Up-regulation and functional effect of cardiac β3-adrenoreceptors in alcoholic monkeys.
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.
Cheng
Heng-Jie
HJ
Department of Internal Medicine-Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Grant
Kathleen A
KA
Han
Qing-Hua
QH
Daunais
James B
JB
Friedman
David P
DP
Masutani
Satoshi
S
Little
William C
WC
Cheng
Che-Ping
CP
D000437:Alcoholism / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002310:Cardiomyopathy, Alcoholic / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3 / Q000096:biosynthesis* / Q000502:physiology; D012646:Self Administration; D015854:Up-Regulation / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology
D022702:Receptors, Adrenergic, beta-3; D000431:Ethanol