Effects of histamine on the twitch tension, intracellular Na+ activity (aiNa), and action potential were simultaneously and continuously measured in the isolated cardiac papillary muscle of guinea pigs. In the driven fiber at 60 beats/ min, histamine induced a concentration-dependent positive inotropic effect, and apparently increased the amplitude of the action potential and shortened the duration at 3 microM, and significantly decreased aiNa by 6.7% from the control value of 4.5 +/- 0.1 mM (n = 6, p < 0.05) at 0.3 microM. Cimetidine at 10 microM did not produce any significant effect but partially antagonized the action of histamine. The respective concentrations of 1 and 3 microM histamine significantly decreased aiNa by 5.4 and 14.3% from the control 5.6 +/- 0.1 mM (n = 6, p < 0.05) in the presence of 10 microM cimetidine. Chlorpheniramine at 10 microM significantly reduced the twitch tension and aiNa, and prolonged the action potential duration. Histamine at 1 microM increased the twitch tension and decreased aiNa from 4.5 +/- 0.1 to 4.1 +/- 0.1 mM (n = 5, p < 0.05) in the presence of 10 microM chlorpheniramine. The combined application of 10 microM cimetidine and 10 microM chlorpheniramine reduced the twitch tension and abolished most effects of histamine. In high potassium solution (16.2 mM), 1 microM histamine significantly decreased aiNa by 12.9% from the control of 3.1 +/- 0.2 mM (n = 5, p < 0.05). The treatment of 0.5 or 1 microM ouabain increased the tension development and aiNa, and abolished the decrease in aiNa produced by the effect of histamine. The results suggest that histamine can directly stimulate Na-K pump in sarcolemma through means of the activation of both H1- and H2-receptors.