Human/porcine endothelin-1 (ET-1) dose-dependently increased perfusion pressure in both Krebs-Henseleit and blood-perfused superior mesenteric arterial bed preparations of the rat. In vitro, it was a partial agonist relative to two analogs, [Ala1,15]- and [Ala3,11]-ET-1, and the maximum response was increased by removal of the endothelium. Endothelial destruction had no effect on the responses to either [Ala1,15]- or [Ala3,11]-ET-1. [Ala1,3,11,15]-ET-1 was not an agonist in vitro but was a partial agonist relative to ET-1 and [Ala1,15]- and [Ala3,11]-ET-1 in vivo. Also, the responses to [Ala1,15]-ET-1 in the blood-perfused preparation were best described by a two-site model. These results suggest that there may be two types of receptor for these peptides. In vivo, 5 mg/kg of indomethacin potentiated the maximum response to ET-1, suggesting that its actions may be opposed by vasodilator cyclo-oxygenase products.