We used standard microelectrode techniques to study the histamine induced or enhanced delayed afterdepolarization (DAD) and triggered activity (TA) of guinea-pig papillary muscle superfused with low-potassium Tyrode's solution. Before histamine, a series of driven action potentials did not induce DAD and TA. Immediately after histamine (10(-5)M), DAD was induced and, finally, TA was induced after high rate pacing (150/min to 300/min). The effect of histamine was antagonized by cimetidine (5 X 10(-6) to 5 X 10(-5)M) but not by diphenhydramine. Also, the amplitude of DAD decreased after verapamil (10(-7) to 3 X 10(-6)M) and lidocaine (4 X 10(-5) to 8 X 10(-5)M). To investigate indirect evidence of increased cyclic AMP mediation in this histamine induced DAD, we studied the effects of a phosphodiesterase inhibitor (papaverine 10(-5)M) or activator (N-methylimidazole 20 mM) on the histamine induced or enhanced DAD. The former enhanced and the latter depressed the histamine-induced (or enhanced) DAD. Thus, histamine may induce or enhance the DAD and TA by increasing the slow inward current. This mechanism may be mediated by histamine H2-receptors and the adenylate cyclase system in the cardiac ventricular muscle.