of major signaling molecules, such as cyclic AMP and protein kinase A, in different subcellular compartments; the effects of inhibition of phosphodiesterases on cAMP production; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca(2+ handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of [Ca(2+]i transients; changes in intracellular and transmembrane Ca(2+ fluxes; and [Na(+]i fluxes and dynamics. The model elucidates complex interactions of ionic currents upon activation of β1-adrenoceptors at different stimulation frequencies, which ultimately lead to a relatively modest increase in action potential duration and significant increase in [Ca(2+]i transients. In particular, the model includes two subpopulations of the L-type Ca(2+ channels, in caveolae and extracaveolae compartments, and their effects on the action potential and [Ca(2+]i transients are investigated. The presented model can be used by researchers for the interpretation of experimental data and for the developments of

  12. Bacterial Adrenergic Sensors Regulate Virulence of Enteric Pathogens in the Gut

    Directory of Open Access Journals (Sweden)

    Cristiano G. Moreira

    2016-06-01

    Full Text Available Enteric pathogens such as enterohemorrhagic Escherichia coli (EHEC and Citrobacter rodentium, which is largely used as a surrogate EHEC model for murine infections, are exposed to several host neurotransmitters in the gut. An important chemical exchange within the gut involves the neurotransmitters epinephrine and/or norepinephrine, extensively reported to increase virulence gene expression in EHEC, acting through two bacterial adrenergic sensors: QseC and QseE. However, EHEC is unable to establish itself and cause its hallmark lesions, attaching and effacing (AE lesions, on murine enterocytes. To address the role of these neurotransmitters during enteric infection, we employed C. rodentium. Both EHEC and C. rodentium harbor the locus of enterocyte effacement (LEE that is necessary for AE lesion formation. Here we show that expression of the LEE, as well as that of other virulence genes in C. rodentium, is also activated by epinephrine and/or norepinephrine. Both QseC and QseE are required for LEE gene activation in C. rodentium, and the qseC and qseE mutants are attenuated for murine infection. C. rodentium has a decreased ability to colonize dopamine β-hydroxylase knockout (Dbh−/− mice, which do not produce epinephrine and norepinephrine. Both adrenergic sensors are required for C. rodentium to sense these neurotransmitters and activate the LEE genes during infection. These data indicate that epinephrine and norepinephrine are sensed by bacterial adrenergic receptors during enteric infection to promote activation of their virulence repertoire. This is the first report of the role of these neurotransmitters during mammalian gastrointestinal (GI infection by a noninvasive pathogen.

  13. 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, Amar A; Tybjaerg-Hansen, Anne; Jensen, Gorm B;

    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...

  14. 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...

  15. A comparison of adrenergic receptors of rat ascites hepatoma AH130 cells with those of normal rat hepatocytes.

    Science.gov (United States)

    Sanae, F; Miyamoto, K; Koshiura, R

    1988-04-01

    The pharmacological specificity of adrenergic receptors in the plasma membrane of rat ascites hepatoma AH130 cells was compared with that in normal rat hepatocytes. The number of [125I]iodocyanopindolol-binding sites was much greater in AH130 cells than in the hepatocytes. We characterized the alpha-adrenergic receptor subtypes using the alpha 1-selective ligand [3H]prazosin and the alpha 2-selective ligand [3H]clonidine. AH130 cells had fewer prazosin-binding sites than the hepatocytes and about 8 times as many clonidine-binding sites of high affinity. The results showed that the adrenergic receptors in AH130 cells have pharmacological properties that are very different from those of the receptors in normal rat hepatocytes.

  16. Changes in number of alpha-adrenergic receptor subtypes in hepatocytes from rats fed 3'-methyl-4-dimethylaminoazobenzene.

    Science.gov (United States)

    Miyamoto, K; Sanae, F; Kohei, K; Nomura, M; Koshiura, R

    1990-01-01

    Changes in numbers of alpha 1- and alpha 2-adrenergic receptors in the plasma membranes of hepatocytes from female Donryu rats given feed containing 0.06% of the carcinogen 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), were examined. alpha 1-Adrenergic receptors, measured in terms of [3H]prazosin binding, decreased to half of the control 2 weeks after the start of this diet, then gradually decreased for the next 22 weeks. alpha 2-Adrenergic receptors, measured in terms of [3H]clonidine binding, transiently increased 3-fold over the control at 2 weeks. These changes in the early period of the 3'-MeDAB diet intake may be related to hepatocarcinogenesis.

  17. β1- and β2-adrenergic stimulation-induced electrogenic transport by human endolymphatic sac epithelium and its clinical implications

    Science.gov (United States)

    Kim, Bo Gyung; Kim, Jin Young; Jung, JinSei; Moon, In Seok; Yoon, Joo-Heon; Choi, Jae Young; Kim, Sung Huhn

    2017-01-01

    The endolymphatic sac (ES) is a cystic structure of the inner ear connected to the cochlea and vestibule, which plays a role in regulating ion homeostasis in inner ear fluid. Disruption of ion homeostasis can cause inner ear disorders with hearing loss and dizziness, such as Meniere’s disease. Herein, we found, for the first time, functional evidence for the involvement of β1- and β2-adrenergic receptors in apical electrogenic ion transport by human ES epithelium by using electrophysiological/pharmacological and molecular biological methods, which were dependent on K+ and Cl− ion transport. The apical electrogenic transport was absent or very weak in ES epithelia of patients with Meniere’s disease. These results suggested that adrenergic stimulation via β1- and β2-adrenergic receptors in the human ES was involved in regulation of inner ear fluid ion homeostasis and impairment of this response could be a pathological mechanism of Meniere’s disease. PMID:28165045

  18. 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.

  19. Recent advances in the molecular pharmacology of the alpha 1-adrenergic receptors.

    Science.gov (United States)

    Guarino, R D; Perez, D M; Piascik, M T

    1996-08-01

    This review is intended to discuss recent developments in the molecular pharmacology of the alpha 1-adrenergic receptor (alpha 1-AR) subtypes. After a brief historical development, we will focus on the more contemporary issues having to do with this receptor family. Emphasis will be put on recent data regarding the cloning, nomenclature, signalling mechanisms, and genomic organization of the alpha 1-AR subtypes. We will also highlight recent mutational studies that identify key amino acid residues involved in ligand binding, as well as the role of the alpha 1-AR subtypes in regulating physiologic processes.

  20. Cholesterol increases kinetic, energetic, and mechanical stability of the human β2-adrenergic receptor

    DEFF Research Database (Denmark)

    Zocher, Michael; Zhang, Cheng; Rasmussen, Søren Gøgsig Faarup;

    2012-01-01

    the kinetic, energetic, and mechanical stability of almost every structural segment at sufficient magnitude to alter the structure and functional relationship of β(2)AR. One exception was the structural core segment of β(2)AR, which establishes multiple ligand binding sites, and its properties were...... to quantify the mechanical strength and flexibility, conformational variability, and kinetic and energetic stability of structural segments stabilizing the human β(2)-adrenergic receptor (β(2)AR) in the absence and presence of the cholesterol analog cholesteryl hemisuccinate (CHS). CHS considerably increased...

  1. Alpha-adrenergic regulation of growth hormone release after electroconvulsive therapy in man.

    Science.gov (United States)

    Vigas, M; Wiedermann, V; Németh, S; Jurcovicová, J; Zigo, L

    1976-01-01

    When electroshcok therapy was administered to male psychiatric patients without anticonvulsive premedication, serum growth hormone (GH) increased; the increase was not prevented by an infusion of 20% glucose (5 ml per min) 20 min prior to electroshock. Therefore, the GH rise is not caused by muscle exercise during convulsions. Infusing 30 mg of phentolamine 40 min prior to electroshcok inhibited the GH response. Phentolamine's effect shows that the stress-induced GH release that follows electroconvulsive therapy is mediated by alpha-adrenergic neurons.

  2. 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

    crystallization, we engineered a beta2AR fusion protein in which T4 lysozyme (T4L) replaces most of the third intracellular loop of the GPCR ("beta2AR-T4L") and showed that this protein retains near-native pharmacologic properties. Analysis of adrenergic receptor ligand-binding mutants within the context...... of the reported high-resolution structure of beta2AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Amino acids known to regulate receptor function are linked through packing interactions and a network of hydrogen bonds, suggesting...

  3. Antidiuretic effect of ritodrine with and without beta-adrenergic blockade.

    Science.gov (United States)

    Gerritse, R; Pinas, I M; Reuwer, P J; Haspels, A A; Charbon, G A; Beijer, H J

    1985-11-01

    Dose-related effects of ritodrine and ritodrine combined with metoprolol on urinary excretion rate were studied in anesthetized dogs. Urine production was abruptly reduced after a total dose of 4 micrograms.kg-1 of ritodrine. This effect could not be antagonized by metoprolol, although the ritodrine-induced decrease of mean arterial pressure and renal arterial blood flow was significantly inhibited. The possible role of fluid retention during tocolytic treatment, even with beta-adrenergic blockade, in the etiology of pulmonary edema is discussed with a review on recent literature.

  4. Exercise training modulates functional sympatholysis and α-adrenergic vasoconstrictor responsiveness in hypertensive and normotensive individuals

    DEFF Research Database (Denmark)

    Mortensen, Stefan; Nyberg, Michael; Gliemann, Lasse;

    2014-01-01

    were measured before and after 8 weeks of aerobic training (3-4 times per week) in eight hypertensive (47 ± 2 years) and eight normotensive untrained individuals (46 ± 1 years) during arterial tyramine infusion, arterial ATP infusion and/or one-legged knee extensions. Before training, exercise......Essential hypertension is linked to an increased sympathetic vasoconstrictor activity and reduced tissue perfusion. We investigated the role of exercise training on functional sympatholysis and postjunctional α-adrenergic responsiveness in individuals with essential hypertension. Leg haemodynamics...... hyperaemia and leg vascular conductance (LVC) were lower in the hypertensive individuals (P

  5. N-terminal {beta}{sub 2}-adrenergic receptor polymorphisms do not correlate with bronchodilator response in asthma families

    Energy Technology Data Exchange (ETDEWEB)

    Holyroyd, K.J.; Dragwa, C.; Xu, J. [Johns Hopkins Medical Institutions, Baltimore, MD (United States)] [and others

    1994-09-01

    Family and twin studies have suggested that susceptibility to asthma is inherited. One clinically relevant phenotype in asthma is the bronchodilator response to beta adrenergic therapy (reversibility) which may also be inherited and vary among asthmatics. Two polymorphisms of the {beta}{sub 2}-adrenergic receptor common to both asthmatic and normal individuals have been reported. One polymorphism, an amino acid polymorphism at position 16, correlated in one study with the need for long-term corticosteriod use in a population of asthmatics. It is conceivable that the increased use of corticosteroids needed to control symptoms in these patients may be explained by a decreased responsiveness to brochodilators mediated through this amino acid polymorphism in the {beta}{sub 2}-adrenergic receptor. However, the response to {beta}{sub 2} bronchodilators was not tested in these patients. In our Dutch asthma families, DNA sequencing of the {beta}{sub 2}-adrenergic receptor has been performed for N-terminal polymorphisms at amino acid positions 16 and 27 in over 100 individuals, and no correlation was found with the increase of FEV{sub 1} in response to bronchodilator. Linkage analysis between bronchodilator response and marker D5S412 near the {beta}{sub 2}-adrenergic receptor gene was performed in 286 sibpairs from these families. Using a bronchodilator response of >10% in FEV{sub 1} as a qualitative definition of affected individuals, there were 145 unaffected sibpairs, 121 sibpairs where one was affected, and 20 in which both were affected. Linear regression analysis of these sibpair data suggested possible linkage (p=0.007). This supports further examination of the {beta}{sub 2}-adrenergic receptor and its regulatory regions for polymorphisms that correlate with the bronchodilator response in asthma families.

  6. Interaction between maropitant and carprofen on sparing of the minimum alveolar concentration for blunting adrenergic response (MAC-BAR) of sevoflurane in dogs

    Science.gov (United States)

    FUKUI, Sho; OOYAMA, Norihiko; TAMURA, Jun; UMAR, Mohammed Ahmed; ISHIZUKA, Tomohito; ITAMI, Takaharu; MIYOSHI, Kenjiro; SANO, Tadashi; YAMASHITA, Kazuto

    2017-01-01

    Maropitant, a neurokinin-1 receptor antagonist, may provide analgesic effects by blocking pharmacological action of substance P. Carprofen is a non-steroidal anti-inflammatory drug commonly used for pain control in dogs. The purpose of this study was to evaluate the effect of a combination of maropitant and carprofen on the minimum alveolar concentration for blunting adrenergic response (MAC-BAR) of sevoflurane in dogs. Six healthy adult beagle dogs were anesthetized with sevoflurane four times with a minimum of 7-day washout period. On each occasion, maropitant (1 mg/kg) alone, carprofen (4 mg/kg) alone, a combination of maropitant (1 mg/kg) and carprofen (4 mg/kg), or saline (0.1 ml/kg) was subcutaneously administered at 1 hr prior to the first electrical stimulation for the sevoflurane MAC-BAR determination. The sevoflurane MAC-BAR was significantly reduced by maropitant alone (2.88 ± 0.73%, P=0.010), carprofen alone (2.96 ± 0.38%, P=0.016) and the combination (2.81 ± 0.51%, P=0.0003), compared with saline (3.37 ± 0.56%). There was no significant difference in the percentage of MAC-BAR reductions between maropitant alone, carprofen alone and the combination. The administration of maropitant alone and carprofen alone produced clinically significant sparing effects on the sevoflurane MAC-BAR in dogs. However, the combination of maropitant and carprofen did not produce any additive effect on the sevoflurane MAC-BAR reduction. Anesthetic premedication with a combination of maropitant and carprofen may not provide any further sparing effect on anesthetic requirement in dogs. PMID:28111373

  7. Search for β2 adrenergic receptor ligands by virtual screening via grid computing and investigation of binding modes by docking and molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Qifeng Bai

    Full Text Available We designed a program called MolGridCal that can be used to screen small molecule database in grid computing on basis of JPPF grid environment. Based on MolGridCal program, we proposed an integrated strategy for virtual screening and binding mode investigation by combining molecular docking, molecular dynamics (MD simulations and free energy calculations. To test the effectiveness of MolGridCal, we screened potential ligands for β2 adrenergic receptor (β2AR from a database containing 50,000 small molecules. MolGridCal can not only send tasks to the grid server automatically, but also can distribute tasks using the screensaver function. As for the results of virtual screening, the known agonist BI-167107 of β2AR is ranked among the top 2% of the screened candidates, indicating MolGridCal program can give reasonable results. To further study the binding mode and refine the results of MolGridCal, more accurate docking and scoring methods are used to estimate the binding affinity for the top three molecules (agonist BI-167107, neutral antagonist alprenolol and inverse agonist ICI 118,551. The results indicate agonist BI-167107 has the best binding affinity. MD simulation and free energy calculation are employed to investigate the dynamic interaction mechanism between the ligands and β2AR. The results show that the agonist BI-167107 also has the lowest binding free energy. This study can provide a new way to perform virtual screening effectively through integrating molecular docking based on grid computing, MD simulations and free energy calculations. The source codes of MolGridCal are freely available at http://molgridcal.codeplex.com.

  8. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels;

    2015-01-01

    A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties...... to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...

  9. Antioxidant effects of calcium antagonists in rat brain homogenates.

    Science.gov (United States)

    Yao, K; Ina, Y; Nagashima, K; Ohmori, K; Ohno, T

    2000-06-01

    We studied the antioxidant activities of calcium antagonists against autoxidation in rat brain homogenates. The homogenates were incubated for 30 min at 37 degrees C with or without a calcium antagonist and subsequently assayed for lipid peroxide content. Percent inhibition of the lipid peroxidation was used as an index of the antioxidant effect. Dihydropyridine calcium antagonists exhibited concentration-dependent (3-300 micromol/l) inhibitory effects against lipid peroxidation. The relative order of antioxidant potency and associated IC50 values (micromol/l) of the calcium antagonists for inhibition of the lipid peroxidation were as follows: nifedipine (51.5)>barnidipine (58.6)>benidipine (71.2)>nicardipine (129.3)>amlodipine (135.5)>nilvadipine (167.3)>nitrendipine (252.1)> diltiazem (>300)=verapamil (>300). These results suggest that some dihydropyridine calcium antagonists show antioxidant properties. The antioxidant effects of the calcium antagonists may contribute to their pharmacological actions.

  10. Sexually antagonistic selection in human male homosexuality.

    Directory of Open Access Journals (Sweden)

    Andrea Camperio Ciani

    Full Text Available Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness, accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  11. Sexually antagonistic selection in human male homosexuality.

    Science.gov (United States)

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-06-18

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  12. Activins and activin antagonists in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Alev Deli; Emanuel Kreidl; Stefan Santifaller; Barbara Trotter; Katja Seir; Walter Berger; Rolf Schulte-Hermann; Chantal Rodgarkia-Dara; Michael Grusch

    2008-01-01

    In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo-or heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.

  13. ETA-receptor antagonists or allosteric modulators?

    DEFF Research Database (Denmark)

    De Mey, Jo G R; Compeer, Matthijs G; Lemkens, Pieter

    2011-01-01

    The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects. In resista......The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects....... In resistance arteries, the long-lasting contractile effects can only be partly and reversibly relaxed by low-molecular-weight ET(A) antagonists (ERAs). However, the neuropeptide calcitonin-gene-related peptide selectively terminates binding of ET1 to ET(A). We propose that ET1 binds polyvalently to ET(A......) and that ERAs and the physiological antagonist allosterically reduce ET(A) functions. Combining the two-state model and the two-domain model of GPCR function and considering receptor activation beyond agonist binding might lead to better anti-endothelinergic drugs. Future studies could lead to compounds...

  14. Zebrafish phenotypic screen identifies novel Notch antagonists.

    Science.gov (United States)

    Velaithan, Vithya; Okuda, Kazuhide Shaun; Ng, Mei Fong; Samat, Norazwana; Leong, Sze Wei; Faudzi, Siti Munirah Mohd; Abas, Faridah; Shaari, Khozirah; Cheong, Sok Ching; Tan, Pei Jean; Patel, Vyomesh

    2017-04-01

    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27(KIP1). Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

  15. Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats.

    Science.gov (United States)

    Frank, J A; Wang, Y; Osorio, O; Matthay, M A

    2000-10-01

    To determine whether beta-adrenergic agonist therapy increases alveolar liquid clearance during the resolution phase of hydrostatic pulmonary edema, we studied alveolar and lung liquid clearance in two animal models of hydrostatic pulmonary edema. Hydrostatic pulmonary edema was induced in sheep by acutely elevating left atrial pressure to 25 cmH(2)O and instilling 6 ml/kg body wt isotonic 5% albumin (prepared from bovine albumin) in normal saline into the distal air spaces of each lung. After 1 h, sheep were treated with a nebulized beta-agonist (salmeterol) or nebulized saline (controls), and left atrial pressure was then returned to normal. beta-Agonist therapy resulted in a 60% increase in alveolar liquid clearance over 3 h (P Ringer lactate). beta-Agonist therapy resulted in a significant decrease in excess lung water (P < 0.01) and significant improvement in arterial blood gases by 2 h (P < 0.03). These preclinical experimental studies support the need for controlled clinical trials to determine whether beta-adrenergic agonist therapy would be of value in accelerating the resolution of hydrostatic pulmonary edema in patients.

  16. Cocaine increases dopaminergic neuron and motor activity via midbrain α1 adrenergic signaling.

    Science.gov (United States)

    Goertz, Richard Brandon; Wanat, Matthew J; Gomez, Jorge A; Brown, Zeliene J; Phillips, Paul E M; Paladini, Carlos A

    2015-03-13

    Cocaine reinforcement is mediated by increased extracellular dopamine levels in the forebrain. This neurochemical effect was thought to require inhibition of dopamine reuptake, but cocaine is still reinforcing even in the absence of the dopamine transporter. Here, we demonstrate that the rapid elevation in dopamine levels and motor activity elicited by cocaine involves α1 receptor activation within the ventral midbrain. Activation of α1 receptors increases dopaminergic neuron burst firing by decreasing the calcium-activated potassium channel current (SK), as well as elevates dopaminergic neuron pacemaker firing through modulation of both SK and the hyperpolarization-activated cation currents (Ih). Furthermore, we found that cocaine increases both the pacemaker and burst-firing frequency of rat ventral-midbrain dopaminergic neurons through an α1 adrenergic receptor-dependent mechanism within the ventral tegmental area and substantia nigra pars compacta. These results demonstrate the mechanism underlying the critical role of α1 adrenergic receptors in the regulation of dopamine neurotransmission and behavior by cocaine.

  17. Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier.

    Directory of Open Access Journals (Sweden)

    Akihiko Urayama

    Full Text Available The impermeability of the adult blood-brain barrier (BBB to lysosomal enzymes impedes the ability to treat the central nervous system manifestations of lysosomal storage diseases. Here, we found that simultaneous stimulation of the alpha1 and alpha2 adrenoreceptor restores in adult mice the high rate of transport for the lysosomal enzyme P-GUS that is seen in neonates but lost with development. Beta adrenergics, other monoamines, and acetylcholine did not restore this transport. A high dose (500 microg/mouse of clonidine, a strong alpha2 and weak alpha1 agonist, was able to act as monotherapy in the stimulation of P-GUS transport. Neither use of alpha1 plus alpha2 agonists nor the high dose clonidine disrupted the BBB to albumin. In situ brain perfusion and immunohistochemistry studies indicated that adrengerics act on transporters already at the luminal surface of brain endothelial cells. These results show that adrenergic stimulation, including monotherapy with clonidine, could be key for CNS enzyme replacement therapy.

  18. Long-acting β2-adrenergic receptor agonist in pediatric asthma

    Directory of Open Access Journals (Sweden)

    Shigemi Yoshihara

    2004-01-01

    Full Text Available Long-acting β2-adrenergic receptor agonists (LABA, a class of agents for the long-term management of childhood bronchial asthma, are recommended for use in combination with steroid inhalation for the treatment of the morning dip in severe childhood asthma. In the present review, salmeterol (SM, a LABA inhalant with a long-acting bronchodilator effect, was compared with the recently introduced tulobuterol patch (TBP in terms of safety and efficacy, based on their respective clinical effects on childhood asthma. From a clinical perspective, both drugs had a preventive effect by suppressing the morning dip and exercise-induced asthma when used concomitantly with an inhaled corticosteroid, and both agents were associated with a lower incidence of adverse effects on the cardiovascular system than oral β2-adrenergic receptor agonists. Based on these findings, both SM and TBP are concluded to be highly efficacious and safe bronchodilator agents that are appropriate for the long-term management of childhood asthma.

  19. Effect of beta-adrenergic stimulants on cytotoxicity of mitomycin C in HeLa cells.

    Science.gov (United States)

    Miyamoto, K; Sanae, F; Iwasaki, M; Koshiura, R

    1982-12-01

    Effects of several autonomic agents on the cytotoxicity of mitomycin C in HeLa cells were studied. When beta-adrenergic stimulants such as isoproterenol, epinephrine, terbutaline and turobuterol were added at concentrations over 10(-14) M 15 to 60 min before mitomycin C, the colony-forming ability of HeLa cells was significantly inhibited more than by mitomycin C alone. The action of isoproterenol and epinephrine on the colony-forming ability of the cells was abolished by propranolol. The intracellular cyclic AMP level of HeLa cells reached the peak of about two-fold the basal level at 30 min after the addition of 10(-8) M isoproterenol. In combination with mitomycin C, the high level of intracellular cyclic AMP induced by isoproterenol was maintained for a significantly longer period in comparison with that by isoproterenol alone, while mitomycin C alone caused essentially no change in the cyclic AMP level. The pretreatment with dibutyryl cyclic AMP also enhanced the effect of mitomycin C. From these findings, it is strongly suggested that the synergistic effect of beta-adrenergic stimulants on the cytotoxicity of mitomycin C is mediated via stimulation of the beta-adrenoceptors of HeLa cells which elevates the intracellular cyclic AMP for a long time in combination with mitomycin C.

