Infusion of endothelin-1 reduced vascular flow in the isolated perfused rat stomach. Concurrent infusion of iloprost and capsaicin, respectively, did not counteract the flow-reduction caused by endothelin-1. Infusion of prostaglandin (PG)F2 alpha caused vasoconstriction and significantly augmented the endothelin-1-induced flow reduction. In vivo, i.v. infusion of endothelin-1 (50 pmol/kg//min for 10 min) did not cause gastric mucosal damage, but enhanced injury produced by intragastric instillation of 20% ethanol. Intragastric administration of iloprost or PGF2 alpha prevented the pro-ulcerogenic effect of endothelin-1. Similarly, stimulation of afferent sensory neurons by intragastric capsaicin (0.5 mg/kg) protected against damage caused by endothelin-1 and 20% ethanol. Functional ablation of afferent sensory neurons by s.c. administration of 125 mg/kg capsaicin markedly enhanced gastric mucosal damage by intraluminal 20% ethanol. This damage was, however, not further increased by infusion of endothelin-1. These findings show that protection against the proulcerogenic effect of endothelin-1 can occur without antagonism of vasoconstriction. The findings also show that parameters involved in protection such as afferent sensory neurons do not contribute to the pro-ulcerogenic effects of endothelin-1 suggesting that protection against and potentiation of damage rely on different mechanisms.