Simultaneous evaluation of the pre- and postsynaptic interactions of alpha-2 adrenergic agents in the phenoxybenzamine-treated dog saphenous vein

International Nuclear Information System (INIS)

Buckner, S.; Morse, P.; DeBernardis, J.; Kyncyl, J.

1986-01-01

Functional alpha-2 adrenergic receptors can be demonstrated on both the neuronal and muscular sides of the sympathetic synapse in the superfused, electrically stimulated, 3 H-NE-loaded dog saphenous vein (DSV). Selective alkylation of the alpha-1 subtype in this tissue by phenoxybenzamine produced a preparation which contained functional alpha adrenergic receptors of only the alpha-2 subtype at both locations and provided an experimental model suitable for differentiating alpha-2 selective compounds according to their pre- vs postsynaptic preference. A number of standard alpha-2 selective agonists and antagonists were tested in this model. None of these agents exhibited any significant degree of presynaptic or postsynaptic selectivity

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

International Nuclear Information System (INIS)

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

1987-01-01

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

KINETIC-ANALYSIS OF SHORT-TERM EFFECTS OF ALPHA-AGONISTS ON GLUCONEOGENESIS IN ISOLATED RAT HEPATOCYTES

NARCIS (Netherlands)

Leverve, X. M.; Groen, A. K.; Verhoeven, A. J.; Tager, J. M.

1985-01-01

Isolated hepatocytes from fasted rats were perifused with glycerol as gluconeogenic substrate. Stimulation of gluconeogenesis with phenylephrine (10(-5) M) as alpha-adrenergic agonist consisted of two distinct phases. The first phase was a transient stimulation of gluconeogenesis and was accompanied

Alpha-2 adrenergic stimulation triggers Achilles tenocyte hypercellularity: Comparison between two model systems.

Science.gov (United States)

Backman, L J; Andersson, G; Fong, G; Alfredson, H; Scott, A; Danielson, P

2013-12-01

The histopathology of tendons with painful tendinopathy is often tendinosis, a fibrosis-like condition of unclear pathogenesis characterized by tissue changes including hypercellularity. The primary tendon cells (tenocytes) have been shown to express adrenoreceptors (mainly alpha-2A) as well as markers of catecholamine production, particularly in tendinosis. It is known that adrenergic stimulation can induce proliferation in other cells. The present study investigated the effects of an exogenously administered alpha-2 adrenergic agonist in an established in vivo Achilles tendinosis model (rabbit) and also in an in vitro human tendon cell culture model. The catecholamine producing enzyme tyrosine hydroxylase and the alpha-2A-adrenoreceptor (α2A AR) were expressed by tenocytes, and alpha-2 adrenergic stimulation had a proliferative effect on these cells, in both models. The proliferation was inhibited by administration of an α2A AR antagonist, and the in vitro model further showed that the proliferative alpha-2A effect was mediated via a mitogenic cell signaling pathway involving phosphorylation of extracellular-signal-regulated kinases 1 and 2. The results indicate that catecholamines produced by tenocytes in tendinosis might contribute to the proliferative nature of the pathology through stimulation of the α2A AR, pointing to a novel target for future therapies. The study furthermore shows that animal models are not necessarily required for all aspects of this research. © 2013 The Authors. Scand J Med Sci Sports published by John Wiley & Sons Ltd.

Correlation between phosphatidylinositol labeling and contraction in rabbit aorta: effect of alpha-1 adrenergic activation

International Nuclear Information System (INIS)

Villalobos-Molina, R.; Uc, M.; Hong, E.; Garcia-Sainz, J.A.

1982-01-01

Activation of rabbit aortic strips with alpha adrenergic agonists increased the labeling (with [ 32 P]Pi) of phosphatidylinositol (PI) and phosphatidic acid and contracted the vascular preparations in dose-related fashion. Epinephrine, norepinephrine and methoxamine produced maximal effects, whereas clonidine behaved as partial agonist and B-HT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazole-[5,4-d] azepin dihydrochloride) was almost without activity in the two experimental models used. Phenylephrine was a full agonist in producing contraction, but failed to elicit the maximal increase in PI labeling. The EC50 values to produce contraction of aortic strips were lower for all agonists than those required to increase the incorporation of radioactive phosphate into PI, but there was a good correlation between the two sets of data. The increased PI labeling and contraction of aortic strips induced by epinephrine were antagonized by prazosin and yohimbine in dose-related fashion, but the first alpha blocker was about three orders of magnitude more potent than the second in antagonizing the two effects. The present results indicate that both stimulation of PI labeling and contraction are mediated through activation of alpha-1 adrenoceptors in rabbit aorta

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

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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.

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.

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...

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....

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

OpenAIRE

AR Abyazi Shelmani; M Taherianfard

2007-01-01

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

Potential antisecretory antidiarrheals. 1. Alpha 2-adrenergic aromatic aminoguanidine hydrazones.

Science.gov (United States)

Pitzele, B S; Moormann, A E; Gullikson, G W; Albin, D; Bianchi, R G; Palicharla, P; Sanguinetti, E L; Walters, D E

1988-01-01

Guanabenz, a centrally acting antihypertensive agent, has been shown to have intestinal antisecretory properties. A series of aromatic aminoguanidine hydrazones was made in an effort to separate the antisecretory and cardiovascular activities. Benzaldehyde, naphthaldehyde, and tetralone derivatives were synthesized. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber using a rabbit ileum preparation. A number of compounds, including members of each structural class, were active upon subcutaneous administration in the rat. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The compound displaying the best separation of activities was the aminoguanidine hydrazone of 2,6-dimethyl-4-hydroxybenzaldehyde (20).

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

DEFF Research Database (Denmark)

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

1982-01-01

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

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

International Nuclear Information System (INIS)

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

1991-01-01

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

Effects of alpha-2 agonists on renal function in hypertensive humans.

Science.gov (United States)

Goldberg, M; Gehr, M

1985-01-01

Centrally acting adrenergic agonists, by decreasing peripheral adrenergic activity, are effective antihypertensive agents. The older agents, however, especially methyldopa, have been associated with weight gain, clinical edema, and antihypertensive tolerance when used as monotherapy. While acute studies in humans have demonstrated weight gain and sodium retention with clonidine and guanabenz, chronic administration results in a decrease in weight and plasma volume. The absence of chronic weight gain and of sodium retention could be the result of a counterbalance between hypotension-related antinatriuresis, secondary to a decrease in glomerular filtration rate and renal blood flow, and natriuretic activity, as a result of a decrease in renal sympathetic tone. Whereas natriuresis and water diuresis have been demonstrated in animals with acute clonidine or guanabenz administration, this has not been demonstrated in humans. Recent studies in which saline administration was used to precondition humans to a subsequent natriuretic stimulus (i.e., guanabenz-induced decreased renal adrenergic activity) resulted in stabilization of renal blood flow and natriuresis. Selective reduction renal sympathetic activity affecting salt and water transport may explain why guanabenz and probably also clonidine seem to be devoid of the sodium/fluid-retaining properties that are common with other antihypertensive agents. Because agents of this class have effects other than pure central alpha-2 agonism (such as alpha-1 activity), they might have confounding and counterbalancing side effects leading to sodium and water retention.

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

Science.gov (United States)

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

2012-02-01

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

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

NARCIS (Netherlands)

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

1992-01-01

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

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

International Nuclear Information System (INIS)

Morrow, A.L.

1985-01-01

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

Epidural anesthesia and postoperatory analgesia with alpha-2 adrenergic agonists and lidocaine for ovariohysterectomy in bitches

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Pohl, Virgínia H.; Carregaro, Adriano B.; Lopes, Carlize; Gehrcke, Martielo I.; Muller, Daniel C.M.; Garlet, Clarissa D.

2012-01-01

The aim of this study was to determine the viability and cardiorespiratory effects of the association of epidural alpha-2 adrenergic agonists and lidocaine for ovariohysterectomy (OH) in bitches. Forty-two bitches were spayed under epidural anesthesia with 2.5 mg/kg body weight (BW) of 1% lidocaine with adrenaline (CON) or in association with 0.25 mg/kg BW of xylazine (XYL), 10 μg/kg BW of romifidine (ROM), 30 μg/kg BW of detomidine (DET), 2 μg/kg BW of dexmedetomidine (DEX), or 5 μg/kg BW of clonidine (CLO). Heart rate (HR), respiratory rate (fR) and arterial pressures were monitored immediately before and every 10 min after the epidural procedure. Blood gas and pH analysis were done before, and at 30 and 60 min after the epidural procedure. Animals were submitted to isoflurane anesthesia if they presented a slightest sign of discomfort during the procedure. Time of sensory epidural block and postoperative analgesia were evaluated. All animals in CON and DEX, 5 animals in ROM and CLO, 4 animals in XYL, and 3 in DET required supplementary isoflurane. All groups, except CLO, showed a decrease in HR. There was an increase in arterial pressures in all groups. Postoperative analgesia lasted the longest in XYL. None of the protocols were totally efficient to perform the complete procedure of OH; however, xylazine provided longer postoperative analgesia than the others. PMID:23277701

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

Science.gov (United States)

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

2014-01-01

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

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

Directory of Open Access Journals (Sweden)

AR Abyazi Shelmani

2007-12-01

Full Text Available Introduction: Estrogen and progesterone are supposed to modify pain sensitivity. However, the actual role of each of these steroid hormones in this respect is not well known. Plasma concentrations of these hormones show variation during estrous cycle. The role of alpha2 receptors in tonic pain has been pointed out. The aim of the present study was to investigate the agonist and antagonist effect of alpha2 adrenergic receptors on tonic pain sensitivity during all stages of estrous cycle in female rats. Methods: Xylasine as alpha2 agonist and yohimbin as alpha2 antagonist were used via intraperitoneal route (IP. Adult rats weighing 180-200 grams were used. Animals were maintained on 12h reverse light/dark cycle for 7 days prior to the experiment. Water and food was available ad libitum. Formalin test was performed by subcutaneous injection of 50 l formalin (2.5% solution into the hind paw. Formalin test was performed in all stages of estrous cycle for 60 minutes. Animals were divided into four groups; 1- control group (intact animal, 2- Sham group (animals received 0.2 ml normal saline by IP route, 3- Agonist groups (animals received 0.2 ml xylasine 1, 3 mg/kg body weight by IP route and 4- Antagonist group (animals received 0.2 ml yohimbine 1, 3 mg/kg body weight by IP route. Data were statistically analyzed using 2 way ANOVA test followed by Tukey's test as post-hoc test. P<0.05 was considered significant. Results: Results showed that xylasine significantly (p<0.05 decreases pain sensitivity in all stages of estrous cycle. Analgesic effect of xylasine was maximum in estrus stage of estrous cycle and minimum in metestrus stage of estrous cycle. Yohimbine significantly (p<0.05 increases pain sensitivity in all stages of estrous cycle. Hyperalgesic effect of yohimbine was maximum in metestrus stage of estrous cycle and minimum in estrus stage of estrous cycle. Conclusion: These results indicate that alpha2 adrenergic system and endogenous

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

International Nuclear Information System (INIS)

Schaffer, W.; Williams, R.S.

1986-01-01

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

Endogenous PKI gamma limits the duration of the anti-apoptotic effects of PTH and beta-adrenergic agonists in osteoblasts.

Science.gov (United States)

Chen, Xin; Song, In-Hwan; Dennis, James E; Greenfield, Edward M

2007-05-01

PKI gamma knockdown substantially extended the anti-apoptotic effects of PTH and beta-adrenergic agonists, whereas PKI gamma overexpression decreased these effects. Therefore, inhibition of PKI gamma activity may provide a useful co-therapy in combination with intermittent PTH or beta-adrenergic agonists for bone loss in conditions such as osteoporosis. PTH has both catabolic and anabolic effects on bone, which are primarily caused by cAMP/protein kinase A (PKA) signaling and regulation of gene expression. We previously showed that protein kinase inhibitor-gamma (PKI gamma) is required for efficient termination of cAMP/PKA signaling and gene expression after stimulation with PTH or beta-adrenergic agonists. Inhibition of osteoblast apoptosis is thought to be an important, but transient, mechanism partly responsible for the anabolic effects of intermittent PTH. Therefore, we hypothesized that endogenous PKI gamma also terminates the anti-apoptotic effect of PTH. PKI gamma knockdown by antisense transfection or siRNA was used to examine the ability of endogenous PKI gamma to modulate the anti-apoptotic effects of PTH and beta-adrenergic agonists in ROS 17/2.8 cells. Knockdown of PKI gamma substantially extended the anti-apoptotic effects of PTH, whether apoptosis was induced by etoposide or dexamethasone. In contrast, overexpression of PKI gamma decreased the anti-apoptotic effect of PTH pretreatment. This study is also the first demonstration that beta-adrenergic agonists mimic the anti-apoptotic effects of PTH in osteoblasts. Moreover, PKI gamma knockdown also substantially extended this anti-apoptotic effect of beta-adrenergic agonists. Taken together, these results show that endogenous PKI gamma limits the duration of the anti-apoptotic effects of cAMP/PKA signaling in osteoblasts. Because significant individual variability exists in the anabolic responses to PTH therapy in current clinical treatment of osteoporosis, inhibition of PKI gamma activity may provide a

Alpha 2-adrenoceptor blockade, pituitary-adrenal hormones, and agonistic interactions in rats.

Science.gov (United States)

Haller, J; Barna, I; Kovács, J L

1994-08-01

The effects of adrenergic activation on aggressiveness and the aggression induced endocrine changes were tested in rats. Alpha 2 adrenoceptor blockers were used for enhancing activation of the adrenergic system, and changes in aggressiveness were tested in resident-intruder contests. Three experiments were conducted. In experiment 1, saline injected rats responded to the presence of an opponent by aggression and the increase in plasma ACTH and corticosterone. Intraperitoneal administration of 1 mg/kg CH-38083 (an alpha 2 adrenoceptor antagonist) produced a several fold increase in clinch fighting and mutual upright scores, and also further enhanced the plasma ACTH and corticosterone response. In experiment 2, the effect of three doses (0.5, 1 and 2 mg/kg) of three different alpha 2 adrenoceptor blockers CH-38083, idazoxan and yohimbine were tested. All the substances increased aggression at 0.5 and 1 mg/kg; at 2 mg/kg the effect of idazoxan and yohimbine disappeared, while with CH-38083 an additional increase was obtained. In yohimbine treated animals the enhancement of aggression was reduced already at 1 mg/kg. In experiment 3, indomethacin, a potent inhibitor of the catecholamine-induced ACTH release completely abolished the effects of the alpha 2 adrenoceptor antagonist CH-38083: the intensity of agonistic interactions, as well as ACTH and corticosterone plasma concentrations, returned to control levels. The possible role of catecholamines and the stress hormones in the activation of aggression is discussed.

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...

Modification of certain pharmacological effects of ethanol by lipophilic alpha-1 adrenergic agonists

Energy Technology Data Exchange (ETDEWEB)

Menon, M.K.; Dinovo, E.C.; Haddox, V.G.

1987-09-28

The influence of four centrally-acting alpha-1 adrenoceptor agonists, namely, 2(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587), cirazoline, (-) 1,2,3,4-tetrahydro-8-methoxy-5-methylthio-2-naphthalenamine ((-)SKF 89748A) and 2-(2-methylindazol-4-imino)imidazolidine (Sgd 101/75) on the pharmacological effects of ethanol was investigated. All four drugs reduced the duration of ethanol-induced hypnosis in C57B1/6 mice, this effect being proportional to their relative potencies to exert central alpha-1 agonism. In prazosin-pretreated mice, St 587 failed to reduce the hypnotic effect of ethanol, which provided strong evidence for the role of alpha-1 agonism for the hypnosis reducing effect of St 587. Hyperactivity induced in C57B1/6 mice by a subhypnotic dose of ethanol and St 587 was reported earlier. In the present study, St 587, cirazoline and (-)SKF 89748A produced similar response, but no correlation between this effect and ethanol hypnosis blockade could be established. 19 references, 8 figures, 2 tables.

alpha2-Adrenergic agonists antagonise the anxiolytic-like effect of antidepressants in the four-plate test in mice.

Science.gov (United States)

Massé, Fabienne; Hascoët, Martine; Bourin, Michel

2005-10-14

Selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs) has been reported to be efficient in anxiety disorders. Some animal models have demonstrated an anxiolytic-like effect following acute administration, however, it is not yet known how noradrenergic receptors are implicated in the therapeutic effects of antidepressants (ADs) in anxiety. The effects of two alpha(2)-adrenoceptor agonists (clonidine, guanabenz) on anxiolytic-like effect of two SSRIs (paroxetine and citalopram) and two SNRIs (venlafaxine and milnacipran) were evaluated in the four-plate test (FPT) in mice. Paroxetine (4 mg/kg), citalopram (8 mg/kg), venlafaxine (8 mg/kg), and milnacipran (8 mg/kg) administered intraperitoneally (i.p.) increased the number of punishments accepted by mice in the FPT. Clonidine (0.0039-0.5 mg/kg) and guanabenz (0.03-0.5mg/kg) had no effect on the number of punishments accepted by mice. Clonidine (0.03 and 0.06 mg/kg) and guanabenz (0.125 and 0.5 mg/kg) (i.p. -45 min) reversed the anti-punishment effect of paroxetine, citalopram, venlafaxine and milnacipran (i.p. -30 min). But if the antidepressants are administered 45 min before the test and alpha(2)-adrenoceptor agonists 30 min before the test, alpha(2)-adrenoceptor agonists failed to alter the anti-punishment effect of antidepressants. The results of this present study indicate that alpha(2)-adrenoceptor agonists antagonise the anxiolytic-like effect of antidepressants in mice when they are administered 15 min before the administration of antidepressant suggesting a close inter-regulation between noradrenergic and serotoninergic system in the mechanism of SSRIs and SNRIs in anxiety-like behaviour.

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

International Nuclear Information System (INIS)

Mori, Hideki; Koyama, Tsukasa; Yamashita, Itaru

1991-01-01

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

Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole.

Science.gov (United States)

Hoffman, W E; Kochs, E; Werner, C; Thomas, C; Albrecht, R F

1991-08-01

Dexmedetomidine is an alpha 2-adrenergic agonist that decreases central sympathetic activity and reduces the anesthetic requirement for halothane. We evaluated the effect of dexmedetomidine on neurologic and histopathologic outcome from incomplete cerebral ischemia in the rat. Anesthesia was maintained with a 25-micrograms.kg-1.h-1 fentanyl infusion combined with 70% nitrous oxide. Incomplete ischemia was produced by unilateral carotid artery ligation combined with hemorrhagic hypotension to 35 mmHg for 30 min. Arterial blood gas tensions, pH, and head temperature were maintained at normal levels during the experiment. Four ischemic groups were tested: group 1 (n = 15) received an intraperitoneal (ip) saline injection (control); group 2 (n = 10) received an ip injection of 10 micrograms/kg dexmedetomidine 30 min before ischemia; group 3 (n = 10) received 100 micrograms/kg dexmedetomidine; and group 4 (n = 10) received 100 micrograms/kg dexmedetomidine plus 1 mg/kg atipamezole (an alpha 2-adrenergic antagonist). Neurologic outcome was evaluated for 3 days using a graded deficit score. Histopathology was evaluated in coronal section in caudate and hippocampal tissue segments. Dexmedetomidine (10 and 100 micrograms/kg) significantly decreased plasma catecholamines and improved neurologic and histopathologic outcome in a dose-dependent manner compared to control rats (P less than 0.05). Atipamezole abolished the decrease in catecholamines and the improvement in outcome seen with dexmedetomidine, confirming that these effects were mediated by alpha 2-adrenergic receptors. It is concluded that alpha 2-adrenoreceptor stimulation decreases sympathetic activity and decreases ischemic injury in a model of incomplete cerebral ischemia.

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

International Nuclear Information System (INIS)

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

1984-01-01

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

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

International Nuclear Information System (INIS)

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

1987-01-01

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

Potential of beta-adrenergic agonists for increasing protein deposition in ruminants in developing countries

International Nuclear Information System (INIS)

Berschauer, F.

1989-01-01

Various substituted phenylethanolamines, acting on the sympathetic nervous system, have been shown to increase protein retention (via decreased proteolysis) and reduce fat deposition (via increased lipolysis and reduced lipogenesis) in ruminants and monogastrics. Research with finishing lambs in developed countries show various beta-adrenergic agonists to improve growth rate (by 18%), feed conversion (by 12%) and carcass quality (28% increase in area of longissimus dorsi and 33% reduction in subcutaneous fat). Similar effects of beta-agonists on carcass composition of well fed cattle have been reported. The effects of beta-agonists on livestock in developing countries of the tropics have not yet been investigated, but their effects in increasing metabolic rate suggest that treated ruminants would be more vulnerable to hot environments. Beta-agonists appear to improve nitrogen retention to a greater extent in breeds with a lower potential for muscle growth. In view of this, they might be particularly effective in improving nitrogen retention in tropical breeds which have a low growth potential. This aspect, together with the response of undernourished animals in the developing countries, needs investigation. Beta-adrenergic agonists are not yet registered for use in animal production, but product licenses for some of them are expected to be granted soon. (author). 31 refs, 1 fig., 12 tabs

Commentary: Are alpha-2 agonist really effective in children with tics with comorbid ADHD? A commentary on Whittington et al. (2016).

Science.gov (United States)

Bloch, Michael H

2016-09-01

In this issue, Whittington et al. (2016) present a systematic review that reports the efficacy of three primary treatments for children with Tourette syndrome (TS) - (a) α2-adrenergic receptor agonists; (b) antipsychotic medications; and (c) habit reversal training/comprehensive behavioral intervention. In this commentary, we highlight the large degree of heterogeneity observed in the meta-analysis of trials involving alpha-2 agonist medications and present possible explanations for the observed heterogeneity. Among these possible explanations is the possibility that presence of comorbid ADHD may moderate the efficacy of alpha-2 agonists in the treatment of tic disorder with the medications being more effective in patients with both conditions. The commentary reviews the evidence supporting this possible moderating effect of ADHD and discusses the implications for such a relationship. © 2016 Association for Child and Adolescent Mental Health.

Rotifer neuropharmacology--III. Adrenergic drug effects on Brachionus plicatilis.

Science.gov (United States)

Keshmirian, J; Nogrady, T

1987-01-01

Norepinephrine (NE) induces three pharmacological effects in Brachionus plicatilis. As a result of excitation the rate of ciliary motion and swimming increases, and the animals flip their foot constantly at a rapid rate. This rapid foot flipping was used as a specific model to measure adrenergic effects in B. plicatilis. Phenylephrine induces the same effect at identical efficacy, while isoproterenol and salbutamol, two beta-agonists, show one-half and one-tenth NE efficacy. The beta blocker propranolol and the alpha blocker tolazoline both antagonize foot flipping induced by NE. However, propranolol shows antagonism because it causes foot paralysis by itself. Timolol, another beta blocker but without the membrane effect of propranolol, does not antagonize the alpha receptor mediated NE effect, nor does it cause foot paralysis. Propranolol, timolol and tolazoline also show agonist activity, inducing foot flipping. NE does not antagonize the foot paralysis induced by propranolol, only its anesthetic effect by delaying its onset. These results indicate that the foot flipping induced by NE is a receptor-mediated alpha adrenergic effect, while the foot paralysis is caused by membrane phenomena.

Locus coeruleus alpha-adrenergic-mediated activation of cortical astrocytes in vivo.

Science.gov (United States)

Bekar, Lane K; He, Wei; Nedergaard, Maiken

2008-12-01

The locus coeruleus (LC) provides the sole source of norepinephrine (NE) to the cortex for modulation of cortical synaptic activity in response to salient sensory information. NE has been shown to improve signal-to-noise ratios, sharpen receptive fields and function in learning, memory, and cognitive performance. Although LC-mediated effects on neurons have been addressed, involvement of astrocytes has thus far not been demonstrated in these neuromodulatory functions. Here we show for the 1st time in live mice, that astrocytes exhibit rapid Ca(2+) increases in response to electrical stimulation of the LC. Additionally, robust peripheral stimulation known to result in phasic LC activity leads to Ca(2+) responses in astrocytes throughout sensory cortex that are independent of sensory-driven glutamate-dependent pathways. Furthermore, the astrocytic Ca(2+) transients are competitively modulated by alpha(2)-specific agonist/antagonist combinations known to impact LC output, are sensitive to the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, and are inhibited locally by an alpha-adrenergic antagonist. Future investigations of LC function must therefore consider the possibility that LC neuromodulatory effects are in part derived from activation of astrocytes.

Alpha adrenergic receptors in dog coronary arteries as detected with autoradiography

International Nuclear Information System (INIS)

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

1986-01-01

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

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.

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

Science.gov (United States)

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

2018-01-17

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

Carvedilol and adrenergic agonists suppress the lipopolysaccharide-induced NO production in RAW 264.7 macrophages via the adrenergic receptors

Czech Academy of Sciences Publication Activity Database

Pekarová, Michaela; Králová, Jana; Kubala, Lukáš; Číž, Milan; Papežíková, Ivana; Mačičková, T.; Pečivová, J.; Nosál, R.; Lojek, Antonín

2009-01-01

Roč. 60, č. 1 (2009), s. 143-150 ISSN 0867-5910 R&D Projects: GA AV ČR(CZ) 1QS500040507; GA ČR(CZ) GA524/08/1753 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : carvedilol * adrenergic agonists * nitric oxide Subject RIV: BO - Biophysics Impact factor: 1.489, year: 2009

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

Science.gov (United States)

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

2010-01-01

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

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

Directory of Open Access Journals (Sweden)

Urs M Nater

Full Text Available Alpha-amylase in both blood and saliva has been used as a diagnostic parameter. While studies examining alpha-amylase activity in saliva have shown that it is sensitive to physiological and psychological challenge of the adrenergic system, no challenge studies have attempted to elucidate the role of the adrenergic system in alpha-amylase activity in blood. We set out to examine the impact of psychological and pharmacological challenge on alpha-amylase in blood in two separate studies.In study 1, healthy subjects were examined in a placebo-controlled, double-blind paradigm using yohimbine, an alpha2-adrenergic antagonist. In study 2, subjects were examined in a standardized rest-controlled psychosocial stress protocol. Alpha-amylase activity in blood was repeatedly measured in both studies.Results of study 1 showed that alpha-amylase in blood is subject to stronger increases after injection of yohimbine compared to placebo. In study 2, results showed that there was no significant effect of psychological stress compared to rest.Alpha-amylase in blood increases after pharmacological activation of the adrenergic pathways suggesting that sympathetic receptors are responsible for these changes. Psychological stress, however, does not seem to have an impact on alpha-amylase in blood. Our findings provide insight into the mechanisms underlying activity changes in alpha-amylase in blood in healthy individuals.

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

Science.gov (United States)

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

2018-01-01

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

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

Directory of Open Access Journals (Sweden)

Robert Root-Bernstein

2018-01-01

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

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

International Nuclear Information System (INIS)

Spengler, R.N.

1987-01-01

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

Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens.

Science.gov (United States)

Ovadia, H; Wohlman, A; Mechoulam, R; Weidenfeld, J

1995-02-01

In the present study we have characterized the hypothermic effect of the psychoactive cannabinoid HU-210, by investigating its interaction with the endogenous pyrogens, IL-1 and PGE2. We also studied the involvement of the adrenergic system in mediation of this hypothermic effect. Injection of HU-210 directly into the preoptic area caused a dose dependent reduction of rectal temperature from 37 to 32.1 degrees C. Injection of the non-psychoactive analog, HU-211 which does not bind to brain cannabinoid receptor, did not affect body temperature. Injection of the adrenergic agonists, CGP-12177 and clonidine (beta, and alpha adrenergic agonists, respectively) abrogated the hypothermia induced by HU-210. Injection of the adrenergic antagonists, prazosin (alpha 1) and propranolol (beta) enhanced the hypothermic effect of HU-210. Intracerebral administration of IL-1 or PGE2 to rats pretreated with HU-210 caused a transient inhibition of the hypothermia. The ex vivo rate of basal or bacterial endotoxin-induced synthesis of PGE2 by different brain regions, including the preoptic area was not affected by HU-210 administration. These results suggest that the synthetic cannabinoid HU-210 acts in the preoptic area, probably via the brain cannabinoid receptor to induce hypothermia. The hypothermic effect can be antagonized by adrenergic agonists and enhanced by adrenergic antagonists. HU-210 does not interfere with the pyrogenic effect of IL-1 or PGE2.

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

International Nuclear Information System (INIS)

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

1987-01-01

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

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

DEFF Research Database (Denmark)

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

1999-01-01

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

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.

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.

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

International Nuclear Information System (INIS)

Han, H.M.

1989-01-01

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

Identification of a probable new adrenergic agonist by nuclear magnetic resonance and mass spectrometry

Energy Technology Data Exchange (ETDEWEB)

Boatto, Gianpiero [Department of Toxicological Chemistry, University of Sassari, Sassari (Italy); Culeddu, Nicola [CNR Biomolecular Chemistry Institute, Sassari (Italy); Testa, Cecilia [IZS della Sardegna, Sassari (Italy); Neri, Bruno [IZS delle Regioni Lazio e Toscana, Rome (Italy); Brambilla, Gianfranco [Istituto Superiore di Sanita, Environment Department, Toxicological Chemistry Unit, Rome (Italy)]. E-mail: g.brambi@iss.it; Barbosa, Jorge [LNIV, Lisbon (Portugal); Cruz, Clara [LNIV, Lisbon (Portugal)

2007-03-14

In animal production, it is consolidated the synthesis and the illegal use of growth promoters of new generation, able to skip routine screening and confirmatory analysis. In this work it is reported the nuclear magnetic resonance (NMR) and the mass spectrometry identification of a probable new adrenergic drug found in a feed premix. The substance was selectively purified on alpha 1 acid glycoprotein affinity columns; then its structure was first achieved by recording the {sup 13}C NMR spectrum that gave the total number of carbons of the molecule, successively sorted by DEPT experiments into quaternary, CH, CH{sub 2}, and CH{sub 3} groups. However, the complete assignments of all resonances were derived from the bi-dimensional analysis and the crucial indications from the {sup 1}H-{sup 13}C reverse experiments. Further characterisation was performed by atmospheric pressure chemical ionisation both in positive and negative ion mode, matching the molecular ion and the fragmentation pattern with those of most recently described new adrenergic agonists. After the loss of a ter-butylic group, the structure shows an internal symmetry along with the presence of Chlorine clusters. The proposed formula of the compound, the 8,8'-diamino-9,9'-dichloro-1-terbutyl-1,1',4,4-tetrahydro-5H,5'H-2,2'-bi -1-benzazepine-5,5'-dione, partially resembles that of Zilpaterol for the presence of a heterocyclic ring; Further work is in progress to characterise the structure-activity relationship.

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

International Nuclear Information System (INIS)

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

1982-01-01

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

Historical Overview of the Effect of -Adrenergic Agonists on Beef Cattle Production

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Bradley J. Johnson

2014-05-01

Full Text Available Postnatal muscle hypertrophy of beef cattle is the result of enhanced myofibrillar protein synthesis and reduced protein turnover. Skeletal muscle hypertrophy has been studied in cattle fed β-adrenergic agonists (β-AA, which are receptor-mediated enhancers of protein synthesis and inhibitors of protein degradation. Feeding β-AA to beef cattle increases longissimus muscle cross-sectional area 6% to 40% compared to non-treated cattle. The β-AA have been reported to improve live animal performance, including average daily gain, feed efficiency, hot carcass weight, and dressing percentage. Treatment with β-AA increased mRNA concentration of the β2 or β1-adrenergic receptor and myosin heavy chain IIX in bovine skeletal muscle tissue. This review will examine the effects of skeletal muscle and adipose development with β-AA, and will interpret how the use of β-AA affects performance, body composition, and growth in beef cattle.

Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.

Science.gov (United States)

Maruyama, Tatsuya; Onda, Kenichi; Hayakawa, Masahiko; Matsui, Tetsuo; Takasu, Toshiyuki; Ohta, Mitsuaki

2009-06-01

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.

Agonist-induced affinity alterations of a central nervous system. cap alpha. -bungarotoxin receptor

Energy Technology Data Exchange (ETDEWEB)

Lukas, R.J.; Bennett, E.L.

1979-01-01

The ability of cholinergic agonists to block the specific interaction of ..cap alpha..-bungarotoxin (..cap alpha..-Bgt) with membrane-bound sites derived from rat brain is enhanced when membranes are preincubated with agonist. Thus, pretreatment of ..cap alpha..-Bgt receptors with agonist (but not antagonist) causes transformation of sites to a high-affinity form toward agonist. This change in receptor state occurs with a half-time on the order of minutes, and is fully reversible on dilution of agonist. The results are consistent with the identity of ..cap alpha..-Bgt binding sites as true central nicotinic acetylcholine receptors. Furthermore, this agonist-induced alteration in receptor state may represent an in vitro correlate of physiological desensitization. As determined from the effects of agonist on toxin binding isotherms, and on the rate of toxin binding to specific sites, agonist inhibition of toxin binding to the high-affinity state is non-competitive. This result suggests that there may exist discrete toxin-binding and agonist-binding sites on central toxin receptors.

Co-regulation of the atrial natriuretic factor and cardiac myosin light chain-2 genes during alpha-adrenergic stimulation of neonatal rat ventricular cells. Identification of cis sequences within an embryonic and a constitutive contractile protein gene which mediate inducible expression.

Science.gov (United States)

Knowlton, K U; Baracchini, E; Ross, R S; Harris, A N; Henderson, S A; Evans, S M; Glembotski, C C; Chien, K R

1991-04-25

To study the mechanisms which mediate the transcriptional activation of cardiac genes during alpha adrenergic stimulation, the present study examined the regulated expression of three cardiac genes, a ventricular embryonic gene (atrial natriuretic factor, ANF), a constitutively expressed contractile protein gene (cardiac MLC-2), and a cardiac sodium channel gene. alpha 1-Adrenergic stimulation activates the expression and release of ANF from neonatal ventricular cells. As assessed by RNase protection analyses, treatment with alpha-adrenergic agonists increases the steady-state levels of ANF mRNA by greater than 15-fold. However, a rat cardiac sodium channel gene mRNA is not induced, indicating that alpha-adrenergic stimulation does not lead to an increase in the expression of all cardiac genes. Studies employing a series of rat ANF luciferase and rat MLC-2 luciferase fusion genes identify 315- and 92-base pair cis regulatory sequences within an embryonic gene (ANF) and a constitutively expressed contractile protein gene (MLC-2), respectively, which mediate alpha-adrenergic-inducible gene expression. Transfection of various ANF luciferase reporters into neonatal rat ventricular cells demonstrated that upstream sequences which mediate tissue-specific expression (-3003 to -638) can be segregated from those responsible for inducibility. The lack of inducibility of a cardiac Na+ channel gene, and the segregation of ANF gene sequences which mediate cardiac specific from those which mediate inducible expression, provides further insight into the relationship between muscle-specific and inducible expression during cardiac myocyte hypertrophy. Based on these results, a testable model is proposed for the induction of embryonic cardiac genes and constitutively expressed contractile protein genes and the noninducibility of a subset of cardiac genes during alpha-adrenergic stimulation of neonatal rat ventricular cells.

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

International Nuclear Information System (INIS)

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

1987-01-01

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

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

International Nuclear Information System (INIS)

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

1999-01-01

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

Effect of skin temperature on cutaneous vasodilator response to the β-adrenergic agonist isoproterenol

OpenAIRE

Hodges, Gary J.; Kellogg, Dean L.; Johnson, John M.

2015-01-01

The vascular response to local skin cooling is dependent in part on a cold-induced translocation of α2C-receptors and an increased α-adrenoreceptor function. To discover whether β-adrenergic function might contribute, we examined whether β-receptor sensitivity to the β-agonist isoproterenol was affected by local skin temperature. In seven healthy volunteers, skin blood flow was measured from the forearm by laser-Doppler flowmetry and blood pressure was measured by finger photoplethysmography....

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

Science.gov (United States)

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

2013-01-01

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

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

International Nuclear Information System (INIS)

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

1987-01-01

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

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

Science.gov (United States)

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

2017-11-01

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

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...

COMPARISON OF TWO α2-ADRENERGIC AGONISTS ON URINE CONTAMINATION OF SEMEN COLLECTED BY ELECTROEJACULATION IN CAPTIVE AND SEMI-FREE-RANGING CHEETAH (ACINONYX JUBATUS).

Science.gov (United States)

Marrow, Judilee C; Woc-Colburn, Margarita; Hayek, Lee-Ann C; Marker, Laurie; Murray, Suzan

2015-06-01

Alpha2-adrenergic agonists are used to immobilize many veterinary species, but use has been infrequently linked to urine contamination of semen collected via electroejaculation. The objective of the study was to compare the α2-agonists medetomidine and dexmedetomidine on urine contamination of semen in anesthetized cheetahs (Acinonyx jubatus) during electroejaculation procedures. From 2009-2012, a retrospective medical record review revealed 21 anesthesia events in 12 adult male cheetahs. Animals were immobilized with combinations of Telazol® (2.33±0.43 mg/kg) and ketamine (2.38±1 mg/kg); Telazol (1.17±0.14 mg/kg), ketamine (1.17±0.14 mg/kg), and medetomidine (0.012±0.0017 mg/kg); or Telazol (1.59±0.1 mg/kg), ketamine (1.59±0.1 mg/kg) and dexmedetomidine (0.01±0.001 mg/kg). Semen was successfully collected in all animals; four animals anesthetized with medetomidine had urine contamination (P=0.037). Medetomidine may contribute to urine contamination; however, further investigation is needed to determine significance in cheetahs.

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.

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

OpenAIRE

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

1995-01-01

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

Decreased hepatic response to glucagon, adrenergic agonists, and cAMP in glycogenolysis, gluconeogenesis, and glycolysis in tumor-bearing rats.

