Effects of organic Ca2+ channel antagonists, Ni2+ and ryanodine on the electrophysiological and positive inotropic responses to histamine were examined in isolated guinea-pig left atria. Histamine increased force of contraction, prolonged action potential duration (APD) and hyperpolarized the membrane in a concentration-dependent manner. Histamine at a concentration of 1 mumol/l produced a dual-component positive inotropic response composed of an initial increasing phase (initial component) and a second and late developing, greater positive inotropic phase (second component), whereas causing monophasic changes in APD and resting potential. The electrophysiological and dual-component positive inotropic effects induced by histamine were antagonized by chlorpheniramine (1 mumol/l) but not by cimetidine (10 mumol/l), indicating that both effects are exclusively mediated by H1-receptors. The positive inotropic response to 1 mumol/l histamine was changed by the pretreatment with nifedipine (1 mumol/l) and nisoldipine (1 mumol/l). In the presence of these dihydropyridines, the second component was almost completely abolished, while the initial component was hardly affected. On the other hand, verapamil (3 mumol/l) and diltiazem (10 mumol/l) failed to modify the multiphasic inotropic response to histamine. None of the Ca2+ channel antagonists affected the histamine-induced APD prolongation. In the presence of Ni2+ at a concentration of 0.3 mmol/l, at which it produced no negative inotropic action, the second component of the positive inotropic effect of histamine was specifically suppressed whereas the histamine-induced APD prolongation was unaffected. Preferential attenuation of the second component was also observed in the presence of 30 nmol/l ryanodine.(ABSTRACT TRUNCATED AT 250 WORDS)