A comparison between the adenosine receptors mediating adenylate cyclase inhibition and cardiac depression in the guinea pig heart.

Stable analogues of adenosine were used to investigate the specificity of the receptors mediating its negative chronotropic and inotropic responses in isolated guinea-pig atria. The order of potencies for both responses was NECA = L-PIA = CHA = 2-chloroadenosine much greater than D-PIA. These analogues also inhibited adenylate cyclase in atrial and ventricular membranes, the order of potency being L-PIA = CHA = NECA much greater than D-PIA. The methylxanthines 8-phenyltheophylline, 1,3-diethyl-8-phenylxanthine and isobutylmethylxanthine antagonized both the pharmacologic responses of these agonists and their effect on adenylate cyclase. Antagonism produced by the methylxanthines was competitive as indicated by linear Schild plots for all three antagonists. The affinity constants obtained for the chronotropic and inotropic responses were similar to those obtained for adenylate cyclase inhibition. These results suggest that the negative inotropic and chronotropic effects of adenosine are mediated by RI adenosine receptors coupled to inhibition of adenylate cyclase.