Science.gov (United States)

Biazi, Giuliana R; Frasson, Isabele G; Miksza, Daniele R; de Morais, Hely; de Fatima Silva, Flaviane; Bertolini, Gisele L; de Souza, Helenir M

2018-05-15

The response to glucagon and adrenaline in cancer cachexia is poorly known. The aim of this study was to investigate the response to glucagon, adrenergic agonists (α and β) and cyclic adenosine monophosphate (cAMP) on glycogenolysis, gluconeogenesis, and glycolysis in liver perfusion of Walker-256 tumor-bearing rats with advanced cachexia. Liver ATP content was also investigated. Rats without tumor (healthy) were used as controls. Agonists α (phenylephrine) and β (isoproterenol) adrenergic, instead of adrenaline, and cAMP, the second messenger of glucagon and isoproterenol, were used in an attempt to identify mechanisms involved in the responses. Glucagon (1 nM) stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis in the liver of healthy and tumor-bearing rats, but their effects were lower in tumor-bearing rats. Isoproterenol (20 µM) stimulated glycogenolysis, gluconeogenesis, and glycolysis in healthy rats and had virtually no effect in tumor-bearing rats. cAMP (9 µM) also stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis in healthy rats but had practically no effect in tumor-bearing rats. Phenylephrine (2 µM) stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis and these effects were also lower in tumor-bearing rats than in healthy. Liver ATP content was lower in tumor-bearing rats. In conclusion, tumor-bearing rats with advanced cachexia showed a decreased hepatic response to glucagon, adrenergic agonists (α and β), and cAMP in glycogenolysis, gluconeogenesis, and glycolysis, which may be due to a reduced rate of regulatory enzyme phosphorylation caused by the low ATP levels in the liver. © 2018 Wiley Periodicals, Inc.

Clonidine, an alpha2-receptor agonist, diminishes GABAergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus.

Science.gov (United States)

Philbin, Kerry E; Bateman, Ryan J; Mendelowitz, David

2010-08-06

In hypertension, there is an autonomic imbalance in which sympathetic activity dominates over parasympathetic control. Parasympathetic activity to the heart originates from cardiac vagal neurons located in the nucleus ambiguus. Presympathetic neurons that project to sympathetic neurons in the spinal cord are located in the ventral brainstem in close proximity to cardiac vagal neurons, and many of these presympathetic neurons are catecholaminergic. In addition to their projection to the spinal cord, many of these presympathetic neurons have axon collaterals that arborize into neighboring cardiorespiratory locations and likely release norepinephrine onto nearby neurons. Activation of alpha(2)-adrenergic receptors in the central nervous system evokes a diverse range of physiological effects, including reducing blood pressure. This study tests whether clonidine, an alpha(2)-adrenergic receptor agonist, alters excitatory glutamatergic, and/or inhibitory GABAergic or glycinergic synaptic neurotransmission to cardiac vagal neurons in the nucleus ambiguus. Cardiac vagal neurons were identified in an in vitro brainstem slice preparation, and synaptic events were recording using whole cell voltage clamp methodologies. Clonidine significantly inhibited GABAergic neurotransmission but had no effect on glycinergic or glutamatergic pathways to cardiac vagal neurons. This diminished inhibitory GABAergic neurotransmission to cardiac vagal neurons would increase parasympathetic activity to the heart, decreasing heart rate and blood pressure. The results presented here provide a cellular substrate for the clinical use of clonidine as a treatment for hypertension as well as a role in alleviating posttraumatic stress disorder by evoking an increase in parasympathetic cardiac vagal activity, and a decrease in heart rate and blood pressure. Copyright 2010 Elsevier B.V. All rights reserved.

Drug: D04765 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available agonist ... DG01449 ... alpha2-Adrenergic receptor agonist ... DG01655 ... alpha2-adrenergic receptor specific agonist Other ... DG01718 ... Drugs... for addictive disorder ... DG01717 ... Drugs for opioid depe

Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

Science.gov (United States)

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

2003-01-01

Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

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

International Nuclear Information System (INIS)

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

1991-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

1991-02-01

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

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

Science.gov (United States)

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

2007-06-01

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

Adrenergic regulation of cytoplasmic structures related to secretory processes in pig pinealocytes-an ultrastructural, quantitative study.

Science.gov (United States)

Przybylska-Gornowicz, Barbara; Lewczuk, Bogdan; Ziółkowska, Natalia; Prusik, Magdalena

2017-10-01

Two structures, considered as secretory in nature, are present in the pinealocytes in of the domestic pig show the presence of two structures, which are considered as secretory in nature - the dense core vesicles (DCV) and the membrane bounded (dense) bodies (MBB). The latter are extremely numerous in pig pinealocytes (they occupy 6-20% of the cytoplasm), and the number of MBB changes under different physiological and experimental conditions. Norepinephrine is the main neurotransmitter that regulates the secretion of pineal melatonin. The present study was carried out to 1) clarify whether the DCV and their source - the Golgi apparatus (GA) - as well as the MBB are controlled by norepinephrine, 2) determine the effect of adrenergic stimulation on these structures, and 3) identify the receptors involved in the regulation of these structures. The studies were performed using a static organ culture of pig pineal explants. The explants were incubated in a control medium between 08:00 and 20:00 and in a medium with 10μM norepinephrine or alpha- or beta-adrenoceptor agonists between 20:00 and 08:00 on five consecutive days. The tissues were subsequently prepared for ultrastructural analysis. The results distinctly showed that the DCV, GA and MBB in pig pinealocytes are under adrenergic control. The stimulation of the beta-adrenoceptors resulted in an increase in the numerical density of the DCV and a decrease in the relative volume of the GA in the perikarya, while the incubation with agonists of the alpha1-adrenoceptors was ineffective. The relative volume of the MBB in the perikarya significantly decreased after treatment with both beta-agonists and alpha1-agonists, which suggested the involvement of two types of adrenoceptors in the regulation of these structures. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

DEFF Research Database (Denmark)

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

2007-01-01

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

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

International Nuclear Information System (INIS)

Graziano, M.P.

1984-01-01

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

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

International Nuclear Information System (INIS)

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

1986-01-01

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

Interaction between alpha 2-adrenergic and angiotensin II systems in the control of glomerular hemodynamics as assessed by renal micropuncture in the rat

Science.gov (United States)

Thomson, S. C.; Gabbai, F. B.; Tucker, B. J.; Blantz, R. C.

1992-01-01

The hypothesis that renal alpha 2 adrenoceptors influence nephron filtration rate (SNGFR) via interaction with angiotensin II (AII) was tested by renal micropuncture. The physical determinants of SNGFR were assessed in adult male Munich Wistar rats 5-7 d after ipsilateral surgical renal denervation (DNX). DNX was performed to isolate inhibitory central and presynaptic alpha 2 adrenoceptors from end-organ receptors within the kidney. Two experimental protocols were employed: one to test whether prior AII receptor blockade with saralasin would alter the glomerular hemodynamic response to alpha 2 adrenoceptor stimulation with the selective agonist B-HT 933 under euvolemic conditions, and the other to test whether B-HT 933 would alter the response to exogenous AII under conditions of plasma volume expansion. In euvolemic rats, B-HT 933 caused SNGFR to decline as the result of a decrease in glomerular ultrafiltration coefficient (LpA), an effect that was blocked by saralasin. After plasma volume expansion, B-HT 933 showed no primary effect on LpA but heightened the response of arterial blood pressure, glomerular transcapillary pressure gradient, and LpA to AII. The parallel results of these converse experiments suggest a complementary interaction between renal alpha 2-adrenergic and AII systems in the control of LpA.

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.

Reconstitution of high affinity α2 adrenergic agonist binding by fusion with a pertussis toxin substrate

International Nuclear Information System (INIS)

Kim, M.H.; Neubig, R.R.

1986-01-01

High affinity α 2 adrenergic agonist binding is thought to occur via a coupling of the α 2 receptor with N/sub i/, the inhibitory guanyl nucleotide binding protein. Human platelet membranes pretreated at pH 11.5 exhibit a selective inactivation of agonist binding and N/sub i/. To further study the mechanism of agonist binding, alkali treated membranes (ATM) were mixed with membranes pretreated with 10 μM phenoxybenzamine to block α 2 receptors (POB-M). The combined membrane pellet was incubated in 50% polyethylene glycol (PEG) to promote membrane-membrane fusion and assayed for binding to the α 2 agonist [ 3 H]UK 14,304 (UK) and the antagonist [ 3 H] yohimbine. PEG treatment resulted in a 2-4 fold enhancement of UK binding whereas yohimbine binding was unchanged. No enhancement of UK binding was observed in the absence of PEG treatment. The reconstitution was dependent on the addition of POB-M. They found that a 1:1 ratio of POB-M:ATM was optimal. Reconstituted binding was inhibited by GppNHp. Fusion of rat C6 glioma cell membranes, which do not contain α 2 receptors, also enhanced agonist binding to ATM. Fusion of C6 membranes from cells treated with pertussis toxin did not enhance [ 3 H] UK binding. These data show that a pertussis toxin sensitive membrane component, possibly N/sub i/, can reconstitute high affinity α 2 agonist binding

The adrenergic alpha2 receptor and sexual incentive motivation in male rats.

Science.gov (United States)

Viitamaa, Timo; Haapalinna, Antti; Agmo, Anders

2006-03-01

The purpose of the present series of experiments was to determine whether drugs acting at the alpha2-adrenoceptor modify unconditioned sexual incentive motivation in the male rat. To that end a highly specific agonist, dexmedetomidine, a corresponding antagonist, atipamezole, and a less specific antagonist, yohimbine, were administered to groups of sexually inexperienced male rats. The subjects were tested in a large rectangular arena, where a sexually receptive female and an intact male were employed as incentives. The incentive animals were confined behind a wire mesh in opposite corners of the arena. The animals could see, hear and smell each other, but no sexual interaction was possible. Approach to the incentives constituted the measure of incentive motivation. In addition, the test provided data on ambulatory activity and general arousal. Dexmedetomidine, at a dose of 8 microg/kg, produced a slight reduction of sexual incentive motivation. Ambulatory activity and general arousal were also inhibited. Atipamezole, in doses of 0.1 and 0.3mg/kg enhanced the positive incentive properties of the receptive female. A high dose of 1mg/kg did not have any significant effect. Ambulatory activity was slightly reduced by the two larger doses of atipamezole. Yohimbine had a slight stimulatory effect on sexual incentive motivation at a dose (4 mg/kg) that also reduced ambulatory activity and general arousal. It is concluded that blockade of the adrenergic alpha2 receptor stimulates sexual incentive motivation in the male rat whereas stimulation of it has the opposite effect. At present it is not clear if these drug effects are caused by pre- or postsynaptic actions of the drugs, and the importance of secondary changes in other neurotransmitter systems remains unknown.

Adrenergic receptors are a fallible index of adrenergic denervation hypersensitivity

DEFF Research Database (Denmark)

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

1991-01-01

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

The influence of nifedipine and pertussis toxin (PTX) on vascular responsiveness to alpha1- and alpha2-adrenergic stimulation of isolated femoral arteries

Czech Academy of Sciences Publication Activity Database

Líšková, Silvia; Kuneš, Jaroslav; Paulis, Ĺudovít; Zicha, Josef

2006-01-01

Roč. 48, č. 4 (2006), s. 769-769 ISSN 0194-911X. [Annual Meeting of the European Council for Cardiovascular Research (ECCR) /11./. 29.09.2006-01.10.2006, La Colle sur Loup] R&D Projects: GA MZd NR7786 Institutional research plan: CEZ:AV0Z50110509 Keywords : nifedipine * pertussis toxin * vascular responsiveness * alpha1- and alpha2-adrenergic stimulation * femorel arteria Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

Evaluation of partial beta-adrenoceptor agonist activity.

Science.gov (United States)

Lipworth, B J; Grove, A

1997-01-01

A partial beta-adrenoceptor (beta-AR) agonist will exhibit opposite agonist and antagonist activity depending on the prevailing degree of adrenergic tone or the presence of a beta-AR agonist with higher intrinsic activity. In vivo partial beta-AR agonist activity will be evident at rest with low endogenous adrenergic tone, as for example with chronotropicity (beta 1/beta 2), inotropicity (beta 1) or peripheral vasodilatation and finger tremor (beta 2). beta-AR blocking drugs which have partial agonist activity may exhibit a better therapeutic profile when used for hypertension because of maintained cardiac output without increased systemic vascular resistance, along with an improved lipid profile. In the presence of raised endogenous adrenergic tone such as exercise or an exogenous full agonist, beta-AR subtype antagonist activity will become evident in terms of effects on exercise induced heart rate (beta 1) and potassium (beta 2) responses. Reduction of exercise heart rate will occur to a lesser degree in the case of a beta-adrenoceptor blocker with partial beta 1-AR agonist activity compared with a beta-adrenoceptor blocker devoid of partial agonist activity. This may result in reduced therapeutic efficacy in the treatment of angina on effort when using beta-AR blocking drugs with partial beta 1-AR agonist activity. Effects on exercise hyperkalaemia are determined by the balance between beta 2-AR partial agonist activity and endogenous adrenergic activity. For predominantly beta 2-AR agonist such as salmeterol and salbutamol, potentiation of exercise hyperkalaemia occurs. For predominantly beta 2-AR antagonists such as carteolol, either potentiation or attenuation of exercise hyperkalaemia occurs at low and high doses respectively. beta 2-AR partial agonist activity may also be expressed as antagonism in the presence of an exogenous full agonist, as for example attenuation of fenoterol induced responses by salmeterol. Studies are required to investigate whether

Effects of local anesthetics on cholinergic agonist binding affinity of central nervous system. cap alpha. -bungarotoxin receptors

Energy Technology Data Exchange (ETDEWEB)

Lukas, R.L.; Bennett, E.L.

1979-12-01

In general, pharmacological effects of local anesthetics may be attributed to their ability to reversibly block the propagation of nerve and muscle action potentials. At physiologically potent concentrations, local anesthetics (LA) also act as noncompetitive antagonists of the physiological response of post-synaptic nicotinic acetylcholine receptors (nAChR) to cholinergic agonists, and increase agonist binding affinities of nAChR from electric organ. It is postulated that the primary site of LA action on nAChR function is at the receptor-coupled ionophore. Furthermore, LA-nAChR ionophore interactions are thought to accelerate physiological desensitization of nAChR, manifest biochemically as increased affinity of nAChR for agonist. Specific receptors for ..cap alpha..-bungarotoxin (..cap alpha..-Bgt), a potent competitive antagonist at nAChR sites in the periphery, have been detected in rat central nervous system membrane preparations. The affinity of these central ..cap alpha..-Bgt receptors (..cap alpha..-BgtR) for cholinergic agonists is found to increase on exposure to agonist. Nevertheless, on the basis of inconsistent pharmacological and physiological results, uncertainty remains regarding the relationship between ..cap alpha..-BgtR and authentic nAChR in the CNS, despite a wide body of biochemical and histological evidence consistent with their identity. Reasoning that if CNS ..cap alpha..-BgtR are true in nAChR, coupled to functional ion channels, LA might be expected to cause biochemically measurable increases in ..cap alpha..-BgtR affinity for cholinergic agonists, we have undertaken a study of the effects of LA on the ability of acetylcholine (ACh) to inhibit interaction of ..cap alpha..-BgtR with /sup 3/H-labeled ..cap alpha..-Bgt.

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

Science.gov (United States)

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

2011-11-01

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

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

International Nuclear Information System (INIS)

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

1985-01-01

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

α1A-Subtype adrenergic agonist therapy for the failing right ventricle.

Science.gov (United States)

Cowley, Patrick M; Wang, Guanying; Joshi, Sunil; Swigart, Philip M; Lovett, David H; Simpson, Paul C; Baker, Anthony J

2017-12-01

Failure of the right ventricle (RV) is a serious disease with a poor prognosis and limited treatment options. Signaling by α 1 -adrenergic receptors (α 1 -ARs), in particular the α 1A -subtype, mediate cardioprotective effects in multiple heart failure models. Recent studies have shown that chronic treatment with the α 1A -subtype agonist A61603 improves function and survival in a model of left ventricular failure. The goal of the present study was to determine if chronic A61603 treatment is beneficial in a RV failure model. We used tracheal instillation of the fibrogenic antibiotic bleomycin in mice to induce pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Some mice were chronically treated with a low dose of A61603 (10 ng·kg -1 ·day -1 ). In the bleomycin model of RV failure, chronic A61603 treatment was associated with improved RV fractional shortening and greater in vitro force development by RV muscle preparations. Cell injury markers were reduced with A61603 treatment (serum cardiac troponin I, RV fibrosis, and expression of matrix metalloproteinase-2). RV oxidative stress was reduced (using the probes dihydroethidium and 4-hydroxynonenal). Consistent with lowered RV oxidative stress, A61603 was associated with an increased level of the cellular antioxidant superoxide dismutase 1 and a lower level of the prooxidant NAD(P)H oxidase isoform NOX4. In summary, in the bleomycin model of RV failure, chronic A61603 treatment reduced RV oxidative stress, RV myocyte necrosis, and RV fibrosis and increased both RV function and in vitro force development. These findings suggest that in the context of pulmonary fibrosis, the α 1A -subtype is a potential therapeutic target to treat the failing RV. NEW & NOTEWORTHY Right ventricular (RV) failure is a serious disease with a poor prognosis and no effective treatments. In the mouse bleomycin model of RV failure, we tested the efficacy of a treatment using the α 1A -adrenergic receptor subtype

Antihypertensive effect of alpha- and beta-adrenergic blockade in obese and lean hypertensive subjects.

Science.gov (United States)

Wofford, M R; Anderson, D C; Brown, C A; Jones, D W; Miller, M E; Hall, J E

2001-07-01

The purpose of this study was to determine the contribution of the adrenergic system in mediating hypertension in obese and lean patients. Thirteen obese, hypertensive patients with a body mass index (BMI) > or =28 kg/m2 (obese) and nine lean patients with a BMI lean) were recruited. After a 1-week washout period, participants underwent daytime ambulatory blood pressure monitoring (ABPM). Participants were then treated with the alpha-adrenergic antagonist doxazosin, titrating to 4 mg QHS in 1 week. In the next week, the beta-adrenergic antagonist atenolol was added at an initial dose of 25 mg/day and titrated to 50 mg/day within 1 week. One month after the addition of atenolol, all patients underwent a second ABPM session. There were no differences between the obese and lean subjects in baseline systolic (SBP), diastolic (DBP), or mean arterial pressures (MAP) measured by office recording or ABPM. However, obese subjects had higher heart rates than lean subjects (87.5+/-2.4 v 76.8+/-4.9 beats/min). After 1 month of treatment with the adrenergic blockers, obese patients had a significantly lower SBP (130.0+/-2.5 v 138.9+/-2.1 mm Hg, P = .02) and MAP (99.6+/-2.3 v 107.0+/-1.5 mm Hg, P = .02) than lean patients. Obese patients also tended to have a lower DBP than lean patients (84.3+/-2.5 v 90.9+/-1.6 mm Hg, P = .057), but there was no significant difference in heart rate after 1 month of adrenergic blockade. These results indicate that blood pressure is more sensitive to adrenergic blockade in obese than in lean hypertensive patients and suggest that increased sympathetic activity may be an important factor in the maintenance of hypertension in obesity.

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

OpenAIRE

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

2003-01-01

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

Adrenergic factors regulating cell division in the colonic crypt epithelium during carcinogenesis and in colonic adenoma and adenocarcinoma.

Science.gov (United States)

Kennedy, M F; Tutton, P J; Barkla, D H

1985-09-01

Evidence exists implicating adrenergic factors in the control of intestinal epithelial cell proliferation in both normal and diseased states. In this report, attention is focussed on changes in the amine requirements of proliferating cells during the chemical induction of tumours in the colon of mouse. Cell proliferation rates were measured stathmokinetically. Tumours were induced by s.c. injection of dimethylhydrazine (DMH). Results with a series of adrenoceptor agonists and antagonists suggest that there is an alpha 2-adrenoceptor mediated excitatory effect in normal colon but an alpha 2 adrenoceptor mediated inhibitory effect in adenoma and carcinoma. Alpha 1 adrenoceptors, on the other hand, have an inhibitory effect in normal crypts and in adenomas, and an excitatory effect in carcinomas. Beta adrenoceptors have an inhibitory effect in the normal and DMH-treated crypt, and in adenomas, but not in carcinomas. In the crypt epithelium of DMH-treated mice, two regions on cell proliferation, with differing regulatory factors, could be identified. In the upper region of the carcinogen-exposed crypt is a zone where cell proliferation is stimulated by an alpha 2 adrenergic mechanism, thus resembling the basal region of the normal crypt. By contrast, in the basal region of these crypts, cell proliferation is stimulated by an alpha 1 mechanism, thus resembling a malignant tumour.

Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder

Directory of Open Access Journals (Sweden)

Molly R Belkin

2017-09-01

Full Text Available Clonidine and guanfacine are alpha-2 receptor agonists that decrease sympathetic outflow from the central nervous system. Posttraumatic stress disorder (PTSD is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system. Currently, the only US Food and Drug Administration (FDA-approved medications for PTSD are the selective serotonin reuptake inhibitors (SSRIs sertraline and paroxetine. Sometimes use of the SSRIs may not lead to full remission and symptoms of hyperarousal often persist. This article specifically reviews the literature on alpha-2 receptor agonist use for the treatment of PTSD and concludes that while the evidence base is limited, these agents might be considered useful when SSRIs fail to treat symptoms of agitation and hyperarousal in patients with PTSD.

Does alpha 1-acid glycoprotein act as a non-functional receptor for alpha 1-adrenergic antagonists?

Science.gov (United States)

Qin, M; Oie, S

1994-11-01

The ability of a variety of alpha 1-acid glycoproteins (AAG) to affect the intrinsic activity of the alpha 1-adrenergic antagonist prazosin was studied in rabbit aortic strip preparations. From these studies, the activity of AAG appears to be linked to their ability to bind the antagonist. However, a capability to bind prazosin was not the only requirement for this effect. The removal of sialic acid and partial removal of the galactose and mannose residues by periodate oxidation of human AAG all but eliminated the ability of AAG to affect the intrinsic pharmacologic activity of prazosin, although the binding of prazosin was not significantly affected. The presence of bovine AAG, a protein that has a low ability to bind prazosin, reduced the effect of human AAG on prazosin activity. Based upon these results, we propose that AAG is able to bind in the vicinity of the alpha 1-adrenoceptors, therefore extending the binding region for antagonists in such a way as to decrease the ability of the antagonist to interact with the receptor. The carbohydrate side-chains are important for the binding of AAG in the region of the adrenoceptor.

Interferon-alpha suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist.

LENUS (Irish Health Repository)

Tajuddin, Tariq

2012-02-01

BACKGROUND AND AIM: Neutropenia, a major side-effect of interferon-alpha (IFN-alpha) therapy can be effectively treated by the recombinant form of granulocyte colony stimulating factor (G-CSF), an important growth factor for neutrophils. We hypothesized that IFN-alpha might suppress G-CSF production by peripheral blood mononuclear cells (PBMCs), contributing to the development of neutropenia, and that a toll-like receptor (TLR) agonist might overcome this suppression. METHODS: Fifty-five patients who were receiving IFN-alpha\\/ribavirin combination therapy for chronic hepatitis C virus (HCV) infection were recruited. Absolute neutrophil counts (ANC), monocyte counts and treatment outcome data were recorded. G-CSF levels in the supernatants of PBMCs isolated from the patients and healthy controls were assessed by enzyme-linked immunosorbent assay following 18 h of culture in the absence or presence of IFN- alpha or the TLR7\\/8 agonist, CL097. RESULTS: Therapeutic IFN-alpha caused a significant reduction in neutrophil counts in all patients, with 15 patients requiring therapeutic G-CSF. The reduction in ANC over the course of IFN-alpha treatment was paralleled by a decrease in the ability of PBMCs to produce G-CSF. In vitro G-CSF production by PBMCs was suppressed in the presence of IFN-alpha; however, co-incubation with a TLR7\\/8 agonist significantly enhanced G-CSF secretion by cells obtained both from HCV patients and healthy controls. CONCLUSIONS: Suppressed G-CSF production in the presence of IFN-alpha may contribute to IFN-alpha-induced neutropenia. However, a TLR7\\/8 agonist elicits G-CSF secretion even in the presence of IFN-alpha, suggesting a possible therapeutic role for TLR agonists in treatment of IFN-alpha-induced neutropenia.

Resolution of G(s)alpha and G(q)alpha/G(11)alpha proteins in membrane domains by two-dimensional electrophoresis: the effect of long-term agonist stimulation.

Science.gov (United States)

Matousek, P; Novotný, J; Svoboda, P

2004-01-01

Low-density membrane-domain fractions were prepared from S49 lymphoma cells and clone e2m11 of HEK293 cells expressing a large number of thyrotropin-releasing hormone receptor (TRH-R) and G(11)alpha by flotation on sucrose density gradients. The intact cell structure was broken by detergent-extraction, alkaline-treatment or drastic homogenization. Three types of low-density membranes were resolved by two-dimensional electrophoresis and analyzed for G(s)alpha (S49) or G(q)alpha/G11) (e2m11) content. Four individual immunoblot signals of Gsalpha protein were identified in S49 lymphoma cells indicating complete resolution of the long G(s)alpha L+/-ser and short G(s)alpha S+/-ser variants of G(s)alpha. All these were diminished by prolonged agonist (isoprenaline) stimulation. In e2m11-HEK cells, five different immunoblot signals were detected indicating post-translational modification of G proteins of G(q)alpha/G(11)alpha family. The two major spots corresponding to exogenously (over)expressed G(11)alpha and endogenous G(q)alpha were reduced; the minor spots diminished by hormonal stimulation. Parallel analysis by silver staining of the total protein content indicated that no major changes in protein composition occurred under these conditions. Our data thus indicate that agonist-stimulation of target cells results in down-regulation of all different members of G(s) and G(q)/G(11) families. This agonist-specific effect may be demonstrated in crude membrane as well as domain/raft preparations and it is not accompanied by changes in overall protein composition.

[Alpha but not beta-adrenergic stimulation has a positive inotropic effect associated with alkalinization of intracellular pH].

Science.gov (United States)

Gambassi, G; Lakatta, E G; Capogrossi, M C

1991-01-01

There is increasing evidence that alpha-adrenoceptors also exist in the myocardium and that an increase in force of contraction may be produced by stimulation of these sites. This positive inotropism seems to be dependent either on an increased amount of Ca++ released into the cytosol with each action potential or on increased myofilament responsiveness. In contrast, beta-adrenergic stimulation reduces the sensitivity of the contractile proteins and the positive inotropic effect is due to the activation of L-type calcium channels on the sarcolemma. We used single, isolated, enzymatically dissociated, adult rat ventricular myocytes. Cells were loaded either with the ester derivative of the Ca++ probe Indo-1 or with the intracellular pH probe Snarf-1 and at the same time we measured the contractile parameters and monitored the fluorescence as an index of intracellular calcium concentration or pH value. The single cells (bicarbonate buffer continuously gassed with O2 95%, CO2 5%, Ca++ 1.5 mM, field stimulation 0.5 Hz) were exposed to phenylephrine (50 microM) and nadolol (1 microM). Alpha-adrenergic stimulation increased twitch amplitude (delta ES = 1.93 +/- 0.77, n = 8; p less than 0.05) and showed only a slight increase in Ca++ transient. On the other end, the positive inotropic effect (delta ES = 2.84 +/- 0.86, n = 4; p less than 0.02) obtained with beta-adrenergic stimulation (isoproterenol 50 nM, bicarbonate buffer, Ca++ 0.5 mM, field stimulation 0.2 Hz) was always associated with a large increase in intracellular Ca++ concentration. Isoproterenol did not change intracellular pH (delta pH = 0.006 +/- 0.006, n = 4; NS) while phenylephrine increased it significantly (delta pH = 0.055 +/- 0.011, n = 8; p less than 0.002). Moreover, there was a statistically significant correlation between delta ES and delta pH (R2 = 0.532; p less than 0.05) when phenylephrine was present. This alkalinization as well as the increased contractility was antagonized by treatment with

Protein phosphorylation in isolated human adipocytes - Adrenergic control of the phosphorylation of hormone-sensitive lipase

International Nuclear Information System (INIS)

Smiley, R.M.; Paul, S.; Browning, M.D.; Leibel, R.L.; Hirsch, J.

1990-01-01

The effect of adrenergic agents on protein phosphorylation in human adipocytes was examined. Freshly isolated human fat cells were incubated with 32 PO 4 in order to label intracellular ATP, then treated with a variety of adrenergic and other pharmacologic agents. Treatment with the β-adrenergic agonist isoproterenol led to a significant increase in phosphate content of at least five protein bands (M r 52, 53, 63, 67, 84 kDa). The increase in phosphorylation was partially inhibited by the α-2 agonist clonidine. Epinephrine, a combined α and β agonist, was less effective at increasing phosphate content of the proteins than was isoproterenol. Neither insulin nor the α-1 agonist phenylephrine had any discernible effect on the pattern of protein phosphorylation. The 84 kDa phosphorylated peptide band appears to contain hormone-sensitive lipase, a key enzyme in the lipolytic pathway which is activated by phosphorylation. These results are somewhat different than previously reported results for rat adipocytes, and represent the first report of overall pattern and adrenergic modulation of protein phosphorylation in human adipocytes

Agonist-induced desensitization of adenylyl cyclase in Y1 adrenocortical tumor cells

International Nuclear Information System (INIS)

Olson, M.F.; Tsao, J.; Pon, D.J.; Schimmer, B.P.

1991-01-01

Y1 adrenocortical tumor cells (Y1DS) and Y1 mutants resistant to ACTH-induced desensitization of adenylyl cyclase (Y1DR) were transfected with a gene encoding the mouse beta 2-adrenergic receptor (beta 2-AR). Transfectants expressed beta 2-ARs that were able to stimulate adenylyl cyclase activity and steroid biosynthesis. These transfectants were used to explore the basis for the DR mutation in Y1 cells. The authors demonstrate that beta-adrenergic agonists desensitize the adenylyl cyclase system in transfected Y1DS cells whereas transfected Y1DR cells are resistant to desensitization by beta-adrenergic agonists. The fate of the beta 2-ARs during desensitization was evaluated by photoaffinity labelling with [125I]iodocyanopindolol diazerine. Desensitization of Y1DS transfectants was accompanied by a modest loss in receptor density that was insufficient to account for the complete loss of responsiveness to beta-adrenergic agonists. The extent of receptor loss induced by beta-adrenergic agonists in Y1DR transfectants exceeded that in the Y1DS transfectants indicating that the mutation which protects Y1DR cells from agonist-induced desensitization is prior to receptor down-regulation in the desensitization pathway. From these results we infer that ACTH and isoproterenol desensitize adenylyl cyclase by a common pathway and that receptor loss is not a major component of the desensitization process in these cells

Effect of β2-adrenergic receptor gene (ADRB2 3′ untranslated region polymorphisms on inhaled corticosteroid/long-acting β2-adrenergic agonist response

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Ambrose Helen J

2012-05-01

Full Text Available Abstract Background Evidence suggests that variation in the length of the poly-C repeat in the 3′ untranslated region (3′UTR of the β2-adrenergic receptor gene (ADRB2 may contribute to interindividual variation in β-agonist response. However, methodology in previous studies limited the assessment of the effect of sequence variation in the context of poly-C repeat length. The objectives of this study were to design a novel genotyping method to fully characterize sequence variation in the ADRB2 3′UTR poly-C repeat in asthma patients treated with inhaled corticosteroid and long-acting β2-adrenergic agonist (ICS/LABA combination therapy, and to analyze the effect of the poly-C repeat polymorphism on clinical response. Methods In 2,250 asthma patients randomized to treatment with budesonide/formoterol or fluticasone/salmeterol in a six-month study (AstraZeneca study code: SD-039-0735, sequence diversity in the ADRB2 poly-C repeat region was determined using a novel sequencing-based genotyping method. The relationship between the poly-C repeat polymorphism and the incidence of severe asthma exacerbations, and changes in pulmonary function and asthma symptoms from baseline to the average during the treatment period, were analyzed. Results Poly-C repeat genotypes were assigned in 97% (2,192/2,250 of patients. Of the 13 different poly-C repeat alleles identified, six alleles occurred at a frequency of >5% in one or more population in this study. The repeat length of these six common alleles ranged from 10 to 14 nucleotides. Twelve poly-C repeat genotypes were observed at a frequency of >1%. No evidence of an association between poly-C repeat genotype and the incidence of severe asthma exacerbations was observed. Patients’ pulmonary function measurements improved and asthma symptoms declined when treated with ICS/LABA combination therapy regardless of poly-C repeat genotype. Conclusions The extensive sequence diversity present in the poly

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

Science.gov (United States)

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

2013-12-03

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

Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia.

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Spalink, Christy L; Barnes, Erin; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio

2017-08-01

To report the use of intranasal dexmedetomidine, an α 2 -adrenergic agonist for the acute treatment of refractory adrenergic crisis in patients with familial dysautonomia. Case series. Three patients with genetically confirmed familial dysautonomia (case 1: 20-year-old male; case 2: 43-year-old male; case 3: 26-year-old female) received intranasal dexmedetomidine 2 mcg/kg, half of the dose in each nostril, for the acute treatment of adrenergic crisis. Within 8-17 min of administering the intranasal dose, the adrenergic crisis symptoms abated, and blood pressure and heart rate returned to pre-crises values. Adrenergic crises eventually resumed, and all three patients required hospitalization for investigation of the cause of the crises. Intranasal dexmedetomidine is a feasible and safe acute treatment for adrenergic crisis in patients with familial dysautonomia. Further controlled studies are required to confirm the safety and efficacy in this population.

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

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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.

Neuroprotective and memory-related actions of novel alpha-7 nicotinic agents with different mixed agonist/antagonist properties.

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Meyer, E M; Tay, E T; Zoltewicz, J A; Meyers, C; King, M A; Papke, R L; De Fiebre, C M

1998-03-01

The goals of this study were to develop compounds that were selective and highly efficacious agonists at alpha-7 receptors, while varying in antagonist activity; and to test the hypothesis that these compounds had memory-related and neuroprotective actions associated with both agonist and antagonist alpha-7 receptor activities. Three compounds were identified; E,E-3-(cinnamylidene)anabaseine (3-CA), E,E-3-(2-methoxycinnamylidene) anabaseine (2-MeOCA) and E,E-3-(4-methoxycinnamylidene) anabaseine (4-MeOCA) each displaced [125I]alpha-bungarotoxin binding from rat brain membranes and activated rat alpha-7 receptors in a Xenopus oocyte expression system fully efficaciously. The potency series for binding and receptor activation was 2-MeOCA > 4-MeOCA = 3-CA and 2-MeOCA = 3-CA > 4-MeOCA, respectively. No compound significantly activated oocyte-expressed alpha-4beta-2 receptors. Although each cinnamylidene-anabaseine caused a long-term inhibition of alpha-7 receptors, as measured by ACh-application 5 min later, this inhibition ranged considerably, from less than 20% (3-CA) to 90% (2-MeOCA) at an identical concentration (10 microM). These compounds improved passive avoidance behavior in nucleus basalis lesioned rats, with 2-MeOCA most potent in this respect. In contrast, only 3-CA was neuroprotective against neurite loss during nerve growth factor deprivation in differentiated rat pheochromocytoma (PC12) cells. Choline, an efficacious alpha-7 agonist without antagonist activity, was also protective in this model. These results suggest that the neurite-protective action of alpha-7 receptor agonists may be more sensitive to potential long-term antagonist properties than acute behavioral actions are.

Pertussis toxin-sensitive alpha-adrenergic modulation of voltage - dependent calcium channels in spontaneously hypertensive rats (SHR)

Czech Academy of Sciences Publication Activity Database

Zicha, Josef; Pintérová, Mária; Dobešová, Zdenka; Líšková, Silvia; Kuneš, Jaroslav

2006-01-01

Roč. 24, č. S6 (2006), s. 34-34 ISSN 0263-6352. [Scientific Meeting of the International Society of Hypertension /21./. 15.10.2006-19.10.2006, Fukuoka] R&D Projects: GA MZd(CZ) NR7786 Institutional research plan: CEZ:AV0Z50110509 Keywords : pertussis toxin * alpha adrenergic vasoconstriction * voltage-dependent calcium channels * SHR rat Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

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

International Nuclear Information System (INIS)

Scarpace, P.J.

1987-01-01

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

Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-{alpha}

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Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Han, Xiang Hua [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Dong-Ho [Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Hak-Ju [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of); Hwang, Bang Yeon, E-mail: byhwang@chungbuk.ac.kr [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Sung-Joon, E-mail: junelee@korea.ac.kr [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

2012-06-15

Highlights: Black-Right-Pointing-Pointer Catalposide is a novel ligand for PPAR{alpha}. Black-Right-Pointing-Pointer Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid {beta}-oxidation and synthesis. Black-Right-Pointing-Pointer Catalposdie reduces hepatic triacylglycerides. Black-Right-Pointing-Pointer Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPAR{alpha}) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPAR{alpha} agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPAR{alpha} agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPAR{alpha}. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPAR{alpha} via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

Characterization of a series of anabaseine-derived compounds reveals that the 3-(4)-dimethylaminocinnamylidine derivative is a selective agonist at neuronal nicotinic alpha 7/125I-alpha-bungarotoxin receptor subtypes.

Science.gov (United States)

de Fiebre, C M; Meyer, E M; Henry, J C; Muraskin, S I; Kem, W R; Papke, R L

1995-01-01

Investigation of the naturally occurring, nicotinic agonist anabaseine and novel derivatives has shown that these compounds have cytoprotective and memory-enhancing effects. The hypothesis that these arise at least in part through actions on brain nicotinic receptors was evaluated by examining the ability of these compounds to displace the binding of nicotinic ligands and to affect the function of the alpha 4 beta 2 and alpha 7 receptor subtypes expressed in Xenopus oocytes. The derivative 3-(4)-dimethylaminocinnamylidine anabaseine (DMAC) was found to be a selective alpha 7 receptor agonist; it was more potent than nicotine, acetylcholine, anabaseine, and other derivatives at activating the alpha 7 receptor subtype, while displaying little agonist activity at alpha 4 beta 2 and other receptor subtypes. Compared with anabaseine and the other derivatives, DMAC was the most potent at displacing 125I-alpha-bungarotoxin binding (putative alpha 7) and the least potent at displacing [3H]cytisine binding (putative alpha 4 beta 2) to brain membranes. Independently of agonist activities, all of the novel compounds displayed secondary inhibitory activity at both receptor subtypes. At the alpha 4 beta 2 receptor subtype, inhibition by the 3-(2,4)-dimethoxybenzylidene derivative was enhanced by coapplication of acetylcholine, suggesting a noncompetitive form of inhibition. Anabaseine and nicotine prolonged the time course of activation of alpha 4 beta 2 receptors, compared with acetylcholine, suggesting sequential channel-blocking activity. As selective agonists, anabaseine derivatives such as DMAC may be useful for elucidating the function of alpha 7 nicotinic receptors, including their potential role(s) in the cytoprotective and memory-enhancing effects of nicotinic agents.

