The inotropic effect of histamine on the human myocardium consists of two opposing components: positive, H2-mediated, and negative, H1-mediated. Because adenosine is known to antagonize histamine H2-responses, we assessed whether adenosine may unmask H1-mediated histamine responses in human myocardium. We found that adenosine modulates the stimulatory effects of histamine on pectinate muscles isolated from human right atrium and converts them as a function of its concentration from positive to negative. Further, histamine potentiated the tendency of adenosine to induce cardiac arrest. The H1-blocker pyrilamine antagonized the adenosine-induced suppression of the positive inotropic and chronotropic effects of histamine. Thus, our data indicate that the negative inotropic and chronotropic effects of histamine in the presence of adenosine result in part from an antagonism of H2-mediated increases in rate and contractility, and in part from an unmasking of H1-mediated decreases in the same parameters. Adenosine and histamine may be co-released in response to hypoxia or ischemia. In spite of the protection that adenosine may afford the human myocardium against excessive histamine stimulation, adenosine may also unmask the inhibitory actions of histamine, promoting dysrhythmia, and negative inotropic and chronotropic effects.