Nitric oxide inhibitors ameliorate indomethacin-induced enteropathy in rats

The role of nitric oxide (NO) synthase inhibitors in indomethacin (INDO)-in duced enteropathy was investigated in male Sprague-Dawley rats. Rats were s ubcutaneously administered 5% sodium bicarbonate (controls), two doses of I NDO 7.5 mg/kg, and three different inducible NO synthase (iNOS) inhibitors at various concentrations 24 hr, apart; aminoguanidine (AG), guanidinoethyl disulfide (GED), and n-(3-aminomethyl)benzylacetamidine (1400W). Rats were killed four days after the initial injection and small intestinal mucosa wa s assayed for myeloperoxidase (MPO) activity and iNOS expression by western blot analysis. Serum nitrite/nitrate (NOx) concentration was measured colo rimetrically. INDO produced acute ulcers along the mesenteric border from t he ileum to proximal jejunum. Rats treated with AG (25 and 50 mg/kg), GED ( 2.5 mg/kg), and 1400W (0.1 mg/kg) showed decreased total ulcer length and M PO activity by 51, 72, 53, and 61% and by 58, 88, 68, and 70%, respectively , compared to INDO alone. All inhibitors similarly reduced INDO-enhanced se rum NO., concentrations to its basal levels. Significant iNOS expression wa s detected in INDO-treated rats, but the inhibitors did not alter iNOS expr ession. Our data suggest that NO derived from iNOS may be a key factor in t he pathogenesis of acute INDO-induced enteropathy in rats.