The inducible nitric oxide synthase inhibitor ONO-1714 blunts dextran sulfate sodium colitis in mice

In mice with acute dextran sulfate sodium colitis, we examined the effect o f inducible nitric oxide synthase inhibition by (1S,5S,6R,7R)-7chloro-3-ami no-5methyl-2-azabicyclo[4.1.0]heptane hydrochloride (ONO-1714) on colonic b iochemistry, injury, and inflammation. Colonic luminal nitrate and nitrite were measured by the Griess reaction; inducible nitric oxide synthase messe nger RNA expression by reverse transcription-polymerase chain reaction; and nitrotyrosine by immunohistochemistry. Mice with colitis showed increases in nitrate and nitrite, inducible nitric oxide synthase messenger RNA, and numbers of cells staining for nitrotyrosine. Colonic inflammation was sever e. ONO-1714 inhibited increases in nitrate and nitrite and numbers of nitro tyrosine-positive cells, injury and inflammation also were reduced. Dextran sulfate sodium-induced increases in thiobarbituric acid-reactive substance s, a lipid peroxidation marker, were blunted by ONO-1714, which also inhibi ted increases in mucosal inflammatory cytokines. Nitric oxide produced by i nducible nitric oxide synthase may contribute to colonic inflammation by ni trosation, oxidative damage, and enhanced inflammatory cytokines. (C) 2001 Elsevier Science B.V. All rights reserved.