The effects of histamine on the contractile force, spontaneous rate of contraction, and cyclic AMP and cyclic GMP content were investigated in isolated rabbit cardiac preparations. Histamine had a positive inotropic effect in the left atrium and papillary muscle, and a positive chronotropic effect in the right atrium. Both effects were produced in a concentration-dependent manner. Impromidine also induced the same effect in the left and right atrium as histamine did. The effects produced by histamine and impromidine were antagonized by cimetidine and tiotidine. On the other hand, the positive inotropic response of papillary muscle to histamine was antagonized by mepyramine and chlorpheniramine and was mimicked by 2-(2-pyridyl)ethylamine. Impromidine at a high concentration induced a small increase in the contractile force, an effect which was antagonized by cimetidine. Histamine significantly increased the cyclic AMP levels in both atria but not in papillary muscles. The increase in cyclic AMP was abolished by cimetidine. Histamine also increased cyclic GMP levels in all of the preparations. The increase in cyclic GMP was abolished by chlorpheniramine. The results suggest that both H1- and H2-receptors exist in all parts of the rabbit heart. However, the positive inotropic and chronotropic effects induced by histamine in left and right atrium are mediated predominantly via H2-receptors, whereas the positive inotropic effect in papillary muscle is predominantly mediated via H1 receptors.