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Vol. 280, Issue 2, 1008-1015, 1997

The Effect of Inhibitors of Inducible Nitric Oxide Synthase on Chronic Colitis in the Rhesus Monkey1

Karen A. Ribbons, Mark G. Currie, Jane R. Connor, Pamela T. Manning, Phillip C. Allen, Peter Didier, Marion S. Ratterree, David A. Clark and Mark J. S. Miller

Department of Pediatrics, Louisiana State University Medical Center (K.A.R., D.A.C., M.J.S.M.), New Orleans, Louisiana, Monsanto/G. D. Searle (M.G.C., J.R.C., P.T.M.), St. Louis, Missouri; California Regional Primate Research Center (P.C.A.), Davis, California, Tulane Regional Primate Research Center (P.D., M.S.R.), Covington, Louisiana

GI inflammation is associated with an increase in nitric oxide production and expression of the inducible isoform of nitric oxide synthase (iNOS). Using a spontaneous model of chronic colonic inflammation in rhesus monkeys, which shares morphological and clinical features with ulcerative colitis, we assessed the therapeutic benefit of administration of iNOS inhibitors. Sixteen colitic rhesus monkeys underwent an endoscopy procedure before commencement of the trial, and biopsies from three sites of the colon and plasma were collected. Monkeys were randomly assigned to three treatment groups and were administered by oral bolus 60 mg/kg/day L-N 6-(1-Iminoethyl) lysine, 60 mg/kg/day aminoguanidine or a placebo (0.9% NaCl) twice daily. Monkeys were sacrificed after 10 days, colonic tissue from multiple sites was dissected and processed for histological and biochemical analysis. In rhesus colitis, diarrhea was characterized by a significant increase in fecal water content and daily fecal output. iNOS was localized immunohistochemically in plasma cells and neutrophils in the colonic mucosa and lamina propria, paralleled by enhanced iNOS gene expression determined by reverse-transcriptase polymerase chain reaction. Only L-N 6-(1-imineothyl) lysine administration resulted in a significant reduction in systemic nitric oxide production, and neither of the iNOS inhibitors significantly reduced the histological inflammatory score nor ameliorated diarrheal symptoms. From these findings, we conclude that in this chronic, spontaneous model of colonic inflammation, administering iNOS inhibitors with this treatment regimen did not provide any major therapeutic benefit.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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