We investigated in male rats whether the prolactin releasing effect of systemically infused histamine might be attributed to a vasodilatatory action of the compound. Intraarterial infusion of histamine (3.8 mumol) over 1 min increased the plasma PRL 10-fold. This effect was prevented by prior ia infusion of the H1 receptor antagonist mepyramine and slightly augmented by prior ia infusion of the H2 receptor antagonist cimetidine. At the same time histamine caused an immediate 38% decrease in mean arterial blood pressure, which remained 15% below the initial level during the rest of the 60-min observation period. The depressor effect of histamine was prevented by pretreatment with mepyramine and partly prevented for the first 5 min by pretreatment with cimetidine. Since the H1 receptor seemed to be the predominant mediator of the histamine-induced hypotension and PRL release, a causative interaction is possible. However, when the histamine-induced decrease in blood pressure was prevented by simultaneous iv loading with saline the PRL response to histamine was still evident. Furthermore, when the histamine-induced decrease in blood pressure was mimicked by ia infusion of the vasodilator nitroprusside no effect was observed on PRL secretion. We conclude that the histamine-induced stimulation of PRL secretion is independent of the profound depressor action of the amine.