It was the aim of the present study to gain more insight into the role of extracellular calcium and of calcium from intracellular sources in the development of contractile force in the mammalian heart. In rat Langendorff hearts the effect of nifedipine, verapamil, diltiazem, bepridil and lidoflazine as well as of the intracellularly acting calcium antagonists ryanodine and TMB-8 on the increase of the left ventricular pressure induced by calcium and the sodium ionophore monensin, respectively, was studied. In rat and guinea-pig papillary muscles the influence of nifedipine, ryanodine and lidoflazine on the effect of monensin on the force of contraction was evaluated. Calcium and monensin concentration-dependently increased the left ventricular pressure in rat Langendorff hearts. The calcium-induced effect was characterized by a sharp initial rise of the left ventricular pressure which stabilized at a lower level while monensin elicited a gradual rise of the left ventricular pressure. Nifedipine, verapamil and diltiazem, applied at the EC50 and the EC80 for the reduction of the left ventricular pressure under control conditions, shifted the concentration-response curves for calcium and monensin into the right. Ryanodine, TMB-8, lidoflazine and bepridil, applied at the EC50, displaced the concentration-response curves for calcium and monensin to the right but reduced the maximal increase of the left ventricular pressure. At the EC80, these drugs almost completely abolished the positive inotropic effects elicited by calcium and monensin, respectively. In rat papillary muscles monensin did not influence the basal force of contraction. A clear positive inotropic effect was only observed in the presence of nifedipine. In guinea-pig papillary muscles monensin increased the force of contraction. This effect was not influenced by nifedipine. Lidoflazine and ryanodine suppressed the monensin-induced force of contraction by 40 and 70%, respectively. In rat Langendorff hearts differential mechanisms underlie the calcium and monensin-induced increase of the left ventricular pressure. However, the inhibitory effect of ryanodine shows that the sarcoplasmic reticulum is instrumental for the development a positive inotropic effect by calcium and monensin. Influx of calcium through dihydropyridine-sensitive channels appears not to be directly involved. In addition to calcium entry blockade, bepridil and lidoflazine seem to act at an intracellular site. These drugs may influence the release of calcium from the sarcoplasmic reticulum or directly inhibit the contractile apparatus. The unmasking of the monensin-induced positive inotropic effect in rat but not in guinea-pig papillary muscles by nifedipine further illustrates the importance of dihydropyridine-sensitive calcium channels in the rat heart and their role to supply the sarcoplasmic reticulum with calcium.