  20. 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.

  1. α1B-Adrenoceptors mediate adrenergically-induced renal vasoconstrictions in rats with renal impairment

    Institute of Scientific and Technical Information of China (English)

    Md Abdul Hye KHAN; Munavvar Abdul SATTAR; Nor Azizan ABDULLAH; Edward James JOHNS

    2008-01-01

    Aim: This study examined whether α1B-adrenoceptors are involved in mediating adrenergically-induced renal vasoconstrictor responses in rats with pathophysi-ological and normal physiological states. Methods: Male Wistar Kyoto and spon-taneously hypertensive rats were induced with acute renal failure or experimental early diabetic nephropathy by cisplatin or streptozotocin, respectively. Cisplatin-induced renal failure was confirmed by impaired renal function and pronounced tubular damage. Experimental early diabetic nephropathy was confirmed by hyperglycemia, changes in physiological parameters, and renal function. The hemodynamic study was conducted on anesthetized rats after 7 d of cisplatin (renal failure) and 4 weeks of streptozotocin (experimental early diabetic nephropathy). Results: In the rats with renal failure and experimental early dia-betic nephropathy, there were marked reductions in their baseline renal blood flow (P0.05) in the renal failure and experimental early diabetic nephropathy rats, respectively, as compared to their non-renal failure and non-diabetic nephropathy controls. In the rats with renal impairment, chloroethylclonidine caused either accentuation or attenuation (all P0.05). Conclusion: This study demonstrated the presence of functional α1B-adrenoceptors that mediated the adrenergically-induced renal vaso-constrictions in rats with renal impairment, but not in rats with normal renal function.

  2. β-Adrenergic Control of Hippocampal Function: Subserving the Choreography of Synaptic Information Storage and Memory.

    Science.gov (United States)

    Hagena, Hardy; Hansen, Niels; Manahan-Vaughan, Denise

    2016-04-01

    Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are "earmarked" for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength.The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3 > CA1). Moreover, NA released from the locus coeruleus that acts on β-AR leads to hippocampal LTD and an enhancement of LTD-related memory processing. We propose that NA acting on hippocampal β-AR, that is graded according to the novelty or saliency of the experience, determines the content and persistency of synaptic information storage in the hippocampal subfields and therefore of spatial memories.

  3. 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.

  4. β-Adrenergic-mediated vasodilation in young men and women: cyclooxygenase restrains nitric oxide synthase.

    Science.gov (United States)

    Limberg, Jacqueline K; Johansson, Rebecca E; Peltonen, Garrett L; Harrell, John W; Kellawan, J Mikhail; Eldridge, Marlowe W; Sebranek, Joshua J; Schrage, William G

    2016-03-15

    We tested the hypothesis that women exhibit greater vasodilator responses to β-adrenoceptor stimulation compared with men. We further hypothesized women exhibit a greater contribution of nitric oxide synthase and cyclooxygenase to β-adrenergic-mediated vasodilation compared with men. Forearm blood flow (Doppler ultrasound) was measured in young men (n = 29, 26 ± 1 yr) and women (n = 33, 25 ± 1 yr) during intra-arterial infusion of isoproterenol (β-adrenergic agonist). In subset of subjects, isoproterenol responses were examined before and after local inhibition of nitric oxide synthase [N(G)-monomethyl-l-arginine (l-NMMA); 6 male/10 female] and/or cyclooxygenase (ketorolac; 5 male/5 female). Vascular conductance (blood flow ÷ mean arterial pressure) was calculated to assess vasodilation. Vascular conductance increased with isoproterenol infusion (P 0.99) or women (P = 0.21). In contrast, ketorolac infusion markedly increased isoproterenol-mediated responses in both men (P vasodilation is not different between men and women and sex differences in the independent contribution of nitric oxide synthase and cyclooxygenase to β-mediated vasodilation are not present. However, these data are the first to demonstrate β-adrenoceptor activation of cyclooxygenase suppresses nitric oxide synthase signaling in human forearm microcirculation and may have important implications for neurovascular control in both health and disease.

  5. High-throughput chemiluminometric genotyping of single nucleotide polymorphisms of histamine, serotonin, and adrenergic receptor genes.

    Science.gov (United States)

    Toubanaki, Dimitra K; Christopoulos, Theodore K; Ioannou, Penelope C; Flordellis, Christodoulos S

    2009-02-01

    Several pharmacogenetic studies are focused on the investigation of the relation between the efficacy of various antipsychotic agents (e.g., clozapine) and the genetic profile of the patient with an emphasis on genes that code for neurotransmitter receptors such as histamine, serotonin, and adrenergic receptors. We report a high-throughput method for genotyping of single nucleotide polymorphisms (SNPs) within the genes of histamine H2 receptor (HRH2), serotonin receptor (HTR2A1 and HTR2A2), and beta(3) adrenergic receptor (ADRB3). The method combines the high specificity of allele discrimination by oligonucleotide ligation reaction (OLR) and the superior sensitivity and simplicity of chemiluminometric detection in a microtiter well assay configuration. The genomic region that spans the locus of interest is first amplified by polymerase chain reaction (PCR). Subsequently, an oligonucleotide ligation reaction is performed using a biotinylated common probe and two allele-specific probes that are labeled at the 3' end with digoxigenin and fluorescein. The ligation products are immobilized in polystyrene wells via biotin-streptavidin interaction, and the hybrids are denatured. Detection is accomplished by the addition of alkaline phosphatase-conjugated anti-digoxigenin or anti-fluorescein antibodies in combination with a chemiluminogenic substrate. The ratio of the luminescence signals obtained from digoxigenin and fluorescein indicates the genotype of the sample. The method was applied successfully to the genotyping of 23 blood samples for all four SNPs. The results were in concordance with both PCR-restriction fragment length polymorphism analysis and sequencing.

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

    Energy Technology Data Exchange (ETDEWEB)

    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{sub 2}-adrenergic receptors (AR's) on peripheral blood lymphocytes, via (I{sup 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.

  7. β-Adrenergic Control of Hippocampal Function: Subserving the Choreography of Synaptic Information Storage and Memory

    Science.gov (United States)

    Hagena, Hardy; Hansen, Niels; Manahan-Vaughan, Denise

    2016-01-01

    Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are “earmarked” for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength. The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3 > CA1). Moreover, NA released from the locus coeruleus that acts on β-AR leads to hippocampal LTD and an enhancement of LTD-related memory processing. We propose that NA acting on hippocampal β-AR, that is graded according to the novelty or saliency of the experience, determines the content and persistency of synaptic information storage in the hippocampal subfields and therefore of spatial memories. PMID:26804338

  8. Relaxing action of adrenergic β2-agonists on guinea-pig skinned tracheal muscle

    Directory of Open Access Journals (Sweden)

    Kayo Nemoto

    1999-01-01

    Full Text Available Although adrenergic β2-agonist-induced smooth muscle relaxation has been attributed to increased intracellular cyclic AMP (cAMP, a relaxation response has been observed at low β2-agonist concentrations that do not cause increased cAMP To elucidate the mechanism of tracheal muscle relaxation induced by low concentrations of β2-agonists, we used a guinea-pig skinned tracheal smooth muscle preparation to examine the effects on the contractile protein system. The isotonic contraction of β-escin-treated skinned tracheal muscle from guinea-pig was measured. When the intracellular Ca2+ concentration was maintained at 1 μmol/L in the presence of guanosine 5′-triphosphate (GTP; 100 μmol/L, neither isoproterenol (10nmol/L nor salbutamol (60 nmol/L affected Ca2+ sensitivity, but a significant decrease in Ca2+ sensitivity was observed in the presence of okadaic acid (1 μmol/L. The decrease in Ca2+ sensitivity was a slow response and was blocked by pretreatment with propranolol (1 μmol/L. Forskolin (1 μmol/L did not affect Ca2+ sensitivity. These results suggest that adrenergic b 2-agonists may activate protein phosphatase through an unknown pathway involving the β2-receptor, which enhances dephosphorylation of the myosin light chain and/or thin filament proteins, resulting in relaxation of the tracheal smooth muscle.

  9. Evaluation of H2 receptor antagonists in chronic idiopathic urticaria

    Directory of Open Access Journals (Sweden)

    Minocha Y

    1995-01-01

    Full Text Available H1-antagonist (hydroxyzine hydrochloride in dosage of 10 mg-25 mg thrice a day failed to elicit satisfactory response in 60 out of 170 patients of chronic idiopathic urticaria. Additional administration of H2-antagonist (cimetidine in dosage of 200 mg four times a day, in patients not responding earlier to H1-antagonist alones exhibited moderate to good improvement of various parameters of urticaria in approximately 85% patients

  10. An electrophysiological analysis of the effects of noradrenaline and alpha-receptor antagonists on neuromuscular transmission in mammalian muscular arteries.

    Science.gov (United States)

    Holman, M E; Surprenant, A

    1980-01-01

    1 The effects of exogenously applied noradrenaline (NA) and alpha-adrenoceptor antagonists on the mechanical and intracellularly recorded responses to perivascular nerve stimulation were examined in the rabbit ear artery, rabbit saphenous artery and rat tail artery. 2 Excitatory junction potentials (e.j.ps) and action potentials recorded from these smooth muscles were not blocked or depressed by phentolamine, phenoxybenzamine, prazosin, or labetolol in concentrations as high as 10 microgram/ml. Phentolamine (1 to 10 microgram/ml) depressed neurally-evoked contractions of the ear and saphenous, but not the tail artery, and also depressed the contractions produced by direct muscle stimulation in the ear and saphenous arteries. Prazosin and labetolol (0.1 to 10 microgram/ml) had no effect on the neurally evoked contractile response in any of the arteries examined. 3 The amplitude of the steady-state e.j.p. during repetitive stimulation at 0.45 to 2 Hz was increased by phentolamine or phenoxybenzamine but not by prazosin or labetolol. Phentolamine and phenoxybenzamine also increased the amplitude of the e.j.p. evoked by a single stimulus in the majority of the preparations. 4 Concentrations of NA greater than or equal to 1 microgram/ml depolarized the smooth muscle while concentrations greater than or equal to 0.5 microgram/ml depressed the amplitude of the e.j.ps recorded from these arteries. alpha-Antagonists did not suppress either the NA-induced membrane depolarization or depression of e.j.ps. 5 These observations call into question the physiological relevance of both pre- and postsynaptic alpha-receptors in regard to adrenergic neuromuscular transmission in muscular arteries.

  11. Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density

    NARCIS (Netherlands)

    Veldhuis-Vlug, A G; Oei, L; Souverein, P C; Tanck, M W T; Rivadeneira, F; Zillikens, M C; Kamphuisen, P W; Maitland-van der Zee, A H; de Groot, M C H; Hofman, A; Uitterlinden, A G; Fliers, E; de Boer, A; Bisschop, P H

    2015-01-01

    Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Stu

  12. Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density

    NARCIS (Netherlands)

    A.G. Veldhuis-Vlug; L. Oei (Ling); P. Souverein (Patrick); M.W.T. Tanck (Michael); F. Rivadeneira Ramirez (Fernando); M.C. Zillikens (Carola); P.W. Kamphuisen; A-H. Maitland-van der Zee (Anke-Hilse); M.C.H. de Groot; A. Hofman (Albert); A.G. Uitterlinden (André); E. Fliers (Eric); A.C. de Boer (Anthonius); P.H. Bisschop

    2015-01-01

    textabstractSummary: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in t

  13. Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density

    NARCIS (Netherlands)

    Veldhuis-Vlug, A. G.; Oei, L.; Souverein, P. C.; Tanck, M. W T; Rivadeneira, F.; Zillikens, M. C.; Kamphuisen, P. W.; Maitland - van der Zee, A. H.; de Groot, M. C H; Hofman, A.; Uitterlinden, A. G.; Fliers, E.; de Boer, A.; Bisschop, P. H.

    2015-01-01

    Summary: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rott

  14. Family-based association analysis of beta(2)-adrenergic receptor polymorphisms in the Childhood Asthma Management Program

    NARCIS (Netherlands)

    Silverman, EK; Kwiatkowski, DJ; Sylvia, JS; Lazarus, R; Drazen, JM; Lange, C; Laird, NM; Weiss, ST

    2003-01-01

    Background: beta(2)-Adrenergic receptor (B2AR) polymorphisms have been associated with a variety of asthma-related phenotypes, but association results have been inconsistent across different studies. Objective: We sought to apply family-based association methods to individual single nucleotide polym

  15. The insula modulates arousal-induced reluctance to try novel tastes through adrenergic transmission in the rat

    Science.gov (United States)

    Rojas, Sebastián; Diaz-Galarce, Raúl; Jerez-Baraona, Juan Manuel; Quintana-Donoso, Daisy; Moraga-Amaro, Rodrigo; Stehberg, Jimmy

    2015-01-01

    Reluctance to try novel tastes (neophobia) can be exacerbated in arousing situations, such as when children are under social stress or in rodents, when the new taste is presented in a high arousal context (HA) compared to a low arousal context (LA). The present study aimed at determining whether adrenergic transmission at the Insula regulates the reluctance to try novel tastes induced by arousing contexts. To this end, a combination of systemic and intra-insular manipulations of adrenergic activity was performed before the novel taste (saccharin 0.1%) was presented either in LA or HA contexts in rats. Our results show that systemic adrenergic activity modulates reluctance to try novel tastes. Moreover, intra-insular microinjections of propranolol or norepinephrine (NE) were found to modulate the effects of arousing contexts on reluctance to try novel tastes. Finally, intra-insular propranolol blocked epinephrine-induced increased reluctance, while intra-insular NE blocked oral propranolol-induced decreases in reluctance and increased the reluctance to try novel tastes presented in low arousing contexts. In conclusion, our results suggest that the insula is a critical site for regulating the effects of arousal in the reluctance to try novel tastes via the adrenergic system. PMID:26175672

  16. Subthreshold α2-Adrenergic Activation Counteracts Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Minglin Pan

    2011-01-01

    Full Text Available The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1 receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX- sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

  17. How Can 1+1=3? beta(2)-Adrenergic and Glucocorticoid Receptor Agonist Synergism in Obstructive Airway Diseases

    NARCIS (Netherlands)

    Schmidt, Martina; Michel, Martin C.

    2011-01-01

    For a long time it was believed that beta(2)-adrenergic receptor agonists used in the treatment of obstructive airway diseases worked primarily on airway smooth muscle cells, causing relaxation, whereas glucocorticoids primarily improved airway function via their anti-inflammatory action, indicating

  18. Heterocyclic acetamide and benzamide derivatives as potent and selective beta3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles.

    Science.gov (United States)

    Goble, Stephen D; Wang, Liping; Howell, K Lulu; Bansal, Alka; Berger, Richard; Brockunier, Linda; DiSalvo, Jerry; Feighner, Scott; Harper, Bart; He, Jiafang; Hurley, Amanda; Hreniuk, Donna; Parmee, Emma; Robbins, Michael; Salituro, Gino; Sanfiz, Anthony; Streckfuss, Eric; Watkins, Eloisa; Weber, Ann E; Struthers, Mary; Edmondson, Scott D

    2010-03-15

    A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.

  19. Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4

    DEFF Research Database (Denmark)

    Richter, Wito; Day, Peter; Agrawal, Rani

    2008-01-01

    Beta1- and beta2-adrenergic receptors (betaARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by beta1AR but not beta2AR signaling, and chronic stimulation of the two receptors has opposing...

  20. Participation of beta-adrenergic activity in modulation of GLUT4 expression during fasting and refeeding in rats

    Science.gov (United States)

    Through in vitro studies, several factors have been reported as modulators of GLUT4 gene expression. However, the role(s) of each potential GLUT4 modulator is not completely understood in the in vivo setting. The present study has investigated the hypothesis that beta-adrenergic stimulation particip...

  1. Circadian-related heteromerization of adrenergic and dopamine D₄ receptors modulates melatonin synthesis and release in the pineal gland.

    Directory of Open Access Journals (Sweden)

    Sergio González

    Full Text Available The role of the pineal gland is to translate the rhythmic cycles of night and day encoded by the retina into hormonal signals that are transmitted to the rest of the neuronal system in the form of serotonin and melatonin synthesis and release. Here we describe that the production of both melatonin and serotonin by the pineal gland is regulated by a circadian-related heteromerization of adrenergic and dopamine D₄ receptors. Through α(₁B-D₄ and β₁-D₄ receptor heteromers dopamine inhibits adrenergic receptor signaling and blocks the synthesis of melatonin induced by adrenergic receptor ligands. This inhibition was not observed at hours of the day when D₄ was not expressed. These data provide a new perspective on dopamine function and constitute the first example of a circadian-controlled receptor heteromer. The unanticipated heteromerization between adrenergic and dopamine D₄ receptors provides a feedback mechanism for the neuronal hormone system in the form of dopamine to control circadian inputs.

  2. The Insula modulates arousal-induced reluctance to try novel tastes through adrenergic transmission in the rat

    Directory of Open Access Journals (Sweden)

    Sebastián Andrés Rojas

    2015-06-01

    Full Text Available Reluctance to try novel tastes (neophobia can be exacerbated in arousing situations, such as when children are under social stress or in rodents, when the new taste is presented in a high arousal context (HA compared to a low arousal context (LA. The present study aimed at determining whether adrenergic transmission at the Insula regulates the reluctance to try novel tastes induced by arousing contexts. To this end, a combination of systemic and intra-insular manipulations of adrenergic activity was performed before the novel taste (saccharin 0.1% was presented either in LA or HA contexts in rats. Our results show that systemic adrenergic activity modulates reluctance to try novel tastes. Moreover, intra-insular microinjections of propranolol or norepinephrine were found to modulate the effects of arousing contexts on reluctance to try novel tastes. Finally, intra-insular propranolol blocked epinephrine-induced increased reluctance, while intra-insular norepinephrine blocked oral propranolol-induced decreases in reluctance and increased the reluctance to try novel tastes presented in low arousing contexts. In conclusion, our results suggest that the insula is a critical site for regulating the effects of arousal in the reluctance to try novel tastes via the adrenergic system.

  3. Yohimbine protects against endotoxin-induced acute lung injury by blockade of alpha 2A adrenergic receptor in rats

    Institute of Scientific and Technical Information of China (English)

    LIN Ying; ZHU Xi; YAO Wan-zhen; YANG Yah-lin; A La-ta; CHEN Li

    2011-01-01

    Background Alpha 2A adrenergic receptor (AR) is a subtype of α2 AR belonging to G protein-coupled receptors,and exerts a variety of biological effects. Recent studies have demonstrated that the α2A AR activation was closely related with inflammatory reaction. The present study aimed to investigate the influence of α2A AR antagonist,yohimbine,on the severity of endotoxin-induced acute lung injury in rats.Methods A total of 72 male Sprague-Dawley rats were randomly divided into three groups:control group,lipopolysaccharide (LPS) group and LPS + yohimbine group. Rats were intratracheally administrated with normal saline or LPS (300 μg),and the rats in the LPS + yohimbine group were treated with additional yohimbine (2 mg/kg,i.p) soon after LPS administration. Six,24 and 48 hours after treatment,arterial blood gas analysis was carried out,and optical microscopy was performed to evaluate pathological changes in the lung,and lung injury score was assessed. The count of white blood cells in bronchoalveolar lavage fluid (BALF) was determined. The levels of norepinephrine,tumor necrosis factor (TNF)-α,interleukin (IL)-1β and IL-6 in BALF were measured with enzyme-linked immunosorbent assay.Immunocytochemistry was performed for the detection of α2AAR on inflammatory cells in BALF.Results When compared with the control group,the oxygenation index in the LPS group was significantly decreased,and white blood cell count,the lung histopathological scores,levels of norepinephrine and IL-6 as well as α2A AR expression on inflammatory cells in the BALF were dramatically increased at different time points,and the concentrations of TNF-α and IL-1β were also increased except at 48 hours after LPS administration. The oxygenation index decreased while white blood cell count in BALF and the lung histopathological scores were obviously increased in the LPS +yohimbine group. The level of norepinephrine in BALF was increased at each time interval in the LPS + yohimbine group,and so

  4. IL-1 receptor-antagonist (IL-1Ra) knockout mice show anxiety-like behavior by aging.

    Science.gov (United States)

    Wakabayashi, Chisato; Numakawa, Tadahiro; Odaka, Haruki; Ooshima, Yoshiko; Kiyama, Yuji; Manabe, Toshiya; Kunugi, Hiroshi; Iwakura, Yoichiro

    2015-07-10

    Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus.

  5. [Reaction of population of pulmonary mast cells in rat bronchial asthma under the effect of β-adrenoreceptor antagonists].

    Science.gov (United States)

    Erokhina, I L; Voronchikhin, P A; Okovityĭ, S V; Emel'ianova, O I

    2013-01-01

    Multifunctional granular mast cells (MCs) are among targets in bronchial asthma (BA) therapy. We studied pulmonary MC population in a rat model of BA under the effect of β-adrenoreceptor antagonists and of the latter combined with the standard therapy (glucocorticoid budesonide + β2-adrenergic agonist salbutamol). MCs of different degrees of maturity were identified on paraffin section of lung stained with Alcian blue and Safranin. MC density in the lung of rats with BA increased 1.9 times. Alcian blue-positive immature cells predominated in the lungs of both intact rats and rats with BA. In response to pharmacological agents, the mean MC densities were reduced in 2-2.7 times in all the variants of experiments and were close to the norm. It allows us to suppose that MCs migration from the outside was suppressed and, in consequence of the decline of MC densities, the release of the mediators involved in the progression of BA may be diminished.

  6. Mutually-Antagonistic Interactions in Baseball Networks

    CERN Document Server

    Saavedra, Serguei; McCotter, Trent; Porter, Mason A; Mucha, Peter J

    2009-01-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit interesting structural changes over time. We also find that these networks exhibit a significant network structure that is sensitive to baseball's rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to compare the performance of players who competed under different conditions. We find that a player's position in the network does not correlate with his success in the random walker ranking but instead has a substantial effect on its sensitivity to changes in his own aggregate performance.

  7. Mutually-antagonistic interactions in baseball networks

    Science.gov (United States)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  8. Antagonists of IAP proteins as cancer therapeutics.

    Science.gov (United States)

    Dynek, Jasmin N; Vucic, Domagoj

    2013-05-28

    Inhibitor of apoptosis (IAP) proteins play pivotal roles in cellular survival by blocking apoptosis, modulating signal transduction, and affecting cellular proliferation. Through their interactions with inducers and effectors of apoptosis IAP proteins can effectively suppress apoptosis triggered by diverse stimuli including death receptor signaling, irradiation, chemotherapeutic agents, or growth factor withdrawal. Evasion of apoptosis, in part due to the action of IAP proteins, enhances resistance of cancer cells to treatment with chemotherapeutic agents and contributes to tumor progression. Additionally, IAP genes are known to be subject to amplification, mutation, and chromosomal translocation in human malignancies and autoimmune diseases. In this review we will discuss the role of IAP proteins in cancer and the development of antagonists targeting IAP proteins for cancer treatment.

  9. The Attractiveness of Opposites: Agonists and Antagonists.

    LENUS (Irish Health Repository)

    O'Brien, Tony

    2015-02-02

    ABSTRACT Opioid-induced bowel dysfunction, of which constipation is the most common aspect, is a major limiting factor in the use of opioids for pain management. The availability of an oral, long-acting formulation of oxycodone and naloxone represents a highly significant development in pain management. The combination of an opioid analgesic with an opioid antagonist offers reliable pain control with a significant reduction in the burden of opioid-induced constipation. This report is adapted from paineurope 2014; Issue 3, ©Haymarket Medical Publications Ltd, and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, LTD and is distributed free of charge to healthcare professionals in Europe. Archival issues can be accessed via the website: http:\\/\\/www.paineurope.com at which European health professionals can register online to receive copies of the quarterly publication.

