Co-regulation of mucosal nitric oxide and prostaglandin in gastric adaptive cytoprotection

Objective: The correlation between mucosal generation of nitric oxide (NO) and prostaglandin E₂ (PGE₂) in gastric adaptive cytoprotection was investigated. Materials and Treatment: Male Sprague-Dawley rats were pretreated with either N(w)-nitro-L-arginine methyl ester (L-NAME, 12.5 mg/kg i.v.) or indomethacin (5 mg/kg s.c.). Following that, mild irritant 20% ethanol was administered, 15 min prior to 100% ethanol challenge. Methods: Macroscopic gastric mucosal damage, NO synthase activity, mucosal PGE₂ and leukotriene C₄ (LTC₄) levels were measured. Results: Administration of L-NAME and indomethacin significantly reduced the protective action of 20% ethanol against 100% ethanol-induced gastric mucosal damage. Besides, mucosal activity of constitutive NO (cNO) synthase, but not of the inducible isozyme (iNO synthase), was elevated following 20% ethanol treatment. This was accompanied by a reduction in mucosal leukotriene C₄ level. Indomethacin significantly inhibited mucosal PGE₂ biosynthesis but increased cNO synthase activity. Nevertheless, L-NAME reduced both cNO and iNO formation and prevented the increase in cNO formation caused by 20% ethanol, while enhancing mucosal PGE₂ production. Combined L-NAME and indomethacin treatment markedly potentiated ethanol-induced mucosal damage, and completely prevented the increase in cNO or PGE₂ biosynthesis when either compound was given alone. Conclusions: These findings suggest a co-regulatory relationship between mucosal NO and PG in the gastric defense system, which will be released after activation by the mild irritants to induce cytoprotection.