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Thursday, May 13, 2010

Up-Regulation and Functional Effect of Cardiac β3-Adrenoreceptors in Alcoholic Monkeys



Recent studies link altered cardiac β-adrenergic receptor (AR) signaling to the pathology of alcoholic cardiomyopathy (ACM). However, the alteration and functional effect of β3-AR activation in ACM are unknown.

We tested the hypothesis that chronic alcohol intake causes an up-regulation of cardiac β3-AR, which exacerbates myocyte dysfunction and impairs calcium regulation, thereby directly contributing to the progression of ACM.

We compared myocyte β3- and β1-AR expression and myocyte contractile ([Ca2+]i), transient ([Ca2+]iT), and Ca2+ current (ICa,L) responses to β- and β3-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.

Compared with control myocytes (C), in alcoholic cardiomyocytes, basal cell contraction (dL/dtmax, −39%, H: 69.8 vs. C: 114.6 μm/s), relaxation (dR/dtmax, −37%, 58.2 vs. 92.9 μm/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, β1-AR protein levels decreased by 23% and 42%, but β3-AR protein increased by 46% and 85%, respectively. These changes were associated with altered myocyte functional responses to β-AR agonist, isoproterenol (ISO), and β3-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%).

Chronic alcohol consumption down-regulates cardiac β1- and up-regulates β3-ARs, contributing to the abnormal response to catecholamines in ACM. The up-regulation of cardiac β3-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.


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