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

International Nuclear Information System (INIS)

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

1986-01-01

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

Identification of an endogenous alpha-adrenergic receptor antagonist: studies on its possible role in endocrine and cardiovascular function

International Nuclear Information System (INIS)

Dunbar, J.C.; Wider, M.; House, F.; Campbell, R.

1986-01-01

The concept of α and β adrenergic receptors that are regulated by epinephrine or norepinephrine (NE) is well established. The reported receptor antagonists have been synthetic. A peptide extracted from the duodenal mucosa with α-2 antagonist properties has been identified. It specifically inhibits 3 H-yohimbine binding (α-2) but not 3 H dihydroalprenolol (β) binding in whole brain membranes. Partially purified preparations of the alpha receptor binding inhibitor (ABI) were tested for endocrine pancreatic and cardiovascular effects. When isolated islets were incubated in the presence of ABI with and without NE, ABI along did not alter insulin secretion but completely reversed the NE suppression of glucose stimulated insulin release. Glucagon secretion by these same islets was enhanced by ABI and augmented the stimulatory effect of NE. Intravenous (I.V.) infusion of ABI increased serum insulin in the presence of NE and decreased the serum glucose response to a glucose load. Infusion of ABI into the 4th ventricle, or I.V. resulted in a decrease (50-60%) in systolic and diastolic blood pressure as well as a decrease (10-20%) in heart rate. From these studies the authors conclude that a duodenal peptide with the capacity to inhibit α-2 agonist binding may play a role in endocrine and cardiovascular functions

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

International Nuclear Information System (INIS)

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

1987-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

Larue, D.; Kato, G.

1981-04-09

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

α-2 adrenergic receptor: a radiohistochemical study

International Nuclear Information System (INIS)

Unnerstall, J.R.

1984-01-01

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

Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications.

Science.gov (United States)

Noh, Hyunjin; Yu, Mi Ra; Kim, Hyun Joo; Lee, Ji Hye; Park, Byoung-Won; Wu, I-Hsien; Matsumoto, Motonobu; King, George L

2017-07-01

Macrophage activation is increased in diabetes and correlated with the onset and progression of vascular complications. To identify drugs that could inhibit macrophage activation, we developed a cell-based assay and screened a 1,040 compound library for anti-inflammatory effects. Beta2-adrenergic receptor (β2AR) agonists were identified as the most potent inhibitors of phorbol myristate acetate-induced tumor necrosis factor-α production in rat bone marrow macrophages. In peripheral blood mononuclear cells isolated from streptozotocin-induced diabetic rats, β2AR agonists inhibited diabetes-induced tumor necrosis factor-α production, which was prevented by co-treatment with a selective β2AR blocker. To clarify the underlying mechanisms, THP-1 cells and bone marrow macrophages were exposed to high glucose. High glucose reduced β-arrestin2, a negative regulator of NF-κB activation, and its interaction with IκBα. This subsequently enhanced phosphorylation of IκBα and activation of NF-κB. The β2AR agonists enhanced β-arrestin2 and its interaction with IκBα, leading to downregulation of NF-κB. A siRNA specific for β-arrestin2 reversed β2AR agonist-mediated inhibition of NF-κB activation and inflammatory cytokine production. Treatment of Zucker diabetic fatty rats with a β2AR agonist for 12 weeks attenuated monocyte activation as well as pro-inflammatory and pro-fibrotic responses in the kidneys and heart. Thus, β2AR agonists might have protective effects against diabetic renal and cardiovascular complications. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Sports doping: Emerging designer and therapeutic B2-agonists

NARCIS (Netherlands)

Fragkaki, A.G.; Georgakopoulos, C.; Sterk, S.S.; Nielen, M.W.F.

2013-01-01

Beta2-adrenergic agonists, or ß2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of ß2-agonists is prohibited in sports by the World Anti-Doping

Differential acute and chronic response of protein kinase C in cultured neonatal rat heart myocytes to alpha 1-adrenergic and phorbol ester stimulation.

Science.gov (United States)

Henrich, C J; Simpson, P C

1988-12-01

Both alpha 1-adrenergic agonists (e.g. norepinephrine, NE*) and tumor-promoting phorbol esters (e.g. phorbol myristate acetate, PMA) are known to activate protein kinase C (PKC) (Abdel-Latif, 1986, Niedel and Blackshear, 1986). However, alpha 1 agonists and PMA produce very different effects on cardiac function (see Simpson, 1985; Benfey, 1987; Meidell et al., 1986; Leatherman et al., 1987; Yuan et al., 1987; for examples). PKC activation in heart cells has been studied only for PMA treated perfused heart (Yuan et al., 1987). Therefore, acute activation and chronic regulation of PKC by NE and PMA were compared in cultured neonatal rat heart myocytes. NE acutely and transiently activated PKC, as measured by translocation of PKC activity to the cell particulate fraction (Niedel and Blackshear, 1986). Particulate PKC activity peaked at 23% of total after NE for 30 s, as compared with 8% for control (P less than 0.001). By contrast, acute PKC activation by PMA was more pronounced and persistent, with particulate PKC activity 62% of total at 5 min (P less than 0.001). Calcium/lipid-independent kinase activity increased acutely with PMA, but not with NE. Chronic treatment with NE (24 to 48 h) increased total per cell PKC activity and 3H-phorbol dibutyrate (PDB) binding sites, an index of the number of PKC molecules (Niedel and Blackshear, 1986), by 30 to 60% over control (all P less than 0.05 to 0.01). In contrast with NE, chronic treatment with PMA down-regulated PKC, reducing total per cell PKC activity and 3H-PDB binding sites to 3% and 12% of control, respectively (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of adrenaline and alpha-agonists on net rate of liquid absorption from the pleural space of rabbits.

Science.gov (United States)

Zocchi, L; Raffaini, A; Agostoni, E

1997-05-01

Indirect evidence supporting a solute-coupled liquid absorption from the pleural space of rabbits has recently been provided; moreover, the beta 2-adrenoceptor agonist terbutaline has been found to increase this absorption. In this study the effect of adrenaline and alpha-adrenoceptor agonists on net rate of liquid absorption (Jnet) from albumin Ringer hydrothoraces of various sizes has been determined in anaesthetized rabbits. In hydrothoraces with adrenaline (5 x 10(-6) M) the relationship between Jnet and volume of liquid injected was displaced upwards by 0.09 ml h-1 relative to that in control hydrothoraces (P liquid absorption, since beta-agonists inhibit lymphatic activity while, at relatively high concentrations, they may increase active transport. Conversely, the strong stimulation of lymphatic alpha-receptors that should occur with adrenaline after beta-blockade may fail to increase lymphatic drainage, because it has been shown that the increase in contraction frequency of lymphatics may be balanced by the decrease in their stroke volume. Arterial blood pressure during the hydrothoraces with adrenaline was unchanged. In hydrothoraces with the alpha 2-agonist clonidine (5 x 10(-6) M; a less potent agent than adrenaline) the slope of the relationship between Jnet and volume injected increased by 26% (P liquid load. In hydrothoraces with the alpha 1-agonist phenylephrine (5 x 10(-6) or 10(-7) M) Jnet was simlar to control values.

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

Science.gov (United States)

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

2012-01-01

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

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.

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.

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

International Nuclear Information System (INIS)

Lautens, L.

1986-01-01

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

Effects of adrenergic agents on the expression of zebrafish (Danio rerio) vitellogenin Ao1

International Nuclear Information System (INIS)

Yin Naida; Jin Xia; He Jiangyan; Yin Zhan

2009-01-01

Teleost vitellogenins (VTGs) are large multidomain apolipoproteins, traditionally considered to be estrogen-responsive precursors of the major egg yolk proteins, expressed and synthesized mainly in hepatic tissue. The inducibility of VTGs has made them one of the most frequently used in vivo and in vitro biomarkers of exposure to estrogen-active substances. A significant level of zebrafish vtgAo1, a major estrogen responsive form, has been unexpectedly found in heart tissue in our present studies. Our studies on zebrafish cardiomyopathy, caused by adrenergic agonist treatment, suggest a similar protective function of the cardiac expressed vtgAo1. We hypothesize that its function is to unload surplus intracellular lipids in cardiomyocytes for 'reverse triglyceride transportation' similar to that found in lipid transport proteins in mammals. Our results also demonstrated that zebrafish vtgAo1 mRNA expression in heart can be suppressed by both α-adrenergic agonist, phenylephrine (PE) and β-adrenergic agonist, isoproterenol (ISO). Furthermore, the strong stimulation of zebrafish vtgAo1 expression in plasma induced by the β-adrenergic antagonist, MOXIsylyl, was detected by Enzyme-Linked ImmunoSorbent Assay (ELISA). Such stimulation cannot be suppressed by taMOXIfen, an antagonist to estrogen receptors. Thus, our present data indicate that the production of teleost VTG in vivo can be regulated not only by estrogenic agents, but by adrenergic signals as well.

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

International Nuclear Information System (INIS)

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

1988-01-01

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

Expression of inwardly rectifying potassium channels (GIRKs) and beta-adrenergic regulation of breast cancer cell lines

International Nuclear Information System (INIS)

Plummer, Howard K III; Yu, Qiang; Cakir, Yavuz; Schuller, Hildegard M

2004-01-01

Previous research has indicated that at various organ sites there is a subset of adenocarcinomas that is regulated by beta-adrenergic and arachidonic acid-mediated signal transduction pathways. We wished to determine if this regulation exists in breast adenocarcinomas. Expression of mRNA that encodes a G-protein coupled inwardly rectifying potassium channel (GIRK1) has been shown in tissue samples from approximately 40% of primary human breast cancers. Previously, GIRK channels have been associated with beta-adrenergic signaling. Breast cancer cell lines were screened for GIRK channels by RT-PCR. Cell cultures of breast cancer cells were treated with beta-adrenergic agonists and antagonists, and changes in gene expression were determined by both relative competitive and real time PCR. Potassium flux was determined by flow cytometry and cell signaling was determined by western blotting. Breast cancer cell lines MCF-7, MDA-MB-361 MDA-MB 453, and ZR-75-1 expressed mRNA for the GIRK1 channel, while MDA-MB-468 and MDA-MB-435S did not. GIRK4 was expressed in all six breast cancer cell lines, and GIRK2 was expressed in all but ZR-75-1 and MDA-MB-435. Exposure of MDA-MB-453 cells for 6 days to the beta-blocker propranolol (1 μM) increased the GIRK1 mRNA levels and decreased beta 2 -adrenergic mRNA levels, while treatment for 30 minutes daily for 7 days had no effect. Exposure to a beta-adrenergic agonist and antagonist for 24 hours had no effect on gene expression. The beta adrenergic agonist, formoterol hemifumarate, led to increases in K + flux into MDA-MB-453 cells, and this increase was inhibited by the GIRK channel inhibitor clozapine. The tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a high affinity agonist for beta-adrenergic receptors stimulated activation of Erk 1/2 in MDA-MB-453 cells. Our data suggests β-adrenergic receptors and GIRK channels may play a role in breast cancer

Drug: D08683 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available pha2-Adrenergic receptor agonist ... DG01655 ... alpha2-adrenergic receptor specific agonist Chemical group: DG01321 ... veterinary medici...ne ... CAS: 7361-61-7 PubChem: 96025366 ChEMBL: CHEMBL297362 LigandBox: D08683 NIKKAJI: J8.925G ...

Central beta-adrenergic modulation of cognitive flexibility.

Science.gov (United States)

Beversdorf, David Q; White, Dawn M; Chever, Daquesha C; Hughes, John D; Bornstein, Robert A

2002-12-20

Situational stressors and anxiety impede performance on creativity tests requiring cognitive flexibility. Preliminary research revealed better performance on a task requiring cognitive flexibility, the anagram task, after propranolol (beta-adrenergic antagonist) than after ephedrine (beta-adrenergic agonist). However, propranolol and ephedrine have both peripheral and central beta-adrenergic effects. In order to determine whether noradrenergic modulation of cognitive flexibility is a centrally or peripherally mediated phenomenon, we compared the effects of propranolol (peripheral and central beta-blocker), nadolol (peripheral beta-blocker), and placebo on anagram task performance. Solution latency scores for each subject were compared across the drug conditions. Anagram solution latency scores after propranolol were significantly lower than after nadolol. This suggests a centrally mediated modulatory influence of the noradrenergic system on cognitive flexibility.

Repeated administration of alpha7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases alpha7 nAChR levels in the brain

DEFF Research Database (Denmark)

Christensen, Ditte Z; Mikkelsen, Jens D; Hansen, Henrik H

2010-01-01

AChR binding sites in several brain regions, particularly in the prefrontal cortex. The alpha7 nAChR agonists SSR180711 and PNU-282987 also increase [(125)I]-BTX binding, suggesting that this is a general consequence of alpha7 nAChR agonism. Interestingly, the alpha7 nAChR positive allosteric modulators PNU......The alpha7 nicotinic acetylcholine receptor (nAChR) is an important target for treatment of cognitive deficits in schizophrenia and Alzheimer's disease. However, the receptor desensitizes rapidly in vitro, which has led to concern regarding its applicability as a clinically relevant drug target....... Here we investigate the effects of repeated agonism on alpha7 nAChR receptor levels and responsiveness in vivo in rats. Using [(125)I]-alpha-bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective alpha7 nAChR agonist A-582941 increases the number of alpha7 n...

A Phase 3 Placebo-Controlled, Double Blind, Multi-Site Trial of the alpha-2-adrenergic Agonist, Lofexidine, for Opioid Withdrawal

Science.gov (United States)

Yu, Elmer; Miotto, Karen; Akerele, Evaristo; Montgomery, Ann; Elkashef, Ahmed; Walsh, Robert; Montoya, Ivan; Fischman, Marian W.; Collins, Joseph; McSherry, Frances; Boardman, Kathy; Davies, David K.; O’Brien, Charles P.; Ling, Walter; Kleber, Herbert; Herman, Barbara H.

2008-01-01

Context Lofexidine is an alpha-2-A noradrenergic receptor agonist that is approved in the United Kingdom for the treatment of opioid withdrawal symptoms. Lofexidine has been reported to have more significant effects on decreasing opioid withdrawal symptoms with less hypotension than clonidine. Objective To demonstrate that lofexidine is well tolerated and effective in the alleviation of observationally-defined opioid withdrawal symptoms in opioid dependent individuals undergoing medically supervised opioid detoxification as compared to placebo. Design An inpatient, Phase 3, placebo-controlled, double blind, randomized multi-site trial with three phases: (1) Opioid Agonist Stabilization Phase (days 1–3), (2) Detoxification/Medication or Placebo Phase (days 4–8), and (3) Post Detoxification/Medication Phase (days 9–11). Subjects Sixty-eight opioid dependent subjects were enrolled at three sites with 35 randomized to lofexidine and 33 to placebo. Main Outcome Measure Modified Himmelsbach Opiate Withdrawal Scale (MHOWS) on study day 5 (2nd opioid detoxification treatment day). Results Due to significant findings, the study was terminated early. On the study day 5 MHOWS, subjects treated with lofexidine had significantly lower scores (equating to fewer/less severe withdrawal symptoms) than placebo subjects (Least squares means 19.5 ± 2.1 versus 30.9 ± 2.7; p=0.0019). Lofexidine subjects had significantly better retention in treatment than placebo subjects (38.2% versus 15.2%; Log rank test p=0.01). Conclusions Lofexidine is well tolerated and more efficacious than placebo for reducing opioid withdrawal symptoms in inpatients undergoing medically supervised opioid detoxification. Trial Registration trial registry name A Phase 3 Placebo-Controlled, Double-Blind Multi-Site Trial of Lofexidine for Opiate Withdrawal, registration number NCT00032942, URL for the registry http://clinicaltrials.gov/ct/show/NCT00032942?order=4. PMID:18508207

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

Science.gov (United States)

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

2012-05-17

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

Statins and PPAR{alpha} agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment

Energy Technology Data Exchange (ETDEWEB)

Johnson, Timothy E [Department of Safety Assessment, Merck Research Laboratories, WP45-319, Merck Research Laboratories, West Point, PA 19486 (United States); Zhang, Xiaohua [Department of Biometrics Research, Merck Research Laboratories, West Point, PA 19486 (United States); Shi, Shu [Department of Safety Assessment, Merck Research Laboratories, WP45-319, Merck Research Laboratories, West Point, PA 19486 (United States); Umbenhauer, Diane R [Department of Safety Assessment, Merck Research Laboratories, WP45-319, Merck Research Laboratories, West Point, PA 19486 (United States)

2005-11-01

Statins and fibrates (weak PPAR{alpha} agonists) are prescribed for the treatment of lipid disorders. Both drugs cause myopathy, but with a low incidence, 0.1-0.5%. However, combined statin and fibrate therapy can enhance myopathy risk. We tested the myotoxic potential of PPAR subtype selective agonists alone and in combination with statins in a differentiated rat myotube model. A pharmacologically potent experimental PPAR{alpha} agonist, Compound A, induced myotoxicity as assessed by TUNEL staining at a minimum concentration of 1 nM, while other weaker PPAR{alpha} compounds, for example, WY-14643, Gemfibrozil and Bezafibrate increased the percentage of TUNEL-positive nuclei at micromolar concentrations. In contrast, the PPAR{gamma} agonist Rosiglitazone caused little or no cell death at up to 10 {mu}M and the PPAR{delta} ligand GW-501516 exhibited comparatively less myotoxicity than that seen with Compound A. An experimental statin (Compound B) and Atorvastatin also increased the percentage of TUNEL-positive nuclei and co-treatment with WY-14643, Gemfibrozil or Bezafibrate had less than a full additive effect on statin-induced cell killing. The mechanism of PPAR{alpha} agonist-induced cell death was different from that of statins. Unlike statins, Compound A and WY-14643 did not activate caspase 3/7. In addition, mevalonate and geranylgeraniol reversed the toxicity caused by statins, but did not prevent the cell killing induced by WY-14643. Furthermore, unlike statins, Compound A did not inhibit the isoprenylation of rab4 or rap1a. Interestingly, Compound A and Compound B had differential effects on ATP levels. Taken together, these observations support the hypothesis that in rat myotube cultures, PPAR{alpha} agonism mediates in part the toxicity response to PPAR{alpha} compounds. Furthermore, PPAR{alpha} agonists and statins cause myotoxicity through distinct and independent pathways.

Adrenergic receptor-mediated modulation of striatal firing patterns.

Science.gov (United States)

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

2016-11-01

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

Truncation studies of alpha-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity.

Science.gov (United States)

Haskell-Luevano, C; Sawyer, T K; Hendrata, S; North, C; Panahinia, L; Stum, M; Staples, D J; Castrucci, A M; Hadley, M F; Hruby, V J

1996-01-01

Truncation studies of alpha-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity: PEPTIDES 17(6) 995-1002, 1996.-Systematic analysis of fragment derivatives of the superpotent alpha-MSH analogue. Ac-Ser.Tyr-Ser-Nle4-Glu- His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2(NDP-MSH), led to the discovery of tripeptide agonists possessing prolonged bioactivity in the frog skin assay. Of particular significance to this discovery was Ac-DPhe-Arg-DTrp-NH2, which was the most potent tripeptide in this series exhibiting sustained melanotropic activity. Different pharmacophore models appear to exist that are dependent on the substructure and stereochemistry of the MSH(6-9) "active site." The tripeptides Ac-DPhe-Arg-Trp-NH2, Ac-DPhe-Arg-DTrp-NH2, and Ac-DPhe-DArg-Trp-NH2 stereo-chemical combinations require only Phe7-Xaa8-Trp9, whereas Ac-DPhe-DArg-DTrp-NH2, Ac-Phe-Arg-DTrp-NH2, and Ac-Phe-Arg-Trp-NH2 additionally require His4 for minimal biological activity. Ac-DPhe-Arg-DTrp-NH2 represents a novel prototype lead for the development of MSH-based peptidomimetic agonists.

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

Science.gov (United States)

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

2011-05-01

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

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

Science.gov (United States)

O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

2014-01-01

Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

New β-adrenergic agonists used illicitly as growth promoters in animal breeding: chemical and pharmacodynamic studies

International Nuclear Information System (INIS)

Mazzanti, Gabriela; Daniele, Claudia; Boatto, Gianpiero; Manca, Giuliana; Brambilla, Gianfranco; Loizzo, Alberto

2003-01-01

Clenbuterol and β-adrenergic receptor agonist drugs are illegally used as growth promoters in animal production. Pharmacologically active residues in edible tissues led to intoxication outbreaks in several countries. Pressure of official controls pulsed synthesis of new compounds to escape analytical procedures. We report two new compounds named 'A' and 'G4', found in feeding stuffs. Chemical structure was studied through nuclear magnetic resonance-imaging and infrared spectroscopy, and β 1 - and β 2 -adrenergic activity was evaluated on isolated guinea-pig atrium and trachea in comparison with clenbuterol. Both compounds share with clenbuterol an halogenated aromatic ring with a primary amino group. Main modifications consisted of substitution of secondary amino group with an alkyl chain in compound A and substitution of the ter-butyl group with a benzene ring in compound G4. In guinea-pig trachea these compounds showed myorelaxant potency lower than clenbuterol (EC 50 was 43.8 nM for clenbuterol, 11700 nM for compound A, 2140 nM for G4). On the contrary, in the guinea-pig atrium (heart-beat rate stimulant effect) the compounds were more potent than clenbuterol (EC 50 was 15.2 nM for clenbuterol, 3.4 nM for compound A, 2.8 nM for G4). These pharmacodynamic properties, and stronger lipophilic properties shown by the two compounds may result in increased cardiovascular risk for consumers of illicitly treated animals

Phosphoinositide metabolism and adrenergic receptors in astrocytes

International Nuclear Information System (INIS)

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

1986-01-01

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

The alpha(2a)-adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety.

Science.gov (United States)

Schramm, N L; McDonald, M P; Limbird, L E

2001-07-01

The noradrenergic system is involved in the regulation of many physiological and psychological processes, including the modulation of mood. The alpha(2)-adrenergic receptors (alpha(2)-ARs) modulate norepinephrine release, as well as the release of serotonin and other neurotransmitters, and are therefore potential targets for antidepressant and anxiolytic drug development. The current studies were undertaken to examine the role of the alpha(2A) subtype of alpha(2)-AR in mouse behavioral models of depression and anxiety. We have observed that the genetic knock-out of the alpha(2A)-AR makes mice less active in a modified version of Porsolt's forced swim test and insensitive to the antidepressant effects of the tricyclic drug imipramine in this paradigm. Furthermore, alpha(2A)-AR knock-out mice appear more anxious than wild-type C57 Bl/6 mice in the rearing and light-dark models of anxiety after injection stress. These findings suggest that the alpha(2A)-AR may play a protective role in some forms of depression and anxiety and that the antidepressant effects of imipramine may be mediated by the alpha(2A)-AR.

Effect of skin temperature on cutaneous vasodilator response to the β-adrenergic agonist isoproterenol.

Science.gov (United States)

Hodges, Gary J; Kellogg, Dean L; Johnson, John M

2015-04-01

The vascular response to local skin cooling is dependent in part on a cold-induced translocation of α2C-receptors and an increased α-adrenoreceptor function. To discover whether β-adrenergic function might contribute, we examined whether β-receptor sensitivity to the β-agonist isoproterenol was affected by local skin temperature. In seven healthy volunteers, skin blood flow was measured from the forearm by laser-Doppler flowmetry and blood pressure was measured by finger photoplethysmography. Data were expressed as cutaneous vascular conductance (CVC; laser-Doppler flux/mean arterial blood pressure). Pharmacological agents were administered via intradermal microdialysis. We prepared four skin sites: one site was maintained at a thermoneutral temperature of 34°C (32 ± 10%CVCmax) one site was heated to 39°C (38 ± 11%CVCmax); and two sites were cooled, one to 29°C (22 ± 7%CVCmax) and the other 24°C (16 ± 4%CVCmax). After 20 min at these temperatures to allow stabilization of skin blood flow, isoproterenol was perfused in concentrations of 10, 30, 100, and 300 μM. Each concentration was perfused for 15 min. Relative to the CVC responses to isoproterenol at the thermoneutral skin temperature (34°C) (+21 ± 10%max), low skin temperatures reduced (at 29°C) (+17 ± 6%max) or abolished (at 24°C) (+1 ± 5%max) the vasodilator response, and warm (39°C) skin temperatures enhanced the vasodilator response (+40 ± 9%max) to isoproterenol. These data indicate that β-adrenergic function was influenced by local skin temperature. This finding raises the possibility that a part of the vasoconstrictor response to direct skin cooling could include reduced background β-receptor mediated vasodilation. Copyright © 2015 the American Physiological Society.

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review.

Science.gov (United States)

Cruickshank, Moira; Henderson, Lorna; MacLennan, Graeme; Fraser, Cynthia; Campbell, Marion; Blackwood, Bronagh; Gordon, Anthony; Brazzelli, Miriam

2016-03-01

Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents. To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs. We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014. Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta

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

African Journals Online (AJOL)

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

Adrenergic stimulation promotes T-wave alternans and arrhythmia inducibility in a TNF-alpha genetic mouse model of congestive heart failure.

Science.gov (United States)

Shusterman, Vladimir; McTiernan, Charles F; Goldberg, Anna; Saba, Samir; Salama, Guy; London, Barry

2010-02-01

T-wave alternans (TWA) is a proarrhythmic repolarization instability that is common in congestive heart failure (CHF). Although transgenic mice are commonly used to study the mechanisms of arrhythmogenesis in CHF, little is known about the dynamics of TWA in these species. We hypothesized that TWA is present in a TNF-alpha model of CHF and can be further promoted by adrenergic stimulation. We studied 16 TNF-alpha mice and 12 FVB controls using 1) in vivo intracardiac electrophysiological testing and 2) ambulatory telemetry during 30 min before and after an intraperitoneal injection of isoproterenol. TWA was examined using both linear and nonlinear filtering applied in the time domain. In addition, changes in the mean amplitude of the T wave and area under the T wave were computed. During intracardiac electrophysiological testing, none of the animals had TWA or inducible arrhythmias before the injection of isoproterenol. After the injection, sustained TWA and inducible ventricular tachyarrhythmias were observed in TNF-alpha mice but not in FVB mice. In ambulatory telemetry, before the isoproterenol injection, the cardiac cycle length (CL) was longer in TNF-alpha mice than in FVB mice (98 +/- 9 and 88 +/- 3 ms, P = 0.04). After the injection of isoproterenol, the CL became 8% and 6% shorter in TNF-alpha and FVB mice (P mice, the magnitude of TWA was 1.5-2 times greater than in FVB mice both before and after the isoproterenol injection. The magnitude of TWA increased significantly after the isoproterenol injection compared with the baseline in TNF-alpha mice (P = 0.003) but not in FVB mice. The mean amplitude of the T wave and area under the T wave increased 60% and 80% in FVB mice (P = 0.006 and 0.009) but not in TNF-alpha mice. In conclusion, TWA is present in a TNF-alpha model of CHF and can be further promoted by adrenergic stimulation, along with the enhanced susceptibility for ventricular arrhythmias.

Effect of interleukin 13 on bronchial hyperresponsiveness and the bronchoprotective effect of beta-adrenergic bronchodilators and corticosteroids.

Science.gov (United States)

Townley, Robert G; Gendapodi, Pradeep R; Qutna, Nidal; Evans, Joseph; Romero, Francisco A; Abel, Peter

2009-03-01

Fluticasone affects airway bronchial hyperresponsiveness (BHR) and enhances bronchodilation and bronchoprotection induced by beta-adrenergic agonists. Interleukin 13 (IL-13), however, induces BHR. To test the hypotheses that fluticasone inhibits BHR after either allergen sensitization or IL-13 administration and that fluticasone restores the bronchodilation and bronchoprotective effects of beta-agonists. The BHR to methacholine induced by IL-13 or ovalbumin was determined in BALB/c mice, and the provocation concentration of methacholine that caused an increase in enhanced pause in expiration of 200% (PC200) was calculated. We compared this response to methacholine in control mice with the response after treatment with IL-13 receptor alpha 2-IgGFc fusion protein (IL-13R alpha 2) (an IL-13 blocker), fluticasone, albuterol, salmeterol, fluticasone-albuterol, and fluticasone-salmeterol. IL-13R alpha 2 (PC200, 17.59) completely blocks the BHR-induced effects of IL-13 (PC200, 7.28; P < .005). After IL-13 therapy (PC200, 5.90; P < .005), 1 mg/mL of albuterol (PC200, 3.38; P = .33), fluticasone (PC200, 4.59; P = .40), or fluticasone plus 50 microg/mL of salmeterol (PC200, 5.59; P = .11) showed no significant bronchoprotection. In nonsensitized mice, fluticasone plus 0.25 microg/mL of salmeterol (PC200, 25.90; P < .005) showed significantly greater bronchoprotection than did salmeterol alone (PC200, 11.08; P = .26). Fluticasone plus 0.3 mg/mL of albuterol and fluticasone plus 1 mg/mL of albuterol were significantly more protective than was fluticasone or albuterol alone in ovalbumin-sensitized mice. The protective effects of fluticasone, beta-agonists, and fluticasone plus beta-agonists are significantly less in IL-13-treated mice than in nonsensitized or ovalbumin-sensitized mice.

Effect of alpha 2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat.

Science.gov (United States)

Tazi-Saad, K.; Chariot, J.; Del Tacca, M.; Rozé, C.

1992-01-01

1. The purpose of the present study was to analyze the effects of the alpha 2-adrenoceptor agonists clonidine, guanabenz, detomidine and medetomidine on pepsin secretion in conscious rats provided with gastric chronic fistula and to compare this with acid secretion. 2. Basal interdigestive gastric secretion, which is mainly neurally driven in the rat, and the secretion directly stimulated by the two main stimulants of chief cells, cholecystokinin octapeptide (CCK8) and methacholine, were studied. 3. Basal secretion of pepsin and acid was inhibited by all four drugs with comparable EC50S. 4. CCK-stimulated pepsin and acid secretion was less sensitive than basal pepsin and acid secretion to alpha 2-adrenoceptor inhibition. 5. Methacholine-stimulated pepsin and acid secretion was not changed by clonidine and guanabenz; methacholine-stimulated acid was even marginally increased by clonidine. 6. These results do not favour the presence of alpha 2-receptors on chief cells in the rat stomach. They rather suggest that pepsin inhibition by alpha 2-adrenoceptor agonists is indirect and due to central or peripheral inhibition of the discharge of nerve fibres activating pepsin secretion. PMID:1356566

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

Science.gov (United States)

McIntosh, Victoria J.; Chandrasekera, P. Charukeshi

2011-01-01

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

The inhibition of the dorsal paragigantocellular reticular nucleus induces waking and the activation of all adrenergic and noradrenergic neurons: a combined pharmacological and functional neuroanatomical study.

Science.gov (United States)

Clément, Olivier; Valencia Garcia, Sara; Libourel, Paul-Antoine; Arthaud, Sébastien; Fort, Patrice; Luppi, Pierre-Hervé

2014-01-01

GABAergic neurons specifically active during paradoxical sleep (PS) localized in the dorsal paragigantocellular reticular nucleus (DPGi) are known to be responsible for the cessation of activity of the noradrenergic neurons of the locus coeruleus during PS. In the present study, we therefore sought to determine the role of the DPGi in PS onset and maintenance and in the inhibition of the LC noradrenergic neurons during this state. The effect of the inactivation of DPGi neurons on the sleep-waking cycle was examined in rats by microinjection of muscimol, a GABAA agonist, or clonidine, an alpha-2 adrenergic receptor agonist. Combining immunostaining of the different populations of wake-inducing neurons with that of c-FOS, we then determined whether muscimol inhibition of the DPGi specifically induces the activation of the noradrenergic neurons of the LC. Slow wave sleep and PS were abolished during 3 and 5 h after muscimol injection in the DPGi, respectively. The application of clonidine in the DPGi specifically induced a significant decrease in PS quantities and delayed PS appearance compared to NaCl. We further surprisingly found out that more than 75% of the noradrenergic and adrenergic neurons of all adrenergic and noradrenergic cell groups are activated after muscimol treatment in contrast to the other wake active systems significantly less activated. These results suggest that, in addition to its already know inhibition of LC noradrenergic neurons during PS, the DPGi might inhibit the activity of noradrenergic and adrenergic neurons from all groups during PS, but also to a minor extent during SWS and waking.

The inhibition of the dorsal paragigantocellular reticular nucleus induces waking and the activation of all adrenergic and noradrenergic neurons: a combined pharmacological and functional neuroanatomical study.

Directory of Open Access Journals (Sweden)

Olivier Clément

Full Text Available GABAergic neurons specifically active during paradoxical sleep (PS localized in the dorsal paragigantocellular reticular nucleus (DPGi are known to be responsible for the cessation of activity of the noradrenergic neurons of the locus coeruleus during PS. In the present study, we therefore sought to determine the role of the DPGi in PS onset and maintenance and in the inhibition of the LC noradrenergic neurons during this state. The effect of the inactivation of DPGi neurons on the sleep-waking cycle was examined in rats by microinjection of muscimol, a GABAA agonist, or clonidine, an alpha-2 adrenergic receptor agonist. Combining immunostaining of the different populations of wake-inducing neurons with that of c-FOS, we then determined whether muscimol inhibition of the DPGi specifically induces the activation of the noradrenergic neurons of the LC. Slow wave sleep and PS were abolished during 3 and 5 h after muscimol injection in the DPGi, respectively. The application of clonidine in the DPGi specifically induced a significant decrease in PS quantities and delayed PS appearance compared to NaCl. We further surprisingly found out that more than 75% of the noradrenergic and adrenergic neurons of all adrenergic and noradrenergic cell groups are activated after muscimol treatment in contrast to the other wake active systems significantly less activated. These results suggest that, in addition to its already know inhibition of LC noradrenergic neurons during PS, the DPGi might inhibit the activity of noradrenergic and adrenergic neurons from all groups during PS, but also to a minor extent during SWS and waking.

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

International Nuclear Information System (INIS)

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

1982-01-01

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

Molecular Mechanisms of β2-Adrenergic Receptor Function and Regulation

OpenAIRE

McGraw, Dennis W.; Liggett, Stephen B.

2005-01-01

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

Topical administration of adrenergic receptor pharmaceutics and nerve growth factor

Directory of Open Access Journals (Sweden)

Jena J Steinle

2010-06-01

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

Effectiveness and safety of alpha agonists for ADHD in population between 6 and 19 years: a systematic review

Directory of Open Access Journals (Sweden)

José Calleja

2012-09-01

Full Text Available Introduction: Attention deficit hyperactivity disorder (ADHD is generally treated with pharmacological interventions; psychostimulants are first choice. Other alternatives have been used such as alpha agonists (clonidine, hence it is important to know its effectiveness and safety. Purpose: To identify, synthesize and evaluate the best available evidence on the effectiveness and safety of alpha agonists in treating ADHD in the 6-19 year-old population. Methods: A systematic review of intervention studies that evaluated effectiveness comparing alpha agonists to methylphenidate was conducted. Outcomes measured were educational performance, psychosocial functioning, quality of life and adverse effects. The following databases were searched up to February 2012 in English and Spanish: PubMed/MEDLINE, Lilacs, Cochrane, DARE and National Guideline Clearinghouse. The articles that met the inclusion criteria were assessed by two researchers independently. Results: Of the 34 studies found initially, three were included, among which a systematic review and two clinical guidelines. Conclusions: Clonidine is considered an effective second and third line treatment for ADHD symptoms, but it is less effective than stimulants. Its use is associated with many side effects.

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

International Nuclear Information System (INIS)

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

1987-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

1987-11-01

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

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

DEFF Research Database (Denmark)

Poulsen, Steen Seier; Nexø, Ebba

1985-01-01

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

Infusion of adrenergic receptor agonists and antagonists into the locus coeruleus and ventricular system of the brain. Effects on swim-motivated and spontaneous motor activity.

Science.gov (United States)

Weiss, J M; Simson, P G; Hoffman, L J; Ambrose, M J; Cooper, S; Webster, A

1986-04-01

These studies examined how pharmacological stimulation and blockade of alpha receptors would affect active motor behavior in rats. In experiment I, alpha-2 receptor antagonists (piperoxane, yohimbine) and agonists [clonidine, norepinephrine (NE)] were infused into various locations in the ventricular system of the brain, including the locus coeruleus region, and motor activity was measured. Activity was measured principally in a swim test but spontaneous (ambulatory) activity was also recorded while drugs were being infused. When infused into the locus coeruleus region, small doses of the antagonists piperoxane and yohimbine depressed activity in the swim test while infusion of the agonists clonidine and NE had the opposite effect of stimulating activity. These effects were highly specific to the region of the locus coeruleus, since infusions of these drugs into other nearby locations in the ventricular system or use of larger doses had different, often opposite effects. This was especially true of clonidine and NE which profoundly depressed activity when infused posterior to the locus coeruleus, particularly over the dorsal vagal complex. Infusion of small doses of these drugs into the lateral ventricle had effects similar to infusion into the locus coeruleus region, though less pronounced. Changes in spontaneous motor activity were also observed, but this measure differentiated the groups less well than did the swim test. In experiment II, the predominantly postsynaptic receptor agonists isoproterenol (beta agonist) and phenylephrine (alpha-1 agonist) were infused into the ventricular system. Since infusions of piperoxane and yohimbine into the locus coeruleus that decreased activity in experiment I increase the release of NE by blocking alpha-2 inhibitory receptors on cell bodies and dendrites of the locus coeruleus, experiment II tested whether ventricular infusion of predominantly postsynaptic receptor agonists would also decrease activity in the swim test

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

BACKGROUND & AIMS: In the intact pancreas, bicarbonate secretion is thought to be controlled by a number of regulators, including adrenergic agonists. The aim of this study was to investigate the effects of adrenergic agonists on pancreatic ducts, which are the site of bicarbonate secretion....... 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...

The human thoracic duct is functionally innervated by adrenergic nerves

DEFF Research Database (Denmark)

Telinius, Niklas; Baandrup, Ulrik; Rumessen, Jüri Johs.

