The role of endothelin (ET)-1 as a mediator of small intestinal mucosal perfusion failure and tissue damage was investigated in the rat using intravital fluorescence videomicroscopy. The effects of intravenous infusion of ET-1 (3 nmol/kg) on functional capillary density, mucosal thickness, and the degree of mucosal damage were evaluated. Administration of ET-1 caused pronounced mucosal injury with a significant reduction of mucosal thickness compared with vehicle-treated control animals. Concomitantly, villous functional capillary density was markedly reduced 30 and 90 min after the infusion of ET-1. ETA receptor blockade by pretreatment with BQ 610 or with the novel ETA receptor antagonist ETR-P1/FL peptide prevented ET-1 induced capillary perfusion failure and mucosal damage. In contrast, the ETB receptor antagonist IRL 1038 was not effective. These results indicate that, acting via the ETA receptor, elevated levels of circulating ET-1 under various pathophysiological conditions, such as septic or hemorrhagic shock, might impair nutritive perfusion of the intestinal mucosa and contribute to tissue injury.