Role of Nitric Oxide and Prostaglandin E₂ in Gastroprotection Induced by Lipopolysaccharide in Ethanol-Mediated Damage in Rats

Abstract

Objective: This study was designed to investigate the role of endogenous nitric oxide (NO) and prostaglandin E₂ (PGE₂) in the gastroprotection induced by lipopolysaccharide (LPS). Methods: Ethanol was used to induce gastric lesions in control rats and in rats pretreated with graded doses of LPS administered at different time intervals and with inhibitors of NO synthase or prostaglandin synthesis. The ethanol-induced damage on gastric mucosa was assessed by measuring the extent of the lesion. We evaluated nitrite, a breakdown of NO, and PGE₂ accumulation in ex vivo gastric mucosa. Results: The ex vivo production of both NO and PGE₂ was increased in a dose-dependent manner by LPS injected 5 h before ethanol. Pretreatment with L-N⁶-(1-iminoethyl)lysine(dihydrochloride) inhibited the protection associated with LPS and the ex vivo increase of both NO and PGE₂. Indomethacin was ineffective in suppressing LPS-mediated protection against ethanol-induced damage and in suppressing ex vivo increase of nitrite whereas the ex vivo increase of PGE₂ was prevented in a dose-dependent manner. When ethanol was administered 30 min after LPS, there was a lack of protection and a lack of increase of NO and PGE₂. Conclusion: These results indicate that the reduction in ethanol-mediated damage in LPS-treated rats depends on endogenous PGE₂ formation and on endogenous NO produced by stimulation of inducible NO synthase.