  10. Antagonistic activity of marine sponges associated Actinobacteria

    Institute of Scientific and Technical Information of China (English)

    Selvakumar Dharmaraj; Dhevendaran Kandasamy

    2016-01-01

    Objective: To focus on the isolation and preliminary characterization of marine sponges associated Actinobacteria particularly Streptomyces species and also their antagonistic activities against bacterial and fungal pathogens. Methods: The sponges were collected from Kovalam and Vizhinjam port of south-west coast of Kerala, India. Isolation of strains was carried out from sponge extracts using international Streptomyces project media. For preliminary identification of the strains, morphological (mycelial colouration, soluble pigments, melanoid pigmentation, spore morphology), nutritional uptake (carbon utilisation, amonoacids influence, sodium chloride tolerance), physiological (pH, temperature) and chemotaxonomical characterization were done. Antimicrobial studies were also carried out for the selected strains. Results: With the help of the spicule structures, the collected marine sponges were identified as Callyspongia diffusa, Mycale mytilorum, Tedania anhelans and Dysidea fragilis. Nearly 94 strains were primarily isolated from these sponges and further they were sub-cultured using international Streptomyces project media. The strains exhibited different mycelial colouration (aerial and substrate), soluble and melanoid pigmentations. The strains possessed three types of sporophore morphology namely rectus flexibilis, spiral and retinaculiaperti. Among the 94 isolates, seven exhibited antibacterial and antifungal activities with maximal zone of inhibition of 30 mm. The nutritional, physiological and chemotaxonomical characteristic study helped in the conventional identification of the seven strains and they all suggest that the strains to be grouped under the genus Streptomyces. Conclusions: The present study clearly helps in the preliminary identification of the isolates associated with marine sponges. Antagonistic activities prove the production of antimicrobial metabolites against the pathogens. Marine sponges associated Streptomyces are universally well

  11. Beta adrenergic overstimulation impaired vascular contractility via actin-cytoskeleton disorganization in rabbit cerebral artery.

    Directory of Open Access Journals (Sweden)

    Hyoung Kyu Kim

    Full Text Available BACKGROUND AND PURPOSE: Beta adrenergic overstimulation may increase the vascular damage and stroke. However, the underlying mechanisms of beta adrenergic overstimulation in cerebrovascular dysfunctions are not well known. We investigated the possible cerebrovascular dysfunction response to isoproterenol induced beta-adrenergic overstimulation (ISO in rabbit cerebral arteries (CAs. METHODS: ISO was induced in six weeks aged male New Zealand white rabbit (0.8-1.0 kg by 7-days isoproterenol injection (300 μg/kg/day. We investigated the alteration of protein expression in ISO treated CAs using 2DE proteomics and western blot analysis. Systemic properties of 2DE proteomics result were analyzed using bioinformatics software. ROS generation and following DNA damage were assessed to evaluate deteriorative effect of ISO on CAs. Intracellular Ca(2+ level change and vascular contractile response to vasoactive drug, angiotensin II (Ang II, were assessed to evaluate functional alteration of ISO treated CAs. Ang II-induced ROS generation was assessed to evaluated involvement of ROS generation in CA contractility. RESULTS: Proteomic analysis revealed remarkably decreased expression of cytoskeleton organizing proteins (e.g. actin related protein 1A and 2, α-actin, capping protein Z beta, and vimentin and anti-oxidative stress proteins (e.g. heat shock protein 9A and stress-induced-phosphoprotein 1 in ISO-CAs. As a cause of dysregulation of actin-cytoskeleton organization, we found decreased level of RhoA and ROCK1, which are major regulators of actin-cytoskeleton organization. As functional consequences of proteomic alteration, we found the decreased transient Ca(2+ efflux and constriction response to angiotensin II and high K(+ in ISO-CAs. ISO also increased basal ROS generation and induced oxidative damage in CA; however, it decreased the Ang II-induced ROS generation rate. These results indicate that ISO disrupted actin cytoskeleton proteome network

  12. Beta-adrenergic stimulation reverses the I Kr-I Ks dominant pattern during cardiac action potential.

    Science.gov (United States)

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T; Chen-Izu, Ye

    2014-11-01

    β-Adrenergic stimulation differentially modulates different K(+) channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of I Ks, I Kr, and I K1 currents in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K(+) current to the total repolarization reserve. In this study, we used an innovative AP-clamp sequential dissection technique to directly record the dynamic I Ks, I Kr, and I K1 currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of I Ks, I Kr, and I K1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca(2+) homeostasis. We found that isoproterenol treatment significantly enhanced I Ks, moderately increased I K1, but slightly decreased I Kr in a dose-dependent manner. The dominance pattern of the K(+) currents was I Kr > I K1 > I Ks at the control condition, but reversed to I Kr < I K1 < I Ks following β-adrenergic stimulation. We systematically determined the changes in the relative contribution of I Ks, I Kr, and I K1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K(+) currents in a dose-dependent manner. This knowledge is important for designing antiarrhythmic drug strategies to treat hearts exposed to various sympathetic tones.

  13. 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.

  14. PARTIAL AGONISTS, FULL AGONISTS, ANTAGONISTS - DILEMMAS OF DEFINITION

    NARCIS (Netherlands)

    HOYER, D; BODDEKE, HWGM

    1993-01-01

    The absence of selective antagonists makes receptor characterization difficult, and largely dependent on the use of agonists. However, there has been considerable debate as to whether certain drugs acting at G protein-coupled receptors are better described as agonists, partial agonists or antagonist

  15. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

    NARCIS (Netherlands)

    Al-Inany, Hesham G.; Youssef, Mohamed A.; Ayeleke, Reuben Olugbenga; Brown, Julie; Lam, Wai Sun; Broekmans, Frank J.

    2016-01-01

    Background: Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-oestrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists direct

  16. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    Science.gov (United States)

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  17. Optimisation of GnRH antagonist use in ART

    NARCIS (Netherlands)

    Hamdine, O.

    2014-01-01

    This thesis focuses on the optimisation of controlled ovarian stimulation for IVF using exogenous FSH and GnRH antagonist co-treatment, by studying the timing of the initiation of GnRH antagonist co-medication and the role of ovarian reserve markers in optimising ovarian response and reproductive ou

  18. 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.

  19. Expressions of cardiac sympathetic norepinephrine transporter and β1-adrenergic receptor decreased in aged rats

    Institute of Scientific and Technical Information of China (English)

    He LI; Xiao-qing MA; Fan YE; Jing ZHANG; Xin ZHOU; Zhi-hong WANG; Yu-ming LI; Guo-yuan ZHANG

    2009-01-01

    Evidence suggests that the deterioration of communication between the sympathetic nervous system and cardiovas-cular system always accompanies the aging of human and animals. Cardiac sympathetic norepinephrine (NE) transporter (NET) on presynaptic membrane is a predominant component to eliminate released NE in the synaptic cleff and maintains the sensitivity of the β-adrenergic receptor (β-AR). In the present study, we investigated NET and β1-AR mRNA levels and sympathetic nerve density in cardiac sympathetic ganglion and leff ventricular myocardium in 2- and 16-month-old rats with Northern blot analysis and immunohistochemistry. The expression levels of NET mRNA, NET protein and β1-AR mRNA in the ganglia or myocardia of 16-month-old rats were markedly reduced by 67%, 26%, and 43%, respectively, in comparison with those in 2-month-old rats. Our results also show that aging induces a strong decrease of the catecholaminergic nerve fiber density.

  20. a-Adrenergic vasoconstrictor responsiveness is preserved in the heated human leg

    DEFF Research Database (Denmark)

    Keller, David M; Sander, Mikael; Stallknecht, Bente Merete;

    2010-01-01

    This study tested the hypothesis that passive leg heating attenuates a-adrenergic vasoconstriction within that limb. Femoral blood flow (FBF, femoral artery ultrasound Doppler) and femoral vascular conductance (FVC, FBF/mean arterial blood pressure), as well as calf muscle blood flow (Calf......BF, ¹³³xenon) and calf vascular conductance (CalfVC) were measured during intra-arterial infusion of an a1-adrenoreceptor agonist, phenylephrine (PE, 0.025 to 0.8 µg kg¿1 min¿1) and an a2-adrenoreceptor agonist, BHT-933 (1.0 to 10 µg kg¿1 min¿1) during normothermia and passive leg heating (water-perfused pant...... leg). Passive leg heating (~46¿C water temperature) increased FVC from 4.5 ± 0.5 to 11.9 ± 1.3 ml min¿1 mmHg¿1 (P

  1. 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).

  2. beta2 adrenergic agonists in acute lung injury? The heart of the matter.

    Science.gov (United States)

    Lee, Jae W

    2009-01-01

    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of beta2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to increase the resolution of pulmonary edema. However, the results of clinical trials of beta agonist therapy for ALI/ARDS have been conflicting in terms of benefit. In the previous issue of Critical Care, Briot and colleagues present evidence that may help clarify the inconsistent results. The authors demonstrate that, in oleic acid lung injury in dogs, the inotropic effect of beta agonists may recruit damaged pulmonary capillaries, leading to increased lung endothelial permeability.

  3. 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.

  4. Heterogeneous responses of human limbs to infused adrenergic agonists: a gravitational effect?

    Science.gov (United States)

    Pawelczyk, James A.; Levine, Benjamin D.

    2002-01-01

    Unlike quadrupeds, the legs of humans are regularly exposed to elevated pressures relative to the arms. We hypothesized that this "dependent hypertension" would be associated with altered adrenergic responsiveness. Isoproterenol (0.75-24 ng x 100 ml limb volume-1 x min-1) and phenylephrine (0.025-0.8 microg x 100 ml limb volume-1 x min-1) were infused incrementally in the brachial and femoral arteries of 12 normal volunteers; changes in limb blood flow were quantified by using strain-gauge plethysmography. Compared with the forearm, baseline calf vascular resistance was greater (38.8 +/- 2.5 vs. 26.9 +/- 2.0 mmHg x 100 ml x min x ml-1; P filtration in the legs during standing.

  5. [Beta-3 adrenergic receptor--structure and role in obesity and metabolic disorders].

    Science.gov (United States)

    Wiejak, J; Wyroba, E

    1999-01-01

    Structure and essential motifs of beta 3-adrenergic receptor (known previously as atypical beta-AR), which plays a central role in regulation of lipid metabolism have been described. Obesity results from an imbalance between caloric intake and energy expenditure. The consequence of catecholamine activation of beta 3-AR is increased mobilization of fatty acids from triglyceride stores (lipolysis) in brown and white adipose tissue as well as increased fatty acid beta-oxidation and heat-production via UCP-1 (thermogenesis) in brown adipose tissue. A pharmacokinetic effects of beta 3-agonists and putative involvement of Trp/Arg mutation in beta 3-AR gene in obesity and another metabolic disorders have been discussed.

  6. 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

    in the mutant receptors not by normal catecholamine ligands but instead either by free zinc ions or by zinc or copper ions in complex with small hydrophobic metal-ion chelators. Chelation of the metal ions by small hydrophobic chelators such as phenanthroline or bipyridine protected the cells from the toxic......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...

  7. Adrenergic receptor polymorphisms and autonomic nervous system function in human obesity.

    Science.gov (United States)

    Yasuda, Koichiro; Matsunaga, Tetsuro; Adachi, Tetsuya; Aoki, Norihiko; Tsujimoto, Gozoh; Tsuda, Kinsuke

    2006-09-01

    Adrenergic receptors (ARs) are cell-surface G-protein-coupled receptors for catecholamines. They are essential components of the sympathetic nervous system, organized within the autonomic nervous system (ANS), which controls various physiological functions, including energy homeostasis and metabolism of glucose and lipids. An impairment of ANS function in metabolism is considered to be one of the pathological states associated with human obesity and related metabolic diseases; thus, alterations in AR function might be implicated in the pathophysiology of these diseases. Several studies have suggested an association between obesity phenotypes and some AR polymorphisms. In vitro and human clinical studies indicate that some of these polymorphisms have functional and pathophysiological significance, including the linkage to ANS function. This review summarizes present knowledge of AR polymorphisms related to human obesity, and their association with ANS function.

  8. A lack of α1A-adrenergic receptor-mediated antidepressant-like effects of S-(+)-niguldipine and B8805-033 in the forced swim test.

    Science.gov (United States)

    Kreiner, Grzegorz; Roman, Adam; Zelek-Molik, Agnieszka; Kowalska, Marta; Nalepa, Irena

    2016-06-01

    The α1-adrenergic receptors (α1-ARs), which belong to a G protein-coupled receptor family, consist of three highly homologous subtypes known as α1A-ARs, α1B-ARs, and α1D-ARs. Our previous findings suggested that α1A-ARs are an important target for imipramine and electroconvulsive therapy. The current study sought to evaluate whether S-(+)-niguldipine and B8805-033, two selective antagonists of α1A-ARs, can evoke antidepressant-like effects in the forced swim test in rats. Both compounds were administered at three time points (24, 5, and 1 h before testing), and the effects of three doses (2, 5, and 10 mg/kg) of each compound were investigated. S-(+)-Niguldipine produced no antidepressant-like effects other than a 14% reduction in immobility time at the highest dose. Although B8805-033 at a dose of 2 mg/kg did not influence the rats' behavior, higher B8805-033 doses (5 and 10 mg/kg) produced significant reductions in immobility time (approximately 42 and 44% vs. controls, respectively; P<0.01). However, this effect was abolished by the concomitant administration of WAY100135, a serotonin receptor antagonist, suggesting that the observed antidepressant-like effects of B8805-033 are unrelated to α1A-ARs. Nevertheless, given the current dearth of selective α1A-AR agonists, the question of whether this particular subtype could be involved in antidepressant therapy mechanisms remains unresolved.

  9. Presence and location of adrenergic nerve endings in the dental pulps of mouse molars.

    Science.gov (United States)

    Avery, J K; Cox, C F; Chiego, D J

    1980-09-01

    In all, 30 adult (45-day-old) Swiss Webster mice were used for light and electron microscopic examination of the presence, number, and location of adrenergic endings in the first molar teeth. Prior to sacrifice, 10 animals received i.p. injections at 8, 6, 4, and 2 hours of 0.5 cc of 20 mg/kg solution of 5-hydroxydopamine (5-OH-DA) as a label for adrenergic endings. The animals were then anesthetized, perfused with Karnovsky's fixative, and the teeth were postfixed in Osmic acid, decalcified, embedded in methacrylate, and serial-sectioned. The sections were surveyed by light microscopy, and the number and location of nerve endings containing the reduced 5-OH-DA were recorded. Ten control mice were injected with the vehicle solution and prepared in the same manner. A third series of mice were given a single injection of 5-OH-DA, sacrificed, and prepared for ultrastructural study. The molar pulps were divided into four areas to facilitate examination: pulp horns, coronal pulp, bifurcation area, and root pulp. These four areas were further divided into three zones: odontogenic, vascular-related, and nonvascular-associated. The location and number of endings were evaluated, and an average of approximately 70 endings containing the 5-OH-DA were found in each tooth using light microscopy. These represented 35.5 +/- 5.2 in the pulp horns; 26.1 +/- 2.4 in the central coronal; 5.4 +/- 0.7 in the bifurcation, and 5.6 +/- 0.9 in the root pulp per tooth. Vascular related endings were found in greatest number, the odontogenic zone next, and free endings lease. Verification of location of 5-OH-DA by ultrastructural analysis revealed the false transmitter in vesiculated endings in the four areas and zones of the pulp.

  10. Increased circulating β2-adrenergic receptor autoantibodies are associated with smoking-related emphysema

    Science.gov (United States)

    Hu, Jia-yi; Liu, Bei-bei; Du, Yi-peng; Zhang, Yuan; Zhang, Yi-wei; Zhang, You-yi; Xu, Ming; He, Bei

    2017-01-01

    Smoking is a dominant risk factor for chronic obstructive pulmonary disease (COPD) and emphysema, but not every smoker develops emphysema. Immune responses in smokers vary. Some autoantibodies have been shown to contribute to the development of emphysema in smokers. β2-adrenergic receptors (β2-ARs) are important targets in COPD therapy. β2-adrenergic receptor autoantibodies (β2-AAbs), which may directly affect β2-ARs, were shown to be increased in rats with passive-smoking-induced emphysema in our current preliminary studies. Using cigarette-smoke exposure (CS-exposure) and active-immune (via injections of β2-AR second extracellular loop peptides) rat models, we found that CS-exposed rats showed higher serum β2-AAb levels than control rats before alveolar airspaces became enlarged. Active-immune rats showed increased serum β2-AAb levels, and exhibited alveolar airspace destruction. CS-exposed-active-immune treated rats showed more extensive alveolar airspace destruction than rats undergoing CS-exposure alone. In our current clinical studies, we showed that plasma β2-AAb levels were positively correlated with the RV/TLC (residual volume/total lung capacity) ratio (r = 0.455, p < 0.001) and RV%pred (residual volume/residual volume predicted percentage, r = 0.454, p < 0.001) in 50 smokers; smokers with higher plasma β2-AAb levels exhibited worse alveolar airspace destruction. We suggest that increased circulating β2-AAbs are associated with smoking-related emphysema. PMID:28262783

  11. Effects of adrenalectomy on the alpha-adrenergic regulation of cytosolic free calcium in hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Freudenrich, C.C.; Borle, A.B.

    1988-06-25

    We have previously published that bilateral adrenalectomy in the rat reduces the Ca2+-mediated alpha-adrenergic activation of hepatic glycogenolysis, while it increases the cellular calcium content of hepatocytes. In the experiments presented here, the concentration of cytosolic free calcium (Ca2+i) at rest and in response to epinephrine was measured in aequorin-loaded hepatocytes isolated from sham and adrenalectomized male rats. We found that in adrenalectomized rats the resting Ca2+i was elevated, the rise in Ca2+i evoked by epinephrine was reduced, and the rise in /sup 45/Ca efflux that follows such stimulation was depressed. Furthermore, the slope of the relationship between Ca2+i and calcium efflux was decreased 60% in adrenalectomized. Adrenalectomy did not change Ca2+ release from intracellular calcium pools in response to IP3 in saponin-permeabilized hepatocytes. The EC50 for inositol 1,4,5-triphosphate and the maximal Ca2+ released were similar in both sham and adrenalectomized animals. Finally, the liver calmodulin content determined by radioimmunoassay was not significantly different between sham and adrenalectomized rats. These results suggest that 1) adrenalectomy reduces calcium efflux from the hepatocyte, probably by an effect on the plasma membrane (Ca2+-Mg2+)-ATPase-dependent Ca2+ pump and thus alters cellular calcium homeostasis; 2) adrenalectomy decreases the rise in Ca2+i in response to epinephrine; 3) this decreased rise in Ca2+i is not due to defects in the intracellular Ca2+ storage and mobilization processes; and 4) the effects of adrenalectomy on cellular calcium metabolism and on alpha-adrenergic activation of glycogenolysis are not caused by a reduction in soluble calmodulin.

  12. Radiolabeled meta-iodobenzylguanidine and the adrenergic neurons of salivary glands

    Energy Technology Data Exchange (ETDEWEB)

    Sisson, J.C.; Wieland, D.M.; Jaques, S. Jr.; Sherman, P.; Fisher, S.; Mallette, S.; Meyers, L.; Mangner, T.J.

    1987-01-01

    The handling of radiolabeled meta-iodobenzylguanidine (MIBG) by salivary glands was evaluated. In the submaxillary glands of rats, the uptake of 125I-MIBG was decreased after 1) nerve injury induced by 6-hydroxydopamine, 2) inhibition of the uptake-1 pathway by desmethylimipramine, and 3) surgical denervation. However, the reduction in 125I-MIGB uptake was less than that of 3H-norepinephrine (3H-NE) and of the endogenous content of NE in the glands. Yet, the sympathomimetic phenylpropanolamine displaced about the same fraction of 125I-MIBG as 3H-NE. These results suggest that 40% or more of 125I-MIBG resides in extraneuronal sites but that at least 30% and possibly more lies in the adrenergic nerve terminals. Fasting and feeding rats produced changes in the rates of disappearance of 125I-MIBG and 3H-NE from the submaxillary gland that were different, and the rates of loss of 125I-MIBG cannot be used as an index of adrenergic nerve activity. In man, the concentrations of 123I-MIBG in the salivary glands, particularly the parotid gland, are readily visible and measureable. Imipramine reduced the uptake of 123I-MIBG into parotid glands little or not at all; some of the 123I-MIBG may enter neurons via an imipramine-insensitive pathway, but a substantial fraction probably arrives in intraneuronal locations. Thus, phenylpropanolamine displaced over 50% of the parotid pool of 123I-MIBG. However, in only the most severe case of generalized autonomic neuropathy was the uptake of 123I-MIBG reduced.

  13. Histone H3 phosphorylation in the rat pineal gland: adrenergic regulation and diurnal variation.

    Science.gov (United States)

    Chik, C L; Arnason, T G; Dukewich, W G; Price, D M; Ranger, A; Ho, A K

    2007-04-01

    In this study, we investigated phosphorylation of Ser10 in histone H3 by norepinephrine (NE) in the rat pineal gland. In whole-animal studies, we demonstrated a marked increase in histone H3 phosphorylation in the rat pineal gland during the first half of the dark period. Exposure to light during this period caused a rapid decline in histone H3 phosphorylation with an estimated t1/2 of less than 15 min, indicating a high level of dephosphorylation activity. Corresponding studies in cultured pineal cells revealed that treatment with NE produced an increase in histone H3 phosphorylation that peaked between 2 and 3 h and declined rapidly by 4 h. The NE-induced histone H3 phosphorylation was blocked by cotreatment with propranolol or KT5720, a protein kinase A inhibitor, but not by prazosin or other kinase inhibitors. Moreover, only treatment with dibutyryl cAMP but not other kinase activators mimicked the effect of NE on histone H3 phosphorylation. The NE-stimulated H3 phosphorylation was markedly increased by cotreatment with a serine/threonine phosphatase inhibitor, tautomycin or okadaic acid, supporting a high level of ongoing histone H3 dephosphorylation activity. Together, our results indicate that histone H3 phosphorylation is a naturally occurring event at night in the rat pineal gland that is driven almost exclusively by a NE-->beta-adrenergic-->cAMP/protein kinase A signaling mechanism. This transient histone H3 phosphorylation probably reflects the nocturnal activation of multiple adrenergic-regulated genes in the rat pineal gland.

  14. Multiple interactions between the alpha2C- and beta1-adrenergic receptors influence heart failure survival

    Directory of Open Access Journals (Sweden)

    Case Karen L

    2008-10-01

    Full Text Available Abstract Background Persistent stimulation of cardiac β1-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the α2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (ADRB1 and ADRA2C, respectively on the risk of death/transplant in heart failure patients. Methods Sixteen sequence variations in ADRA2C and 17 sequence variations in ADRB1 were genotyped in a longitudinal study of 655 white heart failure patients. Eleven sequence variations in each gene were polymorphic in the heart failure cohort. Cox proportional hazards modeling was used to identify polymorphisms and potential intra- or intergenic interactions that influenced risk of death or cardiac transplant. A leave-one-out cross-validation method was utilized for internal validation. Results Three polymorphisms in ADRA2C and five polymorphisms in ADRB1 were involved in eight cross-validated epistatic interactions identifying several two-locus genotype classes with significant relative risks ranging from 3.02 to 9.23. There was no evidence of intragenic epistasis. Combining high risk genotype classes across epistatic pairs to take into account linkage disequilibrium, the relative risk of death or transplant was 3.35 (1.82, 6.18 relative to all other genotype classes. Conclusion Multiple polymorphisms act synergistically between the ADRA2C and ADRB1 genes to increase risk of death or cardiac transplant in heart failure patients.