2013-01-01

) that is predominantly adrenergic. TDs harvested from 51 patients undergoing esophageal and cardia cancer surgery were either fixed for structural investigations or maintained in vitro for the functional assessment of innervation by isometric force measurements and electrical field stimulation (EFS). Electron microscopy......, and methacholine was demonstrated by exogenous application to human TD ring segments. Norepinephrine provided the most consistent responses, whereas responses to the other agonists varied. We conclude that the human TD is functionally innervated with both cholinergic and adrenergic components, with the latter...

Actions of alpha2 adrenoceptor ligands at alpha2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for alpha2A adrenoceptors.

Science.gov (United States)

Newman-Tancredi, A; Nicolas, J P; Audinot, V; Gavaudan, S; Verrièle, L; Touzard, M; Chaput, C; Richard, N; Millan, M J

1998-08-01

This study examined the activity of chemically diverse alpha2 adrenoceptor ligands at recombinant human (h) and native rat (r) alpha2A adrenoceptors compared with 5-HT1A receptors. First, in competition binding experiments at h alpha2A and h5-HT1A receptors expressed in CHO cells, several compounds, including the antagonists 1-(2-pyrimidinyl)piperazine (1-PP), (+/-)-idazoxan, benalfocin (SKF 86466), yohimbine and RX 821,002, displayed preference for h alpha2A versus h5-HT1A receptors of only 1.4-, 3.6-, 4-, 10- and 11-fold, respectively (based on differences in pKi values). Clonidine, brimonidine (UK 14304), the benzopyrrolidine fluparoxan and the guanidines guanfacine and guanabenz exhibited intermediate selectivity (22- to 31-fold) for h alpha2A receptors. Only the antagonist atipamezole and the agonist dexmedetomidine (DMT) displayed high preference for alpha2 adrenoceptors (1290- and 91-fold, respectively). Second, the compounds were tested for their ability to induce h5-HT1A receptor-mediated G-protein activation, as indicated by the stimulation of [35S]GTPgammaS binding. All except atipamezole and RX 821,002 exhibited agonist activity, with potencies which correlated with their affinity for h5-HT1A receptors. Relative efficacies (Emax values) were 25-35% for guanabenz, guanfacine, WB 4101 and benalfocin, 50-65% for 1-PP, (+/-)-idazoxan and clonidine, and over 70% for fluparoxan, oxymetazoline and yohimbine (relative to 5-HT = 100%). Yohimbine-induced [35S]GTPgammaS binding was inhibited by the selective 5-HT1A receptor antagonist WAY 100,635. In contrast, RX 821,002 was the only ligand which exhibited antagonist activity at h5-HT1A receptors, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Atipamezole, which exhibited negligeable affinity for 5-HT1A receptors, was inactive. Third, the affinities for r alpha2A differed considerably from the affinities for h alpha2A receptors whereas the affinities for r5-HT1A differed much less from the affinities for h5-HT

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

International Nuclear Information System (INIS)

Hill, D.A.

1989-01-01

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

Impaired modulation of postjunctional α1 - but not α2 -adrenergic vasoconstriction in contracting forearm muscle of postmenopausal women.

Science.gov (United States)

Kruse, Nicholas T; Hughes, William E; Ueda, Kenichi; Hanada, Satoshi; Feider, Andrew J; Iwamoto, Erika; Bock, Joshua M; Casey, Darren P

2018-04-30

Contraction-mediated blunting of postjunctional α-adrenergic vasoconstriction (functional sympatholysis) is attenuated in skeletal muscle of ageing males, brought on by altered postjunctional α 1 - and α 2 -adrenergic receptor sensitivity. The extent to which postjunctional α-adrenergic vasoconstriction occurs in the forearms at rest and during exercise in postmenopausal women remains unknown. The novel findings indicate that contraction-mediated blunting of α 1 - (via intra-arterial infusion of phenylephrine) but not α 2 -adrenergic (via intra-arterial infusion of dexmedetomidine) vasoconstriction was attenuated in postmenopausal women compared to young women. Additional important findings revealed that postjunctional α-adrenergic vasoconstrictor responsiveness at rest does not appear to be affected by age in women. Collectively, these results contribute to our understanding of local neurovascular control at rest and during exercise with age in women. Contraction-mediated blunting of postjunctional α-adrenergic vasoconstriction (functional sympatholysis) is attenuated in older males; however, direct confirmation of this effect remains unknown in postmenopausal women (PMW). The present study examined whether PMW exhibit augmented postjunctional α-adrenergic receptor vasoconstriction at rest and during forearm exercise compared to young women (YW). Eight YW (24 ± 1 years) and eight PMW (65 ± 1 years) completed a series of randomized experimental trials: (1) at rest, (2) under high flow (adenosine infusion) conditions and (3) during 6 min of forearm exercise at relative (20% of maximum) and absolute (7 kg) intensities. Phenylephrine (α 1 -agonist) or dexmedetomidine (α 2 -agonist) was administered during the last 3 min of each trial to elicit α-adrenergic vasoconstriction. Forearm vascular conductance (FVC) was calculated from blood flow and blood pressure. Vasoconstrictor responsiveness was identified as the change in FVC (%) during α-adrenergic

In utero Exposure to beta-2-Adrenergic Receptor Agonist Drugs and Risk for Autism Spectrum Disorders

DEFF Research Database (Denmark)

Gidaya, Nicole B.; Lee, Brian K.; Burstyn, Igor

2016-01-01

OBJECTIVES: The purpose of this study was to investigate associations between use of β-2-adrenergic receptor (B2AR) agonist drugs during pregnancy and risk for autism spectrum disorders (ASD). METHODS: A case-control study was conducted by using Denmark’s health and population registers. Among...... exposure during pregnancy, preconception, and by trimester. RESULTS: In total, 3.7% of cases and 2.9% of controls were exposed to B2ARs during pregnancy. Use of B2ARs during pregnancy was associated with increased risk of ASD, even after adjustment for maternal asthma and other covariates (OR: 1.3, 95% CI......: 1.1–1.5). The elevated risk was observed with use of B2AR during preconception (OR: 1.3, 95% CI: 1.0–1.6), first trimester (OR: 1.3, 95% CI: 1.1–1.5), second trimester (OR: 1.5, 95% CI: 1.1–1.7), and the third trimester (OR: 1.4, 95% CI: 1.1–1.7). There was some evidence that longer B2AR within-pregnancy...

Agonist-induced alterations in lymphocyte β-adrenergic receptor photoaffintiy labelling: effects of phenylarsine oxide

International Nuclear Information System (INIS)

Feldman, R.D.; McArdle, W.; Lai, C.

1986-01-01

In several models, desensitization of the β-adrenergic receptor (βAR) is associated with a decrease in binding of hydrophilic but not hydrophobic βAR ligands. This suggests a sequestration of cell surface βAR. Desensitization of the lymphobyte βAR is also associated with a selective reduction in the photoaffinity labelling of a 55K βAR protein as compared to a 68K βAR protein. In order to examine the relationship between sequestration and reduction in labelling of the 55K peptide, the authors have studied the effect of phenylarsine oxide (PAO; an inhibitor of sequestration) on lymphocyte βAR desensitization. Incubation of cells with PAO prior to desensitization did not block the consequent reduction in isoproterenol-stimulated adenylate cyclase activity. However, the agonist-induced reduction in binding of the hydrophilic βAR ligand CGP-12177 was blocked by PAO (without PAO:57 +/- 4% of control, with PAO: 97 +/- 2% of control). Photolabelling studies with [ 125 I] iodocyanopindolol diazirine revealed that PAO pretreatment also blocked the selective loss in labelling of the 55K βAR protein seen with desensitization. These data suggest that loss of labelling of the 55K protein of the βAR is closely coupled to βAR sequestration

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

International Nuclear Information System (INIS)

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

1986-01-01

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

Effects of the β-Adrenergic Agonist Cimaterol on Growth and Carcass Quality of Monozygotic Friesian Young Bulls at Three Developmental Stages

DEFF Research Database (Denmark)

Vestergaard, Mogens; Sommer, Mario; Klastrup, Signe

1993-01-01

of intake. The animals were slaughtered on day 90 of the treatment period. Without affecting feed intake, CIM treatment increased average daily gain (ADG) by 19% (Pcarcass gain, EUROP conformation and longissimus dorsi area were all...... in cuts from the hind region of the carcass. The percentage of carcass saleable meat increased (Panimals. The effects of cimaterol were evident in all three WG. The results show that cimaterol is effective in stimulating overall growth performance and improving carcass leanness......The objective was to investigate the effects of the β-adrenergic agonist cimaterol (CIM) on growth and carcass quality of Friesian young bulls at different developmental stages. The study comprised three liveweight groups (WG) each of four pairs of monozygotic twins. The average initial liveweight...

Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation

Science.gov (United States)

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

2014-01-01

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

Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation.

Science.gov (United States)

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

2015-03-01

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

Bone marrow adipocytes resist lipolysis and remodeling in response to β-adrenergic stimulation.

Science.gov (United States)

Scheller, Erica L; Khandaker, Shaima; Learman, Brian S; Cawthorn, William P; Anderson, Lindsay M; Pham, H A; Robles, Hero; Wang, Zhaohua; Li, Ziru; Parlee, Sebastian D; Simon, Becky R; Mori, Hiroyuki; Bree, Adam J; Craft, Clarissa S; MacDougald, Ormond A

2018-01-26

Bone marrow adipose tissue (BMAT) is preserved or increased in states of caloric restriction. Similarly, we found that BMAT in the tail vertebrae, but not the red marrow in the tibia, resists loss of neutral lipid with acute, 48-hour fasting in rats. The mechanisms underlying this phenomenon and its seemingly distinct regulation from peripheral white adipose tissue (WAT) remain unknown. To test the role of β-adrenergic stimulation, a major regulator of adipose tissue lipolysis, we examined the responses of BMAT to β-adrenergic agonists. Relative to inguinal WAT, BMAT had reduced phosphorylation of hormone sensitive lipase (HSL) after treatment with pan-β-adrenergic agonist isoproterenol. Phosphorylation of HSL in response to β3-adrenergic agonist CL316,243 was decreased by an additional ~90% (distal tibia BMAT) or could not be detected (tail vertebrae). Ex vivo, adrenergic stimulation of lipolysis in purified BMAT adipocytes was also substantially less than iWAT adipocytes and had site-specific properties. Specifically, regulated bone marrow adipocytes (rBMAs) from proximal tibia and femur underwent lipolysis in response to both CL316,243 and forskolin, while constitutive BMAs from the tail responded only to forskolin. This occurred independently of changes in gene expression of β-adrenergic receptors, which were similar between adipocytes from iWAT and BMAT, and could not be explained by defective coupling of β-adrenergic receptors to lipolytic machinery through caveolin 1. Specifically, we found that whereas caveolin 1 was necessary to mediate maximal stimulation of lipolysis in iWAT, overexpression of caveolin 1 was insufficient to rescue impaired BMAT signaling. Lastly, we tested the ability of BMAT to respond to 72-hour treatment with CL316,243 in vivo. This was sufficient to cause beiging of iWAT adipocytes and a decrease in iWAT adipocyte cell size. By contrast, adipocyte size in the tail BMAT and distal tibia remained unchanged. However, within the

Combination of roflumilast with a beta-2 adrenergic receptor agonist inhibits proinflammatory and profibrotic mediator release from human lung fibroblasts

Directory of Open Access Journals (Sweden)

Tannheimer Stacey L

2012-03-01

Full Text Available Abstract Background Small airway narrowing is an important pathology which impacts lung function in chronic obstructive pulmonary disease (COPD. The accumulation of fibroblasts and myofibroblasts contribute to inflammation, remodeling and fibrosis by production and release of mediators such as cytokines, profibrotic factors and extracellular matrix proteins. This study investigated the effects of the phosphodiesterase 4 inhibitor roflumilast, combined with the long acting β2 adrenergic agonist indacaterol, both approved therapeutics for COPD, on fibroblast functions that contribute to inflammation and airway fibrosis. Methods The effects of roflumilast and indacaterol treatment were characterized on transforming growth factor β1 (TGFβ1-treated normal human lung fibroblasts (NHLF. NHLF were evaluated for expression of the profibrotic mediators endothelin-1 (ET-1 and connective tissue growth factor (CTGF, expression of the myofibroblast marker alpha smooth muscle actin, and fibronectin (FN secretion. Tumor necrosis factor-α (TNF-α was used to induce secretion of chemokine C-X-C motif ligand 10 (CXCL10, chemokine C-C motif ligand 5 (CCL5 and granulocyte macrophage colony-stimulating factor (GM-CSF from NHLF and drug inhibition was assessed. Results Evaluation of roflumilast (1-10 μM showed no significant inhibition alone on TGFβ1-induced ET-1 and CTGF mRNA transcripts, ET-1 and FN protein production, alpha smooth muscle expression, or TNF-α-induced secretion of CXCL10, CCL5 and GM-CSF. A concentration-dependent inhibition of ET-1 and CTGF was shown with indacaterol treatment, and a submaximal concentration was chosen for combination studies. When indacaterol (0.1 nM was added to roflumilast, significant inhibition was seen on all inflammatory and fibrotic mediators evaluated, which was superior to the inhibition seen with either drug alone. Roflumilast plus indacaterol combination treatment resulted in significantly elevated phosphorylation

Wave Reflection and Characteristic Impedance in the Conscious Dog as Influenced by Adrenergic Intervention

National Research Council Canada - National Science Library

Kerkhof, P

2001-01-01

.... Therefore, the specific aims of this study are first to delineate the characteristics of the systemic circulation and second to analyze the influence of adrenergic agonists and blockers on C and Zo...

Effect of formoterol, a long-acting β2-adrenergic agonist, on muscle strength and power output, metabolism and fatigue during maximal sprinting in men

DEFF Research Database (Denmark)

Kalsen, Anders; Hostrup, Morten; Backer, Vibeke

2016-01-01

The aim was to investigate the effect of the long-acting β2-adrenergic agonist formoterol on muscle strength and power output, muscle metabolism and phosphorylation of CaMKII Thr(287) and FXYD1 during maximal sprinting. In a double-blind crossover study, thirteen males (VO2max: 45.0±0.2 (mean±SE) m......L min(-1) kg(-1)) performed a 30-s cycle ergometer sprint after inhalation of either 54 µg formoterol (FOR) or placebo (PLA). Before and after the sprint, muscle biopsies were collected from vastus lateralis and maximal voluntary contraction (MVC) and contractile properties of quadriceps were measured...

Evidence for Alpha Receptors in the Human Ureter

Science.gov (United States)

Madeb, Ralph; Knopf, Joy; Golijanin, Dragan; Bourne, Patricia; Erturk, Erdal

2007-04-01

An immunohistochemical and western blot expression analysis of human ureters was performed in order to characterize the alpha-1-adrenergic receptor distribution along the length of the human ureteral wall. Mapping the distribution will assist in understanding the potential role alpha -1-adrenergic receptors and their subtype density might have in the pathophysiology of ureteral colic and stone passage. Patients diagnosed with renal cancer or bladder cancer undergoing nephrectomy, nephroureterectomy, or cystectomy had ureteral specimens taken from the proximal, mid, distal and tunneled ureter. Tissues were processed for fresh frozen examination and fixed in formalin. None of the ureteral specimens were involved with cancer. Serial histologic sections and immunohistochemical studies were performed using antibodies specific for alpha-1-adrenergic receptor subtypes (alpha 1a, alpha 1b, alpha 1d). The sections were examined under a light microscope and scored as positive or negative. In order to validate and quantify the alpha receptor subtypes along the human ureter. Western blotting techniques were applied. Human ureter stained positively for alpha -1-adrenergic receptors. Immunostaining appeared red, with intense reaction in the smooth muscle of the ureter and endothelium of the neighboring blood vessels. There was differential expression between all the receptors with the highest staining for alpha-1D subtype. The highest protein expression for all three subtypes was in the renal pelvis and decreased with advancement along the ureter to the distal ureter. At the distal ureter, there was marked increase in expression as one progressed towards the ureteral orifice. The same pattern of protein expression was exhibited for all three alpha -1-adrenergic receptor subtypes. We provide preliminary evidence for the ability to detect and quantify the alpha-1-receptor subtypes along the human ureter which to the best of our knowledge has never been done with

Characterization of α2-adrenergic receptors in rat cerebral cortex

International Nuclear Information System (INIS)

Nasseri, A.

1987-01-01

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

Change of expression of renal alpha1-adrenergic receptor and angiotensin II receptor subtypes with aging in rats.

Science.gov (United States)

Li, Yan-Fang; Cao, Xiao-Jing; Bai, Xue-Yuan; Lin, Shu-Peng; Shi, Shu-Tian

2010-04-01

It has been considered that the functional decline of renal vasoconstriction during senescence is associated with an alteration in renal alpha1-adrenergic receptor (alpha1-AR) expression. While alterations in renal angiotensin II receptor (ATR) expression was considered to have an effect on renal structure and function, until now little information has been available concerning alpha1-AR and ATR expression variations over the entire aging continuum. The present study was undertaken to examine the expression levels of alpha1-AR and ATR subtypes in renal tissue during the spectrum running from young adulthood, to middle age, to the presenium, and to the senium. Semiquantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) and Western Blot were used to quantify the messenger RNA (mRNA) and protein levels of alpha1-AR and ATR subtypes in renal tissue in 3-month-old (young adult), 12-month-old (middle age), 18-month-old (presenium) and 24-month-old (senium) Wistar rats. alpha1A-AR expression decreased gradually with aging: it was decreased during middle age, the presenium and the senium, compared, respectively, with young adult values (page and in the senium with respect to the presenium. alpha1B-AR and alpha1D-AR expression were unmodified during senescence. AT1R expression was unaffected by aging during young adulthood and middle age, but exhibited a remarkable downregulation in the presenium and senium periods (prenal alpha1-AR and ATR subtypes during aging. alpha1A-AR expression downregulation may account for the reduced reactivity of renal alpha1-AR to vasoconstrictors and to renal function decline in the senium. Both the downregulation of AT1R and the upregulation of AT2R may be influential in maintaining normal physiological renal function during aging.

Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors.

Science.gov (United States)

Bkaily, Ghassan; El-Bizri, Nesrine; Bui, Michel; Sukarieh, Rami; Jacques, Danielle; Fu, Michael L X

2003-03-01

The effects of methoxamine, a selective alpha1-adrenergic receptor agonist, and the autoantibody directed against the second extracellular loop of alpha1-adrenoceptors were studied on intracellular free Ca2+ levels using confocal microscopy and ionic currents using the whole-cell patch clamp technique in single cells of 10-day-old embryonic chick and 20-week-old fetal human hearts. We observed that like methoxamine, the autoantibody directed against the second extracellular loop of alpha1-adrenoreceptors significantly increased the L-type calcium current (I(Ca(L))) but had no effect on the T-type calcium current (I(Ca(T))), the delayed outward potassium current, or the fast sodium current. This effect of the autoantibody was prevented by a prestimulation of the receptors with methoxamine and vice versa. Moreover, treating the cells with prazosin, a selective alpha1-adrenergic receptor antagonist blocked the methoxamine and the autoantibody-induced increase in I(Ca(L)), respectively. In absence of prazosin, both methoxamine and the autoantibody showed a substantial enhancement in the frequency of cell contraction and that of the concomitant cytosolic and nuclear free Ca2+ variations. The subsequent addition of nifedipine, a specific L-type Ca2+ channel blocker, reversed not only the methoxamine or the autoantibody-induced effect but also completely abolished cell contraction. These results demonstrated that functional alpha1-adrenoceptors exist in both 10-day-old embryonic chick and 20-week-old human fetal hearts and that the autoantibody directed against the second extracellular loop of this type of receptors plays an important role in stimulating their activity via activation of L-type calcium channels. This loop seems to have a functional significance by being the target of alpha1-receptor agonists like methoxamine.

CL316,243, a β3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength.

Science.gov (United States)

Puzzo, Daniela; Raiteri, Roberto; Castaldo, Clotilde; Capasso, Raffaele; Pagano, Ester; Tedesco, Mariateresa; Gulisano, Walter; Drozd, Lisaveta; Lippiello, Pellegrino; Palmeri, Agostino; Scotto, Pietro; Miniaci, Maria Concetta

2016-11-22

Studies in vitro have demonstrated that β3-adrenergic receptors (β3-ARs) regulate protein metabolism in skeletal muscle by promoting protein synthesis and inhibiting protein degradation. In this study, we evaluated whether activation of β3-ARs by the selective agonist CL316,243 modifies the functional and structural properties of skeletal muscles of healthy mice. Daily injections of CL316,243 for 15 days resulted in a significant improvement in muscle force production, assessed by grip strength and weight tests, and an increased myofiber cross-sectional area, indicative of muscle hypertrophy. In addition, atomic force microscopy revealed a significant effect of CL316,243 on the transversal stiffness of isolated muscle fibers. Interestingly, the expression level of mammalian target of rapamycin (mTOR) downstream targets and neuronal nitric oxide synthase (NOS) was also found to be enhanced in tibialis anterior and soleus muscles of CL316,243 treated mice, in accordance with previous data linking β3-ARs to mTOR and NOS signaling pathways. In conclusion, our data suggest that CL316,243 systemic administration might be a novel therapeutic strategy worthy of further investigations in conditions of muscle wasting and weakness associated with aging and muscular diseases.

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

Science.gov (United States)

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

2014-08-15

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

In vitro pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107.

Science.gov (United States)

Malysz, John; Anderson, David J; Grønlien, Jens H; Ji, Jianguo; Bunnelle, William H; Håkerud, Monika; Thorin-Hagene, Kirten; Ween, Hilde; Helfrich, Rosalind; Hu, Min; Gubbins, Earl; Gopalakrishnan, Sujatha; Puttfarcken, Pamela S; Briggs, Clark A; Li, Jinhe; Meyer, Michael D; Dyhring, Tino; Ahring, Philip K; Nielsen, Elsebet Ø; Peters, Dan; Timmermann, Daniel B; Gopalakrishnan, Murali

2010-09-01

Enhancement of alpha7 nicotinic acetylcholine receptor (nAChR) activity is considered a therapeutic approach for ameliorating cognitive deficits present in Alzheimer's disease and schizophrenia. In this study, we describe the in vitro profile of a novel selective alpha7 nAChR agonist, 5-(6-[(3R)-1-azabicyclo[2,2,2]oct-3-yloxy]pyridazin-3-yl)-1H-indole (ABT-107). ABT-107 displayed high affinity binding to alpha7 nAChRs [rat or human cortex, [(3)H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane (A-585539), K(i) = 0.2-0.6 nM or [(3)H]methyllycaconitine (MLA), 7 nM] that was at least 100-fold selective versus non-alpha7 nAChRs and other receptors. Functionally, ABT-107 did not evoke detectible currents in Xenopus oocytes expressing human or nonhuman alpha3beta4, chimeric (alpha6/alpha3)beta4, or 5-HT(3A) receptors, and weak or negligible Ca(2+) responses in human neuroblastoma IMR-32 cells (alpha3* function) and human alpha4beta2 and alpha4beta4 nAChRs expressed in human embryonic kidney 293 cells. ABT-107 potently evoked human and rat alpha7 nAChR current responses in oocytes (EC(50), 50-90 nM total charge, approximately 80% normalized to acetylcholine) that were enhanced by the positive allosteric modulator (PAM) 4-[5-(4-chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulfonamide (A-867744). In rat hippocampus, ABT-107 alone evoked alpha7-like currents, which were inhibited by the alpha7 antagonist MLA. In dentate gyrus granule cells, ABT-107 enhanced spontaneous inhibitory postsynaptic current activity when coapplied with A-867744. In the presence of an alpha7 PAM [A-867744 or N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-120596)], the addition of ABT-107 elicited MLA-sensitive alpha7 nAChR-mediated Ca(2+) signals in IMR-32 cells and rat cortical cultures and enhanced extracellular signal-regulated kinase phosphorylation in differentiated PC-12 cells. ABT-107 was also effective in protecting rat

Sports doping: emerging designer and therapeutic β2-agonists.

Science.gov (United States)

Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

2013-10-21

Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future. © 2013.

Crystal structure of the β2 adrenergic receptor-Gs protein complex

DEFF Research Database (Denmark)

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

2011-01-01

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

Effects of catecholamine agonists and antagonists on alcohol uptake in rats with different stages of experimental alcoholism

Energy Technology Data Exchange (ETDEWEB)

Burov, Yu V; Varov, A I

1985-02-01

The effects of various catecholamine agonists and antagonists on 15% ethanol ingestion by outbred albino rats were studied in relation to the stage of experimental alcoholism. In animals with stage I and II alcoholism, alcohol intake was most profoundly inhibited by administration of alpha-adrenoblockers (AA), klofelin, and alpha-methyl-DOPA (AMD), while L-DOPA and cocaine stimulated a significant increase in ethanol ingestion. In stage III alcoholism, both AA and L-DOPA depressed alcohol intake, while AMD and haloperidol had a stimulatory effect. It appears, therefore, that different neurochemical mechanisms are involved in alcohol dependence in different stages of experimental alcoholism in the rat. Furthermore, it seems evident that alpha-adrenergic receptors have a key function in maintaining alcohol dependence. In well-established physical dependence, the importance of the noradrenergic system seems to diminish and dopaminergic mechanisms appear to become predominant. Consequently, in the initial stages of alcoholism, agents which depress the noradrenergic system seem indicated, while at the stage of physical dependence agents which normalize noradrenergic mechanisms and depress dopaminergic mechanisms should be considered. 13 references.

Substrate utilization and thermogenic responses to beta-adrenergic stimulation in obese subjects with NIDDM.

NARCIS (Netherlands)

Blaak, E.E.; Saris, W.H.M.; Wolffenbuttel, B.H.R.

1999-01-01

OBJECTIVE: This study intended to investigate disturbances in beta-adrenergically-mediated substrate utilization and thermogenesis in obese subjects with mild non insulin-dependent diabetes mellitus (NIDDM). DESIGN: Following a baseline period of 30 min, the beta-agonist isoproterenol (ISO) was

Substrate utilization and thermogenic responses to beta-adrenergic stimulation in obese subjects with NIDDM

NARCIS (Netherlands)

Blaak, E E; Saris, W H; Wolffenbuttel, B H

OBJECTIVE: This study intended to investigate disturbances in beta-adrenergically-mediated substrate utilization and thermogenesis in obese subjects with mild non insulin-dependent diabetes mellitus (NIDDM). DESIGN: Following a baseline period of 30 min, the beta-agonist isoproterenol (ISO) was

The delta-opioid receptor agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] synergistically enhances the locomotor-activating effects of some psychomotor stimulants, but not direct dopamine agonists, in rats.

Science.gov (United States)

Jutkiewicz, Emily M; Baladi, Michelle G; Folk, John E; Rice, Kenner C; Woods, James H

2008-02-01

The nonpeptidic delta-opioid agonist SNC80 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] produces many stimulant-like behavioral effects in rodents and monkeys, such as locomotor stimulation, generalization to cocaine in discrimination procedures, and antiparkinsonian effects. Tolerance to the locomotor-stimulating effects of SNC80 develops after a single administration of SNC80 in rats; it is not known whether cross-tolerance develops to the effects of other stimulant compounds. In the initial studies to determine whether SNC80 produced cross-tolerance to other stimulant compounds, it was discovered that amphetamine-stimulated locomotor activity was greatly enhanced in SNC80-pretreated rats. This study evaluated acute cross-tolerance between delta-opioid agonists and other locomotor-stimulating drugs. Locomotor activity was measured in male Sprague-Dawley rats implanted with radiotransmitters, and activity levels were recorded in the home cage environment. Three-hour SNC80 pretreatment produced tolerance to further delta-opioid receptor stimulation but also augmented greatly amphetamine-stimulated locomotor activity in a dose-dependent manner. Pretreatments with other delta-opioid agonists, (+)BW373U86 [(+)-4-[alpha(R)-alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide] and oxymorphindole (17-methyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2',3'-indolomorphinan), also modified amphetamine-induced activity levels. SNC80 pretreatment enhanced the stimulatory effects of the dopamine/norepinephrine transporter ligands cocaine and nomifensine (1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinanmine maleate salt), but not the direct dopamine receptor agonists SKF81297 [R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide] and quinpirole [trans-(-)-(4alphaR)-4,4a, 5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g] quinoline

Beta-Adrenergic gene therapy for cardiovascular disease

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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.

Anti-obesogenic effects of WY14643 (PPAR-alpha agonist): Hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice.

Science.gov (United States)

Veiga, Flavia Maria Silva; Graus-Nunes, Francielle; Rachid, Tamiris Lima; Barreto, Aline Barcellos; Mandarim-de-Lacerda, Carlos Alberto; Souza-Mello, Vanessa

2017-09-01

Non-alcoholic fatty liver disease (NAFLD) presents with growing prevalence worldwide, though its pharmacological treatment remains to be established. This study aimed to evaluate the effects of a PPAR-alpha agonist on liver tissue structure, ultrastructure, and metabolism, focusing on gene and protein expression of de novo lipogenesis and gluconeogenesis pathways, in diet-induced obese mice. Male C57BL/6 mice (three months old) received a control diet (C, 10% of lipids, n = 10) or a high-fat diet (HFD, 50% of lipids, n = 10) for ten weeks. These groups were subdivided to receive the treatment (n = 5 per group): C, C-alpha (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the control diet), HFD and HFD-alpha group (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the HFD). The effects were compared with biometrical, biochemical, molecular biology and transmission electron microscopy (TEM) analyses. HFD showed greater body mass (BM) and insulinemia than C, both of which were tackled by the treatment in the HFD-alpha group. Increased hepatic protein expression of glucose-6-phosphatase, CHREBP and gene expression of PEPCK in HFD points to increased gluconeogenesis. Treatment rescued these parameters in the HFD-alpha group, eliciting a reduced hepatic glucose output, confirmed by the smaller GLUT2 expression in HFD-alpha than in HFD. Conversely, favored de novo lipogenesis was found in the HFD group by the increased expression of PPAR-gamma, and its target gene SREBP-1, FAS and GK when compared to C. The treatment yielded a marked reduction in the expression of all lipogenic factors. TEM analyses showed a greater numerical density of mitochondria per area of tissue in treated than in untreated groups, suggesting an increase in beta-oxidation and the consequent NAFLD control. PPAR-alpha activation reduced BM and treated insulin resistance (IR) and NAFLD by increasing the number of mitochondria and reducing hepatic gluconeogenesis and de novo lipogenesis protein and gene

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

International Nuclear Information System (INIS)

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

1988-01-01

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

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

Science.gov (United States)

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

2017-12-01

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

Dgroup: DG01001 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available ific agonist Other ... DG01718 ... Drugs for addictive disorder ... DG01717 ... Drugs for op...ioid dependence ATC code: N07BC04 Alpha2b-adrenergic receptor agonist, Drugs used in opioid dependence, Antihypertensives ADRA2B [HSA:151] [KO:K04139] ...

Pharmacogenetics of the β2-Adrenergic Receptor Gene

Science.gov (United States)

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

2009-01-01

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

Effect of alpha1-blockers on stentless ureteroscopic lithotripsy

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Jianguo Zhu

2016-02-01

Full Text Available ABSTRACT Objective To evaluate the clinical efficiency of alpha1-adrenergic antagonists on stentless ureteroscopic lithotripsy treating uncomplicated lower ureteral stones. Materials and Methods From January 2007 to January 2013, 84 patients who have uncomplicated lower ureteral stones treated by ureteroscopic intracorporeal lithotripsy with the holmium laser were analyzed. The patients were divided into two groups, group A (44 patients received indwelled double-J stents and group B (40 patients were treated by alpha1-adrenergic antagonists without stents. All cases of group B were treated with alpha1 blocker for 1 week. Results The mean operative time of group A was significantly longer than group B. The incidences of hematuria, flank/abdominal pain, frequency/urgency after surgery were statistically different between both groups. The stone-free rate of each group was 100%. Conclusions The effect of alpha1-adrenergic antagonists is more significant than indwelling stent after ureteroscopic lithotripsy in treating uncomplicated lower ureteral stones.

Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-alpha and -delta, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening

NARCIS (Netherlands)

Ratziu, V.; Harrison, S.A.; Francque, S.; Bedossa, P.; Lehert, P.; Serfaty, L.; Romero-Gomez, M.; Boursier, J.; Abdelmalek, M.; Caldwell, S.; Drenth, J.P.; Anstee, Q.M.; Hum, D.; Hanf, R.; Roudot, A.; Megnien, S.; Staels, B.; Sanyal, A.

2016-01-01

BACKGROUND & AIMS: Elafibranor is an agonist of the peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-delta. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy

Adrenergic effects on secretion of amylase from the rat salivary glands

DEFF Research Database (Denmark)

Poulsen, Steen Seier; Nexø, Ebba

1988-01-01

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

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.

Role of alpha- and beta-adrenergic receptors in cardiomyocyte differentiation from murine-induced pluripotent stem cells.

Science.gov (United States)

Li, Xiao-Li; Zeng, Di; Chen, Yan; Ding, Lu; Li, Wen-Ju; Wei, Ting; Ou, Dong-Bo; Yan, Song; Wang, Bin; Zheng, Qiang-Sun

2017-02-01

Induced pluripotent stem cell (iPSC)-derived cardiomyocytes are a promising source of cells for regenerative heart disease therapies, but progress towards their use has been limited by their low differentiation efficiency and high cellular heterogeneity. Previous studies have demonstrated expression of adrenergic receptors (ARs) in stem cells after differentiation; however, roles of ARs in fate specification of stem cells, particularly in cardiomyocyte differentiation and development, have not been characterized. Murine-induced pluripotent stem cells (miPSCs) were cultured in hanging drops to form embryoid bodies, cells of which were then differentiated into cardiomyocytes. To determine whether ARs regulated miPSC differentiation into cardiac lineages, effects of the AR agonist, epinephrine (EPI), on miPSC differentiation and underlying signalling mechanisms, were evaluated. Treatment with EPI, robustly enhanced miPSC cardiac differentiation, as indicated by increased expression levels of cardiac-specific markers, GATA4, Nkx2.5 and Tnnt2. Although β-AR signalling is the foremost signalling pathway in cardiomyocytes, EPI-enhanced cardiac differentiation depended more on α-AR signalling than β-AR signalling. In addition, selective activation of α 1 -AR signalling with specific agonists induced vigorous cardiomyocyte differentiation, whereas selective activation of α 2 - or β-AR signalling induced no or less differentiation, respectively. EPI- and α 1 -AR-dependent cardiomyocyte differentiation from miPSCs occurred through specific promotion of CPC proliferation via the MEK-ERK1/2 pathway and regulation of miPS cell-cycle progression. These results demonstrate that activation of ARs, particularly of α 1 -ARs, promoted miPSC differentiation into cardiac lineages via MEK-ERK1/2 signalling. © 2016 John Wiley & Sons Ltd.

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

Science.gov (United States)

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

2015-01-01

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

Alpha-2A Adrenoceptor Agonist Guanfacine Restores Diuretic Efficiency in Experimental Cirrhotic Ascites: Comparison with Clonidine.

Directory of Open Access Journals (Sweden)

Giovanni Sansoè

Full Text Available In human cirrhosis, adrenergic hyperfunction causes proximal tubular fluid retention and contributes to diuretic-resistant ascites, and clonidine, a sympatholytic drug, improves natriuresis in difficult-to-treat ascites.To compare clonidine (aspecific α2-adrenoceptor agonist to SSP-002021R (prodrug of guanfacine, specific α2A-receptor agonist, both associated with diuretics, in experimental cirrhotic ascites.Six groups of 12 rats were studied: controls (G1; controls receiving furosemide and potassium canrenoate (G2; rats with ascitic cirrhosis due to 14-week CCl4 treatment (G3; cirrhotic rats treated (over the 11th-14th CCl4 weeks with furosemide and canrenoate (G4, furosemide, canrenoate and clonidine (G5, or diuretics and SSP002021R (G6. Three rats of each group had their hormonal status and renal function assessed at the end of 11th, 12th, 13th, and 14th weeks of respective treatments.Cirrhotic rats in G3 and G4 gained weight over the 12th-14th CCl4 weeks. In G4, brief increase in sodium excretion over the 11th-12th weeks preceded worsening of inulin clearance and natriuresis (diuretic resistance. In comparison with G4, the addition of clonidine (G5 or guanfacine (G6 to diuretics improved, respectively, sodium excretion over the 11th-12th CCl4 weeks, or GFR and electrolytes excretion over the 13th-14th CCl4 weeks. Natriuretic responses in G5 and G6 were accompanied by reduced catecholamine serum levels.α2A-receptor agonists restore glomerular filtration rate and natriuresis, and delay diuretic-resistant ascites in experimental advanced cirrhosis. Clonidine ameliorates diuretic-dependent natriuresis just for a short time.

Decreased agonist sensitivity of human GABA(A) receptors by an amino acid variant, isoleucine to valine, in the alpha1 subunit.

Science.gov (United States)

Westh-Hansen, S E; Rasmussen, P B; Hastrup, S; Nabekura, J; Noguchi, K; Akaike, N; Witt, M R; Nielsen, M

1997-06-25

Recombinant human GABA(A) receptors were investigated in vitro by coexpression of cDNAs coding for alpha1, beta2, and gamma2 subunits in the baculovirus/Sf-9 insect cell system. We report that a single amino acid exchange (isoleucine 121 to valine 121) in the N-terminal, extracellular part of the alpha1 subunit induces a marked decrease in agonist GABA(A) receptor ligand sensitivity. The potency of muscimol and GABA to inhibit the binding of the GABA(A) receptor antagonist [3H]SR 95531 (2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide) was higher in receptor complexes of alpha1(ile 121) beta2gamma2 than in those of alpha1(val 121) beta2gamma2 (IC50 values were 32-fold and 26-fold lower for muscimol and GABA, respectively). The apparent affinity of the GABA(A) receptor antagonist bicuculline methiodide to inhibit the binding of [3H]SR 95531 did not differ between the two receptor complex variants. Electrophysiological measurements of GABA induced whole-cell Cl- currents showed a ten-fold decrease in the GABA(A) receptor sensitivity of alpha1 (val 121) beta2gamma2 as compared to alpha1(ile 121) beta2gamma2 receptor complexes. Thus, a relatively small change in the primary structure of the alpha1 subunit leads to a decrease selective for GABA(A) receptor sensitivity to agonist ligands, since no changes were observed in a GABA(A) receptor antagonist affinity and benzodiazepine receptor binding.

