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

Objective: The cellular basis of alterations in beta -adrenergic signal tra nsduction in rats with chronic heart failure (CHF) remains unclear. The aim of the present study was to examine this signal transduction system in iso lated ventricular cardiomyocytes of rats with CHF. We focused on changes in the levels of stimulatory (Gs) and inhibitory G-proteins (Gi). Methods: CH F was induced in male Wistar rats by coronary artery ligation (CAL). Hemody namic and biochemical parameters were measured 8 weeks after CAL. Alteratio ns in contractile function and Ca2+ transients via beta -adrenergic recepto r signaling of cardiomyocytes isolated from rats with CHF were characterize d by simultaneous measurements of cell shortening and fura-2 fluorescence i ntensity. Results: Coronary artery-ligated rats showed symptoms of CHF, suc h as decreased contractile function, increased left ventricular volume, dec reased chamber stiffness, and about 40% infarct formation of the left ventr icle, by 8 weeks after surgery. The contractile function and Ca2+ dynamics of cardiomyocytes from the rats with CHF remained normal under basal condit ions. Only cardiac cell length was increased. The responses of peak shorten ing, fura-2 fluorescence ratio amplitude, and cAMP content to beta -adrenoc eptor stimulation were reduced in cardiomyocytes of the rats with CHF, wher eas direct stimulation of adenylate cyclase did not affect the response of these variables. Cardiomyocyte Gs alpha protein was decreased, whereas no c hanges in Gi alpha proteins were seen in these cells. Increases in tissue G s alpha and Gi alpha proteins in the scar zone were detected. The results o n tissue levels of collagen and G-proteins in the viable left ventricle app eared to depend on the presence of nonmyocytes. Conclusions: The results su ggest that impaired contractile function of cardiomyocytes is unlikely to a ccount for global LV contractile dysfunction, and that down-regulation of b eta -adrenoceptors occurs in cardiomyocytes per se. The difference in chang es of G-protein between the cardiomyocyte and myocardial tissue suggests an appreciable contribution of nonmyocytes to myocardial G-protein levels. (C ) 2001 Elsevier Science B.V. All rights reserved.