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

1 Department of Physiology, University of the Witwatersrand, Johannesburg, South Africa; and Departments of 2 Medicine and 3 Physiology, University of Massachusetts, Worcester, Massachusetts 01655 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/d t 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-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191, 10 7 M). The A 2a receptor agonist carboxyethylphenethyl-aminoethyl-carboxyamido-adenosine (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 × 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. A 3 receptor; perfused hearts; ventricular myocytes; isoproterenol; calcium