  15. The impact of β 2 adrenergic receptor polymorphisms on the outcomes in cardiovascular diseases

    Directory of Open Access Journals (Sweden)

    Ersilia Cipolletta

    2014-12-01

    Full Text Available Cardiovascular diseases (CVD include a heterogeneous group of multifactorial conditions and represent the major health problem in the western society. Many studies have evidenced that inter-individual variability affects the prognosis and the response to pharmacological treatment in patients with CVD. The identification of genetic markers to select patients more susceptible to develop cardiovascular complications has a therapeutic interest for undertaking individualized therapeutic approach. The sympathetic nervous system acts through adrenergic receptor subtypes and plays a key role in the development and prognosis of CVD. In particular, β-2 adrenergic receptors (β2AR, expressed in a wide variety of tissues, are critical regulators of cardiac output, peripheral vascular resistance and metabolism. Several variations with multiple single-nucleotide polymorphisms have been identified in β2AR gene. There are 3 common β2AR polymorphisms characterized in more detail for their influence on functional receptor activity. In particular, the changing an arginine for a glycine at position 16 of the receptor protein (Arg16Gly is associated with increased agonist-induced down-regulation; the substitution of glutamine with glutamic acid at position 27 (Gln27Glu leads to resistance to down-regulation; the substitution of threonine with isoleucine (Thr164Ile at position 164 causes receptor uncoupling from the G protein. Many studies have indicated the association of β2AR polymorphisms with various cardiovascular and metabolic diseases and have contributed to indicate the β2AR gene variants an appropriate target for investigating possible links between receptor polymorphisms, drug responses and susceptibility to CVD. However, the reports on the association of β2AR polymorphisms with clinical outcomes of CVD have been contradictory. In this review, we will illustrate the effects of β2ARs genetic variability on the management of CVD.

  16. Diaphragm arterioles are less responsive to alpha1- adrenergic constriction than gastrocnemius arterioles.

    Science.gov (United States)

    Aaker, Aaron; Laughlin, M H

    2002-05-01

    The sympathetic nervous system has greater influence on vascular resistance in low-oxidative, fast-twitch skeletal muscle than in high-oxidative skeletal muscle (17). The purpose of this study was to test the hypothesis that arterioles isolated from low-oxidative, fast-twitch skeletal muscle [the white portion of gastrocnemius (WG)] possess greater responsiveness to adrenergic constriction than arterioles isolated from high-oxidative skeletal muscle [red portion of the gastrocnemius muscle (RG) and diaphragm (Dia)]. Second-order arterioles (2As) were isolated from WG, RG, and Dia of rats and reactivity examined in vitro. Results reveal that Dia 2As constrict less to norepinephrine (NE) (10(-9) to 10 (-4) M) than 2As from RG and WG, which exhibited similar NE-induced constrictions. This difference was not endothelium dependent, because responses of denuded 2As were similar to those of intact arterioles. The blunted NE-induced constrictor response of Dia 2As appears to be the result of differences in alpha1-receptor effects because 1) arterioles from Dia also responded less to selective alpha1-receptor stimulation with phenylephrine than RG and WG arterioles; 2) arterioles from Dia, RG, and WG dilated similarly to isoproterenol (10(-9) to 10(-4) M) and did not respond to selective alpha2-receptor stimulation with UK-14304; and 3) endothelin-1 produced similar constriction in 2As from Dia, RG, and WG. We conclude that differences in oxidative capacity and/or fiber type composition of muscle tissue do not explain different NE responsiveness of Dia 2As compared with 2As from gastrocnemius muscle. Differences in alpha1-adrenergic constrictor responsiveness among arterioles in skeletal muscle may contribute to nonuniform muscle blood flow responses observed during exercise and serve to maintain blood flow to Dia during exercise-induced increases in sympathetic nerve activity.

  17. Adrenergic responsiveness is reduced, while baseline cardiac function is preserved in old adult conscious monkeys

    Science.gov (United States)

    Sato, N.; Kiuchi, K.; Shen, Y. T.; Vatner, S. F.; Vatner, D. E.

    1995-01-01

    To examine the physiological deficit to adrenergic stimulation with aging, five younger adult (3 +/- 1 yr old) and nine older adult (17 +/- 1 yr old) healthy monkeys were studied after instrumentation with a left ventricular (LV) pressure gauge, aortic and left atrial catheters, and aortic flow probes to measure cardiac output directly. There were no significant changes in baseline hemodynamics in conscious older monkeys. For example, an index of contractility, the first derivative of LV pressure (LV dP/dt) was similar (3,191 +/- 240, young vs. 3,225 +/- 71 mmHg/s, old) as well as in isovolumic relaxation, tau (24.3 +/- 1.7 ms, young vs. 23.0 +/- 1.0 ms, old) was similar. However, inotropic, lusitropic, and chronotropic responses to isoproterenol (Iso; 0.1 micrograms/kg), norepinephrine (NE; 0.4 micrograms/kg), and forskolin (For; 75 nmol/kg) were significantly (P monkeys. For example. Iso increased LV dP/dt by by 146 +/- 14% in younger monkeys and by only 70 +/- 5% in older monkeys. Iso also reduced tau more in younger monkeys (-28 +/- 7%) compared with older monkeys (-13 +/- 3%). Furthermore, peripheral vascular responsiveness to Iso, NE, For, and phenylephrine (PE; 5 micrograms/kg) was significantly (P monkeys. For example, phenylephrine (5 micrograms/kg) increased total peripheral resistence by 69 +/- 4% in younger monkeys and by only 45 +/- 3% in older monkeys. Thus in older monkeys without associated cardiovascular disease, baseline hemodynamics are preserved, but adrenergic receptor responsiveness is reduced systemically, not just in the heart.

  18. Mapping genetic variants associated with beta-adrenergic responses in inbred mice.

    Directory of Open Access Journals (Sweden)

    Micha Hersch

    Full Text Available β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS addressing the values and susceptibility of cardiovascular-related traits to a selective β(1-blocker, Atenolol (ate, and a β-agonist, Isoproterenol (iso. The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA, a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8. An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6. Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD. Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied.

  19. Zinc and water intake in rats: investigation of adrenergic and opiatergic central mechanisms

    Directory of Open Access Journals (Sweden)

    J.B. Fregoneze

    1999-10-01

    Full Text Available We have demonstrated that central administration of zinc in minute amounts induces a significant antidipsogenic action in dehydrated rats as well as in rats under central cholinergic and angiotensinergic stimulation. Here we show that acute third ventricle injections of zinc also block water intake induced by central ß-adrenergic stimulation in Wistar rats (190-250 g. Central inhibition of opioid pathways by naloxone reverses the zinc-induced antidipsogenic effect in dehydrated rats. After 120 min, rats receiving third ventricle injections of isoproterenol (160 nmol/rat exhibited a significant increase in water intake (5.78 ± 0.54 ml/100 g body weight compared to saline-treated controls (0.15 ± 0.07 ml/100 g body weight. Pretreatment with zinc (3.0, 30.0 and 300.0 pmol/rat, 45 min before isoproterenol injection blocked water intake in a dose-dependent way. At the highest dose employed a complete blockade was demonstrable (0.54 ± 0.2 ml/100 g body weight. After 120 min, control (NaAc-treated dehydrated rats, as expected, exhibited a high water intake (7.36 ± 0.39 ml/100 g body weight. Central administration of zinc blocked this response (2.5 ± 0.77 ml/100 g body weight. Naloxone pretreatment (82.5 nmol/rat, 30 min before zinc administration reverted the water intake to the high levels observed in zinc-free dehydrated animals (7.04 ± 0.56 ml/100 g body weight. These data indicate that zinc is able to block water intake induced by central ß-adrenergic stimulation and that zinc-induced blockade of water intake in dehydrated rats may be, at least in part, due to stimulation of central opioid peptides.

  20. Atropine increases the positive adrenergic effects of norepinephrine : A pilot study.

    NARCIS (Netherlands)

    Kalmar, A.F.; Weening, Mariska; Struys, Michel; Scheeren, Thomas

    2012-01-01

    Background and Goal of Study: Atropine is a competitive antagonist of cholinergic receptors and is widely used to blunt the increased vagal tone that is often caused by surgical manipulations. It increases heart rate(HR) with minimal effects on mean arterial pressure(MAP) and cardiac output(CO). Nor

  1. 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

    to selectively bind agonist- or antagonist-occupied receptors. When expressed as intrabodies, they inhibited G protein activation (cyclic AMP accumulation), G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation, β-arrestin recruitment, and receptor internalization to varying extents...

  2. HBK-7 - A new xanthone derivative and a 5-HT1A receptor antagonist with antidepressant-like properties.

    Science.gov (United States)

    Pytka, Karolina; Kazek, Grzegorz; Siwek, Agata; Mordyl, Barbara; Głuch-Lutwin, Monika; Rapacz, Anna; Olczyk, Adrian; Gałuszka, Adam; Waszkielewicz, Anna; Marona, Henryk; Sapa, Jacek; Filipek, Barbara; Zygmunt, Małgorzata

    2016-01-01

    Xanthone derivatives possess many biological properties, including neuroprotective, antioxidant or antidepressant-like. In this study we aimed to investigate antidepressant- and anxiolytic-like properties of a new xanthone derivative - 6-methoxy-4-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-7), as well as its possible mechanism of action, and the influence on cognitive and motor function. HBK-7 in our earlier studies showed high affinity for serotonergic 5-HT1A receptor. We determined the affinity of HBK-7 for CNS receptors and transporters using radioligand assays and examined its intrinsic activity towards 5-HT1A receptor. We evaluated antidepressant- and anxiolytic-like activity of HBK-7 in the mouse forced swim test, and four-plate test, respectively. We examined the influence on locomotor activity in mice to determine if the effect observed in the forced swim test was specific. We used step-through passive avoidance and rotarod tests to evaluate the influence of HBK-7 on cognitive and motor function, respectively. HBK-7 showed moderate affinity for dopaminergic D2 receptor and very low for serotonergic 5-HT2A, adrenergic α2 receptors, as well as serotonin transporter. Functional studies revealed that HBK-7 was a 5-HT1A receptor antagonist. HBK-7 (10mg/kg) decreased immobility time in the forced swim test. Combined treatment with sub-effective doses of HBK-7 and fluoxetine reduced immobility of mice in the forced swim test. Pretreatment with p-chlorophenylalanine and WAY-100,635 antagonized the antidepressant-like effect of HBK-7. Neither of the treatments influenced locomotor activity of mice. HBK-7 at antidepressant-like dose did not impair memory or motor coordination in mice. We demonstrated that HBK-7 was a 5-HT1A receptor antagonist with potent, comparable to mianserin, antidepressant-like activity. HBK-7 mediated its effect through serotonergic system and its antidepressant-like action required the activation of 5-HT1A receptors. At active

  3. Time sequence of changes in the responsiveness of glycogen breakdown to adrenergic agonists in perfused liver of rats with insulin-induced hypoglycemia

    Directory of Open Access Journals (Sweden)

    Vardanega-Peicher M.

    2000-01-01

    Full Text Available The time-course changes of the responsiveness of glycogen breakdown to a- and ß-adrenergic agonists during insulin-induced hypoglycemia (IIH were investigated. Blood glucose levels were decreased prior to the alteration in the hepatic responsiveness to adrenergic agonists. The activation of hepatic glucose production and glycogenolysis by phenylephrine (2 µM and isoproterenol (20 µM was decreased in IIH. The changes in the responsiveness of glycogen catabolism were first observed for isoproterenol and later for phenylephrine. Hepatic ß-adrenergic receptors showed a higher degree of adrenergic desensitization than did a-receptors. Liver glycogen synthase activity, glycogen content and the catabolic effect of dibutyryl cyclic AMP (the ß-receptor second messenger were not affected by IIH.

  4. Natural Diterpenes from Coffee, Cafestol, and Kahweol Induce Peripheral Antinoceception by Adrenergic System Interaction.

    Science.gov (United States)

    Guzzo, Luciana Souza; Castor, Marina Gomes Miranda E; Perez, Andrea de Castro; Duarte, Igor Dimitri Gama; Romero, Thiago Roberto Lima

    2016-01-01

    Cafestol and kahweol are diterpenes found only in the non-saponified lipid fraction of coffee. They are released during boiling and retained in the filtration process. Previous studies have shown peripheral antinociception induced by endogenous opioid peptides released by these diterpenes. Considering that the activation of the opioid system leads to a noradrenaline release, the aim of this study was to verify the participation of the noradrenergic system in the peripheral antinociception induced by cafestol and kahweol. Hyperalgesia was induced by an intraplantar injection of prostaglandin E2 (2 µg). Cafestol or kahweol (80 µg/paw) were administered locally into the right hindpaw alone, and after the agents α 2-adrenoceptor antagonist yohimbine (5, 10 and 20 µg/paw), α 2 A-adrenoceptor antagonist BRL 44 408 (40 µg/paw), α 2B-adrenoceptor antagonist imiloxan (40 µg/paw), α 2 C-adrenoceptor antagonist rauwolscine (10, 15 and 20 µg/paw), α 2D-adrenoceptor antagonist RX 821 002 (40 µg/paw), α 1-adrenoceptor antagonist prazosin (0.5, 1 and 2 µg/paw), or β-adrenoceptor antagonist propranolol (150, 300 and 600 ng/paw), respectively. Noradrenaline reuptake inhibitor reboxetine (30 µg/paw) was administered prior to cafestol or kahweol low dose (40 µg/paw) and guanetidine 3 days prior to the experiment (30 mg/kg, once a day), depleting the noradrenaline storage. Intraplantar injection of cafestol or kahweol (80 µg/paw) induced a peripheral antinociception against hyperalgesia induced by PGE2. This effect was reversed by intraplantar injections of yohimbine, rauwolscine, prazosin and propranolol. Reboxetine injection intensified the antinociceptive effect of cafestol or kahweol low-dose, and guanethidine reversed almost 70 % of the cafestol or kahweol-induced peripheral antinociception. This study gives evidence that the noradrenergic system participates in cafestol and kahweol-induced peripheral antinociception with the

  5. β-Adrenergic stimulation increases Cav3.1 activity in cardiac myocytes through protein kinase A.

    Directory of Open Access Journals (Sweden)

    Yingxin Li

    Full Text Available The T-type Ca(2+ channel (TTCC plays important roles in cellular excitability and Ca(2+ regulation. In the heart, TTCC is found in the sinoatrial nodal (SAN and conduction cells. Cav3.1 encodes one of the three types of TTCCs. To date, there is no report regarding the regulation of Cav3.1 by β-adrenergic agonists, which is the topic of this study. Ventricular myocytes (VMs from Cav3.1 double transgenic (TG mice and SAN cells from wild type, Cav3.1 knockout, or Cav3.2 knockout mice were used to study β-adrenergic regulation of overexpressed or native Cav3.1-mediated T-type Ca(2+ current (I(Ca-T(3.1. I(Ca-T(3.1 was not found in control VMs but was robust in all examined TG-VMs. A β-adrenergic agonist (isoproterenol, ISO and a cyclic AMP analog (dibutyryl-cAMP significantly increased I(Ca-T(3.1 as well as I(Ca-L in TG-VMs at both physiological and room temperatures. The ISO effect on I(Ca-L and I(Ca-T in TG myocytes was blocked by H89, a PKA inhibitor. I(Ca-T was detected in control wildtype SAN cells but not in Cav3.1 knockout SAN cells, indicating the identity of I(Ca-T in normal SAN cells is mediated by Cav3.1. Real-time PCR confirmed the presence of Cav3.1 mRNA but not mRNAs of Cav3.2 and Cav3.3 in the SAN. I(Ca-T in SAN cells from wild type or Cav3.2 knockout mice was significantly increased by ISO, suggesting native Cav3.1 channels can be upregulated by the β-adrenergic (β-AR system. In conclusion, β-adrenergic stimulation increases I(Ca-T(3.1 in cardiomyocytes(, which is mediated by the cAMP/PKA pathway. The upregulation of I(Ca-T(3.1 by the β-adrenergic system could play important roles in cellular functions involving Cav3.1.

  6. Fine Tuning of a Type 1 Interferon Antagonist.

    Directory of Open Access Journals (Sweden)

    Victoria Urin

    Full Text Available Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition.

  7. Nalmefene: radioimmunoassay for a new opioid antagonist.

    Science.gov (United States)

    Dixon, R; Hsiao, J; Taaffe, W; Hahn, E; Tuttle, R

    1984-11-01

    A specific radioimmunoassay (RIA) has been developed for the quantitation of a new opioid antagonist, nalmefene, in human plasma. The method employs a rabbit antiserum to an albumin conjugate of naltrexone-6-(O-carboxymethyl)oxime and [3H]naltrexone as the radioligand. Assay specificity was achieved by extraction of nalmefene from plasma at pH 9 into ether prior to RIA. The procedure has a limit of sensitivity of 0.2 ng/mL of nalmefene using a 0.5-mL sample of plasma for analysis. The intra- and interassay coefficients of variation did not exceed 5.6 and 11%, respectively. The specificity of the RIA was established by demonstrating excellent agreement (r = 0.99) with a less sensitive and more time consuming HPLC procedure in the analysis of clinical plasma samples. The use of the RIA for the pharmacokinetic evaluation of nalmefene is illustrated with plasma concentration profiles of the drug in humans following intravenous and oral administration.

  8. Antagonistic Neural Networks Underlying Differentiated Leadership Roles

    Directory of Open Access Journals (Sweden)

    Richard Eleftherios Boyatzis

    2014-03-01

    Full Text Available The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950’s. Recent research in neuroscience suggests that the division between task oriented and socio-emotional oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks -- the Task Positive Network (TPN and the Default Mode Network (DMN. Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success.

  9. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

    Science.gov (United States)

    Khanfar, Mohammad A; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  10. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Mohammad eKhanfar

    2016-05-01

    Full Text Available With the very recent market approval of pitolisant (Wakix®, the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  11. Identification of a novel conformationally constrained glucagon receptor antagonist.

    Science.gov (United States)

    Lee, Esther C Y; Tu, Meihua; Stevens, Benjamin D; Bian, Jianwei; Aspnes, Gary; Perreault, Christian; Sammons, Matthew F; Wright, Stephen W; Litchfield, John; Kalgutkar, Amit S; Sharma, Raman; Didiuk, Mary T; Ebner, David C; Filipski, Kevin J; Brown, Janice; Atkinson, Karen; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel

    2014-02-01

    Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.

  12. New potential uroselective NO-donor alpha1-antagonists.

    Science.gov (United States)

    Boschi, Donatella; Tron, Gian Cesare; Di Stilo, Antonella; Fruttero, Roberta; Gasco, Alberto; Poggesi, Elena; Motta, Gianni; Leonardi, Amedeo

    2003-08-14

    A recent uroselective alpha(1)-adrenoceptor antagonist, REC15/2739, has been joined with nitrooxy and furoxan NO-donor moieties to give new NO-donor alpha(1)-antagonists. All the compounds studied proved to be potent and selective ligands of human cloned alpha(1a)-receptor subtype. Derivatives 6 and 7 were able to relax the prostatic portion of rat vas deferens contracted by (-)-noradrenaline because of both their alpha(1A)-antagonist and their NO-donor properties.

  13. A case of life-threatening lactic acidosis after smoke inhalation - interference between beta-adrenergic agents and ethanol?

    Science.gov (United States)

    Taboulet, P; Clemessy, J L; Freminet, A; Baud, F J

    1995-12-01

    A 49-year-old male developed bronchospasm and severe lactic acidosis after exposition to fire smoke. The correction of lactic acidosis following beta-adrenergic agents withdrawal, and the transitory increase in lactate after salbutamol reintroduction are consistent with hypersensitivity to salbutamol. However, the plasma lactate concentration (32.6 mmol/l) that we observed 9.5 h after admission is far above those currently seen after administration of beta-adrenergic agents. We searched for causes able to potentiate the adverse effects of these drugs and we noticed that our patient had a high plasma ethanol level (2.4 g/l). Alcohol metabolism in the liver results in generation of high NADH/NAD+ ratios, thus reducing lactate liver clearance. This observation suggests that plasma lactate levels should be monitored closely in alcoholic patients treated with beta-mimetic agents.

  14. Osmotic versus adrenergic control of ion transport by ionocytes of Fundulus heteroclitus in the cold

    DEFF Research Database (Denmark)

    Tait, Janet C; Mercer, Evan W; Gerber, Lucie;

    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 Isc at 21°C and 5°C (measured at acclimation temperature), was significantly inhibited by the α2-adrenergic agonist clonidine...... inhibition of Isc, 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...

  15. Glucose-induced thermogenesis in patients with small cell lung carcinoma. The effect of acute beta-adrenergic inhibition

    DEFF Research Database (Denmark)

    Simonsen, L; Bülow, J; Tuxen, C

    1994-01-01

    Seven patients with histologically verified small cell lung carcinoma were given an oral glucose load of 75 g on two occasions to examine the effect of glucose on whole body and forearm thermogenesis with and without acute beta-adrenergic inhibition with propranolol. Whole body energy expenditure...... was measured by the open circuit ventilated hood system. Forearm blood flow was measured by venous occlusion strain-gauge plethysmography. The uptake of oxygen in the forearm was calculated as the product of the forearm blood flow and the difference in arteriovenous oxygen concentration. The glucose......-induced forearm oxygen uptake in the period 60-120 min following the glucose load was significantly reduced after beta-adrenergic inhibition from 103 +/- 28 mumol 100 g-1 60 min-1 to 29 +/- 29 mumol 100 g-1 60 min-1 (P blood was not increased...

  16. The relationship between some beta-adrenergic mediated responses and plasma concentrations of adrenaline and cyclic AMP in man

    DEFF Research Database (Denmark)

    Philipsen, E K; Myhre, John Gabriel; Larsen, S;

    1990-01-01

    concentrations at low adrenaline infusion rates was prevented, whereas a small increase in cyclic AMP was found at high adrenaline infusion rates, probably owing to incomplete beta-receptor blockade. Likewise, the adrenaline-induced increments in blood substrates (glucose, lactate, glycerol and beta......To test the hypothesis that increments in plasma cyclic AMP during beta-adrenergic stimulation reflect integrated second messenger function of the tissues activated by the agonist, graded adrenaline infusion resulting in plasma adrenaline concentrations within the physiological range was performed...... hydroxybutyric acid) were significantly reduced but not completely prevented by beta-blockade. We conclude that an altered relationship between beta-agonist concentrations and plasma cyclic AMP may provide evidence for the existence of differences in beta-adrenergic sensitivity in man....

  17. The pharmacological properties of lipophilic calcium antagonists.

    Science.gov (United States)

    van Zwieten, P A

    1998-01-01

    Several types of calcium antagonists (CA) (verapamil, diltiazem, nifedipine and related drugs) may be used as antihypertensives. In practice, the dihydropyridines (nifedipine and related drugs) are the CA used most frequently as antihypertensives. Apart from the lowering of blood pressure CA may lead to other, theoretically beneficial, effects: regression of left ventricular and vascular hypertrophy, renal protection, weak natriuretic, weak antiplatelet, anti-ischaemic and antiatherogenic activity. Several new dihydropyridine CA have been introduced in recent years. The advantages of the newer compounds, such as amlodipine, felodipine, isradipine, lacidipine and lercanidipine, may include: vasoselectivity, hence little or no cardiodepressant activity; an improved kinetic profile, resulting in a slow onset and long duration of action, fewer side-effects such as reflex tachycardia and headache, owing to the slow onset of the antihypertensive action. For a few newer CA a predominant effect on specialized circulatory beds (renal, coronary and cerebral) has been claimed. The new CA, which are clearly lipophilic, deserve special attention. Owing to the lipophilic character of such compounds considerable concentration occurs in lipid-containing membrane depots. The CA thus concentrated are slowly released from these depots and, subsequently, reach their targets, the L-type calcium channels. This phenomenon explains both the slow onset and the long duration of action of these CA. Owing to the slow onset of action reflex tachycardia is virtually absent. The long duration of action allows satisfactory control of blood pressure in hypertensives by means of a single daily dose. A few lipophilic dihydropyridine CA are vasoselective. This property implies that at therapeutic, vasodilatory dosages no cardiodepressant activity occurs. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine CA. It is an effective vasodilator

  18. ß2 -adrenergic receptor Thr164IIe polymorphism, blood pressure and ischaemic heart disease in 66¿750 individuals

    DEFF Research Database (Denmark)

    Thomsen, M; Dahl, Morten; Tybjaerg-Hansen, A;

    2012-01-01

    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 cause lifelong elevated smooth musc...... tone. We tested the hypothesis that Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of cardiovascular disease (CVD)....

  19. Melatonin receptor-mediated protection against myocardial ischaemia/reperfusion injury: role of its anti-adrenergic actions.

