PHOSPHORAMIDON, AN INHIBITOR OF ENDOTHELIN-CONVERTING ENZYME, PREVENTS INDOMETHACIN-INDUCED GASTRIC-MUCOSAL DAMAGE IN RATS

Endothelin-1 (ET-1) is produced from inactive precursor big ET-1 by en dothelin-converting enzyme-1 (ECE-1), a membrane-bound metalloprotease , structurally similar to another metalloprotease, neutral endopeptida se 24.11 (NEP). Although both phosphoramidon and thiorphan are metallo protease inhibitors, the ECE activity is inhibited by phosphoramidon b ut not by thiorphan, a specific inhibitor of NEP. Therefore, to invest igate whether an ECE inhibitor can prevent indomethacin-induced gastri c mucosal damage in rats, we compared the effects between the two meta lloprotease inhibitors on both gastric mucosal integrity and the level s of ET-1 and big ET-1 in gastric tissue. Phosphoramidon significantly decreased ET-1 levels, causing a concomitant big ET-1 increase and do se-dependently attenuated indomethacin-induced gastric mucosal damage. By contrast, thiorphan neither changed the ratio of ET-1/big ET-1 nor attenuated the damage. In conclusion, the prevention of gastric mucos al damage by an ECE inhibitor indicates that endogenous ET-1 may play an important role in the pathogenesis of indomethacin-induced gastric mucosal damage. (C) 1998 Elsevier Science Inc.