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Up‐Regulation and Functional Effect of Cardiac β 3 ‐Adrenoreceptors in Alcoholic Monkeys
Author(s) -
Cheng HengJie,
Grant Kathleen A.,
Han QingHua,
Daunais James B.,
Friedman David P.,
Masutani Satoshi,
Little William C.,
Cheng ChePing
Publication year - 2010
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2010.01194.x
Subject(s) - alcoholic cardiomyopathy , myocyte , ventricle , medicine , endocrinology , basal (medicine) , beta (programming language) , contraction (grammar) , receptor , adrenergic receptor , chemistry , cardiac myocyte , cardiomyopathy , heart failure , computer science , insulin , programming language
Background: Recent studies link altered cardiac β‐adrenergic receptor (AR) signaling to the pathology of alcoholic cardiomyopathy (ACM). However, the alteration and functional effect of β 3 ‐AR activation in ACM are unknown. We tested the hypothesis that chronic alcohol intake causes an up‐regulation of cardiac β 3 ‐AR, which exacerbates myocyte dysfunction and impairs calcium regulation, thereby directly contributing to the progression of ACM. Methods: We compared myocyte β 3 ‐ and β 1 ‐AR expression and myocyte contractile ([Ca 2+ ] i ), transient ([Ca 2+ ] iT ), and Ca 2+ current (I Ca,L ) responses to β‐ and β 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/dt max , −39%, H: 69.8 vs. C: 114.6 μm/s), relaxation (dR/dt max , −37%, 58.2 vs. 92.9 μm/s), [Ca 2+ ] iT (−34%, 0.23 vs. 0.35), and I Ca,L (−25%, 4.8 vs. 6.4pA/pF) were all significantly reduced. Compared with controls, in moderate and heavy drinkers, β 1 ‐AR protein levels decreased by 23% and 42%, but β 3 ‐AR protein increased by 46% and 85%, respectively. These changes were associated with altered myocyte functional responses to β‐AR agonist, isoproterenol (ISO), and β 3 ‐AR agonist, BRL‐37344 (BRL). Compared with controls, in alcoholic myocytes, ISO (10 −8 M) produced significantly smaller increases in dL/dt max (H: 40% vs. C: 71%), dR/dt max (37% vs. 52%), [Ca 2+ ] iT (17% vs. 37%), and I Ca,L (17% vs. 27%), but BRL (10 −8 M) produced a significantly greater decrease in dL/dt max (H: −23% vs. C: −11%), [Ca 2+ ] iT (−30% vs. −11%), and I Ca,L (−28% vs. −17%). Conclusions: Chronic alcohol consumption down‐regulates cardiac β 1 ‐ and up‐regulates β 3 ‐ARs, contributing to the abnormal response to catecholamines in ACM. The up‐regulation of cardiac β 3 ‐AR signaling enhances inhibition of LV myocyte contraction and relaxation and exacerbates the dysfunctional [Ca 2+ ] i regulation and, thus, may precede the development of ACM.