    Science.gov (United States)

    Genade, Sonia; Genis, Amanda; Ytrehus, Kirsti; Huisamen, Barbara; Lochner, Amanda

    2008-11-01

    Melatonin has potent cardioprotective properties. These actions have been attributed to its free radical scavenging and anti-oxidant actions, but may also be receptor mediated. Melatonin also exerts powerful anti-adrenergic actions based on its effects on contractility of isolated papillary muscles. The aims of this study were to determine whether melatonin also has anti-adrenergic effects on the isolated perfused rat heart, to determine the mechanism thereof and to establish whether these actions contribute to protection of the heart during ischaemia/reperfusion. The results showed that melatonin (50 microM) caused a significant reduction in both isoproterenol (10(-7) M) and forskolin (10(-6) M) induced cAMP production and that both these responses were melatonin receptor dependent, since the blocker, luzindole (5 x 10(-6) M) abolished this effect. Nitric oxide (NO), as well as guanylyl cyclase are involved, as L-NAME (50 microM), an NO synthase inhibitor and ODQ (20 microM), a guanylyl cyclase inhibitor, significantly counteracted the effects of melatonin. Protein kinase C (PKC), as indicated by the use of the inhibitor bisindolylmaleimide (50 microM), also play a role in melatonin's anti-adrenergic actions. These actions of melatonin are involved in its cardioprotection: simultaneous administration of L-NAME or ODQ with melatonin, before and after 35 min regional ischaemia, completely abolished its cardioprotection. PKC, on the other hand, had no effect on the melatonin-induced reduction in infarct size. Cardioprotection by melatonin was associated with a significant activation of PKB/Akt and attenuated activation of the pro-apoptotic kinase, p38MAPK during early reperfusion. In summary, the results show that melatonin-induced cardioprotection may be receptor dependent, and that its anti-adrenergic actions, mediated by NOS and guanylyl cyclase activation, are important contributors.

  20. Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and Metastasis

    Science.gov (United States)

    2015-10-01

    1 AWARD NUMBER: W81XWH-13-1-0439 TITLE: Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and...treatment of breast cancer often experience severe and chronic psychological stress. The sympathetic nervous system (SNS) is an important pathway by which...Sephton SE, McDonald PG, et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer . 2006;6:240-8. 3

  1. 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.

  2. A SELECTIVE ANTAGONIST OF MINERALOCORTICOID RECEPTOR EPLERENONE IN CARDIOLOGY PRACTICE

    Directory of Open Access Journals (Sweden)

    B. B. Gegenava

    2015-09-01

    Full Text Available The role of aldosterone in pathophysiological processes is considered. The effects of the selective antagonist of mineralocorticoid receptor eplerenone are analyzed. The advantages of eplerenone compared with spironolactone are discussed.

  3. Structure-based drug design identifies novel LPA3 antagonists.

    Science.gov (United States)

    Fells, James I; Tsukahara, Ryoko; Liu, Jianxiong; Tigyi, Gabor; Parrill, Abby L

    2009-11-01

    Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-yl]acetic acid) was identified as a weak selective LPA(3) antagonist (IC(50)=4504 nM) in a virtual screening effort to optimize a dual LPA(2 and 3) antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA(3) receptor by 200 nM LPA with IC(50) values of 752 nM and 2992 nM. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA(3) receptor antagonists. The results of the combined computational and experimental screening are reported.

  4. Secondary prevention with calcium antagonists after acute myocardial infarction

    DEFF Research Database (Denmark)

    Hansen, J F

    1992-01-01

    Experimental studies have demonstrated that the 3 calcium antagonists nifedipine, diltiazem, and verapamil have a comparable effect in the prevention of myocardial damage during ischaemia. Secondary prevention trials after acute myocardial infarction, which aimed at improving survival...

  5. Perampanel: A Selective AMPA Antagonist for Treating Seizures

    OpenAIRE

    Krauss, Gregory L.

    2013-01-01

    Perampanel is a selective, noncompetitive AMPA receptor antagonist that has recently been approved for treating localization-related epilepsy. This article reviews the pharmacology, clinical development, efficacy, and safety/tolerability of perampanel.

  6. Complications of TNF-α antagonists and iron homeostasis

    Science.gov (United States)

    TNF-α is a central regulator of inflammation and its blockade downregulates other proinflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficia...

  7. Targeting beta- and alpha-adrenergic receptors differentially shifts Th1, Th2, and inflammatory cytokine profiles in immune organs to attenuate adjuvant arthritis

    Directory of Open Access Journals (Sweden)

    Dianne eLorton

    2014-08-01

    Full Text Available The sympathetic nervous system (SNS regulates host defense responses and restores homeostasis. SNS-immune regulation is altered in rheumatoid arthritis (RA and rodent models of RA, characterized by nerve remodeling in immune organs and defective adrenergic receptor (AR signaling to immune cell targets that typically promotes or suppresses inflammation via α- and β2-AR activation, respectively, and indirectly drives humoral immunity by blocking Th1 cytokine secretion. Here, we investigate how β2-AR stimulation and/or α-AR blockade at disease onset affects disease pathology and cytokine profiles in relevant immune organs from male Lewis rats with adjuvant-induced arthritis (AA. Rats challenged to induce AA were treated with terbutaline (TERB, a β2-AR agonist (600 μg/kg/day and/or phentolamine (PHEN, an α-AR antagonist (5.0 mg/kg/day or vehicle from disease onset through severe disease. We report that in spleen, mesenteric (MLN and draining lymph node (DLN cells, TERB reduces proliferation, an effect independent of IL-2. TERB also fails to shift Th cytokines from a Th1 to Th2 profile in spleen and MLN (no effect on IFN-γ and DLN (greater IFN-γ cells. In splenocytes, TERB, PHEN and co-treatment (PT promotes an anti-inflammatory profile (greater IL-10 and lowers TNF-α (PT only. In DLN cells, drug treatments do not affect inflammatory profiles, except PT, which raised IL-10. In MLN cells, TERB or PHEN lowers MLN cell secretion of TNF-α or IL-10, respectively. Collectively, our findings indicate disrupted β2-AR, but not α-AR signaling in AA. Aberrant β2-AR signaling consequently derails the sympathetic regulation of lymphocyte expansion, Th cell differentiation, and inflammation in the spleen, DLNs and MLNs that is required for immune system homeostasis. Importantly, this study provides potential mechanisms through which reestablished balance between α- and β2-AR function in the immune system ameliorates inflammation and joint

  8. Metabolic response to various beta-adrenoceptor agonists in beta3-adrenoceptor knockout mice: evidence for a new beta-adrenergic receptor in brown adipose tissue.

    Science.gov (United States)

    Preitner, F; Muzzin, P; Revelli, J P; Seydoux, J; Galitzky, J; Berlan, M; Lafontan, M; Giacobino, J P

    1998-08-01

    The beta3-adrenoceptor plays an important role in the adrenergic response of brown and white adipose tissues (BAT and WAT). In this study, in vitro metabolic responses to beta-adrenoceptor stimulation were compared in adipose tissues of beta3-adrenoceptor knockout and wild type mice. The measured parameters were BAT fragment oxygen uptake (MO2) and isolated white adipocyte lipolysis. In BAT of wild type mice (-)-norepinephrine maximally stimulated MO2 4.1+/-0.8 fold. Similar maximal stimulations were obtained with beta1-, beta2- or beta3-adrenoceptor selective agonists (dobutamine 5.1+/-0.3, terbutaline 5.3+/-0.3 and CL 316,243 4.8+/-0.9 fold, respectively); in BAT of beta3-adrenoceptor knockout mice, the beta1- and beta2-responses were fully conserved. In BAT of wild type mice, the beta1/beta2-antagonist and beta3-partial agonist CGP 12177 elicited a maximal MO2 response (4.7+/-0.4 fold). In beta3-adrenoceptor knockout BAT, this response was fully conserved despite an absence of response to CL 316,243. This unexpected result suggests that an atypical beta-adrenoceptor, distinct from the beta1-, beta2- and beta3-subtypes and referred to as a putative beta4-adrenoceptor is present in BAT and that it can mediate in vitro a maximal MO2 stimulation. In isolated white adipocytes of wild type mice, (-)-epinephrine maximally stimulated lipolysis 12.1+/-2.6 fold. Similar maximal stimulations were obtained with beta1-, beta2- or beta3-adrenoceptor selective agonists (TO509 12+/-2, procaterol 11+/-3, CL 316,243 11+/-3 fold, respectively) or with CGP 12177 (7.1+/-1.5 fold). In isolated white adipocytes of beta3-adrenoceptor knockout mice, the lipolytic responses to (-)epinephrine, to the beta1-, beta2-, beta3-adrenoceptor selective agonists and to CGP 12177 were almost or totally depressed, whereas those to ACTH, forskolin and dibutyryl cyclic AMP were conserved.

  9. Metabolic response to various β-adrenoceptor agonists in β3-adrenoceptor knockout mice: Evidence for a new β-adrenergic receptor in brown adipose tissue

    Science.gov (United States)

    Preitner, Frédéric; Muzzin, Patrick; Revelli, Jean-Pierre; Seydoux, Josiane; Galitzky, Jean; Berlan, Michel; Lafontan, Max; Giacobino, Jean-Paul

    1998-01-01

    The β3-adrenoceptor plays an important role in the adrenergic response of brown and white adipose tissues (BAT and WAT). In this study, in vitro metabolic responses to β-adrenoceptor stimulation were compared in adipose tissues of β3-adrenoceptor knockout and wild type mice. The measured parameters were BAT fragment oxygen uptake (MO2) and isolated white adipocyte lipolysis. In BAT of wild type mice (−)-norepinephrine maximally stimulated MO2 4.1±0.8 fold. Similar maximal stimulations were obtained with β1-,β2- or β3-adrenoceptor selective agonists (dobutamine 5.1±0.3, terbutaline 5.3±0.3 and CL 316,243 4.8±0.9 fold, respectively); in BAT of β3-adrenoceptor knockout mice, the β1- and β2-responses were fully conserved. In BAT of wild type mice, the β1/β2-antagonist and β3-partial agonist CGP 12177 elicited a maximal MO2 response (4.7±0.4 fold). In β3-adrenoceptor knockout BAT, this response was fully conserved despite an absence of response to CL 316,243. This unexpected result suggests that an atypical β-adrenoceptor, distinct from the β1-, β2- and β3-subtypes and referred to as a putative β4-adrenoceptor is present in BAT and that it can mediate in vitro a maximal MO2 stimulation. In isolated white adipocytes of wild type mice, (−)-epinephrine maximally stimulated lipolysis 12.1±2.6 fold. Similar maximal stimulations were obtained with β1-, β2- or β3-adrenoceptor selective agonists (TO509 12±2, procaterol 11±3, CL 316,243 11±3 fold, respectively) or with CGP 12177 (7.1±1.5 fold). In isolated white adipocytes of β3-adrenoceptor knockout mice, the lipolytic responses to (−)epinephrine, to the β1-, β2-, β3-adrenoceptor selective agonists and to CGP 12177 were almost or totally depressed, whereas those to ACTH, forskolin and dibutyryl cyclic AMP were conserved. PMID:9756384

  10. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor...... antagonists as adjuvant single drugs to reduce trauma-, blood transfusion- and sepsis-induced immunosuppression has led to research in combined treatment regimens in major surgery, particularly, of patients operated on for malignant diseases....

  11. Structure-activity relationships of benzothiazole GPR35 antagonists.

    Science.gov (United States)

    Abdalhameed, Manahil M; Zhao, Pingwei; Hurst, Dow P; Reggio, Patricia H; Abood, Mary E; Croatt, Mitchell P

    2017-02-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound.

  12. Deficiency of interleukin-1 receptor antagonist responsive to anakinra.

    Science.gov (United States)

    Schnellbacher, Charlotte; Ciocca, Giovanna; Menendez, Roxanna; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Duarte, Ana M; Rivas-Chacon, Rafael

    2013-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy.

  13. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    OpenAIRE

    Mohammad eKhanfar; Anna eAffini; Kiril eLutsenko; Katarina eNikolic; Stefania eButini; Holger eStark

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex...

  14. Interleukin-2 receptor antagonists as induction therapy after heart transplantation

    DEFF Research Database (Denmark)

    Møller, Christian H; Gustafsson, Finn; Gluud, Christian;

    2008-01-01

    About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras.......About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras....

  15. Protein kinase Cζ regulates phospholipase D activity in rat-1 fibroblasts expressing the α1A adrenergic receptor

    Directory of Open Access Journals (Sweden)

    Bourgoin Sylvain G

    2004-01-01

    Full Text Available Abstract Background Phenylephrine (PHE, an α1 adrenergic receptor agonist, increases phospholipase D (PLD activity, independent of classical and novel protein kinase C (PKC isoforms, in rat-1 fibroblasts expressing α1A adrenergic receptors. The aim of this study was to determine the contribution of atypical PKCζ to PLD activation in response to PHE in these cells. Results PHE stimulated a PLD activity as demonstrated by phosphatidylethanol production. PHE increased PKCζ translocation to the particulate cell fraction in parallel with a time-dependent decrease in its activity. PKCζ activity was reduced at 2 and 5 min and returned to a sub-basal level within 10–15 min. Ectopic expression of kinase-dead PKCζ, but not constitutively active PKCζ, potentiated PLD activation elicited by PHE. A cell-permeable pseudosubstrate inhibitor of PKCζ reduced basal PKCζ activity and abolished PHE-induced PLD activation. Conclusion α1A adrenergic receptor stimulation promotes the activation of a PLD activity by a mechanism dependent on PKCζ; Our data also suggest that catalytic activation of PKCζ is not required for PLD stimulation.

  16. The Effect of Prolonged Exposure to Low Frequency Electromagnetic Fields on α1 Adrenergic System of Isolated Colon in Rats

    Directory of Open Access Journals (Sweden)

    A Bahaodini

    2013-03-01

    Full Text Available Introduction: Prolonged exposure to electromagnetic fields (EMF influences digestive system specially its motility. The present study was performed in order to study the effects of exposure to low frequency EMF on the adrenergic system of large intestine. Methods: In this experimental study, thirty adult male rats were divided into three groups: First group (experimental included 10 male rats that were exposed to 1000µT and 50Hz for 140 days in the on solenoid. Second group (shahed included 10 rats that were kept at same condition as the first group except that the solenoid was off. Third group (control included 10 rats that were kept in a normal condition. Mechanical activity of the isolated strips of colon that were inserted to organ bath contained Kerebs solution(CaCl2 2/5, KCL 4/7, KH2Po41/2, MgSo4 1/2, NaHCO3 25, NaCl 118, glucose11, PH=7.4 (37°C and they were linked to power lab force transducer to record cumulative doses of Phenylephrin. The data was analyzed using t- test at p<0.05 as a significant level. Results: The results showed no significant difference regarding long- term exposure to low frequency Electromagnetic field on adrenergic receptor α 1 adrenergic receptor sensitivities.

  17. Environmental novelty activates β2-adrenergic signaling to prevent the impairment of hippocampal LTP by Aβ oligomers.

    Science.gov (United States)

    Li, Shaomin; Jin, Ming; Zhang, Dainan; Yang, Ting; Koeglsperger, Thomas; Fu, Hongjun; Selkoe, Dennis J

    2013-03-06

    A central question about human brain aging is whether cognitive enrichment slows the development of Alzheimer changes. Here, we show that prolonged exposure to an enriched environment (EE) facilitated signaling in the hippocampus of wild-type mice that promoted long-term potentiation. A key feature of the EE effect was activation of β2-adrenergic receptors and downstream cAMP/PKA signaling. This EE pathway prevented LTP inhibition by soluble oligomers of amyloid β-protein (Aβ) isolated from AD cortex. Protection by EE occurred in both young and middle-aged wild-type mice. Exposure to novelty afforded greater protection than did aerobic exercise. Mice chronically fed a β-adrenergic agonist without EE were protected from hippocampal impairment by Aβ oligomers. Thus, EE enhances hippocampal synaptic plasticity by activating β-adrenoceptor signaling and mitigating synaptotoxicity of human Aβ oligomers. These mechanistic insights support using prolonged exposure to cognitive novelty and/or oral β-adrenergic agonists to lessen the effects of Aβ accumulation during aging.

  18. Polymorphisms in α- and β-Adrenergic Receptor Genes, Hypertension, and Obstructive Sleep Apnea: The Skaraborg Sleep Study

    Directory of Open Access Journals (Sweden)

    Kristina Bengtsson Boström

    2010-01-01

    Full Text Available The sympathetic nervous system and the adrenergic receptors play an important role in regulation of blood pressure. This study explored the associations between functional polymorphisms of the α2B-, β1-, and β2-adrenergic receptor genes and obstructive sleep apnea (OSA in hypertensive patients and hypertension in patients with OSA in a populationbased sample of 157 hypertensive patients and 181 healthy control subjects. Only the Arg389Gly polymorphism of the β1-adrenergic receptor gene was associated with increased risk for mild OSA in hypertensive patients (Arg/Arg versus Gly/Arg/Gly/Gly, 2.1, 95% CI, 1.02–4.7. Hypertensive men carrying the Arg389Arg genotype had higher crude and age-adjusted AHI than carriers of the Arg389Gly/Gly389Gly genotypes. When adjusted also for BMI this difference became borderline significant. This difference was not observed in women. The risk of hypertension in mild OSA was associated with increasing number of Arg-alleles (Arg/Arg OR 5.4, 95% CI 1.4–21.2.

  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. The pineal gland: A model for adrenergic modulation of ubiquitin ligases

    Science.gov (United States)

    Liu, Wenjun; Reiter, Russel J.

    2017-01-01

    responsive, in vitro, to treatment with a cyclic AMP analog, and norepinephrine. All previously described 24-hour rhythms in the pineal require an intact sympathetic input from the superior cervical ganglia. Conclusions The Hartley dataset thus provides evidence that the pineal gland is a highly useful model for studying adrenergically dependent mechanisms regulating variations in ubiquitin ligases, ubiquitin conjugases, and deubiquitinases, mechanisms that may be physiologically relevant not only in the pineal gland, but in all adrenergically innervated tissue. PMID:28212404

  1. Interaction of selected vasodilating beta-blockers with adrenergic receptors in human cardiovascular tissues

    Energy Technology Data Exchange (ETDEWEB)

    Monopoli, A.; Forlani, A.; Bevilacqua, M.; Vago, T.; Norbiato, G.; Bertora, P.; Biglioli, P.; Alamanni, F.; Ongini, E. (Essex Italia, Subsidiary of Schering-Plough, Milan)

    1989-07-01

    beta- And alpha 1-adrenoceptor antagonist properties of bufuralol, carvedilol, celiprolol, dilevalol, labetalol, and pindolol were investigated in human myocardium and mammary artery using binding techniques and functional studies. In myocardial membranes, beta-adrenoceptor antagonists showed monophasic competition isotherms for (125I)pindolol binding with high affinity (Ki from 1-100 nM), except for celiprolol which displayed a biphasic competition isotherm (pKi = 6.4 +/- 0.06 for beta 1- and 4.8 +/- 0.07 for beta 2-adrenoceptors). Drug interactions with alpha 1-adrenoceptors were evaluated in human mammary artery by (3H)prazosin binding and by measuring contractile responses to norepinephrine (NE). Labetalol and carvedilol showed a moderate affinity for alpha 1-adrenoceptors (pKi = 6.2 +/- 0.01 and 6.1 +/- 0.06, respectively), and inhibited NE-induced contractions (pA2 = 6.93 +/- 0.23 and 8.64 +/- 0.24, respectively). Dilevalol, bufuralol, and pindolol displayed weak effect both in binding (Ki in micromolar range) and functional experiments (pA2 = 5.98, 5.54, and 6.23, respectively). Celiprolol did not show antagonist properties up to 100 microM in functional studies, but displayed a slight affinity for alpha 1-adrenoceptors in binding studies. The data indicate that the vasodilating activity of these beta-adrenoceptor antagonists is caused in some instances by an alpha 1-adrenoceptor antagonism (labetalol, carvedilol), whereas for the others alternative mechanisms should be considered.

  2. Pharmacological tolerance to alpha 1-adrenergic receptor antagonism mediated by terazosin in humans.

    OpenAIRE

    Vincent, J; Dachman, W; Blaschke, T F; Hoffman, B. B.

    1992-01-01

    Chronic administration of alpha 1-receptor antagonists is associated with loss of clinical efficacy, especially in congestive heart failure, although the mechanism is uncertain. To evaluate changes in venous alpha 1-adrenoceptor responsiveness during chronic alpha 1-adrenoceptor blockade, dose-response curves to phenylephrine and angiotensin II were constructed in 10 healthy subjects before, during, and after administration of terazosin 1 mg orally for 28 d. Terazosin initially shifted the do...

  3. 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 receptor (β2AR) 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.

  4. Direct effect of cadmium on blood pressure and adrenergic system in the cat

    Energy Technology Data Exchange (ETDEWEB)

    Revis, N.W.; Bingham, G.

    1984-01-01

    The dose-response effect of cadmium on systolic and diastolic pressure were measured in the cat after injecting a bolus of cadmium intravenously. In animals treated with 100, 125, or 150 ug cadmium/kg BW systolic and diastolic pressure were both significantly increased. These increases were gradual as the dose Cd was increased from 75 to 125 ug. In an attempt to determine the mechanism associated with cadmium-induced hypertension in the cat the effect of this element on the adrenergic system was studied. The effect of ..cap alpha.. and BETA agonists on cadmium-induced increase in blood pressure were determined by the injection of either propranolol or phentolamine at 20 mg/kg BW. The hypertensive effect of 125 ug Cd was abolished by phentolamine but not by propranolol suggesting, that Cd may induce the release of norepinephrine from storage sites. In support of this suggestion we observed in cats treated with 125 ug Cd a significant increase in plasma norepinephrine which was not affected by propranolol or phentolamine injections. However reserpine pretreatment abolished both the increase in plasma norepinephrine and the cadmium-induced hypertensive effect. The data suggest that the associated mechanism of cadmium-induced hypertension may be related to the effect of this element of the release of norepinephrine. Increases in the extracellular levels of this neurotransmitter in turn provokes a rise in blood pressure through its interaction with the receptors of vascular smooth muscle cells. 38 references, 7 figures, 1 table.

  5. Peptide YY antagonizes beta-adrenergic-stimulated release of insulin in dogs

    Energy Technology Data Exchange (ETDEWEB)

    Greeley, G.H. Jr.; Lluis, F.; Gomex, G.; Ishizuka, J.; Holland, B.; Thompson, J.C. (Univ. of Texas Medical Branch, Galveston (USA))

    1988-04-01

    Peptide YY (PYY) and neuropeptide Y (NPY) are peptides of 36 amino acids that share structural homologies with pancreatic polypeptide (PP). PP is predominantly found in the endocrine pancreas. PYY is primarily found in mucosal endocrine cells of the distal ileum, colon, and rectum, whereas NPY is found in both the peripheral and central nervous system. Previous studies indicate that these peptides can interact with the autonomic nervous system. The objective of the present experiments was to study the effect of PYY on neurally stimulated insulin release in conscious dogs. Intravenous administration of PYY (100, 200, and 400 pmol{center dot}kg{sup {minus}1} {center dot}h{sup {minus}1}) reduced 2-DG-stimulated insulin release in a dose-dependent manner (P <0.05) without affecting plasma glucose levels. Administration of NPY, but not PP, reduced 2-DG-stimulated release of insulin. The inhibitory action of PYY on 2-DG-stimulated insulin release persisted in the presence of atropine or phentolamine treatment; however, hexamethonium alone or phentolamine plus propranolol treatment blocked the inhibitory action of PYY. Release of insulin stimulated by the {beta}-agonist isoproterenol was also inhibited by PYY. These results indicate that PYY can inhibit autonomic neurotransmission by a mechanism that may involve ganglionic or postganglionic inhibition of {beta}-adrenergic stimulation. The findings suggest a role for PYY and NPY in the autonomic regulation of insulin release.

