Up-regulation and functional effect of cardiac β3-adrenoreceptors in alcoholic monkeys.

Abstract

BACKGROUND:

Recent studies link altered cardiac beta-adrenergic receptor (AR) signaling to the pathology of alcoholic cardiomyopathy (ACM). However, the alteration and functional effect of beta(3)-AR activation in ACM are unknown. We tested the hypothesis that chronic alcohol intake causes an up-regulation of cardiac beta(3)-AR, which exacerbates myocyte dysfunction and impairs calcium regulation, thereby directly contributing to the progression of ACM.

METHODS:

We compared myocyte beta(3)- and beta(1)-AR expression and myocyte contractile ([Ca(2+)](i)), transient ([Ca(2+)](iT)), and Ca(2+) current (I(Ca,L)) responses to beta- and beta(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 microm/s), relaxation (dR/dt(max), -37%, 58.2 vs. 92.9 microm/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, beta(1)-AR protein levels decreased by 23% and 42%, but beta(3)-AR protein increased by 46% and 85%, respectively. These changes were associated with altered myocyte functional responses to beta-AR agonist, isoproterenol (ISO), and beta(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 beta(1)- and up-regulates beta(3)-ARs, contributing to the abnormal response to catecholamines in ACM. The up-regulation of cardiac beta(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.

• Authors: Heng-Jie Cheng, Kathleen A Grant, Qing-Hua Han, James B Daunais, David P Friedman, Satoshi Masutani, William C Little, Che-Ping Cheng
• Journal: Alcoholism, clinical and experimental research (Alcohol Clin Exp Res) Vol. 34 Issue 7 Pg. 1171-81 (Jul 2010) ISSN: 1530-0277 [Electronic] England
• PMID: 20477780 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Adrenergic, beta-3
• Ethanol

Topics

• Alcoholism (metabolism, physiopathology)
• Animals
• Calcium Signaling (drug effects, physiology)
• Cardiomyopathy, Alcoholic (metabolism, physiopathology)
• Disease Models, Animal
• Ethanol (administration & dosage)
• Female
• Macaca fascicularis
• Macaca mulatta
• Male
• Myocytes, Cardiac (metabolism, pathology, physiology)
• Receptors, Adrenergic, beta-3 (biosynthesis, physiology)
• Self Administration
• Up-Regulation (physiology)
• Ventricular Dysfunction, Left (metabolism, physiopathology)