This study was undertaken to investigate whether or not dopamine receptors are responsible for the cardiac action of domperidone and to gain a better understanding of the mechanism of the cardiac effects of this compound. In isolated electrically driven guinea-pig atria, domperidone (0.1-30 microM) produced a negative inotropic effect (-56.7 +/- 4.9% at 30 microM) and at a concentration of 0.1 microM significantly decreased the positive inotropic response to histamine (0.5-271 microM). In spontaneously beating guinea-pig atria, domperidone failed to modify the chronotropic responses elicited by dopamine and noradrenaline. In the isolated guinea-pig ileum, domperidone alone did not produce any effect, but produced a right-ward displacement of the contractile dose-response curve to histamine. At concentrations of 0.01, 0.1 and 1 microM, domperidone also depressed the maximum response to histamine. The results obtained suggest that the negative inotropic effect of domperidone is not due to dopamine or adrenergic receptor antagonism. This cardiac effect of domperidone can be partially explained by its influence on the effects of histamine acting on H1-receptors, although other mechanisms may be involved.