Role of nitric oxide in pathogenesis of gastric mucosal damage induced by compound [formula omitted] in rats

Abstract

We examined the effects of various nitric oxide synthase (NOS) inhibitors on development of gastric lesions induced by compound 48 80 ( 48 80 ) in rats and investigated the roles of NO and inducible NOS (iNOS) in inflammatory gastric responses. Animals were given 48 80 (1 mg/kg, ip) once daily for 4 days, and the stomachs were examined for lesions 24 h after the final administration. NOS inhbitors such as L-NAME, L-NMMA, aminoguanidine or dexamethasone were administered for 4 days during 48 80 treatment. The repeated administration of 48 80 caused damage in the stomach with severe edema in the submucosa. These lesions induced by 48 80 were dose-dependently prevented by concurrent administration of L-NAME. The protective effect of L-NAME on 48 80 - induced gastric lesions was mimicked by L-NMMA, aminoguanidine as well as dexamethasone, and significantly antagonized by co-administration of L-arginine but not by D-arginine. Acid secretion was slightly decreased after 48 80 treatment, but was significantly augmented by the combined administration of L-NAME with 48 80 . The mucosal MPO activity, TBA reactants and vascular permeability in the stomach were all increased after 48 80 treatment, but these changes were also significantly mitigated by co-administration of L-NAME. The Ca 2+-independent NOS activity in the mucosa was increased four times during 48 80 treatment, and this change was also inhibited by dexamethasone. These results suggest that: 1) the repeated administration of 48 80 induced inflammatory gastric lesions in the rat stomach; 2) the pathogenic mechanism of these lesions involves endogenous NO produced by iNOS, in addition to oxyradical formation; and 3) the deleterious role of NO during 48 80 treatment may be accounted for by a cytotoxic action of peroxynitrite, which is formed in the presence of NO and superoxide radicals.