Local intra-arterial administration of endothelin-1 induced small intestinal mucosal damage in rats in a dose-dependent manner. A remarkable decrease in mucosal blood flow (15% of control values) was observed by a laser Doppler flowmetry 10 min after injection of endothelin-1 (1 nmol/kg). Endothelin-1 at this dose induced significant hemorrhagic and necrotic lesions in the small intestinal mucosa 30 min after the injection. Decreased mucosal blood flow was attenuated to some extent by the pretreatment with platelet-activating factor (PAF) inhibitor, CV-6209, superoxide dismutase plus catalase or the calcium antagonist, nicorandil. All these inhibitors significantly prevented the endothe-lin-1 -induced ischemic necrotic damage in the small intestine. These results suggest a potential role of endothelin-1 in the pathogenesis of ischemic bowel diseases in clinical situations and also the possibility that PAF and oxygen-derived free radicals may be involved as secondary mediators in endothelin-induced intestinal tissue damage.