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Cardiovascular Research 2001 50(1):34-45; doi:10.1016/S0008-6363(01)00203-6
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

Characterization of cardiac myocyte and tissue β-adrenergic signal transduction in rats with heart failure

Hiroyuki Yoshidaa, Kouichi Tanonakaa, Yuki Miyamotoa, Tsutomu Abea, Masaya Takahashia, Madhu B Anand-Srivastavab and Satoshi Takeoa,*

aDepartment of Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
bDepartment of Physiology, Faculty of Medicine, University of Montreal, Montreal, Canada

* Corresponding author. Tel.: +81-426-76-4583; fax: +81-426-76-5560 takeos{at}ps.toyaku.ac.jp

Objective: The cellular basis of alterations in β-adrenergic signal transduction in rats with chronic heart failure (CHF) remains unclear. The aim of the present study was to examine this signal transduction system in isolated ventricular cardiomyocytes of rats with CHF. We focused on changes in the levels of stimulatory (Gs) and inhibitory G-proteins (Gi). Methods: CHF was induced in male Wistar rats by coronary artery ligation (CAL). Hemodynamic and biochemical parameters were measured 8 weeks after CAL. Alterations in contractile function and Ca2+ transients via β-adrenergic receptor signaling of cardiomyocytes isolated from rats with CHF were characterized by simultaneous measurements of cell shortening and fura-2 fluorescence intensity. Results: Coronary artery-ligated rats showed symptoms of CHF, such as decreased contractile function, increased left ventricular volume, decreased chamber stiffness, and about 40% infarct formation of the left ventricle, by 8 weeks after surgery. The contractile function and Ca2+ dynamics of cardiomyocytes from the rats with CHF remained normal under basal conditions. Only cardiac cell length was increased. The responses of peak shortening, fura-2 fluorescence ratio amplitude, and cAMP content to β-adrenoceptor stimulation were reduced in cardiomyocytes of the rats with CHF, whereas direct stimulation of adenylate cyclase did not affect the response of these variables. Cardiomyocyte Gs{alpha} protein was decreased, whereas no changes in Gi{alpha} proteins were seen in these cells. Increases in tissue Gs{alpha} and Gi{alpha} proteins in the scar zone were detected. The results on tissue levels of collagen and G-proteins in the viable left ventricle appeared to depend on the presence of nonmyocytes. Conclusions: The results suggest that impaired contractile function of cardiomyocytes is unlikely to account for global LV contractile dysfunction, and that down-regulation of β-adrenoceptors occurs in cardiomyocytes per se. The difference in changes of G-protein between the cardiomyocyte and myocardial tissue suggests an appreciable contribution of nonmyocytes to myocardial G-protein levels.

KEYWORDS Adrenergic (ant)agonists; Calcium (cellular); Contractile function; G-proteins; Heart failure; Myocytes; Signal transduction


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