Modification by islet-activating protein of direct and indirect inhibitory actions of adenosine on rat atrial contraction in relation to cyclic nucleotide metabolism.

Adenosine decreased the force of contraction of isolated rat left atria (direct action) and inhibited the positive inotropic action of isoproterenol (indirect action). The direct action of adenosine was not accompanied by changes in cyclic nucleotide levels, while the isoproterenol-induced increase in cyclic AMP level was reduced by the nucleoside. Reserpine pretreatment and pindolol did not affect the direct action of adenosine. Both the direct and indirect actions of adenosine were enhanced by dipyridamole and dilazep and inhibited by 1-methyl-3-isobutylxanthine and theophylline. Among adenosine derivatives, N6-phenylisopropyladenosine was most potent, and 2'-deoxyadenosine was least effective in inducing the negative inotropic action in the absence and presence of isoproterenol. In atria pretreated with islet-activating protein (IAP) both the direct and indirect actions of adenosine, and the actions of N6-phenylisopropyladenosine were markedly attenuated compared with those in nontreated atria. The isoproterenol-induced increase in cyclic AMP level was not reduced by adenosine in IAP-treated atria. These results indicate that adenosine produces a dual action on rat atria: it decreases the force of contraction directly by a mechanism independent of cyclic AMP metabolism, and inhibits the positive inotropic action of isoproterenol by reducing the drug-induced accumulation of cyclic AMP. IAP attenuates both of these inhibitory actions of adenosine on rat atria.