In pentobarbital anesthetized cats, i.v. bolus injections of endothelin-1 (ET-1, 1 microgram) and ET-3 (3 micrograms) produced a rapidly appearing but short-lasting fall in aortic blood pressure followed in the case of ET-1 only by a small pressor response. When these peptides were administered repeatedly after 10- to 12-min intervals, there was a gradual attenuation of the hypotension that by the fourth injection was replaced by a monophasic pressor response. The i.v. infusion of ET-1 (0.3 microgram/min) or ET-3 (0.9 microgram/min) for 20 min produced sole systemic vasoconstriction. The decrease in blood pressure produced by an i.v. bolus injection of ET-1 and ET-3 was no longer observed 5 min after the end of the ET-1 or ET-3 infusion. In contrast, the hypotensive activity of bradykinin was not modified after the depressor responses to ET-1 and ET-3 had disappeared. Thus, the failure of i.v. bolus injections of ET-1 and ET-3 to lower blood pressure under these experimental conditions cannot be attributed to the development of tachyphylaxis to endogenous endothelium-derived relaxant factor, which is known to mediate the effects of bradykinin. These results suggest that ET-1 and ET-3 share a single vascular receptor for vasodilation, which becomes refractory upon repeated or maintained exposure to these peptides. Alternatively, this refractoriness may be due to depletion of an intracellular mediator(s) that is jointly used by the membrane binding sites of ET-1 and ET-3. Moreover, the present data suggest that the vasodilator activity of ETs depends on the rate of the peptide administration.