			Home About us Contact

AR Agonist (ar + agonist)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Evidence against ,2 -adrenoceptors mediating relaxation in rat thoracic aortae: ,2 -agonists relaxation depends on interaction with ,1 -adrenoceptors

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2006
Enrique F. Castillo
Abstract In rat aorta, the presence of functional ,2 -adrenoceptors (,2 -AR) was investigated in ring preparations preconstricted with ,1 -adrenergic and non- ,1 -adrenergic agonists. Particularly, the hypothetical interference of ,2 -AR agonists with ,1 -AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to ,2 -AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 × 10,6 m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (,log EC50) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, NG -nitro- l -arginine methyl ester (l -NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective ,2 -AR antagonist, rauwolscine (,1 × 10,6 m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F2, (3 × 10,7 m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration,contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the ,1D -AR selective antagonist, BMY 7378, and rauwolscine. The pA2 and pKB values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the ,1D -AR. The other selective ,2 -AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional ,2 -AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the ,1 -AR), inhibitory and excitatory, interaction with ,1 -ARs. [source]

Up-Regulation and Functional Effect of Cardiac ,3 -Adrenoreceptors in Alcoholic Monkeys

ALCOHOLISM, Issue 7 2010
Heng-Jie Cheng
Background:, Recent studies link altered cardiac ,-adrenergic receptor (AR) signaling to the pathology of alcoholic cardiomyopathy (ACM). However, the alteration and functional effect of ,3 -AR activation in ACM are unknown. We tested the hypothesis that chronic alcohol intake causes an up-regulation of cardiac ,3 -AR, which exacerbates myocyte dysfunction and impairs calcium regulation, thereby directly contributing to the progression of ACM. Methods:, We compared myocyte ,3 - and ,1 -AR expression and myocyte contractile ([Ca2+]i), transient ([Ca2+]iT), and Ca2+ current (ICa,L) responses to ,- and ,3 -AR stimulation in myocytes obtained from left ventricle (LV) tissue samples obtained from 10 normal control (C) and 16 monkeys with self-administered alcohol for 12 months prior to necropsy: 6 moderate (M) and 10 heavy (H) drinkers with group average alcohol intakes of 1.5 ± 0.2 and 3.3 ± 0.2 g/kg/d, respectively. Results:, Compared with control myocytes (C), in alcoholic cardiomyocytes, basal cell contraction (dL/dtmax, ,39%, H: 69.8 vs. C: 114.6 ,m/s), relaxation (dR/dtmax, ,37%, 58.2 vs. 92.9 ,m/s), [Ca2+]iT (,34%, 0.23 vs. 0.35), and ICa,L (,25%, 4.8 vs. 6.4pA/pF) were all significantly reduced. Compared with controls, in moderate and heavy drinkers, ,1 -AR protein levels decreased by 23% and 42%, but ,3 -AR protein increased by 46% and 85%, respectively. These changes were associated with altered myocyte functional responses to ,-AR agonist, isoproterenol (ISO), and ,3 -AR agonist, BRL-37344 (BRL). Compared with controls, in alcoholic myocytes, ISO (10,8 M) produced significantly smaller increases in dL/dtmax (H: 40% vs. C: 71%), dR/dtmax (37% vs. 52%), [Ca2+]iT (17% vs. 37%), and ICa,L (17% vs. 27%), but BRL (10,8 M) produced a significantly greater decrease in dL/dtmax (H: ,23% vs. C: ,11%), [Ca2+]iT (,30% vs. ,11%), and ICa,L (,28% vs. ,17%). Conclusions:, Chronic alcohol consumption down-regulates cardiac ,1 - and up-regulates ,3 -ARs, contributing to the abnormal response to catecholamines in ACM. The up-regulation of cardiac ,3 -AR signaling enhances inhibition of LV myocyte contraction and relaxation and exacerbates the dysfunctional [Ca2+]i regulation and, thus, may precede the development of ACM. [source]

5,-dihydrotestosterone inhibits 1,,25-dihydroxyvitamin D3 -induced expression of CYP24 in human prostate cancer cells

