Adenosine A(1) receptor-mediated antiadrenergic effects are modulated by A(2a) receptor activation in rat heart

Presently, the physiological significance of myocardial adenosine A(2a) rec eptor stimulation is unclear. In this study, the influence of adenosine A(2 a) receptor activation on A(1) receptor-mediated antiadrenergic actions was studied using constant-flow perfused rat hearts and isolated rat ventricul ar myocytes. In isolated perfused hearts, the selective A(2a) receptor anta gonists 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) potenti ated 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-carbox yamidoadenosine (CGS-21680) at 10(-5) M attenuated the antiadrenergic effec t of the selective A(1) receptor agonist 2-chloro-N-6-cyclopentyladenosine (CCPA), whereas CSC did not influence the antiadrenergic action of this ago nist. In isolated ventricular myocytes, CSC potentiated the inhibitory acti on of adenosine on Iso (2 x 10(-7) M)-elicited increases in intracellular C a2+ concentration ([Ca2+](i)) transients but did not influence Iso-induced changes in [Ca2+](i) transients in the absence of exogenous adenosine. Thes e results indicate that adenosine A(2a) receptor antagonists enhance A(1)-r eceptor-induced antiadrenergic responses and that A(2a) receptor agonists a ttenuate (albeit to a modest degree) the antiadrenergic actions of A(1) rec eptor activation. In conclusion, the data in this study support the notion that an important physiological role of A(2a), receptors in the normal mamm alian myocardium is to reduce A(1) receptor-mediated antiadrenergic actions .