Role of endogenous endothelin-1 in stress-induced gastric mucosal damage and acid secretion in rats.

In rats subjected to 8 h water-immersion stress, gastric and duodenal mucosal hemorrhage and erosions were detected by macroscopic and histopathological examination. Moreover, plasma and gastric mucosal endothelin-1 (ET-1) levels rose appreciably in a time-related manner during water immersion, with a higher concentration detected in gastric mucosa. Thus, the percentage increases in plasma (gastric mucosal) ET-1, relative to basal levels, after 1, 4 and 8 h of water immersion were 86(172), 169(322) and 210(391)%, respectively. Likewise, a marked increase of gastric acid output was demonstrated 30 min after water immersion and lasted for 3 h. Pretreatment with the endothelin ET(A)/ET(B) receptor blocker, bosentan (30 and 100 mg kg(-1)), orally, dose-dependently antagonized gastric and duodenal mucosal damage as indicated by reductions in lesion lengths of 67 and 80%, respectively. Similar protective effects on mucosa were observed when bosentan was given by the intramuscular route. On the other hand, bosentan suppressed the rate of acid output by 30.3+/-2.1% in the stressed rats, but had no such effect in non-stressed animals. Taken together, results from this study implicate the endogenous peptide, ET-1, as a powerful mediator of stress-evoked gastro-duodenal mucosal damage and, moreover, present bosentan as a potential protector against hyperacidity and mucosal erosion that occur as a consequence of stress.