THE PROSTATE, Issue 3 2005
Yan-Ru Lou
Abstract BACKGROUND A cross-talk between 1,,25-dihydroxyvitamin D3 [1,,25-(OH)2D3] and 5,-dihydrotestosterone (DHT) in the growth inhibition has been demonstrated, but the mechanism is unknown. METHODS The expression of 25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) was measured using a real-time quantitative RT-PCR assay and the catabolism of 1,,25-(OH)2D3 was measured using a radioreceptor assay. RESULTS Real-time RT-PCR showed that DHT at 1,100 nM significantly inhibited 1,,25-(OH)2D3 -induced expression of 24-hydroxylase in LNCaP cells. Furthermore, the catabolism of 1,,25-(OH)2D3 was decreased by 10 nM DHT. An androgen receptor (AR) antagonist, Casodex antagonized the DHT effect, whereas an AR agonist (due to the mutant AR in LNCaP cells) hydroxyflutamide did not. CONCLUSIONS We demonstrated, for the first time, that DHT reduces the ability of 1,,25-(OH)2D3 to induce 24-hydroxylase expression. Our results not only support the earlier finding of a cross-talk between androgen and vitamin D in human prostate cancer cells but also provide a possible mechanism how androgen and vitamin D signaling pathways may interact. © 2004 Wiley-Liss, Inc. [source]

Evidence against ,2 -adrenoceptors mediating relaxation in rat thoracic aortae: ,2 -agonists relaxation depends on interaction with ,1 -adrenoceptors

,3 -Adrenoceptors in urinary bladder,,

NEUROUROLOGY AND URODYNAMICS, Issue 6 2007
Osamu Yamaguchi
Abstract The ,-adrenoceptor (AR) is currently classified into ,1, ,2, and ,3 subtypes. A third subtype, ,3 -AR, was first identified in adipose tissue, but has also been identified in smooth muscle tissue, particularly in the gastrointestinal tract and urinary bladder smooth muscle. There is a predominant expression of ,3 -AR messenger RNA (mRNA) in human bladder, with 97% of total ,-AR mRNA being represented by the ,3 -AR subtype and only 1.5 and 1.4% by the ,1 -AR and , 2 -AR subtypes, respectively. Moreover, the presence of ,1 -, ,2 -, and ,3 -AR mRNAs in the urothelium of human bladder has been identified. The distribution of ,-AR subtypes mediating detrusor muscle relaxation is species dependent, the predominant subtype being the ,3 -AR in humans. Recent studies have suggested that cAMP-dependent routes are not exclusive mechanisms triggering the ,-AR-mediated relaxation of smooth muscle. It has been demonstrated in rats detrusor muscle that cAMP plays a greater role in ,-adrenergic relaxation against basal tone than against KCl-induced tone and that conversely calcium-activated K+ channels (BKca channels) play a greater role under the latter circumstances. In rat models, ,3 -AR agonists increase bladder capacity without influencing bladder contraction and have only weak cardiovascular side effects. Although this evidence points toward the clinical utility of ,3 -AR agonists as therapy for overactive bladder (OAB), pharmacological differences exist between rat and human ,3 -ARs. Development of compounds with high selectivity for the human ,3 -AR, identified by screening techniques using cell lines transfected with the human ,1 -, ,2 -, and ,3 -AR genes, may mitigate against such problems. The association between the tryptophan 64 arginine polymorphism in the ,3 -AR gene and idiopathic OAB is discussed. Neurourol. Urodynam. 26:752,756, 2007. © 2007 Wiley-Liss, Inc. [source]

Slow-responders to IV ,2 -adrenergic agonist therapy: Defining a novel phenotype in pediatric asthma,

PEDIATRIC PULMONOLOGY, Issue 7 2008
Christopher L. Carroll MD
Abstract Objectives While aerosolized administration of ,2 -adrenergic receptor (,2 -AR) agonists is the mainstay of treatment for pediatric asthma exacerbations, the efficacy of intravenous (IV) delivery is controversial. Failure to demonstrate improved outcomes with IV ,2 -AR agonists may be due to phenotypic differences within this patient population. Our hypothesis is that children who respond more slowly to IV ,2 -AR agonist therapy comprise a distinct phenotype. Methods Retrospective chart review of all children admitted to the ICU for status asthmaticus who were treated with IV terbutaline between December 2002 and September 2006. Results Seventy-eight children were treated with IV terbutaline according to guidelines that adjusted the dose by clinical asthma score. After examining the histogram of duration of terbutaline infusions, a 48-hr cutoff was chosen to define responsiveness. Thirty-eight (49%) children were slow-responders by this definition. There were no significant differences in baseline asthma severity or severity on admission between the slow-responders and responders. Slow-responders required significantly higher total doses of IV terbutaline, higher maximum administration rates, and had longer ICU and hospital length of stay. Conclusion There were significant differences in outcomes between the responders and slow-responders without differences in acute or chronic illness severity. Other factors may have lead to slower response to IV ,2 -agonist therapy. Pediatr Pulmonol. 2008; 43:627,633. © 2008 Wiley-Liss, Inc. [source]