  6. Alpha adrenergic receptor mediation of cardiovascular and metabolic responses to alcohol

    Energy Technology Data Exchange (ETDEWEB)

    Brackett, D.J.; Gauvin, D.V.; Lerner, M.R.; Holloway, F.H.; Wilson, M.F. (Univ. of Oklahoma, Oklahoma City (United States) Veterans Affairs Medical Center, Oklahoma City, OK (United States))

    1992-02-26

    The role of alpha adrenergic receptors in acute cardiovascular and metabolic responses to alcohol (ETOH) have not been clearly defined. In this study two groups of male Sprague-Dawley rats were given intravenous phentolamine mesylate or saline prior to intragastric alcohol to blockade of alpha receptors during alcohol intoxication in conscious rats. ETOH alone evoked an increase in systemic vascular resistance (SVR), heart rate (HR), and blood glucose concentrations (G) and a decrease in mean arterial pressure (MAP), cardiac output (CO), central venous pressure (CVP), respiration rate (RR) and cardiac stroke volume (SV). Blood alcohol concentration (BAC) peaked at 30 min and remained elevated for the four hrs of monitoring. Phentolamine pretreatment produced a decrease in MAP and SV and an increase in HR. However, antagonism of the alpha receptor blocked the decrease in CO and the increase in SVR and G. The decrease in CVP was unaffected. Surprisingly, the early rise and peak in BAC in the phentolamine treated group was attenuated, but was the same as the untreated group during the final 3 hrs. These data suggest that alpha receptors are significant mediators of cardiovascular and glucoregulatory responses elicited by alcohol. Furthermore, alpha receptor blockade appears to effect the absorption and/or distribution of intragastrically administered alcohol.

  7. Adipogenic role of alternatively activated macrophages in β-adrenergic remodeling of white adipose tissue.

    Science.gov (United States)

    Lee, Yun-Hee; Kim, Sang-Nam; Kwon, Hyun-Jung; Maddipati, Krishna Rao; Granneman, James G

    2016-01-01

    De novo brown adipogenesis involves the proliferation and differentiation of progenitors, yet the mechanisms that guide these events in vivo are poorly understood. We previously demonstrated that treatment with a β3-adrenergic receptor (ADRB3) agonist triggers brown/beige adipogenesis in gonadal white adipose tissue following adipocyte death and clearance by tissue macrophages. The close physical relationship between adipocyte progenitors and tissue macrophages suggested that the macrophages that clear dying adipocytes might generate proadipogenic factors. Flow cytometric analysis of macrophages from mice treated with CL 316,243 identified a subpopulation that contained elevated lipid and expressed CD44. Lipidomic analysis of fluorescence-activated cell sorting-isolated macrophages demonstrated that CD44+ macrophages contained four- to five-fold higher levels of the endogenous peroxisome-proliferator activated receptor gamma (PPARγ) ligands 9-hydroxyoctadecadienoic acid (HODE), and 13-HODE compared with CD44- macrophages. Gene expression profiling and immunohistochemistry demonstrated that ADRB3 agonist treatment upregulated expression of ALOX15, the lipoxygenase responsible for generating 9-HODE and 13-HODE. Using an in vitro model of adipocyte efferocytosis, we found that IL-4-primed tissue macrophages accumulated lipid from dying fat cells and upregulated expression of Alox15. Furthermore, treatment of differentiating adipocytes with 9-HODE and 13-HODE potentiated brown/beige adipogenesis. Collectively, these data indicate that noninflammatory removal of adipocyte remnants and coordinated generation of PPARγ ligands by M2 macrophages provides localized adipogenic signals to support de novo brown/beige adipogenesis.

  8. Browning of Subcutaneous White Adipose Tissue in Humans after Severe Adrenergic Stress.

    Science.gov (United States)

    Sidossis, Labros S; Porter, Craig; Saraf, Manish K; Børsheim, Elisabet; Radhakrishnan, Ravi S; Chao, Tony; Ali, Arham; Chondronikola, Maria; Mlcak, Ronald; Finnerty, Celeste C; Hawkins, Hal K; Toliver-Kinsky, Tracy; Herndon, David N

    2015-08-01

    Since the presence of brown adipose tissue (BAT) was confirmed in adult humans, BAT has become a therapeutic target for obesity and insulin resistance. We examined whether human subcutaneous white adipose tissue (sWAT) can adopt a BAT-like phenotype using a clinical model of prolonged and severe adrenergic stress. sWAT samples were collected from severely burned and healthy individuals. A subset of burn victims were prospectively followed during their acute hospitalization. Browning of sWAT was determined by the presence of multilocular adipocytes, uncoupling protein 1 (UCP1), and increased mitochondrial density and respiratory capacity. Multilocular UCP1-positive adipocytes were found in sWAT samples from burn patients. UCP1 mRNA, mitochondrial density, and leak respiratory capacity in sWAT increased after burn trauma. Our data demonstrate that human sWAT can transform from an energy-storing to an energy-dissipating tissue, which opens new research avenues in our quest to prevent and treat obesity and its metabolic complications.

  9. 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.

  10. alpha-Adrenergic control of intestinal circulation in heat-stressed baboons.

    Science.gov (United States)

    Proppe, D W

    1980-05-01

    The mechanisms involved in producing intestinal vasoconstriction during a hyperthermia-producing intestinal vasoconstriction during a hyperthermia-producing environmental heat stress are unknown. Five conscious baboons (Papio anubis), each with chronically implanted catheters and a flow probe around the superior mesenteric artery, were subjected to environmental heating (Ta 40-45 degrees C) to raise their arterial blood temperature (Tbl) 2.0-2.6 degrees C to approximately 39.5 degrees C. Accompanying the gradual rise in Tbl was a fall in mean superior mesenteric artery blood flow (MSMF) and a progressive rise in superior mesenteric vascular resistance (SMR). At peak Tbl, MSMF had fallen 28.8 +/- 0.6% (mean +/- SE) and SMR had risen 50.2 +/- 4.2%. To determine the involvement of the sympathetic nervous system in producing this intestinal vasoconstriction, the baboon was subjected to environmental heating after induction of alpha-adrenergic receptor blockade by phenoxybenzamine or phentolamine. In this state, the rise in Tbl was accompanied by no change in MSMF and a slight, but not statistically significant, rise (7.8 +/- 3.8%) in SMR. Since alpha-receptor blockade nearly completely abolishes intestinal vasoconstriction during heat stress, this intestinal vasoconstriction must be mediated primarily by elevated sympathetic outflow.

  11. Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis.

    Science.gov (United States)

    Fairbanks, Carolyn A; Stone, Laura S; Wilcox, George L

    2009-08-01

    Endogenous, descending noradrenergic fibers impose analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (alpha(2)ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express alpha(2A)AR and alpha(2C)AR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal alpha(2)ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of the six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal alpha(2)AR agonists featured.

  12. Age-associated alterations in hepatic. beta. -adrenergic receptor/adenylate cyclase complex

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-09-01

    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/sup 2 +/-dependent activity of the cyclase was increased by 2.9-fold in 3-mo-old animals and approx. 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 ..beta..-adrenergic receptor, as measured by the binding of (/sup 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 ..beta..-receptors in the high-affinity state. These observations suggest that ..beta..-receptor-mediated hepatic glycogenolysis in the aged rat is predicated upon increases in the density of ..beta..-receptors as well as increased intrinsic activity of the catalytic unit of adenylate cyclase.

  13. Structure of the gene for human. beta. /sub 2/-adrenergic receptor: expression and promoter characterization

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-10-01

    The genomic gene coding for the human ..beta../sub 2/-adrenergic receptor (..beta../sub 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 ..beta../sub 2/AR properties. Southern blot analyses with ..beta../sub 2/AR-specific probes show that a single ..beta../sub 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 ..beta../sub 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.

  14. Beta-adrenergic receptors are differentially expressed in distinct interneuron subtypes in the rat hippocampus.

    Science.gov (United States)

    Cox, David J; Racca, Claudia; LeBeau, Fiona E N

    2008-08-20

    Noradrenaline (NA) acting via beta-adrenergic receptors (betaARs) plays an important role in the modulation of memory in the hippocampus. betaARs have been shown to be expressed in principal cells, but their distribution across different interneuron classes is unknown. We have used specific interneuron markers including calcium binding proteins (parvalbumin, calbindin, and calretinin) and neuropeptides (somatostatin, neuropeptide Y, and cholecystokinin) together with either beta1AR or beta2AR to determine the distribution of these receptors in all major subfields of the hippocampus. We found that beta1AR-expressing interneurons were more prevalent in the CA3 and CA1 regions of the hippocampus than in the dentate gyrus, where they were relatively sparse. beta2AR-expressing interneurons were more uniformly distributed between all three regions of the hippocampus. A high proportion of neuropeptide Y-containing interneurons in the dentate gyrus co-expressed beta2AR. beta1AR labeling was common in interneurons expressing somatostatin and parvalbumin in the CA3 and CA1 regions, particularly in the stratum oriens of these regions. beta2AR labeling was more likely to be found than beta1AR labeling in cholecystokinin-expressing interneurons. In contrast, calretinin-containing interneurons were virtually devoid of beta1AR or beta2AR labeling. These regional and interneuron type-specific differences suggest functionally distinct roles for NA in modulating hippocampal activity via activation of betaARs.

  15. Beta 2-adrenergic receptor activation enhances neurogenesis in Alzheimer’s disease mice

    Institute of Scientific and Technical Information of China (English)

    Gao-shang Chai; Yang-yang Wang; Amina Yasheng; Peng Zhao

    2016-01-01

    Impaired hippocampal neurogenesis is one of the early pathological features of Alzheimer’s disease. Enhancing adult hippocampal neuro-genesis has been pursued as a potential therapeutic strategy for Alzheimer’s disease. Recent studies have demonstrated that environmental novelty activates β2-adrenergic signaling and prevents the memory impairment induced by amyloid-β oligomers. Here, we hypothesized that β2-adrenoceptor activation would enhance neurogenesis and ameliorate memory deifcits in Alzheimer’s disease. To test this hypothe-sis, we investigated the effects and mechanisms of action of β2-adrenoceptor activation on neurogenesis and memory in amyloid precursor protein/presenilin 1 (APP/PS1) mice using the agonist clenbuterol (intraperitoneal injection, 2 mg/kg). We found that β2-adrenoceptor ac-tivation enhanced hippocampal neurogenesis, ameliorated memory deifcits, and increased dendritic branching and the density of dendritic spines. hTese effects were associated with the upregulation of postsynaptic density 95, synapsin 1 and synaptophysin in APP/PS1 mice. Furthermore, β2-adrenoceptor activation decreased cerebral amyloid plaques by decreasing APP phosphorylation at hTr668. hTese ifndings suggest that β2-adrenoceptor activation enhances neurogenesis and ameliorates memory deifcits in APP/PS1 mice.

  16. Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling.

    Science.gov (United States)

    Zhu, Baoling; Liu, Kai; Yang, Chengzhi; Qiao, Yuhui; Li, Zijian

    2016-12-01

    Cardiac remodeling is the pathological basis of various cardiovascular diseases. In this study, we found gender-related differences in β-adrenergic receptor (AR)-mediated pathological cardiac remodeling. Cardiac remodeling model was established by subcutaneous injection of isoprenaline (ISO) for 14 days. Heart rate (HR), mean arterial pressure (MAP), and echocardiography were obtained on 7th and 14th days during ISO administration. Myocardial cross-sectional area and the ratio of heart mass to tibia length (HM/TL) were detected to assess cardiac hypertrophy. Picro-Sirius red staining (picric acid + Sirius red F3B) was used to evaluate cardiac fibrosis. Myocardial capillary density was assessed by immunohistochemistry for von Willebrand factor. Further, real-time PCR was used to measure the expression of β1-AR and β2-AR. Results showed that ISO induced cardiac remodeling, the extent of which was different between female and male mice. The extent of increase in cardiac wall thickness, myocardial cross-sectional area, and collagen deposition in females was less than that in males. However, no gender-related difference was observed in HR, MAP, cardiac function, and myocardial capillary density. The distinctive decrease of β2-AR expression, rather than a decrease of β1-AR expression, seemed to result in gender-related differences in cardiac remodeling.

  17. Adrenergically stimulated blood flow in brown adipose tissue is not dependent on thermogenesis.

    Science.gov (United States)

    Abreu-Vieira, Gustavo; Hagberg, Carolina E; Spalding, Kirsty L; Cannon, Barbara; Nedergaard, Jan

    2015-05-01

    Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen and for the distribution of the generated heat to the rest of the body. Therefore, it is fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here, we present high-resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel noninvasive method to detect BAT perfusion, we demonstrate that adrenergically stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and therefore, it is not a reliable parameter for the estimation of BAT activation and heat generation.

  18. β-adrenergic-blocking drugs and melanoma: current state of the art.

    Science.gov (United States)

    De Giorgi, Vincenzo; Grazzini, Marta; Gandini, Sara; Benemei, Silvia; Asbury, Curtis D; Marchionni, Niccolò; Geppetti, Pierangelo

    2012-11-01

    The purpose of this review is to present the preclinical, epidemiological and clinical data relevant to the association between β-blockers and melanoma progression. Preclinical studies have shown that β-adrenergic receptor (β-AR) signaling can inhibit multiple cellular processes involved in melanoma progression and metastasis. These observations have suggested the possibility that drugs originally intended for the treatment of cardiovascular disease, the β-AR blockers, may provide new therapeutic opportunities for the control of tumor progression. A large number of observational studies demonstrated the protective effect of β-blockers in breast cancer but, more recently, similar findings were also reported in other cancers such as prostate cancer and melanoma. With regard to melanoma, two recently published studies demonstrated a great reduction in the risk of disease progression for each year of treatment with β-blockers. The results from these studies have suggested a potential role for targeting the β-AR pathway in melanoma patients. Questions regarding the type of β-blocker or tumor characteristics, appropriate treatment paradigms and, most importantly, efficacy must be answered in randomized clinical studies before β-blockers can be considered a therapeutic option for patients with melanoma.

  19. β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.

    Science.gov (United States)

    Vijftigschild, Lodewijk A W; Berkers, Gitte; Dekkers, Johanna F; Zomer-van Ommen, Domenique D; Matthes, Elizabeth; Kruisselbrink, Evelien; Vonk, Annelotte; Hensen, Chantal E; Heida-Michel, Sabine; Geerdink, Margot; Janssens, Hettie M; van de Graaf, Eduard A; Bronsveld, Inez; de Winter-de Groot, Karin M; Majoor, Christof J; Heijerman, Harry G M; de Jonge, Hugo R; Hanrahan, John W; van der Ent, Cornelis K; Beekman, Jeffrey M

    2016-09-01

    We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function.We used intestinal organoids to screen a GPCR-modulating compound library and identified β2-adrenergic receptor agonists as the most potent inducers of CFTR function.β2-Agonist-induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules. The in vivo response to treatment with an oral or inhaled β2-agonist (salbutamol) in CF patients with residual CFTR function was evaluated in a pilot study. 10 subjects with a R117H or A455E mutation were included and showed changes in the nasal potential difference measurement after treatment with oral salbutamol, including a significant improvement of the baseline potential difference of the nasal mucosa (+6.35 mV, pCFTR activation when administered ex vivo to organoids.This proof-of-concept study suggests that organoids can be used to identify drugs that activate CFTR function in vivo and to select route of administration.

  20. Binding of adrenergic ligands to liver plasma membrane preparations from the axolotl, Ambystoma mexicanum; the toad, Xenopus laevis; and the Australian lungfish, Neoceratodus forsteri.

    Science.gov (United States)

    Janssens, P A; Grigg, J A

    1988-09-01

    The beta-adrenergic ligand iodocyanopindolol (ICP) bound specifically to hepatic plasma membrane preparations from the axolotl, Ambystoma mexicanum (Bmax, 40 fmol/mg protein (P) at free concentration above 140 pM; KD, 42 pM); the toad, Xenopus laevis (Bmax, 200 fmol/mg P at 1 nM; KD, 300 pM); and the Australian lungfish, Neoceratodus forsteri (Bmax, 100 fmol/mg P at 5 nM). For the lungfish, the Scatchard plot was curved showing two classes of binding site with KD's of 20 and 500 pM. Neither the alpha 1-adrenergic ligand prazosin nor the alpha 2-adrenergic ligand yohimbine bound specifically to hepatic membrane preparations from any of the three species. Several adrenergic ligands displaced ICP from hepatic membrane preparations of all three species with KD's of Axolotl--propranolol, 50 nM; isoprenaline, 600 nM; adrenaline, 10 microM; phenylephrine, 20 microM; noradrenaline, 40 microM; and phentolamine, greater than 100 microM; X. laevis--propranolol, 30 nM; isoprenaline, 100 microM; adrenaline, 200 microM; noradrenaline, 300 microM; phenylephrine, 1 mM; and phentolamine, greater than 1 mM; N. forsteri,--propranolol, 25 nM; isoprenaline, 1 microM; adrenaline, 20 microM; phenylephrine, 35 microM; noradrenaline, 600 microM; and phentolamine, 400 microM. These findings suggest that alpha-adrenergic receptors are not present in hepatic plasma membrane preparations from these three species and that the hepatic actions of catecholamines are mediated via beta-adrenergic receptors. The order of binding of the beta-adrenergic ligands suggests that the receptors are of the beta 2 type.

  1. A pharmacophore model for dopamine D4 receptor antagonists

    Science.gov (United States)

    Boström, Jonas; Gundertofte, Klaus; Liljefors, Tommy

    2000-11-01

    A pharmacophore model for dopamine D4 antagonists has been developed on the basis of a previously reported dopamine D2 model. By using exhaustive conformational analyses (MM3* force field and the GB/SA hydration model) and least-squares molecular superimposition studies, a set of eighteen structurally diverse high affinity D4 antagonists have successfully been accommodated in the D4 pharmacophore model. Enantioselectivities may be rationalized by conformational energies required for the enantiomers to adopt their proposed bioactive conformations. The pharmacophore models for antagonists at the D4 and D2 receptor subtypes have been compared in order to get insight into molecular properties of importance for D2/D4 receptor selectivity. It is concluded that the bioactive conformations of antagonists at the two receptor subtypes are essentially identical. Receptor essential volumes previously identified for the D2 receptor are shown to be present also in the D4 receptor. In addition, a novel receptor essential volume in the D4 receptor, not present in the D2 receptor, has been identified. This feature may be exploited for the design of D4 selective antagonists. However, it is concluded that the major determinant for D2/D4 selectivity is the nature of the interactions between the receptor and aromatic ring systems. The effects of the electronic properties of these ring systems on the affinities for the two receptor subtypes differ substantially.

  2. Structural insights from binding poses of CCR2 and CCR5 with clinically important antagonists: a combined in silico study.

    Directory of Open Access Journals (Sweden)

    Gugan Kothandan

    Full Text Available Chemokine receptors are G protein-coupled receptors that contain seven transmembrane domains. In particular, CCR2 and CCR5 and their ligands have been implicated in the pathophysiology of a number of diseases, including rheumatoid arthritis and multiple sclerosis. Based on their roles in disease, they have been attractive targets for the pharmaceutical industry, and furthermore, targeting both CCR2 and CCR5 can be a useful strategy. Owing to the importance of these receptors, information regarding the binding site is of prime importance. Structural studies have been hampered due to the lack of X-ray crystal structures, and templates with close homologs for comparative modeling. Most of the previous models were based on the bovine rhodopsin and β2-adrenergic receptor. In this study, based on a closer homolog with higher resolution (CXCR4, PDB code: 3ODU 2.5 Å, we constructed three-dimensional models. The main aim of this study was to provide relevant information on binding sites of these receptors. Molecular dynamics simulation was done to refine the homology models and PROCHECK results indicated that the models were reasonable. Here, binding poses were checked with some established inhibitors of high pharmaceutical importance against the modeled receptors. Analysis of interaction modes gave an integrated interpretation with detailed structural information. The binding poses confirmed that the acidic residues Glu291 (CCR2 and Glu283 (CCR5 are important, and we also found some additional residues. Comparisons of binding sites of CCR2/CCR5 were done sequentially and also by docking a potent dual antagonist. Our results can be a starting point for further structure-based drug design.

  3. The effects of the β1 antagonist, metoprolol, on methamphetamine-induced changes in core temperature in the rat.

    Science.gov (United States)

    Harrell, Ricki; Speaker, H Anton; Mitchell, Scott L; Sabol, Karen E

    2015-11-16

    Methamphetamine (METH) results in hyperthermia or hypothermia depending on environmental conditions. Here we studied the role of the β1 adrenergic receptor in mediating METH's temperature effects. Core temperature measurements were made telemetrically over a 7.5h session, two days/week, in test chambers regulated at either 18°C, 24°C, or 30°C ambient temperature. Rats were treated with the β1 antagonist metoprolol (5.0, 10.0, and 15.0mg/kg) alone (Experiment 1), or in combination with 5.0mg/kg METH (Experiment 2). In experiment 3, we combined a lower dose range of metoprolol (0.75, 1.5, and 3.0mg/kg) with 5.0mg/kg METH at 18°C and 30°C. Confirming prior findings, METH alone resulted in hyperthermia in warm (30°) and hypothermia in cool environments (18°C). Metoprolol alone induced small but significant increases in core temperature. In combination, however, metoprolol reduced METH-induced changes in core temperature. Specifically, at 30°C, 3.0, 5.0, 10.0, and 15.0mg/kg metoprolol decreased METH-induced hyperthermia; at 18°C, all six doses of metoprolol enhanced METH-induced hypothermia. Our metoprolol findings suggest that one component of METH's temperature effects involves increasing core temperature at all ambient conditions via β1 receptors. Since β receptors are involved in brown adipose tissue (BAT)-mediated thermogenesis, skeletal muscle-mediated thermogenesis, heart rate, and the metabolism of glucose and lipids, we discuss each of these as possible mechanisms for metoprolol's effects on METH-induced changes in core temperature.

  4. Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT₁A and 5-HT₇ Antagonists in Animal Models.

    Directory of Open Access Journals (Sweden)

    Karolina Pytka

    Full Text Available The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxyethoxy]ethyl}-4-(2-methoxyphenylpiperazynine hydrochloride (HBK-14 and 2-[2-(2-chloro-6-methylphenoxyethoxy]ethyl-4-(2- methoxyphenylpiperazynine dihydrochloride (HBK-15 in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14-FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg and (HBK-15-FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg. We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.

  5. 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.

  6. The Apolipoprotein E Antagonistic Pleiotropy Hypothesis: Review and Recommendations

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Tuminello

    2011-01-01

    Full Text Available Research on apolipoprotein E (APOE has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD. However, research with younger populations of ε4 carriers has suggested that the APOE ε4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area.

  7. Discovery of the improved antagonistic prolactin variants by library screening.

    Science.gov (United States)

    Liu, Yun; Gong, Wei; Breinholt, Jens; Nørskov-Lauritsen, Leif; Zhang, Jinchao; Ma, Qinhong; Chen, Jianhe; Panina, Svetlana; Guo, Wei; Li, Tengkun; Zhang, Jingyuan; Kong, Meng; Liu, Zibing; Mao, Jingjing; Christensen, Leif; Hu, Sean; Wang, Lingyun

    2011-11-01

    Prolactin (PRL), a potent growth stimulator of the mammary epithelium, has been suggested to be a factor contributing to the development and progression of breast and prostate cancer. Several PRL receptor (PRLR) antagonists have been identified in the past decades, but their in vivo growth inhibitory potency was restricted by low receptor affinity, rendering them pharmacologically unattractive for clinical treatment. Thus, higher receptor affinity is essential for the development of improved PRLR antagonistic variants with improved in vivo potency. In this study, we generated Site 1 focused protein libraries of human G129R-PRL mutants and screened for those with increased affinity to the human PRLR. By combining the mutations with enhanced affinities for PRLR, we identified a novel G129R-PRL variant with mutations at Site 1 that render nearly 50-fold increase in the antagonistic potency in vitro.