The selective alpha7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain

DEFF Research Database (Denmark)

Thomsen, M S; Mikkelsen, J D; Timmermann, D B

2008-01-01

to study whether alpha7 nAChR stimulation activates brain regions involved in cognition in juvenile as well as adult individuals. Here, we compared the effects of the novel and selective alpha7 nAChR agonist 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) in the juvenile...... regions critically involved in working memory and attention. Furthermore, this effect is more pronounced in juvenile than adult rats, indicating that the juvenile forebrain is more responsive to alpha7 nAChR stimulation. This observation may be relevant in the treatment of juvenile-onset schizophrenia....

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

NARCIS (Netherlands)

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

1992-01-01

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

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

Science.gov (United States)

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

2016-11-01

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

Blockade of alcohol's amnestic activity in humans by an alpha5 subtype benzodiazepine receptor inverse agonist.

Science.gov (United States)

Nutt, David J; Besson, Marie; Wilson, Susan J; Dawson, Gerard R; Lingford-Hughes, Anne R

2007-12-01

Alcohol produces many subjective and objective effects in man including pleasure, sedation, anxiolysis, plus impaired eye movements and memory. In human volunteers we have used a newly available GABA-A/benzodiazepine receptor inverse agonist that is selective for the alpha5 subtype (a5IA) to evaluate the role of this subtype in mediating these effects of alcohol on the brain. After pre-treatment with a5IA, we found almost complete blockade of the marked impairment caused by alcohol (mean breath concentration 150mg/100ml) of word list learning and partial but non-significant reversal of subjective sedation without effects on other measures such as intoxication, liking, and slowing of eye movements. This action was not due to alterations in alcohol kinetics and so provides the first proof of concept that selectively decreasing GABA-A receptor function at a specific receptor subtype can offset some actions of alcohol in humans. It also supports growing evidence for a key role of the alpha5 subtype in memory. Inverse agonists at other GABA-A receptor subtypes may prove able to reverse other actions of alcohol, and so offer a new approach to understanding the actions of alcohol in the human brain and in the treatment of alcohol related disorders in humans.

Metabolic effects of beta2-agonists in relation to exercise performance

DEFF Research Database (Denmark)

Kalsen, Anders

2015-01-01

athletes. The present PhD thesis is based on four manuscripts in which the acute effects of beta2-agonists on exercise performance were investigated. The aims were 1) to investigate whether supratherapeutic inhalation of beta2-agonists enhances muscle strength, anaerobic performance and aerobic performance......, 2) to uncover the mechanisms behind potential beta2-adrenergic improvements in anaerobic performance, 3) to investigate whether inhalation of beta2-agonists is ergogenic in elite athletes with or without airway hyperresponsiveness (AHR). Results from the studies of the thesis show...... administration of a certain dose, but a further increase in dose does not seem to elicit a greater performance-enhancing effect. Moreover, the effects of beta2-agonists on performance are unaffected by training status and AHR, but athletes with AHR who regularly use beta2-agonists get a reduced ergogenic...

Alpha1a-Adrenoceptor Genetic Variant Triggers Vascular Smooth Muscle Cell Hyperproliferation and Agonist Induced Hypertrophy via EGFR Transactivation Pathway.

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Irina Gradinaru

Full Text Available α1a Adrenergic receptors (α1aARs are the predominant AR subtype in human vascular smooth muscle cells (SMCs. α1aARs in resistance vessels are crucial in the control of blood pressure, yet the impact of naturally occurring human α1aAR genetic variants in cardiovascular disorders remains poorly understood. To this end, we present novel findings demonstrating that 3D cultures of vascular SMCs expressing human α1aAR-247R (247R genetic variant demonstrate significantly increased SMC contractility compared with cells expressing the α1aAR-WT (WT receptor. Stable expression of 247R genetic variant also triggers MMP/EGFR-transactivation dependent serum- and agonist-independent (constitutive hyperproliferation and agonist-dependent hypertrophy of SMCs. Agonist stimulation reduces contractility Using pathway-specific inhibitors we determined that the observed hyperproliferation of 247R-expressing cells is triggered via β-arrestin1/Src/MMP-2/EGFR/ERK-dependent mechanism. MMP-2-specific siRNA inhibited 247R-triggered hyperproliferation indicating MMP-2 involvement in 247R-triggered hyperproliferation in SMCs. β-arrestin1-specific shRNA also inhibited 247R-triggered hyperproliferation but did not affect hypertrophy in 247R-expressing SMCs, indicating that agonist-dependent hypertrophy is independent of β-arrestin1. Our data reveal that in different cardiovascular cells the same human receptor genetic variant can activate alternative modulators of the same signaling pathway. Thus, our findings in SMCs demonstrate that depending on the type of cells expressing the same receptor (or receptor variant, different target-specific inhibitors could be used to modulate aberrant hyperproliferative or hypertrophic pathways in order to restore normal phenotype.

NEW DOPAMINE AGONISTS IN CARDIOVASCULAR THERAPY

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GIRBES, ARJ; VANVELDHUISEN, DJ; SMIT, AJ

1992-01-01

Dopamine, a naturally occurring catecholamine, has been extensively used in intensive care for many years. Dopamine stimulates different types of adrenergic receptors: alpha-1 and -2, beta-1 and -2, and dopamine-1 and -2. The renal effects of dopamine are the result of dopamine-1 receptor (DA1)

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

Science.gov (United States)

Fink, Ann E; LeDoux, Joseph E

2018-05-01

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

Profound and Rapid Reduction in Body Temperature Induced by the Melanocortin Receptor Agonists

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Xu, Yuanzhong; Kim, Eun Ran; Fan, Shengjie; Xia, Yan; Xu, Yong; Huang, Cheng; Tong, Qingchun

2014-01-01

The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5′AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII’s effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature. PMID:25065745

Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists.

Science.gov (United States)

Xu, Yuanzhong; Kim, Eun Ran; Fan, Shengjie; Xia, Yan; Xu, Yong; Huang, Cheng; Tong, Qingchun

2014-08-22

The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5'AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII's effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature. Copyright © 2014 Elsevier Inc. All rights reserved.

A computational psychiatry approach identifies how alpha-2a noradrenergic agonist guanfacine affects feature-based reinforcement learning in the macaque

NARCIS (Netherlands)

Hassani, S.A.; Oemisch, M.; Balcarras, M.; Westendorff, S.; Ardid, S.; van der Meer, M.A.; Tiesinga, P.H.E.; Womelsdorf, T.

2017-01-01

Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor (a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves

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

Science.gov (United States)

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

2013-05-17

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

The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia.

Directory of Open Access Journals (Sweden)

Linda J Bristow

Full Text Available The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R-N-(6-(1H-imidazol-1-yl-4-pyrimidinyl-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043, in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat and 0.29 micromolar (human. BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM. BMS-933043 treatment i improved 24 hour novel object recognition memory in mice (0.1-10 mg/kg, sc, ii reversed MK-801-induced deficits in Y maze performance in mice (1-10 mg/kg, sc and set shift performance in rats (1-10 mg/kg, po and iii reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1-3 mg/kg, po. BMS-933043 also improved auditory gating (0.56-3 mg/kg, sc and mismatch negativity (0.03-3 mg/kg, sc in rats treated with S(+ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.

Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance

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Jacob, G.; Shannon, J. R.; Costa, F.; Furlan, R.; Biaggioni, I.; Mosqueda-Garcia, R.; Robertson, R. M.; Robertson, D.

1999-01-01

BACKGROUND: Chronic orthostatic intolerance (OI) is characterized by symptoms of inadequate cerebral perfusion with standing, in the absence of significant orthostatic hypotension. A heart rate increase of >/=30 bpm is typical. Possible underlying pathophysiologies include hypovolemia, partial dysautonomia, or a primary hyperadrenergic state. We tested the hypothesis that patients with OI have functional abnormalities in autonomic neurons regulating cardiovascular responses. METHODS AND RESULTS: Thirteen patients with chronic OI and 10 control subjects underwent a battery of autonomic tests. Systemic norepinephrine (NE) kinetics were determined with the patients supine and standing before and after tyramine administration. In addition, baroreflex sensitivity, hemodynamic responses to bolus injections of adrenergic agonists, and intrinsic heart rate were determined. Resting supine NE spillover and clearance were similar in both groups. With standing, patients had a greater decrease in NE clearance than control subjects (55+/-5% versus 30+/-7%, Pheart rate 25 bpm was lower in patients than in control subjects (0.5+/-0.05 versus 1.0+/-0.1 microg, Pheart rate was similar in both groups. CONCLUSIONS: The decreased NE clearance with standing, resistance to the NE-releasing effect of tyramine, and increased sensitivity to adrenergic agonists demonstrate dramatically disordered sympathetic cardiovascular regulation in patients with chronic OI.

Neural correlate of resting-state functional connectivity under α2 adrenergic receptor agonist, medetomidine.

Science.gov (United States)

Nasrallah, Fatima A; Lew, Si Kang; Low, Amanda Si-Min; Chuang, Kai-Hsiang

2014-01-01

Correlative fluctuations in functional MRI (fMRI) signals across the brain at rest have been taken as a measure of functional connectivity, but the neural basis of this resting-state MRI (rsMRI) signal is not clear. Previously, we found that the α2 adrenergic agonist, medetomidine, suppressed the rsMRI correlation dose-dependently but not the stimulus evoked activation. To understand the underlying electrophysiology and neurovascular coupling, which might be altered due to the vasoconstrictive nature of medetomidine, somatosensory evoked potential (SEP) and resting electroencephalography (EEG) were measured and correlated with corresponding BOLD signals in rat brains under three dosages of medetomidine. The SEP elicited by electrical stimulation to both forepaws was unchanged regardless of medetomidine dosage, which was consistent with the BOLD activation. Identical relationship between the SEP and BOLD signal under different medetomidine dosages indicates that the neurovascular coupling was not affected. Under resting state, EEG power was the same but a depression of inter-hemispheric EEG coherence in the gamma band was observed at higher medetomidine dosage. Different from medetomidine, both resting EEG power and BOLD power and coherence were significantly suppressed with increased isoflurane level. Such reduction was likely due to suppressed neural activity as shown by diminished SEP and BOLD activation under isoflurane, suggesting different mechanisms of losing synchrony at resting-state. Even though, similarity between electrophysiology and BOLD under stimulation and resting-state implicates a tight neurovascular coupling in both medetomidine and isoflurane. Our results confirm that medetomidine does not suppress neural activity but dissociates connectivity in the somatosensory cortex. The differential effect of medetomidine and its receptor specific action supports the neuronal origin of functional connectivity and implicates the mechanism of its sedative

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.

Blood flow distribution with adrenergic and histaminergic antagonists

International Nuclear Information System (INIS)

Baker, C.H.; Davis, D.L.; Sutton, E.T.

1989-01-01

Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects

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

Science.gov (United States)

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

2014-05-01

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

Epinephrine Injection

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... a class of medications called alpha- and beta-adrenergic agonists (sympathomimetic agents). It works by relaxing the ... itching, swelling, skin redness, fast heartbeat, weak pulse, anxiety, confusion, stomach pain, losing control of urine or ...

Apraclonidine Ophthalmic

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... in a class of medications called alpha-2-adrenergic agonists. It lowers the pressure in the eye ... Duraclon), guanabenz (Wytensin), or methyldopa: insulin; medications for anxiety, mental illness, or seizures; narcotic (opiate) medications for ...

Brimonidine Ophthalmic

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... is in a class of drugs called alpha adrenergic agonists. Brimonidine works by decreasing the amount of ... phenobarbital and secobarbital (Seconal); digoxin (Lanoxin); medications for anxiety, high blood pressure, mental illness, pain, or seizures; ...

Adrenergic influence on gastric mucosal blood flow in gastric fistula dogs

DEFF Research Database (Denmark)

Hovendal, C P; Bech, K; Gottrup, F

1984-01-01

micrograms/kg/min) induced an increase in mucosal blood flow and a similar increase in acid secretion. If the dopamine infusion was preceded by alpha-receptor blockade, a pronounced increase in mucosal blood flow was observed without a similar increase in acid secretion. beta-adrenergic stimulation...

Effects of immunocastration and β-adrenergic agonists on the performance and carcass traits of feedlot finished Nellore cattle.

Science.gov (United States)

Antonelo, D S; Mazon, M R; Nubiato, K E Z; Gómez, J F M; Brigida, D J; Gomes, R C; Netto, A S; Leme, P R; Silva, S L

2017-11-01

β-Adrenergic agonists (β-AA) are non-hormonal growth promoters which promote muscle hypertrophy in supplemented animals. The effects of two β-AA in combination with the immunocastration technique on the performance and carcass traits were evaluated using 96 feedlot Nellore males in a randomized complete block design with two sex conditions (immunocastrated (IC) v. non-castrated (NC)) and three treatments: CON (no β-agonists added), RH (300 mg of ractopamine hydrochloride/day, for 33 days) or ZH (80 mg of zilpaterol·hydrochloride animal/day for 30 days, removed 3 days for required withdrawal period). The trial was carried for 100 days where in the first 70 days animals did not receive β-AA (phase 1) and during the last 30 days they were treated with β-AA (phase 2). The performance and ultrasound measurements of longissimus muscle area (LMA), backfat thickness (BFT) and rump fat thickness (RFT) were evaluated in both phases. No sex condition v. treatment interactions were observed for any trait. The NC animals had higher average daily gain (ADG) and final BW than the IC animals, but they did not differ in dry matter intake (DMI) and feed efficiency (gain to feed). The NC animals showed greater LMA (P=0.0001) and hot carcass weight (P=0.0006), and smaller BFT (P=0.0007), RFT (P=0.0039) and percentage of kidney, pelvic and heart fat (Panimals. The animals fed ZH showed greater ADG (P=0.0002), G : F (Panimals fed ZH diet showed greater LMA (Panimals fed RH and CON diets, whereas RH and CON diets did not differ. Immunocastration decreases muscle development and increases carcass finishing. In contrast, β-AA increases muscle and decreases fat deposition. The ZH has a higher action on the muscle metabolism than animals fed RH diet. However, RH diet achieves a better balance because it has an intermediary performance between non-supplemented and ZH animals and does not decrease the carcass fat.

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

Directory of Open Access Journals (Sweden)

Melissa L. Bates

2017-04-01

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

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

African Journals Online (AJOL)

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

Different pathways of [3H]inositol phosphate formation mediated by α 1a- and α 1b-adrenergic receptors

International Nuclear Information System (INIS)

Wilson, K.M.; Minneman, K.P.

1990-01-01

The types of inositol phosphates (InsPs) formed in response to activation of alpha 1-adrenergic receptor subtypes were determined in collagenase-dispersed renal cells and hepatocytes by high pressure liquid chromatography separation. In hepatocytes, which contain only the alpha 1b subtype, norepinephrine stimulated rapid (10-s) formation of [3H]Ins(1,4,5)P3 and [3H]Ins(1,3,4)P3 and slower (5-min) formation of Ins(1,4)P2 and Ins(1)P. Selective inactivation of alpha 1b receptors by chloroethylclonidine almost completely blocked the effects of norepinephrine in hepatocytes. In renal cells, which contain both alpha 1a and alpha 1b receptors in a 60:40 ratio, norepinephrine did not significantly increase the size of any peaks until 5 min after agonist activation. At this time, only a peak eluting with Ins(1)P and one eluting shortly after Ins(1,4)P2 were significantly elevated. Incubation with norepinephrine for 2 h caused small but significant increases in peaks co-eluting with Ins(1)P and Ins(1,4,5)P3 in renal cells; however, only the increase in Ins(1)P was inhibited by chloroethylclonidine pretreatment. Extraction under neutral conditions suggested that cyclic InsPs may be the primary compounds formed in response to norepinephrine in renal cells. Removal of extracellular Ca2+ caused a 60% reduction in the InsP response to norepinephrine in renal cells but had no effect in hepatocytes. These results suggest that activation of alpha 1a and alpha 1b receptor subtypes results in formation of different InsPs and that the response to alpha 1a activation may require influx of extracellular Ca2+

Ventricular action potential adaptation to regular exercise: role of β-adrenergic and KATP channel function.

Science.gov (United States)

Wang, Xinrui; Fitts, Robert H

2017-08-01

Regular exercise training is known to affect the action potential duration (APD) and improve heart function, but involvement of β-adrenergic receptor (β-AR) subtypes and/or the ATP-sensitive K + (K ATP ) channel is unknown. To address this, female and male Sprague-Dawley rats were randomly assigned to voluntary wheel-running or control groups; they were anesthetized after 6-8 wk of training, and myocytes were isolated. Exercise training significantly increased APD of apex and base myocytes at 1 Hz and decreased APD at 10 Hz. Ca 2+ transient durations reflected the changes in APD, while Ca 2+ transient amplitudes were unaffected by wheel running. The nonselective β-AR agonist isoproterenol shortened the myocyte APD, an effect reduced by wheel running. The isoproterenol-induced shortening of APD was largely reversed by the selective β 1 -AR blocker atenolol, but not the β 2 -AR blocker ICI 118,551, providing evidence that wheel running reduced the sensitivity of the β 1 -AR. At 10 Hz, the K ATP channel inhibitor glibenclamide prolonged the myocyte APD more in exercise-trained than control rats, implicating a role for this channel in the exercise-induced APD shortening at 10 Hz. A novel finding of this work was the dual importance of altered β 1 -AR responsiveness and K ATP channel function in the training-induced regulation of APD. Of physiological importance to the beating heart, the reduced response to adrenergic agonists would enhance cardiac contractility at resting rates, where sympathetic drive is low, by prolonging APD and Ca 2+ influx; during exercise, an increase in K ATP channel activity would shorten APD and, thus, protect the heart against Ca 2+ overload or inadequate filling. NEW & NOTEWORTHY Our data demonstrated that regular exercise prolonged the action potential and Ca 2+ transient durations in myocytes isolated from apex and base regions at 1-Hz and shortened both at 10-Hz stimulation. Novel findings were that wheel running shifted the β-adrenergic

Autonomic receptors in urinary tract: Sex and age differences

International Nuclear Information System (INIS)

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

1990-01-01

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

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

International Nuclear Information System (INIS)

Pisano, M.M.

1986-01-01

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

Localized infusions of the partial alpha 7 nicotinic receptor agonist SSR180711 evoke rapid and transient increases in prefrontal glutamate release

DEFF Research Database (Denmark)

Bortz, D M; Mikkelsen, J D; Bruno, J P

2013-01-01

The ability of local infusions of the alpha 7 nicotinic acetycholine receptor (α7 nAChR) partial agonist SSR180711 to evoke glutamate release in prefrontal cortex was determined in awake rats using a microelectrode array. Infusions of SSR180711 produced dose-dependent increases in glutamate levels...

Vascular adrenergic receptor responses in skeletal muscle in myotonic dystrophy

International Nuclear Information System (INIS)

Mechler, F.; Mastaglia, F.L.

1981-01-01

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

Guanfacine

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... a class of medications called centrally acting alpha2A-adrenergic receptor agonists. Guanfacine treats high blood pressure by ... Crixivan); itraconazole (Onmel, Sporanox); ketoconazole (Nizoral); medications for anxiety, high blood pressure, mental illness, nausea, or seizures; ...

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

DEFF Research Database (Denmark)

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

2018-01-01

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

Activation of vascular cholinergic and adrenergic receptors induced by gamma rays

International Nuclear Information System (INIS)

Alya, G.

1999-10-01

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

Modulation of haloperidol-induced patterns of the transcription factor Nur77 and Nor-1 expression by serotonergic and adrenergic drugs in the mouse brain

Science.gov (United States)

Maheux, Jérôme; Vuillier, Laura; Mahfouz, Mylène; Rouillard, Claude; Lévesque, Daniel

2015-01-01

Different patterns of expression of the transcription factors of Nur77 and Nor-1 are induced following acute administration of typical and atypical antipsychotic drugs. The pharmacological profile of atypical antipsychotics suggests that serotonergic and/or adrenergic receptors might contribute to these reported differences. In order to test this possibility, we examined the abilities of serotonin 5-HT1A and 5-HT2A/2C, and α1- and α2-adrenergic receptor drugs to modify the pattern of Nur77 (NR4A1) and Nor-1 (NR4A3) mRNA expression induced by haloperidol. Various groups of mice were treated with either saline, DOI, a 5-HT2A/2C agonist, MDL11939, a 5-HT2A antagonist, 8-OH-DPAT, a 5-HT1A agonist, prazosin, an α1-adrenergic antagonist and idazoxan, an α2-adrenergic antagonist, alone or in combination with haloperidol. The 5-HT2A/2C agonist DOI alone significantly increased Nur77 expression in the medial striatum and nucleus accumbens. DOI reduced Nor-1 expression, while MDL11939 increased the expression of this transcript in the cortex. Prazosin reduced Nur77 expression in the dorsal striatum and nucleus accumbens. Interestingly, 8-OH-DPAT and MDL11939 partially prevented haloperidol-induced Nur77 up-regulation, while MDL11939 completely abolished Nor-1 expression in the striatum. In addition, MDL11939 decreased haloperidol-induced Nur77 and Nor-1 mRNA levels in the ventral tegmental area. On the contrary, idazoxan (α2 antagonist) consistently potentiated haloperidol-induced Nur77, but not Nor-1 mRNA levels in the striatum, whereas prazosin (α1 antagonist) remained without effect. Taken together, these results show the ability of a 5-HT1A agonist or a 5-HT2A antagonist to reduce haloperidol-induced Nur77 and Nor-1 striatal expression, suggesting that these serotonin receptor subtypes participate in the differential pattern of gene expression induced by typical and atypical antipsychotic drugs. PMID:21524335

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

DEFF Research Database (Denmark)

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

2007-01-01

in lipodystrophic patients compared to nonlipodystrophic patients, whereas luteinizing hormone, follicle-stimulating hormone and prolactin were similar and normal in both study groups. Ratio of subcutaneous to total abdominal fat mass, limb fat, and insulin sensitivity, which were all decreased in lipodystrophic...... patients, correlated positively with both plasma oestradiol and testosterone (n = 31). Glycerol concentration during clamp (a marker of lipolysis) correlated inversely with expression of alpha2A-adrenergic-receptor, ratio of subcutaneous to total abdominal fat mass, and limb fat, respectively. Expression......OBJECTIVE: Circulating oestradiol and testosterone, which have been shown to increase in human immunodeficiency virus (HIV)-infected patients following highly active antiretroviral therapy (HAART), may influence fat distribution and insulin sensitivity. Oestradiol increases subcutaneous adipose...

An investigation into the receptor-regulating effects of the acute administration of opioid agonists and an antagonist on beta adrenergic receptors in the rat cerebral cortex

International Nuclear Information System (INIS)

Roper, I.

1987-01-01

Past and current research indicated that biochemical deviations which might be involved in the etiology and pathophysiology of depression, included abnormalities or imbalances in the noradrenergic, serotonergic, hormonal and possibly in the endogenous opioid, dopaminergic, histaminergic, cholinergic and trace amine systems. In order to investigate a possible link between the noradrenergic system and opioids, it was decided to test the acute effects of opioid administration on cortical beta adrenoceptor numbers and affinity. As these receptors have been most consistently downregulated by antidepressant treatment, they may be involved in the mechanism of antidepressant action of these agents. It was decided to investigate beta adrenoceptor-regulatory effects of opioid treatment. Naloxone was tested alone, with a view to suppressing any possible endogenous opioid influences upon beta receptor status and revealing an effect which would possibly be the opposite of that brought about by the administration of opioid agonists. Naloxone was administered together with morphine to demonstrate that any beta receptor up- or downregulation which might be measured, had indeed been opioid-receptor mediated. It was found that the acute administration of four different mu opioid agonists, naloxone and naloxone plus morphine, did not cause any statistically significant alterations in cortical beta adrenergic receptor numbers or affinity in the rat. A radioactive ligand, the beta adrenoceptor-labelling compound referred to as DHA (L-dihydroalprenolol HCI) was used in this study

A novel nicotinic agonist facilitates induction of long-term potentiation in the rat hippocampus.

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Hunter, B E; de Fiebre, C M; Papke, R L; Kem, W R; Meyer, E M

1994-02-28

Long-term potentiation (LTP) can be modulated by a number of neurotransmitter receptors including muscarinic and GABAergic receptor types. We have found that a novel nicotinic agonist, 2,4-dimethoxybenzylidene anabaseine (DMXB), facilitated the induction of LTP in the hippocampus in a dose-dependent and mecamylamine-sensitive manner. DMXB displaced high affinity nicotinic [125I]alpha-bungarotoxin and [3H]acetylcholine binding in rat brain. Xenopus oocyte studies demonstrated that DMXB has agonist activity at alpha 7 but not alpha 4/beta 2 nicotinic receptor subtypes. These results indicated that DMXB is a novel nicotinic agonist with apparent specificity for the alpha 7/alpha-bungarotoxin nicotinic receptor subtype and indicate that nicotinic receptor activation is capable of modulating the induction of long-term potentiation.

PPAR-alpha agonist treatment increases trefoil factor family-3 expression and attenuates apoptosis in the liver tissue of bile duct-ligated rats.

Science.gov (United States)

Karakan, Tarkan; Kerem, Mustafa; Cindoruk, Mehmet; Engin, Doruk; Alper, Murat; Akın, Okan

2013-01-01

Peroxisome proliferators-activated receptor alpha activation modulates cholesterol metabolism and suppresses bile acid synthesis. The trefoil factor family comprises mucin-associated proteins that increase the viscosity of mucins and help protect epithelial linings from insults. We evaluated the effect of short-term administration of fenofibrate, a peroxisome proliferators activated receptor alpha agonist, on trefoil factor family-3 expression, degree of apoptosis, generation of free radicals, and levels of proinflammatory cytokines in the liver tissue of bile duct-ligated rats. Forty male Wistar rats were randomly divided into four groups: 1 = sham operated, 2 = bile duct ligation, 3 = bile duct-ligated + vehicle (gum Arabic), and 4 = bile duct-ligated + fenofibrate (100 mg/kg/day). All rats were sacrificed on the 7 th day after obtaining blood samples and liver tissue. Liver function tests, tumor necrosis factor-alpha and interleukin 1 beta in serum, and trefoil factor family-3 mRNA expression, degree of apoptosis (TUNEL) and tissue malondialdehyde (malondialdehyde, end-product of lipid peroxidation by reactive oxygen species) in liver tissue were evaluated. Fenofibrate administration significantly reduced serum total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and tumor necrosis factor-alpha and interleukin-1β levels. Apoptosis and malondialdehyde were significantly reduced in the fenofibrate group. Trefoil factor family-3 expression increased with fenofibrate treatment in bile duct-ligated rats. The peroxisome proliferators-activated receptor alpha agonist fenofibrate significantly increased trefoil factor family-3 expression and decreased apoptosis and lipid peroxidation in the liver and attenuated serum levels of proinflammatory cytokines in bile duct-ligated rats. Further studies are needed to determine the protective role of fenofibrate in human cholestatic disorders.

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

Science.gov (United States)

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

2008-06-01

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

Catecholamine-induced vasoconstriction is sensitive to carbonic anhydrase I activation

Directory of Open Access Journals (Sweden)

Puscas I.

2001-01-01

Full Text Available We studied the relationship between alpha- and beta-adrenergic agonists and the activity of carbonic anhydrase I and II in erythrocyte, clinical and vessel studies. Kinetic studies were performed. Adrenergic agonists increased erythrocyte carbonic anhydrase as follows: adrenaline by 75%, noradrenaline by 68%, isoprenaline by 55%, and orciprenaline by 62%. The kinetic data indicated a non-competitive mechanism of action. In clinical studies carbonic anhydrase I from erythrocytes increased by 87% after noradrenaline administration, by 71% after orciprenaline and by 82% after isoprenaline. The increase in carbonic anhydrase I paralleled the increase in blood pressure. Similar results were obtained in vessel studies on piglet vascular smooth muscle. We believe that adrenergic agonists may have a dual mechanism of action: the first one consists of a catecholamine action on its receptor with the formation of a stimulus-receptor complex. The second mechanism proposed completes the first one. By this second component of the mechanism, the same stimulus directly acts on the carbonic anhydrase I isozyme (that might be functionally coupled with adrenergic receptors, so that its activation ensures an adequate pH for stimulus-receptor coupling for signal transduction into the cell, resulting in vasoconstriction.

Opioid antagonists with minimal sedation for opioid withdrawal.

Science.gov (United States)

Gowing, Linda; Ali, Robert; White, Jason M

2017-05-29

Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. To assess the effects of opioid antagonists plus minimal sedation for opioid withdrawal. Comparators were placebo as well as more established approaches to detoxification, such as tapered doses of methadone, adrenergic agonists, buprenorphine and symptomatic medications. We updated our searches of the following databases to December 2016: CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant studies. We included randomised and quasi-randomised controlled clinical trials along with prospective controlled cohort studies comparing opioid antagonists plus minimal sedation versus other approaches or different opioid antagonist regimens for withdrawal in opioid-dependent participants. We used standard methodological procedures expected by Cochrane. Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed.Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha 2 -adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine.Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient

Catecholamine-related gene expression in blood correlates with tic severity in tourette syndrome

NARCIS (Netherlands)

Gunther, Joan; Tian, Yingfang; Stamova, Boryana; Lit, Lisa; Corbett, Blythe; Ander, Brad; Zhan, Xinhua; Jickling, Glen; Bos-Veneman, Netty; Liu, Da; Hoekstra, Pieter; Sharp, Frank

2012-01-01

Tourette syndrome (TS) is a heritable disorder characterized by tics that are decreased in some patients by treatment with alpha adrenergic agonists and dopamine receptor blockers. Thus, this study examines the relationship between catecholamine gene expression in blood and tic severity. TS

Anticonvulsant activity of a mGlu(4alpha) receptor selective agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid.

Science.gov (United States)

Chapman, A G; Talebi, A; Yip, P K; Meldrum, B S

2001-07-20

The metabotropic Group III agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-1), selective for the mGlu(4alpha) receptor, suppresses sound-induced seizures in DBA/2 mice following its intracerebroventricular (i.c.v.) administration (ED(50) 5.6 [2.9-10.7], nmol i.c.v., 15 min, clonic phase) and in genetically epilepsy-prone (GEP) rats following focal administration into the inferior colliculus (ED(50) 0.08 [0.01-0.50], nmol, 60 min, clonic phase). ACPT-1 also protects against clonic seizures induced in DBA/2 mice by the Group I agonist, (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) (ED(50) 0.60 [0.29-1.2], nmol i.c.v.) and by the Group III antagonist, (RS)-alpha-methylserine-O-phosphate (MSOP) (ED(50) 49.3 [37.9-64.1], nmol i.c.v.). Another Group III agonist, (RS)-4-phosphonophenyl-glycine (PPG), preferentially activating the mGlu(8) receptor, previously shown to protect against sound-induced seizures in DBA/2 mice and GEP rats, also protects against seizures induced in DBA/2 by 3,5-DHPG (ED(50) 3.7 [2.4-5.7], nmol i.c.v.) and by the Group III antagonist, MSOP (ED(50) 40.2 [21.0-77.0], nmol i.c.v.). At very high doses (500 nmol i.c.v. and above), Group III antagonists have pro-convulsant and convulsant activity. The anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu(4) receptor agonist ACPT-1, is partially reversed by the co-administration of the Group III antagonists, MSOP, (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) or (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4), in the 20-50 nmol dose range. At doses of 50-200 nmol, MPPG and MAP4 cause further reversal of the ACPT-1 anticonvulsant protection, while the MSOP effect on ACPT-1 protection is abolished at higher doses. In contrast, the anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu(8) receptor agonist PPG, is not

Quantitative protein and fat metabolism in bull calves treated with beta-adrenergic agonist

DEFF Research Database (Denmark)

Chwalibog, André; Jensen, K; Thorbek, G

1996-01-01

Protein and energy utilization and quantitative retention of protein, fat and energy was investigated with 12 Red Danish bulls during two subsequent 6 weeks trials (Sections A and B) at a mean live weight of 195 and 335 kg respectively. Treatments were control (Group 1) and beta-agonist (L-644...... matter, metabolizable energy and digestible protein was of the same magnitude for all groups. The beta-agonist had no significant effect on protein digestibility and metabolizability of energy, but daily live weight gain was significantly higher in the treated bulls. The utilization of digested protein...

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

Science.gov (United States)

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

1985-03-01

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

The β3 Adrenergic Receptor Agonist BRL37344 Exacerbates Atrial Structural Remodeling Through iNOS Uncoupling in Canine Models of Atrial Fibrillation.

Science.gov (United States)

Wang, Xiaobing; Wang, Ruifeng; Liu, Guangzhong; Dong, Jingmei; Zhao, Guanqi; Tian, Jingpu; Sun, Jiayu; Jia, Xiuyue; Wei, Lin; Wang, Yuping; Li, Weimin

2016-01-01

The role of the β3-adrenergic receptor (β3-AR) agonist BRL37344 in atrial fibrillation (AF) structural remodeling and the underlying mechanisms as a therapeutic target were investigated. Four groups of dogs were evaluated: sham, pacing, β3-AR agonist BRL37344 (β3-AGO), and β3-AR antagonist L748337 (β3-ANT) groups. Dogs in the pacing, β3-AGO and β3-ANT groups were subjected to rapid atrial pacing for four weeks. Atrial structure and function, AF inducibility and duration, atrial myocyte apoptosis and interstitial fibrosis were assessed. Atrial superoxide anions were evaluated by fluorescence microscopy and colorimetric assays. Cardiac nitrate+nitrite levels were used to assess nitric oxide (NO) production. Protein and mRNA expression of β3-AR, neuronal NO synthase (nNOS), inducible NO synthase (iNOS), endothelial NO synthase (eNOS) and guanosine triphosphate cyclohydrolase-1 (GCH-1) as well as tetrahydrobiopterin (BH4) levels were measured. β3-AR was up-regulated in AF. Stimulation of β3-AR significantly increased atrial myocyte apoptosis, fibrosis and atrial dilatation, resulting in increased AF induction and prolonged duration. These effects were attenuated by β3-ANT. Moreover, β3-AGO reduced BH4 and NO production and increased superoxide production, which was inhibited by the specific iNOS inhibitor, 1400w β3-AGO also increased iNOS but decreased eNOS and had no effect on nNOS expression in AF. β3-AR stimulation resulted in atrial structural remodeling by increasing iNOS uncoupling and related oxidative stress. β3-AR up-regulation and iNOS uncoupling might be underlying AF therapeutic targets. © 2016 The Author(s) Published by S. Karger AG, Basel.

Oxidation of nutrients in bull calves treated with beta-adrenergic agonists

DEFF Research Database (Denmark)

Chwalibog, André; Jensen, K; Thorbek, G

1996-01-01

Oxidation of protein (OXP), carbohydrate (OXCHO) and fat (OXF) was investigated with 12 growing bulls treated with beta-agonist (L-644, 969) during two 6 weeks trials (Section A and B) at a mean live weight of 195 and 335 kg. Heat production and nutrient oxidation was calculated from gas exchange...

Effects of the pesticide amitraz and its metabolite BTS 27271 on insulin and glucagon secretion from the perfused rat pancreas: involvement of alpha2D-adrenergic receptors.

Science.gov (United States)

Abu-Basha, E A; Yibchok-Anun, S; Hopper, D L; Hsu, W H

1999-11-01

The study purpose was to investigate the direct effect of amitraz, a formamidine insecticide/acaricide, and its active metabolite BTS 27271 on insulin and glucagon secretion from the perfused rat pancreas. Amitraz and BTS 27271 (0.01, 0.1, 1, and 10 micromol/L) inhibited insulin secretion in a concentration-dependent manner. Amitraz increased glucagon secretion at 10 micromol/L, whereas BTS 27271 increased glucagon secretion at 1 and 10 micromol/L. Amitraz- and BTS 27271-induced decreases in insulin secretion and increases in glucagon secretion were not abolished during the 10-minute washout period. During the arginine treatment, both amitraz and BTS 27271 groups (0.1, 1, and 10 micromol/L) had lower insulin secretion and higher glucagon secretion than the control group. Idazoxan, an alpha2A/2D-adrenergic receptor (AR) antagonist, prevented the inhibitory effect of amitraz on insulin secretion in a concentration-dependent manner, but prazosin, an alpha1- and alpha2B/2C-AR antagonist, failed to antagonize the effect of amitraz. These results demonstrate that (1) amitraz and BTS 27271 inhibit insulin and stimulate glucagon secretion from the perfused rat pancreas, (2) amitraz inhibits insulin secretion by activation of alpha2D-ARs, since rats have alpha2D- but not alpha2A-ARs, and (3) amitraz and BTS 27271 may have a high binding affinity to the alpha2D-ARs of pancreatic islets.

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

International Nuclear Information System (INIS)

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

1986-01-01

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

Attenuation of alpha2A-adrenergic receptor expression in neonatal rat brain by RNA interference or antisense oligonucleotide reduced anxiety in adulthood.

Science.gov (United States)

Shishkina, G T; Kalinina, T S; Dygalo, N N

2004-01-01

Brain alpha2-adrenergic receptors (alpha2-ARs) have been implicated in the regulation of anxiety, which is associated with stress. Environmental treatments during neonatal development could modulate the level of brain alpha2-AR expression and alter anxiety in adults, suggesting possible involvement of these receptors in early-life programming of anxiety state. The present study was undertaken to determine whether the reduction of the expression of A subtype of these receptors most abundant in the neonatal brain affects anxiety-related behavior in adulthood. We attenuated the expression of alpha2A-ARs during neonatal life by two different sequence specific approaches, antisense technology and RNA interference. Treatment of rats with the antisense oligodeoxynucleotide or short interfering RNA (siRNA) against alpha2A-ARs on the days 2-4 of their life, produced a marked acute decrease in the levels of both alpha2A-AR mRNA and [3H]RX821002 binding sites in the brainstem into which drugs were injected. The decrease of alpha2A-AR expression in the neonatal brainstem influenced the development of this receptor system in the brain regions as evidenced by the increased number of [3H]RX821002 binding sites in the hypothalamus of adult animals with both neonatal alpha2A-AR knockdown treatments; also in the frontal cortex of antisense-treated, and in the hippocampus of siRNA-treated adult rats. These adult animals also demonstrated a decreased anxiety in the elevated plus-maze as evidenced by an increased number of the open arm entries, greater proportion of time spent in the open arms, and more than a two-fold increase in the number of exploratory head dips. The results provide the first evidence that the reduction in the brain expression of a gene encoding for alpha2A-AR during neonatal life led to the long-term neurochemical and behavioral alterations. The data suggests that alterations in the expression of the receptor-specific gene during critical periods of brain

Adrenergic receptors are a fallible index of adrenergic denervation hypersensitivity

DEFF Research Database (Denmark)

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

1991-01-01

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

Adrenergic bronchodilator overdose

Science.gov (United States)

Adrenergic bronchodilators are inhaled medicines that help open up the airways. They are used to treat asthma and chronic bronchitis. Adrenergic bronchodilator overdose occurs when someone accidentally or intentionally ...

