Endothelin has potent ulcerogenic and vasoconstrictor actions in the stomach

The role of endothelin, an endothelium-derived constricting factor, as a mediator of gastric ulceration was assessed using an ex vivo gastric chamber model in the rat. The rats were pretreated with indomethacin, and endothelin was infused intravenously or intra-arterially at various doses while the stomach was topically "challenged" with 20% ethanol. This concentration of ethanol did not, by itself, produce hemorrhagic damage in the stomach. However, infusion of endothelin rendered the mucosa vulnerable to damage induced by the ethanol. In a dose-dependent manner, endothelin increased the extent of hemorrhagic damage and the efflux of protein from the gastric mucosa. The effects of endothelin were less marked in rats not pretreated with indomethacin. The ulcerogenic actions of endothelin were not significantly affected by pretreatment with a platelet-activating factor antagonist or a leukotriene D4 antagonist. However, topical pretreatment with sodium nitroprusside produced a significant reduction in the damage induced by intravenous endothelin and topically applied ethanol. Endothelin also rendered the stomach vulnerable to damage induced by hydrochloric acid at a concentration (0.15 M) tolerated by control mucosa. Using an in vitro vascularly perfused rat stomach preparation, we found that endothelin produces marked increases in gastric vascular tone at nanomolar concentrations. These results suggest that the factors regulating the release of endothelin, and the balance between endothelial production of relaxing and contracting factors, may be important in the pathogenesis of ulcerative diseases of the stomach.