Adenosine A1 receptor-mediated antiadrenergic effects are modulated by A2a receptor activation in rat heart

Presently, the physiological significance of myocardial adenosine A(2a) receptor stimulation is unclear. In this study, the influence of adenosine A(2a) receptor activation on A(1) receptor-mediated antiadrenergic actions was studied using constant-flow perfused rat hearts and isolated rat ventricular myocytes. In isolated perfused hearts, the selective A(2a) receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]-triazin-5-ylamino]ethyl)phenol (ZM-241385) potentiated adenosine-mediated decreases in isoproterenol (Iso; 10(-8) M)-elicited contractile responses (+dP/dt(max)) in a dose-dependent manner. The effect of ZM-241385 on adenosine-induced antiadrenergic actions was abolished by the selective A(1) receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10(-7) M), but not the selective A(3) receptor antagonist 3-ethyl-5-benzyl-2methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)- 3,5-dicarboxylate (MRS-1191, 10(-7) M). The A(2a) receptor agonist carboxyethylphenethyl-aminoethyl-carboxyamidoadenosine (CGS-21680) at 10(-5) M attenuated the antiadrenergic effect of the selective A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA), whereas CSC did not influence the antiadrenergic action of this agonist. In isolated ventricular myocytes, CSC potentiated the inhibitory action of adenosine on Iso (2 x 10(-7) M)-elicited increases in intracellular Ca(2+) concentration ([Ca(2+)](i)) transients but did not influence Iso-induced changes in [Ca(2+)](i) transients in the absence of exogenous adenosine. These results indicate that adenosine A(2a) receptor antagonists enhance A(1)-receptor-induced antiadrenergic responses and that A(2a) receptor agonists attenuate (albeit to a modest degree) the antiadrenergic actions of A(1) receptor activation. In conclusion, the data in this study support the notion that an important physiological role of A(2a), receptors in the normal mammalian myocardium is to reduce A(1) receptor-mediated antiadrenergic actions.