Histamine is known to enhance left ventricular contractility in the guinea-pig heart by interacting with H2-receptors. We have observed that when the H2-receptor antagonists metiamide and cimetidine (3 X 10(-6) and 10(-5) M) block the positive inotropic effect of histamine, a negative inotropic effect is unmasked. This negative inotropic effect is independent of changes in rate or coronary flow, is mimicked by the selective histamine H1-receptor agonists, pyridylethylamine and thiazolylethylamine (0.3--30 microgram) and is abolished by the H1-receptor antagonist chlorpheniramine (10(-7) and 10(-6) M). Thus, the negative inotropic effect of histamine appears to be mediated by H1-receptors. Our results demonstrate that the inotropic response to histamine consists of two opposing components: an increase in contraction, mediated by H2-receptors, and a decrease in contraction, mediated by H1-receptors.