The amphiphilic peptide adenoregulin enhances agonist binding to A1-adenosine receptors and [35S]GTP gamma S to brain membranes.

Science.gov (United States)

Moni, R W; Romero, F S; Daly, J W

1995-08-01

1. Adenoregulin is an amphilic peptide isolated from skin mucus of the tree frog, Phyllomedusa bicolor. Synthetic adenoregulin enhanced the binding of agonists to several G-protein-coupled receptors in rat brain membranes. 2. The maximal enhancement of agonist binding, and in parentheses, the concentration of adenoregulin affording maximal enhancement were as follows: 60% (20 microM) for A1-adenosine receptors, 30% (100 microM) for A2a-adenosine receptors, 20% (2 microM) for alpha 2-adrenergic receptors, and 30% (10 microM) for 5HT1A receptors. High affinity agonist binding for A1-, alpha 2-, and 5HT1A-receptors was virtually abolished by GTP gamma S in the presence of adenoregulin, but was only partially abolished in its absence. Magnesium ions increased the binding of agonists to receptors and reduced the enhancement elicited by adenoregulin. 3. The effect of adenoregulin on binding of N6-cyclohexyladenosine ([3H]CHA) to A1-receptors was relatively slow and was irreversible. Adenoregulin increased the Bmax value for [3H]CHA binding sites, and the proportion of high affinity states, and slowed the rate of [3H]CHA dissociation. Binding of the A1-selective antagonist, [3H]DPCPX, was maximally enhanced by only 13% at 2 microM adenoregulin. Basal and A1-adenosine receptor-stimulated binding of [35S]GTP gamma S were maximally enhanced 45% and 23%, respectively, by 50 microM adenoregulin. In CHAPS-solubilized membranes from rat cortex, the binding of both [3H]CHA and [3H]DPCPX were enhanced by adenoregulin. Binding of [3H]CHA to membranes from DDT1 MF-2 cells was maximally enhanced 17% at 20 microM adenoregulin. In intact DDT1 MF-2 cells, 20 microM adenoregulin did not potentiate the inhibition of cyclic AMP accumulation mediated via the adenosine A1 receptor. 4. It is proposed that adenoregulin enhances agonist binding through a mechanism involving enhancement of guanyl nucleotide exchange at G-proteins, resulting in a conversion of receptors into a high affinity state

Effects of a-adrenergic agonist and laser trabeculoplasty on plasmoid aqueous humor of glaucomatous rabbits

International Nuclear Information System (INIS)

Ahmed, S.A.

2005-01-01

The present study aimed to determine the protection of blood aqueous barrier by the apraclonidine drops, which is an adrenergic receptor agonist that reduces each of the aqueous humor protein production and the intraocular pressure in glaucomatous rabbits eye before and after treatment with apraclonidine and diode laser trabeculoplasty (DLT).The rabbits were classified into four groups in addition to a normal one. Group (I) was treated with apraclonidine only twice daily, group (II) with apraclonidine before DLT, group (III) with apraclonidine after laser and group (IV) was treated with apraclonidine before and after laser. The aqueous humor was withdrawn from the anterior chamber of the normal and glaucomatous rabbits eye immediately after treatment (direct effect) and one week after treatment for the plasmoid (delayed effect). The intraocular pressure (IOP) was measured then the protein contents and the changes in the molecular structures of aqueous humor proteins were detected using gel column chromatography and electrophoretic mobility. Apraclonidine eye drops led to decrease in IOP and prevented its rise after DLT. The degree of permeability of the barrier was deduced by the amount of protein in the plasmoid aqueous humor after DLT. In normal rabbits, the total protein was increased in the plasmoid aqueous humor. In the four treated groups, the total protein was decreased. The most pronounced decrease was in the group that treated with apraclonidine before and after laser. The change in total protein content was accompanied with change in its molecular weight and electrophoretic mobility. From the obtained results, it could be concluded that the withdrawing of the aqueous humor from the anterior chamber of the eye in appreciable amount leads to reformation of new aqueous humor (plasmoid) with elevated protein concentration. Moreover, the treatment with apraclonidine before DLT completely protected the blood aqueous barrier from disruption caused by laser and

Peroxisome proliferator-activated receptor {alpha} agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

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Antonelli, Alessandro, E-mail: a.antonelli@med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Ferrari, Silvia Martina, E-mail: sm.ferrari@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Frascerra, Silvia, E-mail: lafrasce@gmail.com [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Corrado, Alda, E-mail: dala_res@hotmail.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Pupilli, Cinzia, E-mail: c.pupilli@dfc.unifi.it [Endocrinology Unit, Azienda Ospedaliera Careggi and University of Florence, Viale Morgagni 85, I-50134, Florence (Italy); Bernini, Giampaolo, E-mail: g.bernini@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Benvenga, Salvatore, E-mail: s.benvenga@me.nettuno.it [Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Messina, Piazza Pugliatti 1, I-98122, Messina (Italy); Ferrannini, Ele, E-mail: eferrannini@med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Fallahi, Poupak, E-mail: poupak@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)

2011-07-01

Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR){alpha} activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPAR{alpha} and PPAR{gamma} activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN){gamma} and tumor necrosis factor (TNF){alpha}. IFN{gamma} stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNF{alpha} alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFN{gamma} and TNF{alpha} had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPAR{alpha} activators inhibited the secretion of both chemokines (stimulated with IFN{gamma} and TNF{alpha}) at a level higher (for CXCL10, about 60-72%) than PPAR{gamma} agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFN{gamma} and TNF{alpha} in GD and normal thyrocytes. Furthermore we first show that PPAR{alpha} activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPAR{alpha} may be involved in the modulation of the immune response in the thyroid.

Cholesterol regulates contractility and inotropic response to β2-adrenoceptor agonist in the mouse atria: Involvement of Gi-protein-Akt-NO-pathway.

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Odnoshivkina, Yulia G; Sytchev, Vaycheslav I; Petrov, Alexey M

2017-06-01

Majority of cardiac β2-adrenoceptors is located in cholesterol-rich microdomains. Here, we have investigated the underlying mechanisms by which a slight to moderate cholesterol depletion with methyl-β-cyclodextrin (MβCD, 1 and 5mM) interferes with contractility and inotropic effect of β2-adrenergic agonist (fenoterol, 50μM) in the mouse atria. Treatment with MβCD itself increased amplitude of Ca 2+ transient but did not change the contraction amplitude due to a clamping action of elevated NO. Cholesterol depletion significantly attenuated the positive inotropic response to fenoterol which is accompanied by increase in NO generation and decrease in Ca 2+ transient. Influence of 1mM MβCD on the fenoterol-driven changes in both contractility and NO level was strongly attenuated by inhibition of G i -protein (pertussis toxin), Akt (Akt 1/2 kinase inhibitor) or NO-synthase (L-NAME). After exposure to 5mM MβCD, pertussis toxin or Akt inhibitor could recover the β2-agonist effects on contractility, NO production and Ca 2+ transient, while L-NAME only reduced NO level. An adenylyl cyclase activator (forskolin, 50nM) had no influence on the MβCD-induced changes in the β2-agonist effects. Obtained results suggest that slight cholesterol depletion upregulates G i -protein/Akt/NO-synthase signaling that attenuates the positive inotropic response to β2-adrenergic stimulation without altering the Ca 2+ transient. Whilst moderate cholesterol depletion additionally could suppress the enhancement of the Ca 2+ transient amplitude caused by the β2-adrenergic agonist administration in G i -protein/Akt-dependent but NO-independent manner. Copyright © 2016 Elsevier Ltd. All rights reserved.

In vivo autoradiographic demonstration of β-adrenergic binding sites in adult rat type II alveolar epithelial cells

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Smith, D.M.; Sidhu, M.K.

1984-01-01

Adult male rats were injected intravenously with the muscarinic binding probe 3 H-Quinuclidinyl benzilate (QNB) or the β-adrenergic probe 3 H-dihydroalprenolol (DHA). Other rats were pre-treated with an intraperitoneal injection of a 500-fold excess of L-isoproterenol prior to the DHA. Light microscopic autoradiography of 0.5 μm sections of lung from the QNB group demonstrated very little labelling even after 6 months of exposure. In constrast, trachealis smooth muscle from these animals contained substantial labelling. Autoradiographs of lung from rats injected with DHA demonstrated labelling which was well localized over alveolar septa and concentrated over the cytoplasm of type II cells. Quantitative analysis of labelling in the DHA groups indicated a significant reduction of labelling in animals treated with L-isoproterenol prior to DHA, in both the alveolar parenchyma in general and over type II cells. The results of this study provide morphologic evidence for the uptake and specific binding of β-adrenergic antagonists by the adult lung in vivo, while failing to demonstrate similar binding of a muscarinic probe. In addition, the results demonstrate specific β-adrenergic receptors on type II cells in vivo and substantiate the view of a direct effect of β-adrenergic agonists on alveolar type II cells

Long acting β2-agonist and corticosteroid restore airway glandular cell function altered by bacterial supernatant

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Nawrocki-Raby Béatrice

2010-01-01

Full Text Available Abstract Background Staphylococcus aureus releases virulence factors (VF that may impair the innate protective functions of airway cells. The aim of this study was to determine whether a long-acting β2 adrenergic receptor agonist (salmeterol hydroxynaphthoate, Sal combined with a corticosteroid (fluticasone propionate, FP was able to regulate ion content and cytokine expression by airway glandular cells after exposure to S. aureus supernatant. Methods A human airway glandular cell line was incubated with S. aureus supernatant for 1 h and then treated with the combination Sal/FP for 4 h. The expression of actin and CFTR proteins was analyzed by immunofluorescence. Videomicroscopy was used to evaluate chloride secretion and X-ray microanalysis to measure the intracellular ion and water content. The pro-inflammatory cytokine expression was assessed by RT-PCR and ELISA. Results When the cells were incubated with S. aureus supernatant and then with Sal/FP, the cellular localisation of CFTR was apical compared to the cytoplasmic localisation in cells incubated with S. aureus supernatant alone. The incubation of airway epithelial cells with S. aureus supernatant reduced by 66% the chloride efflux that was fully restored by Sal/FP treatment. We also observed that Sal/FP treatment induced the restoration of ion (Cl and S and water content within the intracellular secretory granules of airway glandular cells and reduced the bacterial supernatant-dependent increase of pro-inflammatory cytokines IL8 and TNFα. Conclusions Our results demonstrate that treatment with the combination of a corticosteroid and a long-acting β2 adrenergic receptor agonist after bacterial infection restores the airway glandular cell function. Abnormal mucus induced by defective ion transport during pulmonary infection could benefit from treatment with a combination of β2 adrenergic receptor agonist and glucocorticoid.

Ganglionic adrenergic action modulates ovarian steroids and nitric oxide in prepubertal rat.

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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.

Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene.

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Tanila, H; Mustonen, K; Sallinen, J; Scheinin, M; Riekkinen, P

1999-02-01

The role of the alpha2C-adrenoceptor subtype in mediating the beneficial effect of alpha2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 microg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha2C-adrenoceptor subtype.

The effects of alpha2-adrenoceptor agents on anti-hyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain.

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Vucković, Sonja M; Tomić, Maja A; Stepanović-Petrović, Radica M; Ugresić, Nenad; Prostran, Milica S; Bosković, Bogdan

2006-11-01

In this study, the effects of yohimbine (alpha2-adrenoceptor antagonist) and clonidine (alpha2-adrenoceptor agonist) on anti-hyperalgesia induced by carbamazepine and oxcarbazepine in a rat model of inflammatory pain were investigated. Carbamazepine (10-40 mg/kg; i.p.) and oxcarbazepine (40-160 mg/kg; i.p.) caused a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A, intraplantarly) in a paw pressure test in rats. Yohimbine (1-3 mg/kg; i.p.) significantly depressed the anti-hyperalgesic effects of carbamazepine and oxcarbazepine, in a dose- and time-dependent manner. Both drug mixtures (carbamazepine-clonidine and oxcarbazepine-clonidine) administered in fixed-dose fractions of the ED50 (1/2, 1/4 and 1/8) caused significant and dose-dependent reduction of the hyperalgesia induced by Con A. Isobolographic analysis revealed a significant synergistic (supra-additive) anti-hyperalgesic effect of both combinations tested. These results indicate that anti-hyperalgesic effects of carbamazepine and oxcarbazepine are, at least partially, mediated by activation of adrenergic alpha2-receptors. In addition, synergistic interaction for anti-hyperalgesia between carbamazepine and clonidine, as well as oxcarbazepine and clonidine in a model of inflammatory hyperalgesia, was demonstrated.

In vivo evaluation of alpha7 nicotinic acetylcholine receptor agonists [11C]A-582941 and [11C]A-844606 in mice and conscious monkeys.

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Jun Toyohara

Full Text Available BACKGROUND: The alpha7 nicotinic acetylcholine receptors (nAChRs play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. The goal of this study was to evaluate the two carbon-11-labeled alpha7 nAChR agonists [(11C]A-582941 and [(11C]A-844606 for their potential as novel positron emission tomography (PET tracers. METHODOLOGY/PRINCIPAL FINDINGS: The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [(11C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective alpha7 nAChR agonist (SSR180711. Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [(11C]A-582941 and [(11C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [(11C]A-582941 and [(11C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711. CONCLUSIONS/SIGNIFICANCE: A nonhuman primate study suggests that [(11C]A-582941 and [(11C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

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

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

2017-06-23

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

Pharmacological, neurochemical, and behavioral profile of JB-788, a new 5-HT1A agonist.

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Picard, M; Morisset, S; Cloix, J F; Bizot, J C; Guerin, M; Beneteau, V; Guillaumet, G; Hevor, T K

2010-09-01

A novel pyridine derivative, 8-{4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl}-8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT(1A) receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area

beta-adrenergic effects on carbohydrate metabolism in the unweighted rat soleus muscle

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Kirby, Christopher R.; Tischler, Marc E.

1990-01-01

The effect of unweighting on the response of the soleus-muscle carbohydrate metabolism to a beta-adrenergic agonist (isoproterenol) was investigated in rats that were subjected to three days of tail-cast suspension. It was found that isoproterenol promoted glycogen degradation in soleus from suspended rats to a higher degree than in weighted soleus from control rats, and had no effect in unweighted digitorum longus. However, isoproterenol did not have a greater inhibitory effect on the net uptake of tritium-labeled 2-deoxy-glucose by the unweighted soleus and that isoproterenol inhibited hexose phosphorylation less in the unweighted than in the control muscle.

Osmotic versus adrenergic control of ion transport by ionocytes of Fundulus heteroclitus in the cold.

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Tait, Janet C; Mercer, Evan W; Gerber, Lucie; Robertson, George N; Marshall, William S

2017-01-01

In eurythermic vertebrates, acclimation to the cold may produce changes in physiological control systems. We hypothesize that relatively direct osmosensitive control will operate better than adrenergic receptor mediated control of ion transport in cold vs. warm conditions. Fish were acclimated to full strength seawater (SW) at 21°C and 5°C for four weeks, gill samples and blood were taken and opercular epithelia mounted in Ussing style chambers. Short-circuit current (I sc ) at 21°C and 5°C (measured at acclimation temperature), was significantly inhibited by the α 2 -adrenergic agonist clonidine but the ED 50 dose was significantly higher in cold conditions (93.8±16.4nM) than in warm epithelia (47.8±8.1nM) and the maximum inhibition was significantly lower in cold (-66.1±2.2%) vs. warm conditions (-85.6±1.3%), indicating lower sensitivity in the cold. β-Adrenergic responses were unchanged. Hypotonic inhibition of I sc , was higher in warm acclimated (-95%), compared to cold acclimated fish (-75%), while hypertonic stimulations were the same, indicating equal responsiveness to hyperosmotic stimuli. Plasma osmolality was significantly elevated in cold acclimated fish and, by TEM, gill ionocytes from cold acclimated fish had significantly shorter mitochondria. These data are consistent with a shift in these eurythermic animals from complex adrenergic control to relatively simple biomechanical osmotic control of ion secretion in the cold. Copyright © 2016. Published by Elsevier Inc.

The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol.

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Jutkiewicz, Emily M; Baladi, Michelle G; Folk, John E; Rice, Kenner C; Woods, James H

2006-06-01

delta-Opioid agonists produce convulsions and antidepressant-like effects in rats. It has been suggested that the antidepressant-like effects are produced through a convulsant mechanism of action either through overt convulsions or nonconvulsive seizures. This study evaluated the convulsive and seizurogenic effects of nonpeptidic delta-opioid agonists at doses that previously were reported to produce antidepressant-like effects. In addition, delta-opioid agonist-induced electroencephalographic (EEG) and behavioral changes were compared with those produced by the chemical convulsant pentylenetetrazol (PTZ). For these studies, EEG changes were recorded using a telemetry system before and after injections of the delta-opioid agonists [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenz (SNC80) and [(+)-4-[alpha(R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide [(+)-BW373U86]. Acute administration of nonpeptidic delta-opioid agonists produced bilateral ictal and paroxysmal spike and/or sharp wave discharges. delta-Opioid agonists produced brief changes in EEG recordings, and tolerance rapidly developed to these effects; however, PTZ produced longer-lasting EEG changes that were exacerbated after repeated administration. Studies with antiepileptic drugs demonstrated that compounds used to treat absence epilepsy blocked the convulsive effects of nonpeptidic delta-opioid agonists. Overall, these data suggest that delta-opioid agonist-induced EEG changes are not required for the antidepressant-like effects of these compounds and that neural circuitry involved in absence epilepsy may be related to delta-opioid agonist-induced convulsions. In terms of therapeutic development, these data suggest that it may be possible to develop delta-opioid agonists devoid of convulsive properties.

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

International Nuclear Information System (INIS)

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

1984-01-01

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

Delayed internalization and lack of recycling in a beta2-adrenergic receptor fused to the G protein alpha-subunit

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Floridi Aristide

2008-10-01

Full Text Available Abstract Background Chimeric proteins obtained by the fusion of a G protein-coupled receptor (GPCR sequence to the N-terminus of the G protein α-subunit have been extensively used to investigate several aspects of GPCR signalling. Although both the receptor and the G protein generally maintain a fully functional state in such polypeptides, original observations made using a chimera between the β2-adrenergic receptor (β2AR and Gαs indicated that the fusion to the α-subunit resulted in a marked reduction of receptor desensitization and down-regulation. To further investigate this phenomenon, we have compared the rates of internalization and recycling between wild-type and Gαs-fused β2AR. Results The rate of agonist-induced internalization, measured as the disappearance of cell surface immunofluorescence in HEK293 cells permanently expressing N-terminus tagged receptors, was reduced three-fold by receptor-G protein fusion. However, both fused and non-fused receptors translocated to the same endocytic compartment, as determined by dual-label confocal analysis of cells co-expressing both proteins and transferrin co-localization. Receptor recycling, determined as the reversion of surface immunofluorescence following the addition of antagonist to cells that were previously exposed to agonist, markedly differed between wild-type and fused receptors. While most of the internalized β2AR returned rapidly to the plasma membrane, β2AR-Gαs did not recycle, and the observed slow recovery for the fusion protein immunofluorescence was entirely accounted for by protein synthesis. Conclusion The covalent linkage between β2AR and Gαs does not appear to alter the initial endocytic translocation of the two proteins, although there is reduced efficiency. It does, however, completely disrupt the process of receptor and G protein recycling. We conclude that the physical separation between receptor and Gα is not necessary for the transit to early endosomes

Regulation of the beta-adrenergic receptor-adenylate cyclase complex of 3T3-L1 fibroblasts by sodium butyrate

International Nuclear Information System (INIS)

Stadel, J.M.; Poksay, K.S.; Nakada, M.T.; Crooke, S.T.

1986-01-01

Mouse 3T3-L1 fibroblasts contain beta-adrenergic receptors (BAR), predominantly of the B 1 subtype. Incubation of these cells with 2-10 mM sodium butyrate (SB) for 24-48 hr results in a switch in the BAR subtype from B 1 to B 2 and promotes a 1.5 to 2.5 fold increase in total BAR number. Other short chain acids were not as effective as SB in promoting changes in BAR. BAR were assayed in membranes prepared from the 3T3-L1 cells using the radiolabeled antagonist [ 125 I]-cyanopindolol and the B 2 selective antagonist ICI 118.551. BAR subtype switch was confirmed functionally by measuring cellular cAMP accumulation in response to agonists. The structure and amount of the alpha subunits of the guanine nucleotide regulatory proteins N/sub s/ and N/sub i/ were determined by ADP-ribosylation using 32 P-NAD and either cholera toxin or pertussis toxin for labeling of the respective subunits. Preincubation of cells with 5 mM SB for 48 hr resulted in a 2-3 fold increase in the labeling of the alpha subunits of both N/sub s/ and N/sub i/. A protein of M/sub r/ = 44,000 showed enhanced labeling by cholera toxin following SB treatment of the cells. These data indicate SB concomitantly regulates expression of BAR subtype and components of the adenylate cyclase in 3T3-L1 cells

alpha2 adrenoceptors are involved in the regulation of the gripping-induced immobility episodes in taiep rats.

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Eguibar, José R; Cortés, Ma Del Carmen; Valencia, Jaime; Arias-Montaño, José A

2006-10-01

In 1989 Holmgren et al. (Holmgren et al. 1989 Lab Anim Sci 39:226-228) described a new mutant rat that developed a progressive motor disturbance during its lifespan. The syndrome is characterized by a tremor in the hind limbs followed by ataxia, episodes of tonic immobility, epilepsy, and paralysis. The acronym of these symptoms (taiep) became the name of this autosomic, recessive mutant rat. The taiep rats are neurological mutant animals with a hypomyelination, followed by a progressive demyelination process. At 7-8 months of age, taiep rats develop immobility episodes (IEs) characterized by a cortical desynchronization, associated with the theta rhythm in the hippocampus and changes of the nucal electromyogram (EMG), whose pattern is like rapid-eye-movement (REM) sleep. These rats also show an altered sleep pattern with an equal REM sleep distribution. This study analyzed therole of alpha(2) adrenoceptors in the expression of gripping-induced IEs in 8-month-old male taiep rats. The alpha(2) adrenoceptor agonists clonidine and xylacine increased the frequency of gripping-induced IEs whereas the alpha(2) antagonists yohimbine and idazoxandecreased or prevented such episodes. These findings correlate with the pharmacological observations in narcoleptic dogs and humans in which alpha(2) adrenergic mechanisms are involved in the modulation of cataplexy. Unexpectedly, the repetitive administration of clonidine resulted in jumping behavior, indicative of phasic activation of extensor musculature. Taken together, our results show that alpha(2) adrenoceptors are involved in the modulation in gripping-induced IEs and after the administration of several doses of clonidine produced phasic motor activation.

Beta agonists in livestock feed: status, health concerns, and international trade.

Science.gov (United States)

Centner, T J; Alvey, J C; Stelzleni, A M

2014-09-01

Since the U.S. Food and Drug Administration approved ractopamine hydrochloride and zilpaterol hydrochloride in animal feeds, usage of those compounds has been a topic of worldwide debate. Ractopamine and zilpaterol are β-adrenergic agonists used as veterinary drugs to increase weight gain in certain animals raised for food. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) established maximum residue limits for ractopamine, which were adopted by the Codex Alimentarius Commission (Codex). No maximum residue limits for zilpaterol have been adopted by JECFA, and new reports of animal mobility issues confront the use of this feed additive. However, many countries disagree with the Codex standards and are restricting or banning meat products containing β agonists. The bans by major importers of U.S. meat products have prompted some to advocate that the United States use the World Trade Organization dispute settlement body. This paper looks at the developments to provide a fuller accounting of what the issues may mean to U.S. firms selling meat products containing residues of β agonists.

Regulation of chick bone growth by leptin and catecholamines.

Science.gov (United States)

Mauro, L J; Wenzel, S J; Sindberg, G M

2010-04-01

Leptin and the sympathetic nervous system have a unique role in linking nutritional status to skeletal metabolism in mammals. Such a regulatory mechanism has not been identified in birds but would be beneficial to signal information about energy reserves to an organ system essential for locomotion, reproduction, and survival. To explore this potential role of leptin and the sympathetic nervous system in birds, an ex vivo chick tibiotarsal model was used to test the effects of leptin and sympathetic activity on longitudinal bone growth and the expression of chondrocyte markers. Reverse transcription-PCR analysis revealed the expression of chicken leptin receptor mRNA as well as both alpha-adrenergic (alpha1A, alpha2A, alpha2B, alpha2C) and beta adrenergic (beta1, beta2) receptor subtype mRNA in the whole bone. Incubation with norepinephrine (NE; 0, 10, or 100 microM for 4 d) caused a significant increase in distal condyle length as compared with vehicle-treated, contralateral tibiotarsi. In contrast, no change in condyle length was detected after leptin treatment (0 or 10 nM or 1 microM for 4 d). Analysis of cell proliferation by bromodeoxyuridine incorporation revealed no increase in bromodeoxyuridine-positive cells in the condyles in response to leptin or NE treatments. Real-time PCR analysis showed that NE enhanced type X collagen mRNA expression, a marker of mature hypertrophic chondrocytes, with no effect on type II collagen mRNA, the matrix protein secreted by proliferating chondrocytes. Leptin treatment had no effect on the expression of either matrix protein. Treatment with agonists specific for alpha- or beta-adrenergic receptors indicates that the activation of alpha-adrenergic receptors is most likely responsible for the sympathetic effect on type X collagen gene expression. These results suggest that NE and other sympathetic agonists have positive effects on bone elongation and the changes in critical genes associated with this process. These

Cardiac β-adrenergic responsiveness of obese Zucker rats: The role of AMPK.

Science.gov (United States)

Bussey, Carol T; Thaung, Hp Aye; Hughes, Gillian; Bahn, Andrew; Lamberts, Regis R

2018-06-05

What is the central question of the study? What is the main finding and its importance? 1. Is the reduced signalling of AMPK, a key regulator of energy homeostasis in the heart, responsible for the reduced β-adrenergic responsiveness of the heart in obesity? 2. Inhibition of AMPK in isolated hearts prevented the reduced cardiac β-adrenergic responsiveness of obese rats, which was accompanied by reduced phosphorylation of AMPK, a proxy of AMPK activity. This suggests a direct functional link between β-adrenergic responsiveness and AMPK signalling in the heart, and that AMPK might be an important target to restore the β-adrenergic responsiveness in the heart in obesity. The obesity epidemic impacts heavily on cardiovascular health, in part due to changes in cardiac metabolism. AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis in the heart, and is regulated by β-adrenoceptors (AR) under normal conditions. In obesity, chronic sympathetic overactivation leads to impaired cardiac β-AR responsiveness, although it is unclear whether AMPK signalling, downstream of β-AR, contributes to this dysfunction. Therefore, we aimed to determine whether reduced AMPK signalling is responsible for the reduced β-AR responsiveness in obesity. In isolated hearts of lean and obese Zucker rats, we tested β-AR responsiveness to β 1 -AR agonist isoproterenol (ISO, 1 × 10 -10 - 5 × 10 -8  M) in the absence and presence of the AMPK inhibitor compound C (CC, 10 μM). β 1 -AR expression and AMPK phosphorylation were assessed by Western blot. β-Adrenergic responsiveness was reduced in the hearts of obese rats (LogEC50 of ISO-developed pressure dose-response curves: lean -8.53 ± 0.13 vs. obese -8.35 ± 0.10 10 x M; p  0.05, n = 6 per group). β 1 -AR expression and AMPK phosphorylation were reduced in hearts of obese rats (AMPK at Thr 172 : lean 1.73 ± 0.17 vs. lean CC 0.81 ± 0.13, and obese 1.18 ± 0.09 vs. obese CC 0.81 ± 0

Quetiapine reverse paclitaxel-induced neuropathic pain in mice: Role of Alpha2- adrenergic receptors

Directory of Open Access Journals (Sweden)

Alireza Abed

2017-11-01

Full Text Available Objective(s: Paclitaxel-induced peripheral neuropathy is a common adverse effect of cancer chemo -therapy. This neuropathy has a profound impact on quality of life and patient’s survival. Preventing and treating paclitaxel-induced peripheral neuropathy is a major concern. First- and second-generation antipsychotics have shown analgesic effects both in humans and animals. Quetiapine is a novel atypical antipsychotic with low propensity to induce extrapyramidal or hyperprolactinemia side effects. The present study was designed to investigate the effects of quetiapine on the development and expression of neuropathic pain induced by paclitaxel in mice and the role of α2-adrenoceptors on its antinociception. Materials and Methods: Paclitaxel (2 mg/kg IP was injected for five consecutive days which resulted in thermal hyperalgesia and mechanical and cold allodynia. Results: Early administration of quetiapine from the 1st day until the 5th day (5, 10, and 15 mg/kg PO did not affect thermal, mechanical, and cold stimuli and could not prevent the development of neuropathic pain. In contrast, when quetiapine (10 and 15 mg/kg PO administration was started on the 6th day after the first paclitaxel injections, once the model had been established, and given daily until the 10th day, heat hyperalgesia and mechanical and cold allodynia were significantly attenuated. Also, the effect of quetiapine on heat hyperalgesia was reversed by pretreatment with yohimbine, as an alpha-2 adrenergic receptor antagonist. Conclusion: These results indicate that quetiapine, when administered after nerve injury can reverse the expression of neuropathic pain. Also, we conclude that α2-adrenoceptors participate in the antinociceptive effects of quetiapine.

Alpha1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses.

Science.gov (United States)

Solecki, Wojciech B; Szklarczyk, Klaudia; Klasa, Adam; Pradel, Kamil; Dobrzański, Grzegorz; Przewłocki, Ryszard

2017-08-01

Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha 1 -adrenergic receptor (α 1 -AR) signaling in the VTA affects conditioned fear. The role of α 1 -AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α 1 -AR blockade in the mammillary bodies (MB) - a brain region with α 1 -AR expression adjacent to the VTA. Intra-VTA but not intra-MB α 1 -AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α 1 -AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α 1 -AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α 1 -AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α 1 -AR signaling in the regulation of stress responsiveness and fear memory. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

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.

Adrenergic Modulation Regulates the Dendritic Excitability of Layer 5 Pyramidal Neurons In Vivo

Directory of Open Access Journals (Sweden)

Christina Labarrera

2018-04-01

Full Text Available Summary: The excitability of the apical tuft of layer 5 pyramidal neurons is thought to play a crucial role in behavioral performance and synaptic plasticity. We show that the excitability of the apical tuft is sensitive to adrenergic neuromodulation. Using two-photon dendritic Ca2+ imaging and in vivo whole-cell and extracellular recordings in awake mice, we show that application of the α2A-adrenoceptor agonist guanfacine increases the probability of dendritic Ca2+ events in the tuft and lowers the threshold for dendritic Ca2+ spikes. We further show that these effects are likely to be mediated by the dendritic current Ih. Modulation of Ih in a realistic compartmental model controlled both the generation and magnitude of dendritic calcium spikes in the apical tuft. These findings suggest that adrenergic neuromodulation may affect cognitive processes such as sensory integration, attention, and working memory by regulating the sensitivity of layer 5 pyramidal neurons to top-down inputs. : Labarrera et al. show that noradrenergic neuromodulation can be an effective way to regulate the interaction between different input streams of information processed by an individual neuron. These findings may have important implications for our understanding of how adrenergic neuromodulation affects sensory integration, attention, and working memory. Keywords: cortical layer 5 pyramidal neuron, dendrites, norepinephrine, HCN, Ih, Ca2+ spike, apical tuft, guanfacine, ADHD, somatosensory cortex

Effect of beta-agonists on LAM progression and treatment.

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Le, Kang; Steagall, Wendy K; Stylianou, Mario; Pacheco-Rodriguez, Gustavo; Darling, Thomas N; Vaughan, Martha; Moss, Joel

2018-01-30

Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2 The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s over time in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Because beta-agonists increase cAMP and PKA activity, we investigated effects of PKA activation on the mTOR pathway. Human skin TSC2 +/- fibroblasts or LAM lung cells incubated short-term with isoproterenol (beta-agonist) showed a sirolimus-independent increase in phosphorylation of S6, a downstream effector of the mTOR pathway, and increased cell growth. Cells incubated long-term with isoproterenol, which may lead to beta-adrenergic receptor desensitization, did not show increased S6 phosphorylation. Inhibition of PKA blocked the isoproterenol effect on S6 phosphorylation. Thus, activation of PKA by beta-agonists increased phospho-S6 independent of mTOR, an effect abrogated by beta-agonist-driven receptor desensitization. In agreement, retrospective clinical data from patients with LAM suggested that a combination of bronchodilators in conjunction with sirolimus may be preferable to sirolimus alone for stabilization of pulmonary function.

Virtual screening studies of Chinese medicine Coptidis Rhizoma as alpha7 nicotinic acetylcholine receptor agonists for treatment of Alzheimer's disease

Science.gov (United States)

Xiang, Li; Xu, Youdong; Zhang, Yan; Meng, Xianli; Wang, Ping

2015-04-01

Alzheimer's disease (AD) is an age-related neurodegenerative disease. Extensive in vitro and in vivo experiments have proved that the decreased activity of the cholinergic neuron is responsible for the memory and cognition deterioration. The alpha7 nicotinic acetylcholine receptor (α7-nAChR) is proposed to a drug target of AD, and compounds which acting as α7-nAChR agonists are considered as candidates in AD treatment. Chinese medicine CoptidisRhizoma and its compounds are reported in various anti-AD effects. In this study, virtual screening, docking approaches and hydrogen bond analyses were applied to screen potential α7-nAChR agonists from CoptidisRhizome. The 3D structure of the protein was obtained from PDB database. 87 reported compounds were included in this research and their structures were accessed by NCBI Pubchem. Docking analysis of the compounds was performed using AutoDock 4.2 and AutoDock Vina. The images of the binding modes hydrogen bonds and the hydrophobic interaction were rendered with PyMOL1.5.0.4. and LigPlot+ respectively. Finally, N-tran-feruloyltyramine, isolariciresinol, flavanone, secoisolariciresinol, (+)-lariciresinol and dihydrochalcone, exhibited the lowest docking energy of protein-ligand complex. The results indicate these 6 compounds are potential α7 nAChR agonists, and expected to be effective in AD treatment.

A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure.

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Zhang, Xiaojian; Shen, Chengwu; Zhai, Shujun; Liu, Yukun; Yue, Wen-Wei; Han, Li

2016-10-01

Adrenergic β-blockers are drugs that bind to, but do not activate β-adrenergic receptors. Instead they block the actions of β-adrenergic agonists and are used for the treatment of various diseases such as cardiac arrhythmias, angina pectoris, myocardial infarction, hypertension, headache, migraines, stress, anxiety, prostate cancer, and heart failure. Several meta-analysis studies have shown that β-blockers improve the heart function and reduce the risks of cardiovascular events, rate of mortality, and sudden death through chronic heart failure (CHF) of patients. The present study identified results from recent meta-analyses of β-adrenergic blockers and their usefulness in CHF. Databases including Medline/Embase/Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched for the periods May, 1985 to March, 2011 and June, 2013 to August, 2015, and a number of studies identified. Results of those studies showed that use of β-blockers was associated with decreased sudden cardiac death in patients with heart failure. However, contradictory results have also been reported. The present meta-analysis aimed to determine the efficacy of β-blockers on mortality and morbidity in patients with heart failure. The results showed that mortality was significantly reduced by β-blocker treatment prior to the surgery of heart failure patients. The results from the meta-analysis studies showed that β-blocker treatment in heart failure patients correlated with a significant decrease in long-term mortality, even in patients that meet one or more exclusion criteria of the MERIT-HF study. In summary, the findings of the current meta-analysis revealed beneficial effects different β-blockers have on patients with heart failure or related heart disease.

Women at Altitude: Effects of Menstrual Cycle Phase and Alpha-Adrenergic Blockade on High Altitude Acclimatization

National Research Council Canada - National Science Library

Moore, Lorna

1998-01-01

.... Results indicated that the effects of the menstrual cycle were modest. In year 2, we evaluated the safety and efficacy of administering an a-adrenergic blocker and made selected observations during a brief exposure to an altitude of 4300 m...

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

International Nuclear Information System (INIS)

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

2004-01-01

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

Zolpidem, a selective GABA(A) receptor alpha1 subunit agonist, induces comparable Fos expression in oxytocinergic neurons of the hypothalamic paraventricular and accessory but not supraoptic nuclei in the rat

DEFF Research Database (Denmark)

Kiss, Alexander; Søderman, Andreas; Bundzikova, Jana

2006-01-01

Functional activation of oxytocinergic (OXY) cells in the hypothalamic paraventricular (PVN), supraoptic (SON), and accessory (ACC) nuclei was investigated in response to acute treatment with Zolpidem (a GABA(A) receptor agonist with selectivity for alpha(1) subunits) utilizing dual Fos/OXY immun...

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

Science.gov (United States)

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

2018-03-02

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

Central venous pressure and mean circulatory filling pressure in the dogfish Squalus acanthias: adrenergic control and role of the pericardium.

