Histamine produced a dose-dependent relaxation of uterine strips obtained from the estrogen-primed rat uterus. The responses to histamine were blocked competitively by metiamide (10(-8)-10(-8) M), a specific H2-receptor antagonist. Propranolol, a selective beta-receptor blocker also produced competitive antagonism of the responses to histamine in the same dose range (10(-8)-10(-6) M). The pA2 value obtained for metiamide (8.9) was not significantly different from that obtained for propranolol (8.6). Nialamide (2.2 X 10(-6) M), the monoamine oxidase inhibitor, and cocaine (4.3 X 10(-6) M), the selective noradrenaline uptake blocker, potentiated the responses to histamine. However bretylium (2.4 X 10(-5) M), and adrenergic neuron blocker inhibited the responses to histamine. The combined effect of tyramine and histamine was found to be additive. Our data suggest that the histamine-induced relaxation of rat uterus may be produced through the stimulation of presynaptic H2-receptors which causes the release of noradrenaline. The released noradrenaline acts on the postsynaptic beta-receptors and produces relaxation of the rat uterus.