Because histamine and adenosine are coreleased from the ischemic heart, we investigated the effects of their interaction on human myocardium. Surgical specimens of human right atrium (i.e., pectinate muscles) responded to histamine with increases in spontaneous rate and contractile force. Adenosine, and the A1-selective adenosine agonist N6-cyclopentyladenosine (CPA), reduced the spontaneous rate and suppressed the positive chronotropic and inotropic effects of histamine. CPA was more potent than adenosine in slowing the spontaneous rate and in suppressing histamine's positive chronotropic effect, suggesting that the responses to CPA and adenosine are A1-mediated. CPA was also more potent than adenosine in attenuating histamine's positive inotropic effect on human ventricular papillary muscle. The adenosine-induced suppression of histamine's effects on pectinate muscles was mimicked by carbachol, which like adenosine is known to attenuate H2-mediated histamine-induced adenylate cyclase activation. The H1-selective histamine antagonist pyrilamine potentiated histamine's chronotropic and inotropic responses, and inhibited the attenuation of these responses by adenosine or carbachol. In contrast, pyrilamine failed to modify the adenosine-induced attenuation of the cardiac stimulatory effects of dimaprit, an H2-selective histamine agonist. Our data suggest that adenosine-induced suppression of histamine's positive chronotropic and inotropic effects on human myocardium results both from an A1-mediated attenuation of H2-stimulatory effects and from the uncovering of H1 negative chronotropic and inotropic effects. Thus, the results of the histamine-adenosine interaction may exceed the "retaliatory" purpose of adenosine release and uncover H1-mediated myocardial depression.