Science.gov (United States)

Sandblom, Erik; Axelsson, Michael; Farrell, Anthony P

2006-11-01

Subambient central venous pressure (Pven) and modulation of venous return through cardiac suction (vis a fronte) characterizes the venous circulation in sharks. Venous capacitance was estimated in the dogfish Squalus acanthias by measuring the mean circulatory filling pressure (MCFP) during transient occlusion of cardiac outflow. We tested the hypothesis that venous return and cardiac preload can be altered additionally through adrenergic changes of venous capacitance. The experiments involved the surgical opening of the pericardium to place a perivascular occluder around the conus arteriosus. Another control group was identically instrumented, but lacked the occluder, and was subjected to the same pharmacological protocol to evaluate how pericardioectomy affected cardiovascular status. Routine Pven was negative (-0.08+/-0.02 kPa) in control fish but positive (0.09+/-0.01 kPa) in the pericardioectomized group. Injections of 5 microg/kg body mass (Mb) of epinephrine and phenylephrine (100 microg/kg Mb) increased Pven and MCFP, whereas isoproterenol (1 microg/kg Mb) decreased both variables. Thus, constriction and relaxation of the venous vasculature were mediated through the respective stimulation of alpha- and beta-adrenergic receptors. Alpha-adrenergic blockade with prazosin (1 mg/kg Mb) attenuated the responses to phenylephrine and decreased resting Pven in pericardioectomized animals. Our results provide convincing evidence for adrenergic control of the venous vasculature in elasmobranchs, although the pericardium is clearly an important component in the modulation of venous function. Thus active changes in venous capacitance have previously been underestimated as an important means of modulating venous return and cardiac performance in this group.

Reciprocal modulation of helper Th1 and Th17 cells by the β2-adrenergic receptor agonist drug terbutaline.

Science.gov (United States)

Carvajal Gonczi, Catalina M; Tabatabaei Shafiei, Mahdieh; East, Ashley; Martire, Erika; Maurice-Ventouris, Meagane H I; Darlington, Peter J

2017-09-01

Catecholamine hormones are powerful regulators of the immune system produced by the sympathetic nervous system (SNS). They regulate the adaptive immune system by altering T-cell differentiation into T helper (Th) 1 and Th2 cell subsets, but the effect on Th17 cells is not known. Th17 cells, defined, in part, by chemokine receptor CCR6 and cytokine interleukin (IL)-17A, are crucial for mediating certain pathogen-specific responses and are linked with several autoimmune diseases. We demonstrated that a proportion of human Th17 cells express beta 2-adrenergic receptor (β2AR), a G protein-coupled receptor that responds to catecholamines. Activation of peripheral blood mononuclear cells, which were obtained from venous blood drawn from healthy volunteers, with anti-cluster of differentiation 3 (CD3) and anti-CD28 and with a β2-agonist drug, terbutaline (TERB), augmented IL-17A levels (P < 0.01) in the majority of samples. TERB reduced interferon gamma (IFNγ) indicating that IL-17A and IFNγ are reciprocally regulated. Similar reciprocal regulation was observed with dbcAMP. Proliferation of Th cells was monitored by carboxyfluorescein diacetate N-succinimidyl ester labeling and flow cytometry with antibody staining for CD3 and CD4. TERB increased proliferation by a small but significant margin (P < 0.001). Next, Th17 cells (CD4 + CXCR3 - CCR6 + ) were purified using an immunomagnetic positive selection kit, which removes all other mononuclear cells. TERB increased IL-17A from purified Th17 cells, which argues that TERB acts directly on Th17 cells. Thus, hormone signals from the SNS maintain a balance of Th cells subtypes through the β2AR. © 2017 Federation of European Biochemical Societies.

Protective effect of an alpha 7 nicotinic acetylcholine receptor agonist against enterovirus 71 infection in neuronal cells.

Science.gov (United States)

Song, Feng Xia; Zhao, Lin Qing; Zhu, Ru Nan; Song, Qin Wei; Deng, Jie; Tian, Run; Wang, Fang; Qian, Yuan

2018-01-01

Enterovirus 71, as one of the dominant pathogens associated with severe hand, foot, and mouth disease, has been well reported to trigger severe neurological symptoms among young children over the last decade, particularly among children in the Asia-Pacific region. To date, no effective antiviral agent has been developed for the treatment of severe enterovirus 71 infection. PNU-282987, a selective alpha 7 nicotinic acetylcholine receptor (α7nAChR) agonist, has been reported to have a neuroprotective effect by participating in inflammatory regulation in previous studies. Therefore, in the present study, we aimed to assess the cell-protective effect of PNU-282987 against enterovirus 71 infection in neuronal cells, and to discuss potential mechanisms underlying this cell-protective effect in order to elucidate the potential impact of such agonists in the treatment of neurotropic viral infection. We observed that treatment with PNU-282987 improved cell viability and inhibited viral replication in enterovirus 71-infected SH-SY5Y cells. Further investigation revealed that inhibition of enterovirus 71 production by PNU-282987 is likely associated with events of RNA replication, and that increased levels of INF mRNA and its downstream antiviral proteins stimulated by the JAK-STAT2 pathway may contribute to the antiviral effect of PNU-282987. Moreover, our findings suggest that both the antiviral and anti-inflammatory effects of PNU-282987 may contribute to the neural protective effect of the drug in enterovirus 71-infected cells. Taken together, the results suggest that selective α7nAChR agonists may represent viable candidates for future therapeutic treatment of severe enterovirus 71 infection, and for other cases of neurotropic viral infection. Copyright © 2017 Elsevier B.V. All rights reserved.

Cocaine potentiates ketamine-induced loss of the righting reflex and sleeping time in mice. Role of catecholamines.

Science.gov (United States)

Vanderwende, C; Spoerlein, M T; Lapollo, J

1982-07-01

Cocaine in graded doses potentiated ketamine-induced loss of the righting reflex and sleeping time. Potentiation of drug-induced sleep with cocaine was not a generalized phenomenon inasmuch as it had no effect on sleep induced by pentobarbital or hexobarbital and decreased sleep induced by phenobarbital. Pentylenetetrazole reduced ketamine sleep but d-amphetamine had a potentiative action. dl-alpha-Methyl-p-tyrosine methyl ester itself increased both the number losing the righting reflex and the sleeping time induced by ketamine. However, the effect cocaine on sleeping time was blocked 3 h after the dl-alpha-methyl-p-tyrosine methyl ester was given. The alpha and beta adrenergic blocking drugs, phenoxybenzamine and propranolol, increased the number of animals losing the righting reflex with ketamine, and phenoxybenzamine lengthened the sleeping time. Alpha and beta adrenergic agonists, l-phenylephrine and isoproterenol, increased the number of animals going to sleep with ketamine but did not significantly alter how long they would sleep. The agonists had no effect on the cocaine interaction with ketamine, whereas the antagonists blocked the effect of cocaine. Both stimulation and blockade of dopamine receptors led to increased loss of the righting reflex and sleeping time with ketamine but only receptor blockade antagonized the effect of cocaine on ketamine-induced sleep. Thus, both the noradrenergic and dopaminergic systems appear to be involved in the ability of cocaine to potentiate ketamine-induced sleep.

Airway reactivity in chronic obstructive pulmonary disease. Failure of in vivo methacholine responsiveness to correlate with cholinergic, adrenergic, or nonadrenergic responses in vitro.

Science.gov (United States)

Taylor, S M; Paré, P D; Armour, C L; Hogg, J C; Schellenberg, R R

1985-07-01

This study aimed to determine whether in vivo airways hyperreactivity was manifested by either enhanced bronchial smooth muscle responses to contractile stimuli or by deficient responses to relaxant stimuli in vitro. Quantitative responses to nebulized methacholine were obtained in 12 human subjects prior to pulmonary resection. The provocative concentration of methacholine producing a 20% reduction in FEV1 (PC20) was calculated, and these values were compared with in vitro responses of bronchial smooth muscle strips from the surgical specimens. Both contractile cholinergic responses and relaxant nonadrenergic noncholinergic dose-response data were obtained for the in vitro bronchial specimens by electrical field stimulation. In addition, cumulative dose responses were obtained to exogenously added methacholine, the beta-adrenergic agonist salbutamol, and the adenylate cyclase activator forskolin. Despite a wide range of PC20 values, the in vivo airway responsiveness did not correlate with any of the in vitro responses examined, suggesting that airway reactivity is not due solely to the responsiveness of smooth muscle to contractile agonists nor to a localized deficiency in the nonadrenergic inhibitory system, beta-adrenergic inhibition, or abnormal cyclic-AMP-mediated pathways of relaxation.

Evaluation of equine electroretinographic responses by using two different electrodes and four different Alpha-2 agonist sedatives

Directory of Open Access Journals (Sweden)

Maurílio Rosa

2014-12-01

Full Text Available ABSTRACT. Rosa M., Botteon P.T.L., Pereira J.S., Brooks D.E. & Rosa M.V.D. Evaluation of equine electroretinographic responses by using two different electrodes and four different Alpha-2 agonist sedatives. [Avaliação da resposta eletroretinográfica de equinos utilizando dois tipos de eletrodos quatro sedativos Alfa-2 agonistas diferentes.] Revista Brasileira de Medicina Veterinária, 36(4:367-374, 2014. Centro de Pesquisa em Oftalmologia Veterinária (CEPOV, Avenida das Américas, 700, Bloco 8, Loja 103J, Barra da Tijuca, Rio de Janeiro, RJ 22640-100, Brasil. E-mail: marcmax@globo.com The aim of this study was the evaluation and comparison of field electroretinographic responses in standing horses using two different active electrodes (DTL- plus™ and ERG-jet®, and four different alpha-2 agonist drugs Xylazine, Romifidine, Detomidine, Medetomidine. Forty healthy horses were evaluated by full field ERG. Horses were randomly allocated into eight groups according four sedative drugs and two electrodes types. In all groups a- and b- wave amplitudes and implicit times were investigated and compared for both eyes. Quality and costs of sedation drugs were estimated. This research leaded to the conclusion that there were no significant differences of a- and b-wave complex results between ERG-jet® and DTL-plus™ electrodes with any sedative type. The ERG-jet® lens proved to be more practical during the examination than the DTL-plus™ electrode. The use of a single dose of xylazine, romifidine, detomidine or medetomidine was sufficient to provide a good level of sedation and muscle relaxation during the ERG examination, although detomidine and medetomidine gave slightly superior results when compared with the otherdrugs in this study. The sedation with xylazine was the least when compared with the other drugs and it was also the cheapest to use. Any of the sedatives and either active electrode tested in this study should permit a good full field

Differential effects of beta-adrenoceptor partial agonists in patients with postural hypotension

DEFF Research Database (Denmark)

Mehlsen, J; Stadeager, C; Trap-Jensen, J

1993-01-01

patients with postural hypotension of different aetiologies. Blood pressure, heart rate and stroke volume were measured in the supine and head-up tilted positions. Left ventricular ejection fraction (LVEF) was measured in the supine position, and vascular resistance, left ventricular volume, and left.......min-1 and LVEF from 0.57 to 0.52, and reduced mean arterial blood pressure from 103 mm Hg to 93 mm Hg. Xamoterol showed beta-adrenoceptor agonistic effects in the supine position through increments in heart rate from 72 to 90 beats.min-1 and LVEF from 0.58 to 0.66, and raised mean arterial blood...... pressure from 108 to 123 mm Hg. It is concluded that the degree of agonist activity of a beta-adrenergic agent is of importance if it is given to a patient with postural hypotension....

Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat

Directory of Open Access Journals (Sweden)

Juan Suárez

2014-01-01

Full Text Available β-adrenergic receptor activation promotes brown adipose tissue (BAT β-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-α (PPARα in white adipose tissue (WAT. Here we explore whether PPARα activation potentiates the effect of β3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association on feeding, thermogenesis, β-oxidation, and lipid and cholesterol metabolism in epididymal (eWAT was monitored. CL316243 (1 mg/kg and OEA (5 mg/kg co-administration over 6 days enhanced the reduction of both food intake and body weight gain, increased the energy expenditure and reduced the respiratory quotient (VCO2/VO2. This negative energy balance agreed with decreased fat mass and increased BAT weight and temperature, as well as with lowered plasma levels of triglycerides, cholesterol, nonessential fatty acids (NEFAs, and the adipokines leptin and TNF-α. Regarding eWAT, CL316243 and OEA treatment elevated levels of the thermogenic factors PPARα and UCP1, reduced p38-MAPK phosphorylation, and promoted brown-like features in the white adipocytes: the mitochondrial (Cox4i1, Cox4i2 and BAT (Fgf21, Prdm16 genes were overexpressed in eWAT. The enhancement of the fatty-acid β-oxidation factors Cpt1b and Acox1 in eWAT was accompanied by an upregulation of de novo lipogenesis and reduced expression of the unsaturated-fatty-acid-synthesis enzyme gene, Scd1. We propose that the combination of β-adrenergic and PPARα receptor agonists promotes therapeutic adipocyte remodelling in eWAT, and therefore has a potential clinical utility in the treatment of obesity.

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

International Nuclear Information System (INIS)

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

1990-01-01

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

Distinct neural pathways mediate alpha7 nicotinic acetylcholine receptor-dependent activation of the forebrain

DEFF Research Database (Denmark)

Thomsen, Morten S; Hay-Schmidt, Anders; Hansen, Henrik H

2010-01-01

alpha(7) nicotinic acetylcholine receptor (nAChR) agonists are candidates for the treatment of cognitive deficits in schizophrenia. Selective alpha(7) nAChR agonists, such as SSR180711, activate neurons in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (ACCshell) in rats, regions...

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

International Nuclear Information System (INIS)

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

1987-01-01

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

Adrenergic receptors in frontal cortex in human brain.

Science.gov (United States)

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

1985-02-05

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

NCBI nr-aa BLAST: CBRC-DMEL-06-0067 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-DMEL-06-0067 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-OLAT-01-0012 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-OLAT-01-0012 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-PABE-21-0006 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PABE-21-0006 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-TNIG-22-0186 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-TNIG-22-0186 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-OCUN-01-1614 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-OCUN-01-1614 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-CJAC-01-0998 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-CJAC-01-0998 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-TGUT-06-0022 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-TGUT-06-0022 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-PTRO-21-0002 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PTRO-21-0002 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-GGAL-04-0044 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-GGAL-04-0044 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-RNOR-03-0467 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-RNOR-03-0467 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-SARA-01-1942 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-SARA-01-1942 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-MMUS-02-0386 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-MMUS-02-0386 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-PMAR-01-0862 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PMAR-01-0862 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-FRUB-02-0703 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-FRUB-02-0703 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-GACU-09-0018 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-GACU-09-0018 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-OCUN-01-0599 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-OCUN-01-0599 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-DSIM-06-0034 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-DSIM-06-0034 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-FRUB-02-0406 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-FRUB-02-0406 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-ACAR-01-0377 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-ACAR-01-0377 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-HSAP-20-0001 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-HSAP-20-0001 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

NCBI nr-aa BLAST: CBRC-CFAM-24-0001 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-CFAM-24-0001 ref|NP_000669.1| alpha-1D-adrenergic receptor [Homo sapiens] sp|P...25100|ADA1D_HUMAN Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (Alpha adrenergic receptor 1a) gb|AAB60351.1| adrenergic alpha-1a receptor protein gb|AAB59487.1| alpha 1a/d adre...nergic receptor dbj|BAA06222.1| alpha1A/D adrenergic rec...eptor [Homo sapiens] emb|CAH70478.1| adrenergic, alpha-1D-, receptor [Homo sapiens] emb|CAC00601.2| adrenergic

Characterization of phosphorylated beta-adrenergic receptors from desensitized turkey erythrocytes

International Nuclear Information System (INIS)

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

1986-01-01

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

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

International Nuclear Information System (INIS)

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

1985-01-01

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

The involvement of peripheral alpha 2-adrenoceptors in the antihyperalgesic effect of oxcarbazepine in a rat model of inflammatory pain.

Science.gov (United States)

Tomić, Maja A; Vucković, Sonja M; Stepanović-Petrović, Radica M; Ugresić, Nenad D; Paranos, Sonja Lj; Prostran, Milica S; Bosković, Bogdan

2007-11-01

We studied whether peripheral alpha2-adrenergic receptors are involved in the antihyperalgesic effects of oxcarbazepine by examining the effects of yohimbine (selective alpha2-adrenoceptor antagonist), BRL 44408 (selective alpha(2A)-adrenoceptor antagonist), MK-912 (selective alpha2C-adrenoceptor antagonist), and clonidine (alpha2-adrenoceptor agonist) on the antihyperalgesic effect of oxcarbazepine in the rat model of inflammatory pain. Rats were intraplantarly (i.pl.) injected with the proinflammatory compound concanavalin A (Con A). A paw-pressure test was used to determine: 1) the development of hyperalgesia induced by Con A; 2) the effects of oxcarbazepine (i.pl.) on Con A-induced hyperalgesia; and 3) the effects of i.pl. yohimbine, BRL 44408, MK-912 and clonidine on the oxcarbazepine antihyperalgesia. Both oxcarbazepine (1000-3000 nmol/paw; i.pl.) and clonidine (1.9-7.5 nmol/paw; i.pl.) produced a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by Con A. Yohimbine (260 and 520 nmol/paw; i.pl.), BRL 44408 (100 and 200 nmol/paw; i.pl.) and MK-912 (10 and 20 nmol/paw; i.pl.) significantly depressed the antihyperalgesic effects of oxcarbazepine (2000 nmol/paw; i.pl.) in a dose-dependent manner. The effects of antagonists were due to local effects since they were not observed after administration into the contralateral hindpaw. Oxcarbazepine and clonidine administered jointly in fixed-dose fractions of the ED(50) (1/4, 1/2, and 3/4) caused significant and dose-dependent reduction of hyperalgesia induced by Con A. Isobolographic analysis revealed an additive antihyperalgesic effect. Our results indicate that the peripheral alpha2A and alpha2C adrenoceptors could be involved in the antihyperalgesic effects of oxcarbazepine in a rat model of inflammatory hyperalgesia.

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

Directory of Open Access Journals (Sweden)

Nicholas Douris

2017-08-01

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

Pharmacologically relevant receptor binding characteristics and 5alpha-reductase inhibitory activity of free Fatty acids contained in saw palmetto extract.

Science.gov (United States)

Abe, Masayuki; Ito, Yoshihiko; Oyunzul, Luvsandorj; Oki-Fujino, Tomomi; Yamada, Shizuo

2009-04-01

Saw palmetto extract (SPE), used widely for the treatment of benign prostatic hyperplasia (BPH) has been shown to bind alpha(1)-adrenergic, muscarinic and 1,4-dihydropyridine (1,4-DHP) calcium channel antagonist receptors. Major constituents of SPE are lauric acid, oleic acid, myristic acid, palmitic acid and linoleic acid. The aim of this study was to investigate binding affinities of these fatty acids for pharmacologically relevant (alpha(1)-adrenergic, muscarinic and 1,4-DHP) receptors. The fatty acids inhibited specific [(3)H]prazosin binding in rat brain in a concentration-dependent manner with IC(50) values of 23.8 to 136 microg/ml, and specific (+)-[(3)H]PN 200-110 binding with IC(50) values of 24.5 to 79.5 microg/ml. Also, lauric acid, oleic acid, myristic acid and linoleic acid inhibited specific [(3)H]N-methylscopolamine ([(3)H]NMS) binding in rat brain with IC(50) values of 56.4 to 169 microg/ml. Palmitic acid had no effect on specific [(3)H]NMS binding. The affinity of oleic acid, myristic acid and linoleic acid for each receptor was greater than the affinity of SPE. Scatchard analysis revealed that oleic acid and lauric acid caused a significant decrease in the maximal number of binding sites (B(max)) for [(3)H]prazosin, [(3)H]NMS and (+)-[(3)H]PN 200-110. The results suggest that lauric acid and oleic acid bind noncompetitively to alpha(1)-adrenergic, muscarinic and 1,4-DHP calcium channel antagonist receptors. We developed a novel and convenient method of determining 5alpha-reductase activity using LC/MS. With this method, SPE was shown to inhibit 5alpha-reductase activity in rat liver with an IC(50) of 101 microg/ml. Similarly, all the fatty acids except palmitic acid inhibited 5alpha-reductase activity, with IC(50) values of 42.1 to 67.6 microg/ml. In conclusion, lauric acid, oleic acid, myristic acid, and linoleic acid, major constituents of SPE, exerted binding activities of alpha(1)-adrenergic, muscarinic and 1,4-DHP receptors and inhibited 5

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

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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.

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/β-agonists

PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

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Monica Puligheddu

Full Text Available Nicotinic acetylcholine receptors (nAChRs are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα, nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p. or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2% for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.. Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key

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

Science.gov (United States)

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

2008-12-01

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

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

International Nuclear Information System (INIS)

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

1986-01-01

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

Discovery of Azetidinone Acids as Conformationally-Constrained Dual PPARalpha/gamma Agonists

Energy Technology Data Exchange (ETDEWEB)

Wang, W.; Devasthale, P; Farrelly, D; Gu, L; Harrity, T; Cap, M; Chu, C; Kunselman, L; Morgan, N; et. al.

2008-01-01

A novel class of azetidinone acid-derived dual PPAR{alpha}/{gamma} agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARa and PPAR? receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

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

Science.gov (United States)

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

2017-11-27

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

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

OpenAIRE

Shogo Sato; Ken Shirato; Kaoru Tachiyashiki; Kazuhiko Imaizumi

2011-01-01

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

A biallelic RFLP of the human. alpha. 2-C4 adrenergic receptor gene (ADRA2RL2) localized on the short arm of chromosome 4 and encoding the putative. alpha. 2B receptor is identified with Bsu 36 L using a 1. 5 kb probe (p ADRA2RL2)

Energy Technology Data Exchange (ETDEWEB)

Hoeche, M.R.; Berrettini, W.H. (Clinical Neurogenetics Branch, Bethesda, MD (USA)); Regan, J.W. (Duke Univ. Medical Center, Durham, NC (USA))

1989-12-11

A 1.5 kb Eco RI cDNA fragment representing the human alpha2-C4 adrenergic receptor (AR) gene encoding the putative alpha2B-AR, containing approximately 1270 bp of the coding and 240 bp of the 3{prime}flanking region, inserted into pSP65, was used as a probe (p ADRA2RL2). This clone was obtained by screening a human kidney lambda GT10 cDNA library with the 0.95 kb Pst I restriction fragment derived from the coding block of the gene for the human platelet alpha2-AR. Hybridization of human genomic DNA digested with Bsu 36 I identifies a two allele polymorphism with bands at 12 kb and 5.8 kb. 20 unrelated North American caucasian subjects were evaluated with frequencies of: A allele, 0.45; B allele, 0.55, heterozygosity (obs), 0.5. This alpha2-AR gene has been mapped in a separation effort in 59 CEPH reference pedigrees to the tip of the short arm of chromosome 4 just proximal to GB (4p 16.3) reported to be linked to the Huntingston's disease gene. Codominant inheritance was observed in seven families with two and three generations, respectively. The number of meioses scored was 95.

Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor [alpha] Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453)

Energy Technology Data Exchange (ETDEWEB)

Li, Jun; Kennedy, Lawrence J.; Shi, Yan; Tao, Shiwei; Ye, Xiang-Yang; Chen, Stephanie Y.; Wang, Ying; Hernndez, Andrs S.; Wang, Wei; Devasthale, Pratik V.; Chen, Sean; Lai, Zhi; Zhang, Hao; Wu, Shung; Smirk, Rebecca A.; Bolton, Scott A.; Ryono, Denis E.; Zhang, Huiping; Lim, Ngiap-Kie; Chen, Bang-Chi; Locke, Kenneth T.; O’Malley, Kevin M.; Zhang, Litao; Srivastava, Rai Ajit; Miao, Bowman; Meyers, Daniel S.; Monshizadegan, Hossain; Search, Debra; Grimm, Denise; Zhang, Rongan; Harrity, Thomas; Kunselman, Lori K.; Cap, Michael; Kadiyala, Pathanjali; Hosagrahara, Vinayak; Zhang, Lisa; Xu, Carrie; Li, Yi-Xin; Muckelbauer, Jodi K.; Chang, Chiehying; An, Yongmi; Krystek, Stanley R.; Blanar, Michael A.; Zahler, Robert; Mukherjee, Ranjan; Cheng, Peter T.W.; Tino, Joseph A. (BMS)

2010-04-12

An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) {alpha} agonist, with an EC{sub 50} of 10 nM for human PPAR{alpha} and 410-fold selectivity vs human PPAR{gamma} in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR{delta}. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPAR{alpha} ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR{alpha} in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

Clonidine treatment delays postnatal motor development and blocks short-term memory in young mice.

Directory of Open Access Journals (Sweden)

Cristina Calvino-Núñez

Full Text Available During the development of the nervous system, the perinatal period is particularly sensitive as neuronal connections are still forming in the brain of the neonate. Alpha2-adrenergic receptors are overexpressed temporarily in proliferative zones in the developing brain, reaching a peak during the first postnatal week of life. Both stimulation and blocking of these receptors during this period alter the development of neural circuits, affecting synaptic connectivity and neuronal responses. They even affect motor and cognitive skills later on in the adult. It's especially important to look for the early neurological consequences resulting from such modifications, because they may go unnoticed. The main objective of the present study has been to reaffirm the importance of the maturation of alpha-adrenergic system in mice, by carrying out a comprehensive examination of motor, behavioral and cognitive effects in neonates, during early postnatal development, following chronic administration of the drug Clonidine, an alpha2 adrenergic system agonist. Our study shows that mice treated postnatally with clonidine present a temporal delay in the appearance of developmental markers, a slow execution of vestibular reflexes during first postnatal week of life and a blockade of the short term memory in the novel object recognition task. Shortly after the treatment the startle response is hyperreactive.

NCBI nr-aa BLAST: CBRC-ACAR-01-0408 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-ACAR-01-0408 ref|NP_000671.2| alpha-1A-adrenergic receptor isoform 1 [Homo sap...iens] sp|P35348|ADA1A_HUMAN Alpha-1A adrenergic receptor (Alpha 1A-adrenoceptor) (Alpha 1A-adrenoreceptor) (Alpha-1C adrenergic... receptor) (Alpha adrenergic receptor 1c) gb|AAB60353.1| adrenergic alpha-1c receptor pro...tein dbj|BAC05926.1| seven transmembrane helix receptor [Homo sapiens] gb|AAQ91331.1| adrenergic

NCBI nr-aa BLAST: CBRC-PTRO-09-0020 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PTRO-09-0020 ref|NP_000671.2| alpha-1A-adrenergic receptor isoform 1 [Homo sap...iens] sp|P35348|ADA1A_HUMAN Alpha-1A adrenergic receptor (Alpha 1A-adrenoceptor) (Alpha 1A-adrenoreceptor) (Alpha-1C adrenergic... receptor) (Alpha adrenergic receptor 1c) gb|AAB60353.1| adrenergic alpha-1c receptor pro...tein dbj|BAC05926.1| seven transmembrane helix receptor [Homo sapiens] gb|AAQ91331.1| adrenergic

The effect of various opiate receptor agonists on the seizure threshold in the rat. Is dynorphin an endogenous anticonvulsant?

Science.gov (United States)

Przewłocka, B; Stala, L; Lasoń, W; Przewłocki, R

1983-01-01

The effects of various opiate receptor agonists on the seizure threshold after an intravenous infusion of pentylenetetrazol were investigated in rats. The mu- and epsilon-receptor agonists, morphine (20-40 micrograms) and beta-endorphin (5-10 micrograms) show proconvulsant properties towards clonic and tonic seizures. The delta-receptor agonist (D-Ala2,D-Leu5-enkephalin, DADL 5-40 micrograms) and alpha-neoendorphin (20-40 micrograms) show pro- and anticonvulsant properties towards clonic and tonic seizures, respectively. Anticonvulsant properties of DADL are possibly due to its action on the spinal cord, since after the intrathecal injection this effect is still observed. Similarities between DADL and alpha-neoendorphin suggest that they may act through the same receptor. The kappa-receptor agonist dynorphin A (5-20 micrograms) and its degradation-resistant analogue D-Arg-dynorphin1-13 (10 micrograms) show significant anticonvulsant properties. Our present results suggest that the kappa-receptor agonist dynorphin may act physiologically as an endogenous anticonvulsant, in contrast to other opioid peptides.

Enhanced basal contractility but reduced excitation-contraction coupling efficiency and beta-adrenergic reserve of hearts with increased Cav1.2 activity.

Science.gov (United States)

Tang, Mingxin; Zhang, Xiaoying; Li, Yingxin; Guan, Yinzheng; Ai, Xiaojie; Szeto, Christopher; Nakayama, Hiroyuki; Zhang, Hongyu; Ge, Shuping; Molkentin, Jeffery D; Houser, Steven R; Chen, Xiongwen

2010-08-01

Cardiac remodeling during heart failure development induces a significant increase in the activity of the L-type Ca(2+) channel (Cav1.2). However, the effects of enhanced Cav1.2 activity on myocyte excitation-contraction (E-C) coupling, cardiac contractility, and its regulation by the beta-adrenergic system are not clear. To recapitulate the increased Cav1.2 activity, a double transgenic (DTG) mouse model overexpressing the Cavbeta2a subunit in a cardiac-specific and inducible manner was established. We studied cardiac (in vivo) and myocyte (in vitro) contractility at baseline and upon beta-adrenergic stimulation. E-C coupling efficiency was evaluated in isolated myocytes as well. The following results were found: 1) in DTG myocytes, L-type Ca(2+) current (I(Ca,L)) density, myocyte fractional shortening (FS), peak Ca(2+) transients, and sarcoplasmic reticulum (SR) Ca(2+) content (caffeine-induced Ca(2+) transient peak) were significantly increased (by 100.8%, 48.8%, 49.8%, and 46.8%, respectively); and 2) cardiac contractility evaluated with echocardiography [ejection fraction (EF) and (FS)] and invasive intra-left ventricular pressure (maximum dP/dt and -dP/dt) measurements were significantly greater in DTG mice than in control mice. However, 1) the cardiac contractility (EF, FS, dP/dt, and -dP/dt)-enhancing effect of the beta-adrenergic agonist isoproterenol (2 microg/g body wt ip) was significantly reduced in DTG mice, which could be attributed to the loss of beta-adrenergic stimulation on contraction, Ca(2+) transients, I(Ca,L), and SR Ca(2+) content in DTG myocytes; and 2) E-C couplng efficiency was significantly lower in DTG myocytes. In conclusion, increasing Cav1.2 activity by promoting its high-activity mode enhances cardiac contractility but decreases E-C coupling efficiency and the adrenergic reserve of the heart.

Defective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma.

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Manveen K Gupta

Full Text Available β2-adrenergic receptor (β2AR agonists (β2-agonist are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. Activation of βARs by β-agonist leads to desensitization (inactivation by phosphorylation through G-protein coupled receptor kinases (GRKs which mediate β-arrestin binding and βAR internalization. Resensitization occurs by dephosphorylation of the endosomal βARs which recycle back to the plasma membrane as agonist-ready receptors. To determine whether the loss in β-agonist response in asthma is due to altered βAR desensitization and/or resensitization, we used primary human airway smooth muscle cells (HASMCs isolated from the lungs of non-asthmatic and fatal-asthmatic subjects. Asthmatic HASMCs have diminished adenylyl cyclase activity and cAMP response to β-agonist as compared to non-asthmatic HASMCs. Confocal microscopy showed significant accumulation of phosphorylated β2ARs in asthmatic HASMCs. Systematic analysis of desensitization components including GRKs and β-arrestin showed no appreciable differences between asthmatic and non-asthmatic HASMCs. However, asthmatic HASMC showed significant increase in PI3Kγ activity and was associated with reduction in PP2A activity. Since reduction in PP2A activity could alter receptor resensitization, endosomal fractions were isolated to assess the agonist ready β2ARs as a measure of resensitization. Despite significant accumulation of β2ARs in the endosomes of asthmatic HASMCs, endosomal β2ARs cannot robustly activate adenylyl cyclase. Furthermore, endosomes from asthmatic HASMCs are associated with significant increase in PI3Kγ and reduced PP2A activity that inhibits β2AR resensitization. Our study shows that resensitization, a process considered to be a homeostasis maintaining passive process is inhibited in asthmatic HASMCs contributing to β2AR dysfunction which may underlie

In vitro bioactivity of 17alpha-estradiol.

Science.gov (United States)

Sievernich, André; Wildt, Ludwig; Lichtenberg-Fraté, Hella

2004-12-01

A miniaturised short-term in vitro assay based on the activation of the human estrogen receptor alpha and genetically modified yeast (Saccharomyces cerevisiae) cells was performed to explore the capacity of this system to monitor the bioactivity of estrogenic compounds, particularly 17alpha- and 17beta-estradiol. Together with the human estrogen receptor (hER)-alpha plasmid, the reporter plasmid containing a yeast-optimised version of the green fluorescent protein (yEGFP) linked to three repeats of the cis-acting estrogen hormone-responsive element (ERE) were expressed in a strain being deleted in the pleiotropic drug resistance transporters Pdr5, Snq2 and Yor1, known to facilitate efflux of organic compounds including steroids and chemotherapeutics. Agonists that bind to hER in vitro trigger estrogen receptor-mediated transcriptional activation of the GFP reporter gene monitored by fluorescence emission at 535 nm. The sensitivity of the assay was tested with various 17alpha- and 17beta-estradiol concentrations, yielding a detection limit of 5 pg/ml (0.018 nM) for the agonist 17beta-E2 in solvent and in human charcoal-stripped serum using a S. cerevisiae pdr5, snq2 and yor1 mutant strain. For 17alpha-estradiol only, at approximately 1500 pg/ml a similar fluorescence response compared to 100 pg/ml 17beta-E2 was observed implicating a much weaker potency of this stereoisomer. The specificity of the system was tested by expression of a truncated hER lacking the ligand-binding domain E and by administration of the androgen, 4-androsten 3,17 dione. Both controls did not yield an increase in fluorescence emission. This fluorescence emission assay enables detection of estrogenic biological activity induced by direct agonists, such as 17beta-E2 at concentrations similar to those found in human sera or by estrogen-like chemicals.

Alpha2-adrenoceptor modulation of long-term potentiation elicited in vivo in rat occipital cortex.

Science.gov (United States)

Mondaca, Mauricio; Hernández, Alejandro; Pérez, Hernán; Valladares, Luis; Sierralta, Walter; Fernández, Victor; Soto-Moyano, Rubén

2004-09-24

Pretreatment with the alpha(2)-adrenoceptor agonist clonidine (31.25, 62.5, or 125 microg/kg, i.p.) dose-dependently reduced long-term potentiation (LTP) elicited in vivo in the occipital cortex of anesthetized rats, whereas pretreatment with the alpha(2)-adrenoceptor antagonist yohimbine (0.133, 0.4, or 1.2 mg/kg, i.p.) increased neocortical LTP in a dose-dependent fashion. These effects could be related to the reported disruptive and facilitatory actions induced on memory formation by pretreatment with alpha(2)-adrenoceptor agonists and antagonists, respectively.

Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan.

Science.gov (United States)

Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Takagi, Mai; Sei, Kazunari; Yang, Min; Hirotsuji, Junji; Hu, Jianying; Nishikawa, Jun-ichi; Nakanishi, Tsuyoshi; Ike, Michihiko

2010-04-01

This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) alpha in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan. To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARalpha agonist contamination in the river basins. RARalpha agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARalpha agonists are always present and widespread in the rivers. Comparative investigation of RARalpha and estrogen receptor alpha agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARalpha agonist contamination was entirely different from that of the estrogenic compound contamination. This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARalpha agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARalpha agonists in the rivers. Although a trial conducted to identify RARalpha agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARalpha agonistic activity were not RAs (natural RAR ligands) and 4-oxo-RAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China. These findings suggest that there are unknown RARalpha agonists with high

Adrenergic blockade in diabetic and uninephrectomized rats

DEFF Research Database (Denmark)

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

1999-01-01

The present study reports on the effects of adrenergic blocking agents on the renal growth and on the renal content and urinary excretion of epidermal growth factor (EGF) in streptozotocin-induced diabetic or uninephrectomized rats. Diabetic and uninephrectomized rats were allocated to groups...... treated with either saline or adrenergic antagonists and compared to controls and sham-operated controls, respectively. 24-hour urine samples were obtained on days 7, 14, and 21 and renal tissue samples on day 21. The 24-hour urinary excretion of EGF from controls and saline-treated diabetic rats...... was comparable. In adrenergic antagonist treated diabetic rats, it was reduced by at least 40% throughout the study period. Uninephrectomy caused a 50% reduction in the urinary excretion of EGF. This was not influenced by treatment with an adrenergic antagonist. After 3 weeks, saline-treated diabetic rats had...

Alpha7 nicotinic receptor mediated protection against ethanol-induced cytotoxicity in PC12 cells.

Science.gov (United States)

Li, Y; King, M A; Grimes, J; Smith, N; de Fiebre, C M; Meyer, E M

1999-01-16

Ethanol caused a concentration-dependent loss of PC12 cells over a 24 h interval, accompanied by an increase in intracellular calcium. The specific alpha7 nicotinic receptor partial agonist DMXB attenuated both of these ethanol-induced actions at a concentration (3 microM) found previously to protect against apoptotic and necrotic cell loss. The alpha7 nicotinic receptor antagonist methylylaconitine blocked the neuroprotective action of DMXB when applied with but not 30 min after the agonist. These results indicate that activation of alpha7 nicotinic receptors may be therapeutically useful in preventing ethanol-neurotoxicity. Copyright 1999 Elsevier Science B.V.

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

DEFF Research Database (Denmark)

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

2014-01-01

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

IGF and myostatin pathways are respectively induced during the earlier and the later stages of skeletal muscle hypertrophy induced by clenbuterol, a β₂-adrenergic agonist.

Science.gov (United States)

Abo, Tokuhisa; Iida, Ryo-Hei; Kaneko, Syuhei; Suga, Takeo; Yamada, Hiroyuki; Hamada, Yoshiki; Yamane, Akira

2012-12-01

Clenbuterol, a β₂-adrenergic agonist, increases the hypertrophy of skeletal muscle. Insulin-like growth factor (IGF) is reported to work as a potent positive regulator in the clenbuterol-induced hypertrophy of skeletal muscles. However, the precise regulatory mechanism for the hypertrophy of skeletal muscle induced by clenbuterol is unknown. Myostatin, a member of the TGFβ super family, is a negative regulator of muscle growth. The aim of the present study is to elucidate the function of myostatin and IGF in the hypertrophy of rat masseter muscle induced by clenbuterol. To investigate the function of myostatin and IGF in regulatory mechanism for the clenbuterol-induced hypertrophy of skeletal muscles, we analysed the expression of myostatin and phosphorylation levels of myostatin and IGF signaling components in the masseter muscle of rat to which clenbuterol was orally administered for 21 days. Hypertrophy of the rat masseter muscle was induced between 3 and 14 days of oral administration of clenbuterol and was terminated at 21 days. The expression of myostatin and the phosphorylation of smad2/3 were elevated at 21 days. The phosphorylation of IGF receptor 1 (IGFR1) and akt1 was elevated at 3 and 7 days. These results suggest that myostatin functions as a negative regulator in the later stages in the hypertrophy of rat masseter muscle induced by clenbuterol, whereas IGF works as a positive regulator in the earlier stages. Copyright © 2012 John Wiley & Sons, Ltd.

