In the present work we have examined the effects of histamine on electrophysiological parameters of isolated cardiocytes acutely dissociated from adult guinea pigs. The whole cell patch clamp technique was used to examine action potential and currents. Stable recordings of calcium current (average peak amplitude of 563 +/- 256 pA per cell, n = 83) were obtained. Application of histamine (5 nM-10 microM) resulted in marked modification of action potentials and calcium current. Calcium current was enhanced by histamine in a concentration-dependent manner (half-maximal dose, 10 nM) up to 315% of the control level. Action potentials were prolonged by small doses of histamine whereas larger doses caused voltage instabilities and spontaneous arrhythmic bursts. Histamine effects were reduced by cimetidine and ranitidine (1 microM), two H2-receptor antagonists. After the calcium current was increased by intracellular perfusion of micromolar cyclic AMP saturating doses of histamine had no effect. Micromolar concentrations of acetylcholine rapidly antagonized the histamine effect. The latter results indicate that the response to histamine is based on H2-receptor-mediated activation of adenylate cyclase and cyclic AMP regulation of phosphorylation of calcium channel.