ROLE OF NITRIC-OXIDE IN PATHOGENESIS OF GASTRIC-MUCOSAL DAMAGE-INDUCED BY COMPOUND-48 80 IN RATS/

We examined the effects of various nitric oxide synthase (NOS) inhibit ors 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 inhibitors such as L-NAME, L-NM MA, aminoguanidine or dexamethasone were administered for 4 days durin g 48/80 treatment. The repeated administration of 48/80 caused damage in the stomach with severe edema in the submucosa. These lesions induc ed by 48/80 were dose-dependently prevented by concurrent administrati on of L-NAME. The protective effect of L-NAME on 48/80-induced gastric lesions was mimicked by L-NMMA, aminoguanidine as well as dexamethaso ne, and significantly antagonized by co-administration of L-arginine b ut not by D-arginine. Acid secretion was slightly decreased after 48/8 0 treatment, but was significantly augmented by the combined administr ation of L-NAME with 48/80. The mucosal MPO activity, TEA reactants an d vascular permeability in the stomach were all increased after 48/80 treatment, but these changes were also significantly mitigated by co-a dministration of L-NAME. The Ca2+-independent NOS activity in the muco sa was increased four times during 48/80 treatment, and this change wa s 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 invol ves endogenous NO produced by iNOS, in addition to oxyradical formatio n; and 3) the deleterious role of NO during 48/80 treatment may be acc ounted for by a cytotoxic action of peroxynitrite, which is formed in the presence of NO and superoxide radicals.