THE EFFECT OF INHIBITORS OF INDUCIBLE NITRIC-OXIDE SYNTHASE ON CHRONIC COLITIS IN THE RHESUS-MONKEY

GI inflammation is associated with an increase in nitric oxide product ion and expression of the inducible isoform of nitric oxide synthase ( iNOS). Using a spontaneous model of chronic colonic inflammation in rh esus monkeys, which shares morphological and clinical features with ul cerative colitis, we assessed the therapeutic benefit of administratio n of iNOS inhibitors. Sixteen colitic rhesus monkeys underwent an endo scopy procedure before commencement of the trial, and biopsies from th ree sites of the colon and plasma were collected. Monkeys were randoml y assigned to three treatment groups and were administered by oral bol us 60 mg/kg/day L-N-6-(1-Iminoethyl) lysine, 60 mg/kg/day aminoguanidi ne or a placebo (0.9% NaCl) twice daily. Monkeys were sacrificed after 10 days, colonic tissue from multiple sites was dissected and process ed for histological and biochemical analysis. In rhesus colitis, diarr hea was characterized by a significant increase in fecal water content and daily fecal output. iNOS was localized immunohistochemically in p lasma cells and neutrophils in the colonic mucosa and lamina propria, paralleled by enhanced iNOS gene expression determined by reverse-tran scriptase 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 red uced the histological inflammatory score nor ameliorated diarrheal sym ptoms. From these findings, we conclude that in this chronic, spontane ous model of colonic inflammation, administering iNOS inhibitors with this treatment regimen did not provide any major therapeutic benefit.