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...

Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

Energy Technology Data Exchange (ETDEWEB)

Choi, Yoon Jung [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Lee, Jue Yeon [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Lee, Seung Jin [Department of Industrial Pharmacy, College of Pharmacy, Ewha Womans University, Seoul (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Chung, Chong-Pyoung [Department of Periodontology, School of Dentistry, Seoul National University, Seoul (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Park, Yoon Jeong, E-mail: parkyj@snu.ac.kr [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of)

2011-12-16

Highlights: Black-Right-Pointing-Pointer Doxazocin directly up-regulated bone metabolism at a low dose. Black-Right-Pointing-Pointer Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. Black-Right-Pointing-Pointer This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor {gamma}, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and

Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

International Nuclear Information System (INIS)

Choi, Yoon Jung; Lee, Jue Yeon; Lee, Seung Jin; Chung, Chong-Pyoung; Park, Yoon Jeong

2011-01-01

Highlights: ► Doxazocin directly up-regulated bone metabolism at a low dose. ► Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. ► This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor γ, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and according to our data doxazosin might be useful for application in the field of bone

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

Science.gov (United States)

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

2014-02-01

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

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

DEFF Research Database (Denmark)

Gottrup, F; Hovendal, C; Bech, K

1984-01-01

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

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.

Activation of peroxisome proliferator-activated receptor-{alpha} enhances fatty acid oxidation in human adipocytes

Energy Technology Data Exchange (ETDEWEB)

Lee, Joo-Young; Hashizaki, Hikari; Goto, Tsuyoshi; Sakamoto, Tomoya; Takahashi, Nobuyuki [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Kawada, Teruo, E-mail: fat@kais.kyoto-u.ac.jp [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan)

2011-04-22

Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of adipocyte differentiation marker genes and GPDH activity in human adipocytes. {yields} PPAR{alpha} activation also increased insulin-dependent glucose uptake in human adipocytes. {yields} PPAR{alpha} activation did not affect lipid accumulation in human adipocytes. {yields} PPAR{alpha} activation increased fatty acid oxidation through induction of fatty acid oxidation-related genes in human adipocytes. -- Abstract: Peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) is a key regulator for maintaining whole-body energy balance. However, the physiological functions of PPAR{alpha} in adipocytes have been unclarified. We examined the functions of PPAR{alpha} using human multipotent adipose tissue-derived stem cells as a human adipocyte model. Activation of PPAR{alpha} by GW7647, a potent PPAR{alpha} agonist, increased the mRNA expression levels of adipocyte differentiation marker genes such as PPAR{gamma}, adipocyte-specific fatty acid-binding protein, and lipoprotein lipase and increased both GPDH activity and insulin-dependent glucose uptake level. The findings indicate that PPAR{alpha} activation stimulates adipocyte differentiation. However, lipid accumulation was not changed, which is usually observed when PPAR{gamma} is activated. On the other hand, PPAR{alpha} activation by GW7647 treatment induced the mRNA expression of fatty acid oxidation-related genes such as CPT-1B and AOX in a PPAR{alpha}-dependent manner. Moreover, PPAR{alpha} activation increased the production of CO{sub 2} and acid soluble metabolites, which are products of fatty acid oxidation, and increased oxygen consumption rate in human adipocytes. The data indicate that activation of PPAR{alpha} stimulates both adipocyte differentiation and fatty acid oxidation in human adipocytes, suggesting that PPAR{alpha} agonists could improve insulin resistance without lipid accumulation in adipocytes. The expected

Adrenergic-induced enhancement of brain barrier system permeability to small nonelectrolytes: choroid plexus versus cerebral capillaries

International Nuclear Information System (INIS)

Murphy, V.A.; Johanson, C.E.

1985-01-01

Acute hypertension induced by adrenergic agents opens up the blood-CSF barrier (choroid plexus) to nonelectrolyte and protein tracers. Sprague-Dawley adult rats anesthetized with ketamine were given an intravenous bolus of either epinephrine (10 micrograms/kg), phenylephrine (100 micrograms/kg), isoproterenol (10 micrograms/kg), or D,L-amphetamine (2 mg/kg). Tracers were injected simultaneously with test agents, and the animals killed 10 min later. Epinephrine raised MABP by 57 mm Hg, to a peak pressure of 160 mm Hg; and it increased the volume of distribution (Vd) of urea, mannitol, and 125 I-bovine serum albumin in CSF by 1.5-, 2.7-, and 30-fold, respectively. There was enhanced uptake by lateral and fourth ventricle choroid plexuses, cerebral cortex, cerebellum, medulla, and thalamus. Phenylephrine also elevated MABP to 160 mm Hg, but it increased permeation of tracers into CSF (and several brain regions) to a lesser extent than epinephrine, attributable to protective vasoconstriction associated with alpha-agonist activity. Ratio analysis of Vd data provides evidence that augmented permeation of nonelectrolyte tracers in acute hypertension occurs predominantly by diffusion rather than vesicular transport. It is postulated that elevated MABP distends the central cores of choroid plexus villi and cerebral capillaries, with resultant stretching and opening of tight junctions in both barrier systems; with less hindrance to diffusion, urea and mannitol are cleared at rates closer to free diffusion. Neither isoproterenol (decreased MABP by 40 mm Hg) nor amphetamine (did not alter MABP) significantly opened the choroid plexus or blood-brain barrier to tracers

NCBI nr-aa BLAST: CBRC-TNIG-01-0000 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-TNIG-01-0000 ref|NP_036871.2| adrenergic receptor, alpha 2a [Rattus norvegicus...] sp|P22909|ADA2A_RAT Alpha-2A adrenergic receptor (Alpha-2A adrenoceptor) (Alpha-2A adrenoreceptor) (Alpha-...2AAR) (CA2-47) (Alpha-2D adrenergic receptor) gb|AAC24959.1| alpha2D adrenergic receptor [Rattus norvegicus] NP_036871.2 4e-41 37% ...

NCBI nr-aa BLAST: CBRC-MMUS-19-0098 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-MMUS-19-0098 ref|NP_036871.2| adrenergic receptor, alpha 2a [Rattus norvegicus...] sp|P22909|ADA2A_RAT Alpha-2A adrenergic receptor (Alpha-2A adrenoceptor) (Alpha-2A adrenoreceptor) (Alpha-...2AAR) (CA2-47) (Alpha-2D adrenergic receptor) gb|AAC24959.1| alpha2D adrenergic receptor [Rattus norvegicus] NP_036871.2 0.0 97% ...

β-adrenergic receptor responsiveness in aging heart and clinical implications

Science.gov (United States)

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

2014-01-01

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

Amiloride interacts with renal α- and β-adrenergic receptors

International Nuclear Information System (INIS)

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

1987-01-01

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

NCBI nr-aa BLAST: CBRC-PABE-21-0006 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-PABE-21-0006 sp|P97714|ADA1D_MOUSE Alpha-1D adrenergic receptor (Alpha 1D-adre...noceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic receptor) gb|AAB47042.1| alpha 1d-adrenergic recept...or [Mus sp.] dbj|BAA90312.1| alpha 1D adrenergic receptor [Mus musculus] P97714 0.0 78% ...

NCBI nr-aa BLAST: CBRC-RNOR-03-0467 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-RNOR-03-0467 ref|NP_077809.1| adrenergic receptor, alpha 1d [Rattus norvegicus...] sp|P23944|ADA1D_RAT Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (RA42) gb|AAB59704.1| alpha 1a/d adrenergic receptor NP_077809.1 0.0 99% ...

NCBI nr-aa BLAST: CBRC-GGAL-04-0044 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-GGAL-04-0044 ref|NP_077809.1| adrenergic receptor, alpha 1d [Rattus norvegicus...] sp|P23944|ADA1D_RAT Alpha-1D adrenergic receptor (Alpha 1D-adrenoceptor) (Alpha 1D-adrenoreceptor) (Alpha-1A adrenergic... receptor) (RA42) gb|AAB59704.1| alpha 1a/d adrenergic receptor NP_077809.1 1e-171 59% ...

G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations

DEFF Research Database (Denmark)

Ísberg, Vignir; Balle, Thomas; Sander, Tommy

2011-01-01

molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability......A 5-HT(2A) receptor model was constructed by homology modeling based on the ß(2)-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT(2A) receptor model was transferred into an active conformation by an agonist ligand and a G(aq) peptide in four subsequent steered...

Exercise training modulates functional sympatholysis and alpha-adrenergic vasoconstrictor responsiveness in hypertensive and normotensive individuals

DEFF Research Database (Denmark)

Mortensen, Stefan Peter; Nyberg, Michael Permin; Gliemann Hybholt, Lasse

2014-01-01

were measured before and after 8 weeks of aerobic training (3-4 times/week) in 8 hypertensive (47 ± 2 years) and 8 normotensive untrained individuals (46 ± 1 years) during arterial tyramine infusion, arterial ATP infusion and/or one-legged knee extensions. Before training, exercise hypaeremia and leg......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...... vascular conductance (LVC) were lower in the hypertensive individuals (P Training lowered blood pressure in the hypertensive individuals (P

β3-Adrenergic Regulation of EPC Features Through Manipulation of the Bone Marrow MSC Niche.

Science.gov (United States)

Vafaei, Rana; Nassiri, Seyed Mahdi; Siavashi, Vahid

2017-12-01

Mesenchymal stem cells (MSCs) reside in a specific niche in the bone marrow, however, biological features of this niche are still not fully understood. Given the interactions of MSCs with endothelial cells in different tissues, bone marrow MSC niche may influence the biological features of endothelial progenitor cells (EPCs). To understand the role of the sympathetic nervous system in regulation of the MSC niche, we examined whether the manipulation of the MSC niche via β3-adrenergic signals will affect EPC features. A selective β3 agonist (BRL37344) or a β3 antagonist (SR59230A) was administered in mice for 2 weeks to determine the potential effects of these regimens on the population of CD133 + stem cells in the bone marrow. Then, bone marrow-derived MSCs and EPCs were harvested and expanded from the mice to examine the effect of changes in the MSC niche on EPC features. Improved MSC colony forming potency with increased bone marrow stromal cell-derived factor 1 (SDF-1) (also known as C-X-C motif chemokine 12 [CXCL12]) expression was shown as a result of intensification of the bone marrow adrenergic signals through BRL37344 injection. On the other hand, the blockage of these signals limited the expression level of SDF-1 and resulted in bone marrow enrichment of CD133 + cells. Manipulation of the MSC niche and decreased SDF-1 expression via SR59230A injection also prompted EPCs to form more colonies with augmented proliferation and differentiation capacity. Overall, our results indicate that the β3-adrenergic signals regulate the MSC niche, thereby resulting in modulation of EPC biological features. J. Cell. Biochem. 118: 4753-4761, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Alterations in vasodilator-stimulated phosphoprotein (VASP) phosphorylation: associations with asthmatic phenotype, airway inflammation and β2-agonist use

Science.gov (United States)

Hastie, Annette T; Wu, Min; Foster, Gayle C; Hawkins, Gregory A; Batra, Vikas; Rybinski, Katherine A; Cirelli, Rosemary; Zangrilli, James G; Peters, Stephen P

2006-01-01

Background Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1) injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2) regular in vivo β2-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion. Methods Bronchial epithelium was obtained from asthmatic and non-asthmatic normal subjects before and after segmental allergen challenge, and after regularly inhaled albuterol, in three separate protocols. VASP phosphorylation was examined in Western blots of epithelial samples. DNA was obtained for β2-adrenergic receptor haplotype determination. Results Although VASP phosphorylation increased, it was not significantly greater after allergen challenge in asthmatics or normals. However, VASP phosphorylation in epithelium of nonasthmatic normal subjects was double that observed in asthmatic subjects, both at baseline and after challenge. Regularly inhaled albuterol significantly increased VASP phosphorylation in asthmatic subjects in both unchallenged and antigen challenged lung segment epithelium. There was also a significant increase in epithelial cells in the bronchoalveolar lavage of the unchallenged lung segment after regular inhalation of albuterol but not of placebo. The haplotypes of the β2-adrenergic receptor did not appear to associate with increased or decreased phosphorylation of VASP. Conclusion Decreased VASP phosphorylation was observed in epithelial cells of asthmatics compared to nonasthmatic normals, despite response to β-agonist. The decreased

Alterations in vasodilator-stimulated phosphoprotein (VASP phosphorylation: associations with asthmatic phenotype, airway inflammation and β2-agonist use

Directory of Open Access Journals (Sweden)

Cirelli Rosemary

2006-02-01

Full Text Available Abstract Background Vasodilator-stimulated phosphoprotein (VASP mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1 injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2 regular in vivo β2-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion. Methods Bronchial epithelium was obtained from asthmatic and non-asthmatic normal subjects before and after segmental allergen challenge, and after regularly inhaled albuterol, in three separate protocols. VASP phosphorylation was examined in Western blots of epithelial samples. DNA was obtained for β2-adrenergic receptor haplotype determination. Results Although VASP phosphorylation increased, it was not significantly greater after allergen challenge in asthmatics or normals. However, VASP phosphorylation in epithelium of nonasthmatic normal subjects was double that observed in asthmatic subjects, both at baseline and after challenge. Regularly inhaled albuterol significantly increased VASP phosphorylation in asthmatic subjects in both unchallenged and antigen challenged lung segment epithelium. There was also a significant increase in epithelial cells in the bronchoalveolar lavage of the unchallenged lung segment after regular inhalation of albuterol but not of placebo. The haplotypes of the β2-adrenergic receptor did not appear to associate with increased or decreased phosphorylation of VASP. Conclusion Decreased VASP phosphorylation was observed in epithelial cells of asthmatics compared to nonasthmatic normals, despite response to β-agonist

β2-Adrenergic Receptor Knockout Mice Exhibit A Diabetic Retinopathy Phenotype

Science.gov (United States)

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

2013-01-01

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

PPARα-Independent Arterial Smooth Muscle Relaxant Effects of PPARα Agonists

Directory of Open Access Journals (Sweden)

Neerupma Silswal

2012-01-01

Full Text Available We sought to determine direct vascular effects of peroxisome proliferator-activated receptor alpha (PPARα agonists using isolated mouse aortas and middle cerebral arteries (MCAs. The PPARα agonists GW7647, WY14643, and gemfibrozil acutely relaxed aortas held under isometric tension and dilated pressurized MCAs with the following order of potency: GW7647≫WY14643>gemfibrozil. Responses were endothelium-independent, and the use of PPARα deficient mice demonstrated that responses were also PPARα-independent. Pretreating arteries with high extracellular K+ attenuated PPARα agonist-mediated relaxations in the aorta, but not in the MCA. In the aorta, the ATP sensitive potassium (KATP channel blocker glibenclamide also impaired relaxations whereas the other K+ channel inhibitors, 4-aminopyridine and Iberiotoxin, had no effect. In aortas, GW7647 and WY14643 elevated cGMP levels by stimulating soluble guanylyl cyclase (sGC, and inhibition of sGC with ODQ blunted relaxations to PPARα agonists. In the MCA, dilations were inhibited by the protein kinase C (PKC activator, phorbol 12,13-dibutyrate, and also by ODQ. Our results demonstrated acute, nonreceptor-mediated relaxant effects of PPARα agonists on smooth muscle of mouse arteries. Responses to PPARα agonists in the aorta involved KATP channels and sGC, whereas in the MCA the PKC and sGC pathways also appeared to contribute to the response.

Molecular interactions of agonist and inverse agonist ligands at serotonin 5-HT2C G protein-coupled receptors: computational ligand docking and molecular dynamics studies validated by experimental mutagenesis results

Science.gov (United States)

Córdova-Sintjago, Tania C.; Liu, Yue; Booth, Raymond G.

2015-02-01

To understand molecular determinants for ligand activation of the serotonin 5-HT2C G protein-coupled receptor (GPCR), a drug target for obesity and neuropsychiatric disorders, a 5-HT2C homology model was built according to an adrenergic β2 GPCR (β2AR) structure and validated using a 5-HT2B GPCR crystal structure. The models were equilibrated in a simulated phosphatidyl choline membrane for ligand docking and molecular dynamics studies. Ligands included (2S, 4R)-(-)-trans-4-(3'-bromo- and trifluoro-phenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalene-2-amine (3'-Br-PAT and 3'-CF3-PAT), a 5-HT2C agonist and inverse agonist, respectively. Distinct interactions of 3'-Br-PAT and 3'-CF3-PAT at the wild-type (WT) 5-HT2C receptor model were observed and experimental 5-HT2C receptor mutagenesis studies were undertaken to validate the modelling results. For example, the inverse agonist 3'-CF3-PAT docked deeper in the WT 5-HT2C binding pocket and altered the orientation of transmembrane helices (TM) 6 in comparison to the agonist 3'-Br-PAT, suggesting that changes in TM orientation that result from ligand binding impact function. For both PATs, mutation of 5-HT2C residues S3.36, T3.37, and F5.47 to alanine resulted in significantly decreased affinity, as predicted from modelling results. It was concluded that upon PAT binding, 5-HT2C residues T3.37 and F5.47 in TMs 3 and 5, respectively, engage in inter-helical interactions with TMs 4 and 6, respectively. The movement of TMs 5 and 6 upon agonist and inverse agonist ligand binding observed in the 5-HT2C receptor modelling studies was similar to movements reported for the activation and deactivation of the β2AR, suggesting common mechanisms among aminergic neurotransmitter GPCRs.

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

Science.gov (United States)

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

2018-06-01

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

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

Science.gov (United States)

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

2010-01-01

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

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

International Nuclear Information System (INIS)

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

2005-01-01

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

Adrenal medullary regulation of rat renal cortical adrenergic receptors

International Nuclear Information System (INIS)

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

1987-01-01

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

Specificity and impact of adrenergic projections to the midbrain dopamine system

Science.gov (United States)

Mejias-Aponte, Carlos A.

2016-01-01

Dopamine (DA) is a neuromodulator that regulates different brain circuits involved in cognitive functions, motor coordination, and emotions. Dysregulation of DA is associated with many neurological and psychiatric disorders such as Parkinson’s disease and substance abuse. Several lines of research have shown that the midbrain DA system is regulated by the central adrenergic system. This review focuses on adrenergic interactions with midbrain DA neurons. It discusses the current neuroanatomy including source of adrenergic innervation, type of synapses, and adrenoceptors expression. It also discusses adrenergic regulation of DA cell activity and neurotransmitter release. Finally, it reviews several neurological and psychiatric disorders where changes in adrenergic system are associated with dysregulation of the midbrain DA system. PMID:26820641

The selective alpha7 nicotinic acetylcholine receptor agonist PNU-282987 [N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride] enhances GABAergic synaptic activity in brain slices and restores auditory gating deficits in anesthetized rats.

Science.gov (United States)

Hajós, M; Hurst, R S; Hoffmann, W E; Krause, M; Wall, T M; Higdon, N R; Groppi, V E

2005-03-01

Schizophrenic patients are thought to have an impaired ability to process sensory information. This deficit leads to disrupted auditory gating measured electrophysiologically as a reduced suppression of the second of paired auditoryevoked responses (P50) and is proposed to be associated with decreased function and/or expression of the homomeric alpha7 nicotinic acetylcholine receptor (nAChR). Here, we provide evidence that N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-282987), a novel selective agonist of the alpha7 nAChR, evoked whole-cell currents from cultured rat hippocampal neurons that were sensitive to the selective alpha7 nAChR antagonist methyllycaconitine (MLA) and enhanced GABAergic synaptic activity when applied to hippocampal slices. Amphetamine-induced sensory gating deficit, determined by auditory-evoked potentials in hippocampal CA3 region, was restored by systemic administration of PNU-282987 in chloral hydrate-anesthetized rats. Auditory gating of rat reticular thalamic neurons was also disrupted by amphetamine; however, PNU-282987 normalized gating deficit only in a subset of tested neurons (6 of 11). Furthermore, PNU-282987 improved the inherent hippocampal gating deficit occurring in a subpopulation of anesthetized rats, and enhanced amphetamine-induced hippocampal oscillation. We propose that the alpha7 nAChR agonist PNU-282987, via modulating/enhancing hippocampal GABAergic neurotransmission, improves auditory gating and enhances hippocampal oscillatory activity. These results provide further support for the concept that drugs that selectively activate alpha7 nAChRs may offer a novel, potential pharmacotherapy in treatment of schizophrenia.

Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus.

Science.gov (United States)

Dahl, D; Sarvey, J M

1989-01-01

The study presented here indicates that norepinephrine (NE) selectively induces long-lasting modifications of synaptically mediated responses in the dentate gyrus of the rat hippocampal slice. A low concentration of NE (1.0 microM; in the presence of 50 microM phentolamine, an alpha-adrenergic antagonist) or a 1.0 microM concentration of the specific beta-adrenergic agonist isoproterenol induced long-lasting pathway-specific alterations of granule cell electrophysiological responses. Excitatory postsynaptic potentials and population spikes evoked by stimulation of the medial perforant pathway (PP) were potentiated for more than 45 min. In contrast, responses to lateral PP stimulation were depressed for the same period. Both potentiation and depression were blocked by the beta-adrenergic antagonist propranolol (1.0 microM). These results indicate that NE can act differentially on projections to the dentate gyrus arising in the entorhinal cortex. Such selective persistent modifications of cortical circuits may be involved in processes in the mammalian brain underlying attention, learning, and memory. PMID:2734319

Nature and regulation of the insulin receptor: structure and function

International Nuclear Information System (INIS)

Czech, M.P.

1985-01-01

Native, cell-surface insulin receptor consists of two glycoprotein subunit types with apparent masses of about 125,000 daltons (alpha subunit) and 90,000 daltons (beta subunit). The alpha and beta insulin-receptor subunits seem to have distinct functions such that alpha appears to bind hormone whereas beta appears to possess intrinsic tyrosine kinase activity. In detergent extracts, insulin activates receptor autophosphorylation of tyrosine residues on its beta subunit, whereas in the presence of reductant, the alpha subunit is also phosphorylated. In intact cells, insulin activates serine/threonine phosphorylation of insulin receptor beta subunit as well as tyrosine phosphorylation. The biological role of the receptor-associated tyrosine kinase is not known. The insulin receptor kinase is regulated by beta-adrenergic agonists and other agents that elevate cAMP in adipocytes, presumably via the cAMP-dependent protein kinase. Such agents decrease receptor affinity for insulin and partially uncouple receptor tyrosine kinase activity from activation by insulin. These effects appear to contribute to the biological antagonism between insulin and beta-agonists. These data suggest the hypothesis that a complex network of tyrosine and serine/threonine phosphorylations on the insulin receptor modulate its binding and kinase activities in an antagonistic manner

Glutamine 57 at the complementary binding site face is a key determinant of morantel selectivity for {alpha}7 nicotinic receptors.

Science.gov (United States)

Bartos, Mariana; Price, Kerry L; Lummis, Sarah C R; Bouzat, Cecilia

2009-08-07

Nicotinic receptors (AChRs) play key roles in synaptic transmission. We explored activation of neuronal alpha7 and mammalian muscle AChRs by morantel and oxantel. Our results revealed a novel action of morantel as a high efficacy and more potent agonist than ACh of alpha7 receptors. The EC(50) for activation by morantel of both alpha7 and alpha7-5HT(3A) receptors is 7-fold lower than that determined for ACh. The minimum morantel concentration required to activate alpha7-5HT(3A) channels is 6-fold lower than that of ACh, and activation episodes are more prolonged than in the presence of ACh. By contrast, oxantel is a weak agonist of alpha7 and alpha7-5HT(3A), and both drugs are very low efficacy agonists of muscle AChRs. The replacement of Gln(57) in alpha7 by glycine, which is found in the equivalent position of the muscle AChR, decreases the efficacy for activation and turns morantel into a partial agonist. The reverse mutation in the muscle AChR (epsilonG57Q) increases 7-fold the efficacy of morantel. The mutations do not affect activation by ACh or oxantel, indicating that this position is selective for morantel. In silico studies show that the tetrahydropyrimidinyl group, common to both drugs, is close to Trp(149) of the principal face of the binding site, whereas the other cyclic group is proximal to Gln(57) of the complementary face in morantel but not in oxantel. Thus, position 57 at the complementary face is a key determinant of the high selectivity of morantel for alpha7. These results provide new information for further progress in drug design.

Intact calcium signaling in adrenergic-deficient embryonic mouse hearts.

Science.gov (United States)

Peoples, Jessica N; Taylor, David G; Katchman, Alexander N; Ebert, Steven N

2018-01-22

Mouse embryos that lack the ability to produce the adrenergic hormones, norepinephrine (NE) and epinephrine (EPI), due to disruption of the dopamine beta-hydroxylase (Dbh -/- ) gene inevitably perish from heart failure during mid-gestation. Since adrenergic stimulation is well-known to enhance calcium signaling in developing as well as adult myocardium, and impairments in calcium signaling are typically associated with heart failure, we hypothesized that adrenergic-deficient embryonic hearts would display deficiencies in cardiac calcium signaling relative to adrenergic-competent controls at a developmental stage immediately preceding the onset of heart failure, which first appears beginning or shortly after mouse embryonic day 10.5 (E10.5). To test this hypothesis, we used ratiometric fluorescent calcium imaging techniques to measure cytosolic calcium transients, [Ca 2+ ] i in isolated E10.5 mouse hearts. Our results show that spontaneous [Ca 2+ ] i oscillations were intact and robustly responded to a variety of stimuli including extracellular calcium (5 mM), caffeine (5 mM), and NE (100 nM) in a manner that was indistinguishable from controls. Further, we show similar patterns of distribution (via immunofluorescent histochemical staining) and activity (via patch-clamp recording techniques) for the major voltage-gated plasma membrane calcium channel responsible for the L-type calcium current, I Ca,L , in adrenergic-deficient and control embryonic cardiac cells. These results demonstrate that despite the absence of vital adrenergic hormones that consistently leads to embryonic lethality in vivo, intracellular and extracellular calcium signaling remain essentially intact and functional in embryonic mouse hearts through E10.5. These findings suggest that adrenergic stimulation is not required for the development of intracellular calcium oscillations or extracellular calcium signaling through I Ca,L and that aberrant calcium signaling does not likely contribute

NCBI nr-aa BLAST: CBRC-XTRO-01-3247 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-XTRO-01-3247 sp|P97718|ADA1A_MOUSE Alpha-1A adrenergic receptor (Alpha 1A-adre...noceptor) (Alpha 1A-adrenoreceptor) (Alpha-1C adrenergic receptor) gb|AAC02658.1| alpha 1A-adrenergic receptor [Mus musculus] P97718 0.0 69% ...

NCBI nr-aa BLAST: CBRC-MMUS-14-0085 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-MMUS-14-0085 sp|P97718|ADA1A_MOUSE Alpha-1A adrenergic receptor (Alpha 1A-adre...noceptor) (Alpha 1A-adrenoreceptor) (Alpha-1C adrenergic receptor) gb|AAC02658.1| alpha 1A-adrenergic receptor [Mus musculus] P97718 0.0 99% ...

Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats

DEFF Research Database (Denmark)

Thomsen, Morten Skøtt; El-Sayed, Mona; Mikkelsen, Jens D

2011-01-01

of repeated administration of α7 nAChR agonists. We further compare the effect of agonists to that of α7 nAChR positive allosteric modulators (PAMs), which do not induce upregulation of the α7 nAChR. Using the social discrimination test as a measure of short-term memory, we show that the α7 nAChR agonist A......-582941 improves short-term memory immediately after repeated (7× daily), but not a single administration. The α7 nAChR PAMs PNU-120596 and AVL-3288 do not affect short-term memory immediately after a single or repeated administration. This demonstrates a fundamental difference in the behavioral effects...... of agonists and PAMs that may be relevant for clinical development. Importantly, A-582941 and AVL-3288 increase short-term memory 24 hrs after repeated, but not a single, administration, suggesting that repeated administration of both agonists and PAMs may produce sustained effects on cognitive performance...

Activation of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

Energy Technology Data Exchange (ETDEWEB)

Kimura, Rino [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Takahashi, Nobuyuki, E-mail: nobu@kais.kyoto-u.ac.jp [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Murota, Kaeko [Department of Life Science, School of Science and Engineering, Kinki University, Osaka 770-8503 (Japan); Yamada, Yuko [Laboratory of Physiological Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Moriyama, Tatsuya [Department of Applied Cell Biology, Graduate School of Agriculture, Kinki University, Nara 631-8505 (Japan); Goto, Tsuyoshi; Kawada, Teruo [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan)

2011-06-24

Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. {yields} PPAR{alpha} activation also increased oxygen consumption rate and CO{sub 2} production and decreased secretion of triglyceride and ApoB from Caco-2 cells. {yields} Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO{sub 2} production in small intestinal epithelial cells. {yields} Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. {yields} It suggested that intestinal lipid metabolism regulated by PPAR{alpha} activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-{alpha} which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPAR{alpha} activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPAR{alpha} activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPAR{alpha} agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and

2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R-2-((2-(1H-Indol-2-ylethylamino-1-Phenylethan-1-ol with Human β3-Adrenergic Activity

Directory of Open Access Journals (Sweden)

Gastón Apablaza

2017-03-01

Full Text Available The β3 adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration in USA and the MHRA (Medicines and Healthcare products Regulatory Agency in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis study on a series of potent β3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β3 adrenergic activity is given.

Evidence of changes in alpha-1/AT1 receptor function generated by diet-induced obesity.

Science.gov (United States)

Juarez, Esther; Tufiño, Cecilia; Querejeta, Enrique; Bracho-Valdes, Ismael; Bobadilla-Lugo, Rosa A

2017-11-01

To study whether hypercaloric diet-induced obesity deteriorates vascular contractility of rat aorta through functional changes in α 1 adrenergic and/or AT1 Angiotensin II receptors. Angiotensin II- or phenylephrine-induced contraction was tested on isolated aorta rings with and without endothelium from female Wistar rats fed for 7 weeks with hypercaloric diet or standard diet. Vascular expression of Angiotensin II Receptor type 1 (AT1R), Angiotensin II Receptor type 2 (AT2R), Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), inducible Nitric Oxide Synthase (iNOS) and endothelial Nitric Oxide Synthase (eNOS), as well as blood pressure, glucose, insulin and angiotensin II blood levels were measured. Diet-induced obesity did not significantly change agonist-induced contractions (Emax and pD 2 hypercaloric diet vs standard diet n.s.d.) of both intact (e+) or endothelium free (e-) vessels but significantly decrease both phenylephrine and angiotensin II contraction (Emax p obesity did not change angiotensin II AT1, AT2 receptor proteins expression but reduced COX-1 and NOS2 ( p obesity produces alterations in vascular adrenergic and angiotensin II receptor dynamics that suggest an endothelium-dependent adrenergic/angiotensin II crosstalk. These changes reflect early-stage vascular responses to obesity.

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.

The peroxisome proliferator-activated receptor alpha agonist fenofibrate has no effect on insulin sensitivity compared to atorvastatin in type 2 diabetes mellitus; a randomised, double-blind controlled trial.

Science.gov (United States)

Black, R Neil A; Ennis, Cieran N; Young, Ian S; Hunter, Steven J; Atkinson, A Brew; Bell, Patrick M

2014-01-01

Assess insulin sensitivity after treatment with a selective PPAR-alpha agonist compared to an HMG CoA reductase inhibitor in human subjects with type 2 diabetes mellitus. Thirteen subjects with Type 2 diabetes mellitus were studied in a double-blind crossover design with 4-week placebo run-in and washout and 12-week treatment periods, randomised to micronised fenofibrate 267 mg or atorvastatin 10mg daily followed by the alternate drug in the second period. Insulin resistance was measured using the isoglycaemic hyperinsulinaemic clamp method with isotope dilution. Weight, physical activity and other medications did not change. Total cholesterol (mean +/- standard error) was 4.60+/-0.21 versus 3.9+/-0.22 mmol/L after fenofibrate and atorvastatin respectively, p19 versus 1.95+/-0.23 mmol/L, p1.64+/-0.23 versus 1.84+/-0.26 mmol/L, pInsulin-stimulated whole-body glucose disposal (35.4+/-3.1 versus 33.2+/-3.0 μmol/kg/min) and nadir endogenous glucose production (6.2+/-1.4 versus 7.0+/-1.1 μmol/kg/min) revealed no significant differences in effects of the treatments. In human subjects with Type 2 diabetes mellitus there were characteristic differences in lipid profile changes but no difference in insulin sensitivity after treatment with micronised fenofibrate compared to atorvastatin. This study finds no evidence of increased insulin sensitivity using this selective PPAR-alpha agonist over a commonly used statin at these doses. Copyright © 2014 Elsevier Inc. All rights reserved.

Nitric oxide and the non-adrenergic non-cholinergic neurotransmission

NARCIS (Netherlands)

Boeckxstaens, G. E.; Pelckmans, P. A.

1997-01-01

In the early 1960s, the first evidence was reported demonstrating neurally mediated responses in the presence of adrenergic and cholinergic antagonists, leading to the introduction of the concept of non-adrenergic non-cholinergic neurotransmission. The inhibitory component of this part of the

In vitro study of alpha 2-adrenoceptor turnover and metabolism using the adenocarcinoma cell line HT29

International Nuclear Information System (INIS)

Paris, H.; Taouis, M.; Galitzky, J.

1987-01-01

The biosynthesis rate of the receptor was studied in postconfluent HT29 cells, when its density expressed as fmol/mg of cell membrane protein is constant, by following the recovery of the receptor binding capacity after blockade with the non-reversible alpha-adrenergic antagonist benextramine. Study of the inhibition of [ 3 H]yohimbine and [ 3 H]UK-14,304 binding showed that benextramine was a more potent antagonist at alpha 2-adrenoceptor than phenoxybenzamine. The incubation of intact HT29 cells for 30 min in the presence of 10(-5) M benextramine irreversibly blocked more than 95% of the alpha 2-adrenoceptors and totally suppressed the inhibitory effect of UK-14,304 on cyclic AMP production. The blockade appeared specific, since benextramine effects were prevented by alpha 2-adrenergic agents. Moreover, neither vasoactive intestinal polypeptide responsiveness nor other tested aspects of the regulation of the adenylate cyclase was altered by the treatment. Study of the time course of receptor recovery after irreversible blockade indicated that alpha 2-adrenoceptors reappeared in the cells with a monoexponential kinetic. The linearization of the repopulation curve obtained with the labeled antagonist [ 3 H]yohimbine allowed the determination of the rate constant for receptor degradation (k = 0.0268 +/- 0.0025 hr-1) and the rate of receptor synthesis (6.91 +/- 0.64 fmol/mg of cell membrane protein/hr) corresponding to the synthesis of about 500 receptors/cell/hr. The alpha 2-adrenoceptor half-life was 26 +/- 3 hr. Measurement of the biological effects associated to the alpha-adrenoceptor stimulation during the course of receptor recovery indicated a relationship between the number of cell receptors and the percentage of inhibition of the cyclic AMP accumulation induced by forskolin

Effects of the new imidazopyridine CL 86-02-01 on isolated papillary muscle of guinea-pig hearts.

Science.gov (United States)

Studenik, C; Lemmens-Gruber, R; Heistracher, P

1998-06-01

Inotropic activity and the effect of CL 86-02-01 (2-(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imidazo[4,5-c]pyridine hydrochloride, CAS 109 792-24-7) on membrane resting and action potentials were studied in isolated guinea-pig papillary muscles. Membrane resting potential and action potential parameters were not significantly changed, while CL 86-02-01 exerted a concentration-dependent inotropic effect by increasing the maximum rate of force development and maximum rate of force relaxation. Time to peak force, relaxation time and total contraction time were reduced. These effects are similar to those of beta-adrenergic drugs and phosphodiesterase inhibitors, but markedly differ from those described for other positive inotropic agents like cardiac glycosides, calcium agonists, alpha-adrenergic drugs or increased extracellular calcium concentration.

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

International Nuclear Information System (INIS)

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

1989-01-01

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

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

International Nuclear Information System (INIS)

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

1988-01-01

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

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

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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.

Adrenergic Blockade Bi-directionally and Asymmetrically Alters Functional Brain-Heart Communication and Prolongs Electrical Activities of the Brain and Heart during Asphyxic Cardiac Arrest

Science.gov (United States)

Tian, Fangyun; Liu, Tiecheng; Xu, Gang; Li, Duan; Ghazi, Talha; Shick, Trevor; Sajjad, Azeem; Wang, Michael M.; Farrehi, Peter; Borjigin, Jimo

2018-01-01

Sudden cardiac arrest is a leading cause of death in the United States. The neurophysiological mechanism underlying sudden death is not well understood. Previously we have shown that the brain is highly stimulated in dying animals and that asphyxia-induced death could be delayed by blocking the intact brain-heart neuronal connection. These studies suggest that the autonomic nervous system plays an important role in mediating sudden cardiac arrest. In this study, we tested the effectiveness of phentolamine and atenolol, individually or combined, in prolonging functionality of the vital organs in CO2-mediated asphyxic cardiac arrest model. Rats received either saline, phentolamine, atenolol, or phentolamine plus atenolol, 30 min before the onset of asphyxia. Electrocardiogram (ECG) and electroencephalogram (EEG) signals were simultaneously collected from each rat during the entire process and investigated for cardiac and brain functions using a battery of analytic tools. We found that adrenergic blockade significantly suppressed the initial decline of cardiac output, prolonged electrical activities of both brain and heart, asymmetrically altered functional connectivity within the brain, and altered, bi-directionally and asymmetrically, functional, and effective connectivity between the brain and heart. The protective effects of adrenergic blockers paralleled the suppression of brain and heart connectivity, especially in the right hemisphere associated with central regulation of sympathetic function. Collectively, our results demonstrate that blockade of brain-heart connection via alpha- and beta-adrenergic blockers significantly prolonged the detectable activities of both the heart and the brain in asphyxic rat. The beneficial effects of combined alpha and beta blockers may help extend the survival of cardiac arrest patients. PMID:29487541