SULFHYDRYL BLOCKER-INDUCED RAT COLONIC INFLAMMATION IS AMELIORATED BY INHIBITION OF NITRIC-OXIDE SYNTHASE

Background & Aims: Sulfhydryl compounds are essential in maintaining mucosal integrity, and nitric oxide may contribute to tissue injury. The aim of this study was to characterize experimental colitis induced by a sulfhydryl blocker. Methods: Colitis was induced in rats by intracolonic administration of 0.1 mL 3% iodoacetamide with and without addition of 0.1 mg/mL N-G-nitro-L-arginine methyl ester (L-NAME) to the drinking water. After death, the distal colonic segment was resected and weighed, and mucosal inflammatory mediator, myeloperoxidase, and NO synthase activities were determined. Results: Iodoacetamide induced multifocal mucosal erosions and ulceration that were present for up to 1 week. At 3 weeks, the mucosa was almost intact. Colonic wet weight was maximal at 7 days. Myeloperoxidase activity and NO generation were increased in the first 72 hours, and NO synthase activity and prostaglandin E(2) generation were increased up to 21 days. Leukotriene B-4 and leukotriene C-4 generation were increased up to 14 days. One week after iodoacetamide plus L-NAME treatment, lesion area was reduced by 85% and NO synthase activity by 52%. Conclusions: Inflammatory mediators have an important contribution to the pathogenesis of colonic injury induced by a sulfhydryl alkylator. The protective effect of L-NAME indicates that NO contributes to tissue injury and that its modulation may be a novel approach to treat inflammatory bowel disease.