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

Heng Jie Cheng, Kathleen A. Grant, Qing Hua Han, James B. Daunais, David P. Friedman, Satoshi Masutani, William C. Little, Che Ping Cheng

    Research output: Contribution to journalArticle

    14 Scopus citations

    Abstract

    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 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. Methods: 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. Results: 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 I Ca,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%). Conclusions: 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.

    Original languageEnglish (US)
    Pages (from-to)1171-1181
    Number of pages11
    JournalAlcoholism: Clinical and Experimental Research
    Volume34
    Issue number7
    DOIs
    StatePublished - Jul 2010

    Keywords

    • Alcoholic Cardiomyopathy
    • Contractility
    • [Ca] Regulation
    • β-Adrenergic Agonists
    • β-Adrenergic Receptor

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • Toxicology
    • Psychiatry and Mental health

    Fingerprint Dive into the research topics of 'Up-regulation and functional effect of cardiac β<sub>3</sub>- adrenoreceptors in alcoholic monkeys'. Together they form a unique fingerprint.

  • Cite this

    Cheng, H. J., Grant, K. A., Han, Q. H., Daunais, J. B., Friedman, D. P., Masutani, S., Little, W. C., & Cheng, C. P. (2010). Up-regulation and functional effect of cardiac β3- adrenoreceptors in alcoholic monkeys. Alcoholism: Clinical and Experimental Research, 34(7), 1171-1181. https://doi.org/10.1111/j.1530-0277.2010.01194.x