  8. ANTAGONISTIC BACTERIA AGAINST SCHIZOPHYLLUM COMMUNE FR. IN PENINSULAR MALAYSIA

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    ANTARJO DIKIN

    2006-01-01

    Full Text Available Schizophyllum commune Fr., is one of the important fungi, causes brown germ and seed rot of oil palm. Biodiversity of antagonistic bacteria from oil palm plantations in Peninsular Malaysia is expected to support in development of biopesticide. Isolation with liquid assay and screening antagonistic bacteria using dual culture assay were carried out in the bioexploration. A total of 265 bacterial isolates from plant parts of oil palm screened 52 antagonistic bacterial isolates against 5. commune. Bacterial isolates were identified by using Biolog* Identification System i.e. Bacillus macroccanus, B. thermoglucosidasius, Burkholderia cepacia, B. gladioli, B. multivorans, B pyrrocinia, B. spinosa, Corynebacterium agropyri, C. misitidis, Enterobacter aerogenes, Microbacterium testaceum, Pseudomonas aeruginosa, P. citronellolis, Rhodococcus rhodochrous, Serratia ficaria, Serratia sp., S. marcescens, Staphylococcus sciuri, Sternotrophomonas maltophilia.

  9. Neuroprotective Effects of Glutamate Antagonists and Extracellular Acidity

    Science.gov (United States)

    Kaku, David A.; Giffard, Rona G.; Choi, Dennis W.

    1993-06-01

    Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isox-azolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.

  10. First Irish birth following IVF therapy using antagonist protocol.

    LENUS (Irish Health Repository)

    Mocanu, E V

    2012-02-01

    BACKGROUND: During in vitro fertilization (IVF), the prevention of a premature LH surge was traditionally achieved using a gonadotrophin releasing hormone agonist (GnRH-a), and more recently, a GnRH antagonist. AIMS: We report a case of a 37 year old treated using the GnRH antagonist in a second completed cycle of IVF. METHODS: IVF was performed for primary infertility of 5-year duration due to frozen pelvis secondary to endometriosis. RESULTS: Following controlled ovarian hyperstimulation, oocyte recovery and fertilization, cleavage and transfer of two zygotes, a pregnancy established. A twin gestation was diagnosed at 7-weeks scan and pregnancy ended with the delivery of twin girls by emergency caesarean section. CONCLUSION: This is a first report of a delivery following IVF using the antagonist protocol in Ireland. Such therapy is patient friendly and its use should be introduced on a larger scale in clinical practice.

  11. Development and characterization of high affinity leptins and leptin antagonists.

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-02-11

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.

  12. Development and Characterization of High Affinity Leptins and Leptin Antagonists*

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-01-01

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin. PMID:21119198

  13. β-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model.

    Science.gov (United States)

    Negroni, Jorge A; Morotti, Stefano; Lascano, Elena C; Gomes, Aldrin V; Grandi, Eleonora; Puglisi, José L; Bers, Donald M

    2015-04-01

    A five-state model of myofilament contraction was integrated into a well-established rabbit ventricular myocyte model of ion channels, Ca(2+) transporters and kinase signaling to analyze the relative contribution of different phosphorylation targets to the overall mechanical response driven by β-adrenergic stimulation (β-AS). β-AS effect on sarcoplasmic reticulum Ca(2+) handling, Ca(2+), K(+) and Cl(-) currents, and Na(+)/K(+)-ATPase properties was included based on experimental data. The inotropic effect on the myofilaments was represented as reduced myofilament Ca(2+) sensitivity (XBCa) and titin stiffness, and increased cross-bridge (XB) cycling rate (XBcy). Assuming independent roles of XBCa and XBcy, the model reproduced experimental β-AS responses on action potentials and Ca(2+) transient amplitude and kinetics. It also replicated the behavior of force-Ca(2+), release-restretch, length-step, stiffness-frequency and force-velocity relationships, and increased force and shortening in isometric and isotonic twitch contractions. The β-AS effect was then switched off from individual targets to analyze their relative impact on contractility. Preventing β-AS effects on L-type Ca(2+) channels or phospholamban limited Ca(2+) transients and contractile responses in parallel, while blocking phospholemman and K(+) channel (IKs) effects enhanced Ca(2+) and inotropy. Removal of β-AS effects from XBCa enhanced contractile force while decreasing peak Ca(2+) (due to greater Ca(2+) buffering), but had less effect on shortening. Conversely, preventing β-AS effects on XBcy preserved Ca(2+) transient effects, but blunted inotropy (both isometric force and especially shortening). Removal of titin effects had little impact on contraction. Finally, exclusion of β-AS from XBCa and XBcy while preserving effects on other targets resulted in preserved peak isometric force response (with slower kinetics) but nearly abolished enhanced shortening. β-AS effects on XBCa and XBcy

  14. Developmental α₂-adrenergic regulation of noradrenergic synaptic facilitation at cerebellar GABAergic synapses.

    Science.gov (United States)

    Hirono, M; Nagao, S; Obata, K

    2014-01-03

    In the central nervous system, the normal development of neuronal circuits requires adequate temporal activation of receptors for individual neurotransmitters. Previous studies have demonstrated that α₂-adrenoceptor (α₂-AR) activation eliminates spontaneous action potentials of interneurons in the cerebellar molecular layer (MLIs) and subsequently reduces the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in Purkinje cells (PCs) after the second postnatal week. The magnitude of the α₂-adrenergic reduction in sIPSC frequency is enhanced during the third postnatal week because of an increase in firing-derived sIPSCs. However, little is known about the effects of α₂-AR activation by noradrenaline (NA) on cerebellar GABAergic synaptic transmission that is accompanied by the activation of other AR subtypes, α₁- and β-ARs. Here, we developmentally examined the roles of α₂-AR activation in the noradrenergic facilitation of sIPSCs in cerebellar PCs. Until the second postnatal week, when substantial inhibitory effects of α₂-ARs are absent, NA potentiated sIPSCs and maintained the increased sIPSC frequency, suggesting that NA causes long-lasting facilitation of GABAergic synaptic transmission through α₁- and β-AR activation. After the second postnatal week, NA transiently increased the sIPSC frequency, whereas blocking α₂-ARs sustained the noradrenergic sIPSC facilitation and increase in the firing rate of MLIs, suggesting that α₂-AR activation suppresses the noradrenergic facilitation of GABAergic synaptic transmission. The simultaneous activation of α₁- and β-ARs by their specific agonists mimicked the persistent facilitation of sIPSC frequency, which required extracellular signal-regulated kinase 1/2 activation. These findings indicate that NA acts as a neurotrophic factor that strengthens GABAergic synaptic transmission in the developing cerebellar cortex and that α₂-ARs temporally restrain the noradrenergic

  15. β2-Adrenergic ion-channel coupled receptors as conformational motion detectors.

    Directory of Open Access Journals (Sweden)

    Lydia N Caro

    Full Text Available Ion Channel-Coupled Receptors (ICCRs are artificial proteins comprised of a G protein-coupled receptor and a fused ion channel, engineered to couple channel gating to ligand binding. These novel biological objects have potential use in drug screening and functional characterization, in addition to providing new tools in the synthetic biology repertoire as synthetic K(+-selective ligand-gated channels. The ICCR concept was previously validated with fusion proteins between the K(+ channel Kir6.2 and muscarinic M(2 or dopaminergic D(2 receptors. Here, we extend the concept to the distinct, longer β(2-adrenergic receptor which, unlike M(2 and D(2 receptors, displayed barely detectable surface expression in our Xenopus oocyte expression system and did not couple to Kir6.2 when unmodified. Here, we show that a Kir6.2-binding protein, the N-terminal transmembrane domain of the sulfonylurea receptor, can greatly increase plasma membrane expression of β(2 constructs. We then demonstrate how engineering of both receptor and channel can produce β(2-Kir6.2 ICCRs. Specifically, removal of 62-72 residues from the cytoplasmic C-terminus of the receptor was required to enable coupling, suggesting that ligand-dependent conformational changes do not efficiently propagate to the distal C-terminus. Characterization of the β(2 ICCRs demonstrated that full and partial agonists had the same coupling efficacy, that an inverse agonist had no effect and that the stabilizing mutation E122 W reduced agonist-induced coupling efficacy without affecting affinity. Because the ICCRs are expected to report motions of the receptor C-terminus, these results provide novel insights into the conformational dynamics of the β(2 receptor.

  16. β-Adrenergic receptor subtype signaling in heart:From bench to bedside

    Institute of Scientific and Technical Information of China (English)

    Anthony Yiu Ho WOO; Rui-ping XIAO

    2012-01-01

    β-Adrenergic receptor (βAR) stimulation by the sympathetic nervous system or circulating catecholamines is broadly involved in peripheral blood circulation,metabolic regulation,muscle contraction,and central neural activities.In the heart,acute βAR stimulation serves as the most powerful means to regulate cardiac output in response to a fight-or-flight situation,whereas chronic βAR stimulation plays an important role in physiological and pathological cardiac remodeling.There are three βAR subtypes,β1AR,β2AR and β3AR,in cardiac myocytes.Over the past two decades,we systematically investi-gated the molecular and cellular mechanisms underlying the different even opposite functional roles of β1AR and β2AR subtypes in regulating cardiac structure and function,with keen interest in the development of novel therapies based on our discoveries.We have made three major discoveries,including (1) dual coupling of β2AR to Gs and Gi proteins in cardiomyocytes,(2) cardioprotection by β2AR signaling in improving cardiac function and myocyte viability,and (3) PKA-independent,CaMKII-mediated β1AR apoptotic and maladaptive remodeling signaling in the heart.Based on these discoveries and salutary effects of β1AR blockade on patients with heart failure,we envision that activation of β2AR in combination with clinically used β1AR blockade should provide a safer and more effective therapy for the treatment of heart failure.

  17. β-Adrenergic modulation of skeletal muscle contraction: key role of excitation-contraction coupling.

    Science.gov (United States)

    Cairns, Simeon P; Borrani, Fabio

    2015-11-01

    Our aim is to describe the acute effects of catecholamines/β-adrenergic agonists on contraction of non-fatigued skeletal muscle in animals and humans, and explain the mechanisms involved. Adrenaline/β-agonists (0.1-30 μm) generally augment peak force across animal species (positive inotropic effect) and abbreviate relaxation of slow-twitch muscles (positive lusitropic effect). A peak force reduction also occurs in slow-twitch muscles in some conditions. β2 -Adrenoceptor stimulation activates distinct cyclic AMP-dependent protein kinases to phosphorylate multiple target proteins. β-Agonists modulate sarcolemmal processes (increased resting membrane potential and action potential amplitude) via enhanced Na(+) -K(+) pump and Na(+) -K(+) -2Cl(-) cotransporter function, but this does not increase force. Myofibrillar Ca(2+) sensitivity and maximum Ca(2+) -activated force are unchanged. All force potentiation involves amplified myoplasmic Ca(2+) transients consequent to increased Ca(2+) release from sarcoplasmic reticulum (SR). This unequivocally requires phosphorylation of SR Ca(2+) release channels/ryanodine receptors (RyR1) which sensitize the Ca(2+) -induced Ca(2+) release mechanism. Enhanced trans-sarcolemmal Ca(2+) influx through phosphorylated voltage-activated Ca(2+) channels contributes to force potentiation in diaphragm and amphibian muscle, but not mammalian limb muscle. Phosphorylation of phospholamban increases SR Ca(2+) pump activity in slow-twitch fibres but does not augment force; this process accelerates relaxation and may depress force. Greater Ca(2+) loading of SR may assist force potentiation in fast-twitch muscle. Some human studies show no significant force potentiation which appears to be related to the β-agonist concentration used. Indeed high-dose β-agonists (∼0.1 μm) enhance SR Ca(2+) -release rates, maximum voluntary contraction strength and peak Wingate power in trained humans. The combined findings can explain how adrenaline

  18. Withania somnifera ameliorates lead-induced augmentation of adrenergic response in rat portal vein

    Directory of Open Access Journals (Sweden)

    Subrata Kumar Hore

    2013-01-01

    Full Text Available Objectives: Present study was undertaken to elucidate the ameliorating potential of Withania somnifera root extract (WRE against lead-induced augmentation of adrenergic response in rat portal vein. Materials and Methods: In-vitro studies were conducted on effect of lead alone and lead+WRE on rat-isolated portal vein while in-vivo studies were done in three groups of 12 rats each; Group-II and III received 0.5% lead acetate and 1.0% WRE + 0.5% lead acetate, respectively, in drinking water for 12 weeks whereas group-I served as control. Adrenaline and noradrenaline levels in brain and blood were determined by HPLC assay while vascular reactivity of portal vein to lead and WRE was determined by measuring the isometric tension. Results: Following in-vitro exposure, lead did not alter the contractile effect of phenylephrine. In-vivo studies revealed that contractile effect of lead on portal vein was significantly potentiated and it was antagonized by prazosin (10 -7 M and WRE (1%. WRE treatment significantly reduced elevated blood noradrenaline (37.80% and restored noradrenaline level in brain (39.39% in lead-exposed animals. These values were almost comparable to the control group. But it failed to significantly affect the blood and brain adrenaline levels. Conclusions: Results suggest that following pre-exposure of rats to WRE, lead-induced augmentation of alpha 1 -adrenoceptors mediated response was reversed possibly by regulating catecholamine release from nerve endings. Thus, WRE may be useful in therapeutic management of lead-induced hypertension.

  19. Relationship between the Mutation of IRS-1 Gene and β3-adrenergic Receptor Gene

    Institute of Scientific and Technical Information of China (English)

    丁国宪; 沈捷; 陈家伟

    2001-01-01

    Objective To explore the relationship between the mutation of Insulin receptor substrate-1 ( IRS-1) gene and β3-adrenergic receptor (β3-AR) gene associated with insulin resistance, to further elucidate the etiology and pathogenesis of type 2 DM, hypertension and coronary heart disease. Methods 281 Chinese subjects are divided into three groups according to the oral glucose tolerance test (OGTT), The subjects were genotyped for the codon 64 of β3-AR gene, the codon 972 of IRS-1 gene polymorphisms by applying polymerase chain reaction (PCR) restriction fragment-length polymorphisms (RFLP) screening. Results Our study found that there was significantly increased frequency of IRS-1 gene mutation in IGT subjects and type 2 DM patients (P<0.05, 0.01, respectively), increased frequency of β3-AR gene mutation in type 2 DM patients (P<0.01), compared with NGT subjects. After adjusted for age, sex and plasma glucose, the level of insulin was significantly correlated with polymorphism of IRS-1 gene and β3-AR gene (P<0.001 in all ) by multiple regression analysis. In the models of Logistic regression, type 2 DM is closely related to age and family history (OR=3.1966, 1.4670; P=0.0272, 0.009; respectively), and to the polymorphism of β3-AR gene (OR=1.7380, P=0.0356), but not related to the polymorphism of IRS-1 gene. Conclusions These results suggest that mutation of IRS-1 gene may be the risk factor for insulin resistance, whereas mutation of β3-AR gene may be a common risk factor for insulin resistance, obesity, type 2 DM and hypertension.

  20. Simultaneous stimulation of GABA and beta adrenergic receptors stabilizes isotypes of activated adenylyl cyclase heterocomplex

    Directory of Open Access Journals (Sweden)

    Robichon Alain

    2004-06-01

    Full Text Available Abstract Background We investigated how the synthesis of cAMP, stimulated by isoproterenol acting through β-adrenoreceptors and Gs, is strongly amplified by simultaneous incubation with baclofen. Baclofen is an agonist of δ-aminobutyric acid type B receptors [GABAB], known to inhibit adenylyl cyclase via Gi. Because these agents have opposite effects on cAMP levels, the unexpected increase in cAMP synthesis when they are applied simultaneously has been intensively investigated. From previous reports, it appears that cyclase type II contributes most significantly to this phenomenon. Results We found that simultaneous application of isoproterenol and baclofen specifically influences the association/dissociation of molecules involved in the induction and termination of cyclase activity. Beta/gamma from [GABA]B receptor-coupled Gi has a higher affinity for adenylyl cyclase isoform(s when these isoforms are co-associated with Gs. Our data also suggest that, when beta/gamma and Gαs are associated with adenylyl cyclase isoform(s, beta/gamma from [GABA]B receptor-coupled Gi retards the GTPase activity of Gαs from adrenergic receptor. These reciprocal regulations of subunits of the adenylyl cyclase complex might be responsible for the drastic increase of cAMP synthesis in response to the simultaneous signals. Conclusions Simultaneous signals arriving at a particular synapse converge on molecular detectors of coincidence and trigger specific biochemical events. We hypothesize that this phenomenon comes from the complex molecular architectures involved, including scaffolding proteins that make reciprocal interactions between associated molecules possible. The biochemistry of simultaneous signaling is addressed as a key to synaptic function.

  1. Dynamics of β-adrenergic/cAMP signaling and morphological changes in cultured astrocytes.

    Science.gov (United States)

    Vardjan, Nina; Kreft, Marko; Zorec, Robert

    2014-04-01

    The morphology of astrocytes, likely regulated by cAMP, determines the structural association between astrocytes and the synapse, consequently modulating synaptic function. β-Adrenergic receptors (β-AR), which increase cytosolic cAMP concentration ([cAMP]i ), may affect cell morphology. However, the real-time dynamics of β-AR-mediated cAMP signaling in single live astrocytes and its effect on cell morphology have not been studied. We used the fluorescence resonance energy transfer (FRET)-based cAMP biosensor Epac1-camps to study time-dependent changes in [cAMP]i ; morphological changes in primary rat astrocytes were monitored by real-time confocal microscopy. Stimulation of β-AR by adrenaline, noradrenaline, and isoprenaline, a specific agonist of β-AR, rapidly increased [cAMP]i (∼15 s). The FRET signal response, mediated via β-AR, was faster than in the presence of forskolin (twofold) and dibutyryl-cAMP (>35-fold), which directly activate adenylyl cyclase and Epac1-camps, respectively, likely due to slow entry of these agents into the cytosol. Oscillations in [cAMP]i have not been recorded, indicating that cAMP-dependent processes operate in a slow time domain. Most Epac1-camps expressing astrocytes revealed a morphological change upon β-AR activation and attained a stellate morphology within 1 h. The morphological changes exhibited a bell-shaped dependency on [cAMP]i . The 5-10% decrease in cell cross-sectional area and the 30-50% increase in cell perimeter are likely due to withdrawal of the cytoplasm to the perinuclear region and the appearance of protrusions on the surface of astrocytes. Because astrocyte processes ensheath neurons, β-AR/cAMP-mediated morphological changes can modify the geometry of the extracellular space, affecting synaptic, neuronal, and astrocyte functions in health and disease.

  2. Fundamental and clinical studies on imaging of adrenergic nervous system of the heart, using radioiodinated metaiodobenzylguanidine

    Energy Technology Data Exchange (ETDEWEB)

    Matsunari, Ichiro (Kanazawa Univ. (Japan). School of Medicine)

    1991-04-01

    The purpose of this study was to investigate the myocardial distribution of radioiodonated metaiodobenzylguanidine (MIBG) in normal and reserpinized rats and to evaluate myocardial adrenergic innervation and function in patients with hypertrophic cardiomyopathy (HCM). The distribution of MIBG in the rat heart was higher in the right ventricle, basal segment and epicardial segment, which is mostly compatible with previous reports on the distribution and uptake of norepinephrine in the heart. The increased uptake of MIBG in the epicardial segment was a new finding, which seemed to indicate the difference of innervation between the epicardial and endocardial segments of the left ventricle in the rat heart. The uptake of MIBG was decreased in the reserpinized rats by 64% compared with that of the control, indicating there was MIBG uptake into intra-ventricular sites. Dual isotope autoradiogram also showed a decreased uptake of MIBG into the endocardium. The dual isotope autoradiogram revealed a significant decrease of MIBG uptake and a homogeneous distribution of {sup 201}Tl in the denervated myocardium, induced by phenol application. Single photon emission computerized tomography (SPECT) with {sup 123}I-MIBG and {sup 201}Tl was performed in 29 patients with HCM. In the visual evaluation of the SPECT images, the {sup 123}I-MIBG uptake was substantially lower than the {sup 201}Tl uptake in the hypertrophied septum in the early (20 minutes after infection) image in 48% of the HCM patients, suggesting less extraneuronal uptake in the human heart than in the rat heart. The septal {sup 123}I-MIBG/{sup 201}Tl uptake ratio at 20 minutes and 3 hours after injection inversely related with the septal thickness (R=-0.49 and R=-0.53). Significant positive correlation was observed between the septal MIBG clearance and the septal thickness (R=0.51). The MIBG clearance and uptake in conjunction with the {sup 201}Tl study seemed to reflect the severity of hypertrophy in HCM. (J.P.N.).

  3. Sleep-deprivation regulates α-2 adrenergic responses of rat hypocretin/orexin neurons.

    Directory of Open Access Journals (Sweden)

    Aaron Uschakov

    Full Text Available We recently demonstrated, in rat brain slices, that the usual excitation by noradrenaline (NA of hypocretin/orexin (hcrt/orx neurons was changed to an inhibition following sleep deprivation (SD. Here we describe that in control condition (CC, i.e. following 2 hours of natural sleep in the morning, the α(2-adrenergic receptor (α(2-AR agonist, clonidine, had no effect on hcrt/orx neurons, whereas following 2 hours of SD (SDC, it hyperpolarized the neurons by activating G-protein-gated inwardly rectifying potassium (GIRK channels. Since concentrations of clonidine up to a thousand times (100 µM higher than those effective in SDC (100 nM, were completely ineffective in CC, a change in the availability of G-proteins is unlikely to explain the difference between the two conditions. To test whether the absence of effect of clonidine in CC could be due to a down-regulation of GIRK channels, we applied baclofen, a GABA(B agonist known to also activate GIRK channels, and found that it hyperpolarized hcrt/orx neurons in that condition. Moreover, baclofen occluded the response to clonidine in SDC, indicating that absence of effect of clonidine in CC could not be attributed to down-regulation of GIRK channels. We finally tested whether α(2-ARs were still available at the membrane in CC and found that clonidine could reduce calcium currents, indicating that α(2-ARs associated with calcium channels remain available in that condition. Taken together, these results suggest that a pool of α(2-ARs associated with GIRK channels is normally down-regulated (or desensitized in hcrt/orx neurons to only become available for their inhibition following sleep deprivation.

  4. An assessment of the antagonistic activity of reactive blue 2 at P1- and P2-purinoceptors: supporting evidence for purinergic innervation of the rabbit portal vein.

    Science.gov (United States)

    Reilly, W M; Saville, V L; Burnstock, G

    1987-08-04

    A comparison of the effect of the putative adenosine 5'-triphosphate (ATP) antagonist, reactive blue 2, was made on the inhibitory responses to exogenous purines and non-adrenergic, non-cholinergic nerve stimulation in the rabbit portal vein, a preparation possessing both P1- and P2Y-purinoceptors, and on the excitatory responses to alpha, beta-methylene ATP in the rat portal vein where P2X-purinoceptors are present. In the ergotamine-contracted rabbit portal vein, ATP, adenosine and isoprenaline induced concentration-dependent relaxations. Reactive blue 2 (10-50 microM) produced a 2-9-fold shift to the right of the concentration-response curve to ATP, while the responses to adenosine and isoprenaline were not significantly altered. The inhibition of ATP assessed in the concentration-response curves appeared to be non-competitive. Electrical field stimulation of the ergotamine-contracted rabbit portal vein produced frequency-dependent relaxations that were abolished following incubation with tetrodotoxin (1 microM) and were inhibited by reactive blue 2 (30-50 microM), in a concentration-dependent manner. The rat portal vein contracted in response to the application of exogenous noradrenaline and alpha, beta-methylene ATP. Responses to both alpha, beta-methylene ATP (a P2X-purinoceptor agonist) and noradrenaline were not significantly inhibited by concentrations of reactive blue 2 that produced inhibition of the P2Y-mediated responses of the rabbit portal vein. In conclusion, it is suggested that reactive blue 2 is a non-competitive P2Y-purinoceptor antagonist, although the drug has a narrow range of activity and non-specific side effects become apparent at high concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Interleukin-1-receptor antagonist in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

    2007-01-01

    BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell...... proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive...

