Altered signal transduction in cardiac ventricle overexpressing A(1)-adenosine receptors

Objective: The aim of the present study was to assess the effects of A(1)-adenosine receptor (A1-AR) stimulation in ventricle of A(1)-adenosine receptor overexpressing mice (transgenic mice, TG). Methods: Effects of the A(1)-adenosine receptor agonist R-PIA ((-)-N-6-phenylisopropyladenosine) on phosphorylation of phospholamban (PLB), Ca2+ transients, Ca2+ currents and cell shortening were studied in isolated ventricular cardiomyocytes. Results: R-PIA alone did not affect contractility in isolated electrically stimulated cardiomyocytes from wild-type mice (WT) or TG. However, after pre-stimulation of beta-adrenoceptors by isoproterenol, R-PIA reduced contractility in cardiomyocytes from WT but increased contractility in TG. Under the same conditions, R-PIA reduced isoproterenol-stimulated currents through L-type Ca2+ channels, Ca2+ transients and phosphorylation of PLB in cardiomyocytes from WT. In contrast, R-PIA diminished phospholamban phosphorylation induced by isoproterenol but augmented isoproterenol-elevated currents through L-type Ca2+ channels, and isoproterenol-heightened Ca2+ transients in cardiomyocytes from TG. Conclusions: We suggest that A(1)-adenosine receptor overexpression reverses the interaction of beta-adrenergic and A(1)-adenosine receptor stimulation, at least in part. Hence, the receptor/effector coupling is dependent on receptor density in this model. (C) 2003 European Society of Cardiology. Published by Elsevier B.V All rights reserved.