The Modulation of Gastric Mucosal Integrity by Endothelin-1 and Prostacyclin

Abstract

Summary The interaction of the vasoconstrictor peptide, endothelin-1 (ET-1), and the endothelium-derived vasodilator eicosanoid, prostacyclin, was examined as it pertains to the modulation of gastric mucosal integrity. Using an ex vivo chamber preparation of the rat stomach, the effects of intravenous ET-1 on the susceptibility of the mucosa to damage induced by topical application of an irritant, 20% ethanol, were examined. ET-1 significantly augmented gastric hemorrhagic damage induced by the irritant when administered at concentrations in the 10–⁷ to 10–⁶M range. Pretreatment with indomethacin at a dose that inhibited gastric prostacyclin synthesis by over 85% resulted in significant augmentation of the ulcerogenic actions of ET-1. The damaging actions of ET-1 could be significantly reduced by topical pretreatment of the gastric mucosa with prostacyclin (5–50 $mUg/ml). This pretreatment also significantly reduced the hypertension and hemoconcentration observed following ET-1 administration. ET-1 also significantly augmented the susceptibility of the gastric mucosa to injury induced by hydrochloric acid. Oral administration of 150 mM HC1 produced little or no gastric damage in control rats. However, a 5-min intravenous infusion of ET-1 produced significant increases in the severity of acid-induced gastric damage in a concentration-dependent manner (10–⁷ to 10–⁶M). These results demonstrate that ET-1 is a potent ulcerogenic agent in the rat stomach. The ulcerogenic actions of ET-1 can be significantly augmented by indomethacin and significantly reduced by prostacyclin, suggesting that the balance between endothelial cell release of ET-1 and prostacyclin may be an important factor in modulating gastric mucosal integrity.