  6. Barnidipine, a long-acting slow onset calcium antagonist.

    Science.gov (United States)

    Korstanje, C

    2000-11-01

    Barnidipine is a stereochemically pure dihydropyridine calcium antagonist with a high potency. The drug showed a slow onset and long-lasting vasorelaxating effect in vitro, and strong antihypertensive activity in hypertension models. Barnidipine was shown to have a high vasoselectivity and offered protection in cardiac and renal ischaemia models. The in vitro drug:drug interaction profile suggests a low potential for clinically relevant interactions with concomitant medication. It can be anticipated that barnidipine is an attractive calcium antagonist, offering good blood pressure control without compensatory baroreflex activity.

  7. Hyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist

    Science.gov (United States)

    Johnson, David G.; Ulichny Goebel, Camy; Hruby, Victor J.; Bregman, Marvin D.; Trivedi, Dev

    1982-02-01

    The glucagon analog [l-Nα-trinitrophenylhistidine, 12-homoarginine]-glucagon (THG) was examined for its ability to lower blood glucose concentrations in rats made diabetic with streptozotocin. In vitro, THG is a potent antagonist of glucagon activation of the hepatic adenylate cyclase assay system. Intravenous bolus injections of THG caused rapid decreases (20 to 35 percent) of short duration in blood glucose. Continuous infusion of low concentrations of the inhibitor led to larger sustained decreases in blood glucose (30 to 65 percent). These studies demonstrate that a glucagon receptor antagonist can substantially reduce blood glucose levels in diabetic animals without addition of exogenous insulin.

  8. Metabolic activity of brown, "beige," and white adipose tissues in response to chronic adrenergic stimulation in male mice.

    Science.gov (United States)

    Labbé, Sébastien M; Caron, Alexandre; Chechi, Kanta; Laplante, Mathieu; Lecomte, Roger; Richard, Denis

    2016-07-01

    Classical brown adipocytes such as those found in interscapular brown adipose tissue (iBAT) represent energy-burning cells, which have been postulated to play a pivotal role in energy metabolism. Brown adipocytes can also be found in white adipose tissue (WAT) depots [e.g., inguinal WAT (iWAT)] following adrenergic stimulation, and they have been referred to as "beige" adipocytes. Whether the presence of these adipocytes, which gives iWAT a beige appearance, can confer a white depot with some thermogenic activity remains to be seen. In consequence, we designed the present study to investigate the metabolic activity of iBAT, iWAT, and epididymal white depots in mice. Mice were either 1) kept at thermoneutrality (30°C), 2) kept at 30°C and treated daily for 14 days with an adrenergic agonist [CL-316,243 (CL)], or 3) housed at 10°C for 14 days. Metabolic activity was assessed using positron emission tomography imaging with fluoro-[(18)F]deoxyglucose (glucose uptake), fluoro-[(18)F]thiaheptadecanoic acid (fatty acid uptake), and [(11)C]acetate (oxidative activity). In each group, substrate uptakes and oxidative activity were measured in anesthetized mice in response to acute CL. Our results revealed iBAT as a major site of metabolic activity, which exhibited enhanced glucose and nonesterified fatty acid uptakes and oxidative activity in response to chronic cold and CL. On the other hand, beige adipose tissue failed to exhibit appreciable increase in oxidative activity in response to chronic cold and CL. Altogether, our results suggest that the contribution of beige fat to acute-CL-induced metabolic activity is low compared with that of iBAT, even after sustained adrenergic stimulation.

  9. Beta 2-adrenergic receptor gene association with overweight and asthma in children and adolescents and its relationship with physical fitness

    Directory of Open Access Journals (Sweden)

    Neiva Leite

    2015-12-01

    Full Text Available Objective: To investigate the association of Arg16Gly and Gln27Glu polymorphisms of β2-adrenergic receptor gene (ADRB2 with the occurrence of asthma and overweight and the gene's influence on anthropometric, clinic, biochemical and physical fitness variables in children and adolescents. Methods: Subjects were evaluated for allelic frequencies of the β2-adrenergic receptor gene, height, weight, body mass index (BMI, BMI Z-score, waist circumference (WC, pubertal stage, resting heart rate (HRres, blood pressure (BP, total cholesterol (TC, glucose, insulin, high density lipoprotein (HDL-C, low density lipoprotein (LDL-C, triglyceride (TG, Homeostasis Metabolic Assessment (HOMA2-IR, Quantitative Insulin Sensitivity Check Index (QUICKI and maximal oxygen uptake (VO2max. The participants were divided in four groups: overweight asthmatic (n=39, overweight non-asthmatic (n=115, normal weight asthmatic (n=12, and normal weight non-asthmatic (n=40. Results: Regarding the Gln27Glu polymorphism, higher total cholesterol was observed in usual genotype individuals than in genetic variant carriers (p=0.04. No evidence was found that the evaluated polymorphisms are influencing the physical fitness. The Arg16 allele was found more frequently among the normal weight asthmatic group when compared to the normal weight non-asthmatic group (p=0.02, and the Glu27 allele was more frequently found in the overweight asthmatics group when compared to the normal weight non-asthmatic group (p=0.03. Conclusions: The association of Arg16 allele with the occurrence of asthma and of the Glu27 allele with overweight asthmatic adolescents evidenced the contribution of the β2-adrenergic receptor gene to the development of obesity and asthma.

  10. 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.

  11. Insulin resistance impairs endothelial function but not adrenergic reactivity or vascular structure in fructose-fed rats.

    Science.gov (United States)

    Romanko, Olga P; Ali, M Irfan; Mintz, James D; Stepp, David W

    2009-07-01

    Obesity and diabetes are major risk factors for the development of vascular disease in the lower limbs. Previous studies have demonstrated reduced nitric oxide (NO)-mediated vasodilation, increased adrenergic constriction, and inward, atrophic remodeling in the limb circulation of obese Zucker rats, but the component of the "metabolic syndrome" driving these changes is unclear. Because insulin resistance precedes the state of frank diabetes, the current study hypothesized that insulin resistance independent of obesity induced by fructose feeding would impair microvascular function in the skeletal muscle circulation in lean Zucker rats (LZR). A 66% fructose diet impaired glucose tolerance and induced moderate insulin resistance with no changes in whole-body hemodynamics of anesthetized rats (FF-LZR), compared to control LZR. NO-mediated vasodilation of isolated gracilis arteries, assessed in vitro with acetylcholine and sodium nitroprusside, was reduced approximately 20% in FF-LZR vs. LZR. NO-independent cGMP-mediated vasodilation was unimpaired. Pretreatment of isolated vessels with the superoxide scavenger, tempol, improved responses to both vasodilators. Reactivity to adrenergic stimulation was unaltered in FF-LZR vs. LZR, although constriction to endothelin was increased. Structural and passive mechanical characteristics of isolated gracilis arteries were similar in both LZR and FF-LZR. Taken together, these findings indicate that moderate insulin resistance is sufficient to impair endothelial function in an oxidant-dependent manner in the rat hindlimb circulation. Other aspects of skeletal muscle vascular function documented in obese models, specifically adrenergic tone and inward remodeling, must reflect either severe insulin resistance or other aspects of obesity. The factors accounting for nonendothelial vasculopathies remain unknown.

  12. Stress and glucocorticoids impair memory retrieval via β2-adrenergic, Gi/o-coupled suppression of cAMP signaling.

    Science.gov (United States)

    Schutsky, Keith; Ouyang, Ming; Castelino, Christina B; Zhang, Lei; Thomas, Steven A

    2011-10-05

    Acute stress impairs the retrieval of hippocampus-dependent memory, and this effect is mimicked by exogenous administration of stress-responsive glucocorticoid hormones. It has been proposed that glucocorticoids affect memory by promoting the release and/or blocking the reuptake of norepinephrine (NE), a stress-responsive neurotransmitter. It has also been proposed that this enhanced NE signaling impairs memory retrieval by stimulating β(1)-adrenergic receptors and elevating levels of cAMP. In contrast, other evidence indicates that NE, β(1), and cAMP signaling is transiently required for the retrieval of hippocampus-dependent memory. To resolve this discrepancy, wild-type rats and mice with and without gene-targeted mutations were stressed or treated with glucocorticoids and/or adrenergic receptor drugs before testing memory for inhibitory avoidance or fear conditioning. Here we report that glucocorticoids do not require NE to impair retrieval. However, stress- and glucocorticoid-induced impairments of retrieval depend on the activation of β(2) (but not β(1))-adrenergic receptors. Offering an explanation for the opposing functions of these two receptors, the impairing effects of stress, glucocorticoids and β(2) agonists on retrieval are blocked by pertussis toxin, which inactivates signaling by G(i/o)-coupled receptors. In hippocampal slices, β(2) signaling decreases cAMP levels and greatly reduces the increase in cAMP mediated by β(1) signaling. Finally, augmenting cAMP signaling in the hippocampus prevents the impairment of retrieval by systemic β(2) agonists or glucocorticoids. These results demonstrate that the β(2) receptor can be a critical effector of acute stress, and that β(1) and β(2) receptors can have quite distinct roles in CNS signaling and cognition.

  13. Pharmacological evaluation of selective α2c-adrenergic agonists in experimental animal models of nasal congestion.

    Science.gov (United States)

    Jia, Yanlin; Mingo, Garfield G; Hunter, John C; Lieber, Gissela B; Palamanda, Jairam R; Mei, Hong; Boyce, Christopher W; Koss, Michael C; Yu, Yongxin; Cicmil, Milenko; Hey, John A; McLeod, Robbie L

    2014-04-01

    Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective α2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of α2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 µl). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC(80)) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that α2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.

  14. The effect of activation of central adrenergic receptors by clonidine on the excitability of the solitary tract neurons in cats.

    Science.gov (United States)

    Lipski, J; Solnicka, E

    1976-01-01

    The effect of i.v. administered clonidine (10-15 mug/kg) on the evoked potential recorded in the dosal part of medulla oblongata, during carotid sinus nerve stimulation, was studied in chloralose-urethane anaesthetized cats. Clonidine influenced the amplitude and configuration of the evoked potential and the changes were parallel to the blood pressure depressor response. However, the blood pressure drops, evoked by i.v. infusion of papaverine, did not influence the potential. It is concluded that the synaptic transmission from the carotid sinus nerve to the second order neurons in the solatary tract area can be modulated by the clonidine-induced activation of central adrenergic receptors.

  15. 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 the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair...

  16. Human adipose tissue blood flow during prolonged exercise, III. Effect of beta-adrenergic blockade, nicotinic acid and glucose infusion

    DEFF Research Database (Denmark)

    Bülow, J

    1981-01-01

    acid, during acute i.v. beta-adrenergic blockade by propranolol, and during continuous i.v. infusion of glucose. The most pronounced lipid mobilization and utilization during work was seen in the control experiments where ATBF rose 3-fold on average from the initial rest period to the third hour...... of work. No increase in lipolysis and no increase in ATBF were found when lipolysis was blocked by nicotinic acid (0.3 g/h). Propranolol treatment (0.15 mg/kg) reduced lipolysis and nearly abolished the increase in ATBF during exercise. Intravenous administration of glucose (about 0.25 g/min) did...

  17. ß-adrenergic regulation of ion transport in pancreatic ducts: Patch-clamp study of isolated rat pancreatic ducts

    DEFF Research Database (Denmark)

    Novak, I

    1998-01-01

    much smaller effects. At comparable concentrations, it depolarized Vm by a few millivolts. Neither agonist had significant effects on intracellular Ca2+. CONCLUSIONS: This study provides the first direct evidence that adrenergic stimulation, namely, that of beta-adrenoceptors, controls ion transport....... METHODS: Small intralobular ducts were isolated from rat pancreas and studied in vitro by the whole-cell patch clamp technique. Cell membrane voltages and currents were indicators of cellular ion transport. In some ducts, intracellular Ca2+ activity was measured by fluorescence optical methods. RESULTS...... in pancreatic ducts. Similar to secretin, isoproterenol stimulation leads to opening of luminal Cl- channels, and HCO3- enters the lumen in exchange for Cl-....

  18. Studies on responsiveness of hepatoma cells to catecholamines. IV. Lack of adrenergic activation of phosphorylase in rat ascites hepatoma cells.

    Science.gov (United States)

    Miyamoto, K; Yanaoka, T; Sanae, F; Wakusawa, S; Koshiura, R

    1986-10-01

    Glycogen phosphorylase a activity in 7 rat ascites hepatoma cell lines treated with adrenergic agents, phenylephrine, epinephrine and isoproterenol, was investigated as compared with that in freshly isolated rat hepatocytes. Basal phosphorylase activities in hepatoma cells except AH7974 cells were lower than that in hepatocytes. Phosphorylase in hepatoma cells was not activated by any of the agents, while the enzyme activity in hepatocytes was clearly increased in a dose- and time-dependent manner. Phosphorylase in hepatocytes was sensitive to glucagon, but it was found to be insensitive to glucagon in all hepatoma cells. The present results suggest that rat ascites hepatoma cells may escape the glycogenolytic regulation by catecholamines and glucagon.

  19. Renal content and output of epidermal growth factor in long-term adrenergic agonist-treated rats

    DEFF Research Database (Denmark)

    Thulesen, J; Nexø, Ebba; Poulsen, Steen Seier

    2000-01-01

    fractional kidney weight, but initially the urinary excretion of EGF was reduced. The data add further evidence to the suggestion that activity of the sympathetic nervous system influences renal homeostasis of EGF, either directly or indirectly through renal histopathological changes....... used for immunohistochemistry and in situ hybridization. Fractional kidney weight was increased in the alpha-adrenergic agonist-treated group by 35% when compared with controls. Histological examination of the kidney revealed well-defined wedge-shaped areas of tubular dilatations and luminal amorphous...

  20. Endothelin-1-induced modulation of contractile responses elicited by an alpha 1-adrenergic agonist on human corpus cavernosum smooth muscle.

    Science.gov (United States)

    Kim, D C; Gondré, C M; Christ, G J

    1996-03-01

    The goal of these studies was to examine endothelin-1 (ET-1)-induced modulation of contractile responses elicited by the selective alpha 1-adrenergic agonist, phenylephrine (PE), on isolated human corporal tissue strips. Pharmacological studies were conducted on human corporal tissue strips obtained from 22 patients undergoing implantation of penile prostheses for erectile dysfunction. For the purposes of statistical analysis, the patients were stratified into two age groups: A, age or = 60 y (n = 12). The patients were further sub-divided into two diagnostic categories, diabetics (DM, n = 9) and nondiabetics (ND, n = 13). Cumulative concentration-response curves (CRCs) were constructed to the alpha 1-adrenergic agonist, PE, prior to constructing a CRC to a single mixture of PE and ET-1 on the same tissue. A previously described fixed molar ratio (FMR) protocol was used to generate CRCs to mixtures of PE and ET-1. In all cases, for the PE:ET-1 FMRs of 90:10, 80:20 and 70:30, the partial substitution of PE with ET-1 resulted in an approx 3-fold leftward shift in the EC50 of the PE alone CRC with an approx 4% concomitant increase in Emax and a decrease in the slope factor value. There were no significant age- or disease-related differences in any of the logistic parameter estimates that describe the FMR CRC, indicating that there are no detectable age- or disease-related alterations in ET-1-induced amplification of alpha 1-adrenergic-mediated contractions in these studies. In addition, the location of the FMR CRC was precisely predicted by the theoretical CRC for simple additivity of agonist effects. In conclusion, since relatively small increases in ET-1 concentrations were associated with significant increases in alpha 1-adrenergic-mediated contractile responses, these data provide further testimony to the importance of ET-1 in modulating corporal smooth muscle tone, and moreover, establish a conceptual framework for understanding the mechanism of its action(s).

  1. Spatial heterogeneity of blood flow in the dog heart. II. Temporal stability in response to adrenergic stimulation.

    Science.gov (United States)

    Deussen, A; Flesche, C W; Lauer, T; Sonntag, M; Schrader, J

    1996-07-01

    The effects of adrenergic stimulation on local myocardial blood flow in the left ventricle were studied in 13 anaesthetized Beagle dogs using the tracer microsphere technique. Adrenergic stimulation was induced by intravenous infusion of orciprenaline (1-2 microg kg-1 min-1) over 15 min or by electrical stimulation of the left ansa subclavia (10 Hz, 1 ms, 4-8 V) over 5 min. Local myocardial blood flow was analysed in 256 samples with an average (+/-SD) mass of 318+/-49 mg from the left ventricular myocardium using a standardized dissection procedure. Orciprenaline increased the average myocardial blood flow from 0.85+/-0.18 to 1.73+/-0.27 ml min-1 g-1, while oxygen consumption and the pressure-rate product increased by 129 and 119% respectively. The coefficients of variation of local myocardial blood flow, a measure of spatial blood flow heterogeneity, were 0.21 and 0.18 under control and orciprenaline respectively. Except for a slight transmural gradient (endomyocardium/epimyocardium flow ratio 1.19) myocardial blood flow did not exhibit significant spatial gradients. Stimulation with orciprenaline increased the average blood flow in all regions of the left ventricle by comparable extents. However, local blood flow during orciprenaline was significantly lower in samples from regions which had a lower blood flow under resting control conditions. A significant positive relationship was obtained between local myocardial blood flow under resting conditions and orciprenaline (r=0.45+/-0.18). Moreover, after recovery from orciprenaline stimulation (i.e. 40-112 min after the end of orciprenaline infusion) local myocardial blood flow exhibited a high degree of correlation with local flow before orciprenaline (r=0.71+/-0.08). Comparable results were obtained with electrical stimulation of the left ansa subclavia. For the comparison stimulation vs. control, the correlation coefficient of local blood flow was 0.52+/-0.04 and for recovery vs. control 0.77+/-0.06. From these

  2. Effect of Cardiopulmonary Bypass on Beta Adrenergic ReceptorAdenylate Cyclase System on Surfaces of Peripheral Lymphocytes

    Institute of Scientific and Technical Information of China (English)

    LUO Ailin; TIAN Yuke; JIN Shiao

    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.

  3. 5-Hydroxytryptamine3 receptor antagonists and cardiac side effects

    DEFF Research Database (Denmark)

    Brygger, Louise; Herrstedt, Jørn

    2014-01-01

    INTRODUCTION: 5-Hydroxytryptamine3-receptor antagonists (5-HT3-RA) are the most widely used antiemetics in oncology, and although tolerability is high, QTC prolongation has been observed in some patients. AREAS COVERED: The purpose of this article is to outline the risk of cardiac adverse events...

  4. The Effect of Antagonist Muscle Sensory Input on Force Regulation.

    Directory of Open Access Journals (Sweden)

    Tanya Onushko

    Full Text Available The purpose of this study was to understand how stretch-related sensory feedback from an antagonist muscle affects agonist muscle output at different contraction levels in healthy adults. Ten young (25.3 ± 2.4 years, healthy subjects performed constant isometric knee flexion contractions (agonist at 6 torque levels: 5%, 10%, 15%, 20%, 30%, and 40% of their maximal voluntary contraction. For half of the trials, subjects received patellar tendon taps (antagonist sensory feedback during the contraction. We compared error in targeted knee flexion torque and hamstring muscle activity, with and without patellar tendon tapping, across the 6 torque levels. At lower torque levels (5%, 10%, and 15%, subjects produced greater knee torque error following tendon tapping compared with the same torque levels without tendon tapping. In contrast, we did not find any difference in torque output at higher target levels (20%, 30%, and 40% between trials with and without tendon tapping. We also observed a load-dependent increase in the magnitude of agonist muscle activity after tendon taps, with no associated load-dependent increase in agonist and antagonist co-activation, or reflex inhibition from the antagonist tapping. The findings suggest that at relatively low muscle activity there is a deficiency in the ability to correct motor output after sensory disturbances, and cortical centers (versus sub-cortical are likely involved.

  5. Voltage-Gated Calcium Channel Antagonists and Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Bruce Lyeth

    2013-06-01

    Full Text Available Traumatic brain injury (TBI is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i. These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic.

  6. How Hybrid Organizations Turn Antagonistic Assets into Complementarities

    DEFF Research Database (Denmark)

    Hockerts, Kai

    2015-01-01

    This article focuses on people excluded from traditional markets as employees, producers, or consumers on the grounds that they lack the appropriate skills. It describes the processes through which these perceived liabilities can be overcome by so-called hybrid organizations. Hybrids pursue expli...... for complementarities, and by creating demands for antagonistic assets, or by using partnerships....

  7. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn;

    2011-01-01

    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered: Preclin......Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...... antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT2A receptor...

  8. Facilitative and antagonistic interactions between plant viruses in mixed infections.

    Science.gov (United States)

    Syller, Jerzy

    2012-02-01

    Mixed infections of plant viruses are common in nature, and a number of important virus diseases of plants are the outcomes of interactions between causative agents. Multiple infections lead to a variety of intrahost virus-virus interactions, many of which may result in the generation of variants showing novel genetic features, and thus change the genetic structure of the viral population. Hence, virus-virus interactions in plants may be of crucial significance for the understanding of viral pathogenesis and evolution, and consequently for the development of efficient and stable control strategies. The interactions between plant viruses in mixed infections are generally categorized as synergistic or antagonistic. Moreover, mixtures of synergistic and antagonistic interactions, creating usually unpredictable biological and epidemiological consequences, are likely to occur in plants. The mechanisms of some of these are still unknown. This review aims to bring together the current knowledge on the most commonly occurring facilitative and antagonistic interactions between related or unrelated viruses infecting the same host plant. The best characterized implications of these interactions for virus-vector-host relationships are included. The terms 'synergism' and 'helper dependence' for facilitative virus-virus interactions, and 'cross-protection' and 'mutual exclusion' for antagonistic interactions, are applied in this article.

  9. Determinants of effective, safe and convenient vitamin K antagonist use

    NARCIS (Netherlands)

    Kooistra, Hilde Afra Margaretha

    2016-01-01

    Vitamin K antagonists (VKA) are frequently used anticoagulants. They are very effective in preventing atrial fibrillation related strokes and recurrent venous thrombosis. However, it can be difficult to achieve an optimal balance between the efficacy and side effects (bleeding), as the dose response

  10. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  11. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

    NARCIS (Netherlands)

    Parry-Jones, A.R.; Napoli, M. Di; Goldstein, J.N.; Schreuder, F.H.; Tetri, S.; Tatlisumak, T.; Yan, B.; Nieuwenhuizen, K.M.; Dequatre-Ponchelle, N.; Lee-Archer, M.; Horstmann, S.; Wilson, D.; Pomero, F.; Masotti, L.; Lerpiniere, C.; Godoy, D.A.; Cohen, A.S.; Houben, R.; Al-Shahi Salman, R.; Pennati, P.; Fenoglio, L.; Werring, D.; Veltkamp, R.; Wood, E.; Dewey, H.M.; Cordonnier, C.; Klijn, C.J.M.; Meligeni, F.; Davis, S.M.; Huhtakangas, J.; Staals, J.; Rosand, J.; Meretoja, A.

    2015-01-01

    OBJECTIVE: There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different

  12. Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage

    NARCIS (Netherlands)

    Parry-Jones, Adrian R.; Di Napoli, Mario; Goldstein, Joshua N.; Schreuder, Floris H B M; Tetri, Sami; Tatlisumak, Turgut; Yan, Bernard; Van Nieuwenhuizen, Koen M.; Dequatre-Ponchelle, Nelly; Lee-Archer, Matthew; Horstmann, Solveig; Wilson, Duncan; Pomero, Fulvio; Masotti, Luca; Lerpiniere, Christine; Godoy, Daniel Agustin; Cohen, Abigail S.; Houben, Rik; Al-Shahi Salman, Rustam; Pennati, Paolo; Fenoglio, Luigi; Werring, David; Veltkamp, Roland; Wood, Edith; Dewey, Helen M.; Cordonnier, Charlotte; Klijn, Catharina J M; Meligeni, Fabrizio; Davis, Stephen M.; Huhtakangas, Juha; Staals, Julie; Rosand, Jonathan; Meretoja, Atte

    2015-01-01

    Objective There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different

  13. Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists.

    Science.gov (United States)

    Kim, Jeeyeon; Kim, Youngjae; Tae, Jinsung; Yeom, Miyoung; Moon, Bongjin; Huang, Xi-Ping; Roth, Bryan L; Lee, Kangho; Rhim, Hyewhon; Choo, Il Han; Chong, Youhoon; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah

    2013-11-01

    The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT