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 A₁ 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; 10⁸ 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 A₁ receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10⁷ M), but not the selective A₃ receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191, 10⁷ M). The A_2a receptor agonist carboxyethylphenethyl-aminoethyl-carboxyamido-adenosine (CGS-21680) at 10⁵ M attenuated the antiadrenergic effect of the selective A₁ receptor agonist 2-chloro-N⁶-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 × 10⁷ M)-elicited increases in intracellular Ca²⁺ concentration ([Ca²⁺]_i) transients but did not influence Iso-induced changes in [Ca²⁺]_i transients in the absence of exogenous adenosine. These results indicate that adenosine A_2a receptor antagonists enhance A₁-receptor-induced antiadrenergic responses and that A_2a receptor agonists attenuate (albeit to a modest degree) the antiadrenergic actions of A₁ 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 A₁ receptor-mediated antiadrenergic actions.

A₃ receptor; perfused hearts; ventricular myocytes; isoproterenol; calcium

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