Both endothelin-1 (ET-1) and platelet-activating factor (PAF) have been suggested to play a role in the regulation of the cardiovascular system. In view of the limited data regarding the interaction between ET-1 and PAF, the hemodynamic effects of ET-1 and PAF, either alone or in combination, were investigated in the current study. Anesthetized male Sprague Dawley rats received bolus intravenous injections of ET-1 (1 and 2 nmol/kg) and/or PAF (0.075, 0.15 and 0.3 nmol/kg). In some experiments, the ET receptor antagonist, FR-139317 (2.5 or 5 mg/kg), were injected 5 min before the administration of ET-1 or PAF. ET-1 caused a biphasic response consisting of an initial depressor followed by a delayed but sustained pressor response. Injection of PAF to anesthetized rats resulted only in a decrease in arterial blood pressure. Interestingly, the pressor effect of ET-1 was significantly enhanced in the concomitant presence of PAF. Pretreatment with FR-139317 inhibited the magnitude of ET-1-induced hypertension and increased the duration of the depressor action of ET-1. The time-course of PAF-induced decrease of arterial blood pressure was also prolonged in rats pretreated with FR-139317. These data therefore suggested that ET receptors were activated, either directly or indirectly, by PAF, possibly to facilitate the return of blood pressure to resting level following a depressor response. Thus the activation of ET receptors by PAF might result in the enhancement of the pressor response of ET-1 observed in the current study.