EFFECTS OF CHRONIC NITRIC-OXIDE SYNTHASE INHIBITION ON TNB-INDUCED COLITIS IN RATS

Nitric oxide (NO) synthesis is increased in ulcerative colitis, but th e role of NO in colitis is poorly understood. The present study employ ed N-W-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in rats to evaluate the effect of NO on 2,4,6-trinitrobenz enesulphonic acid (TNB)-induced colitis. L-NAME solutions were placed in subcutaneous. osmotic mini-pumps which continuously released L-NAME at 0.042, 0.208, 0.417, or 1.667 mg kg(-1) h(-1). L-NAME dose-depende ntly enhanced lesions in TNB-induced colitis. The two higher doses of L-NAME significantly increased colonic mucosal damage, although there was slight, nonsignificant reduced lesion formation with the lowest do se of L-NAME, 0.042 mg kg(-1) h(-1). A single dose of L-NAME at 100 mg kg(-1) subcutaneously injected daily in TNB-treated rats also increas ed lesions, and these ulcerogenic actions of L-NAME were reversed by L -arginine but not by D-arginine (both at 500 mg kg(-1), s.c.). Only th e highest dose of L-NAME (mini-pump) significantly depressed myelopero xidase (MPO) activity. Faecal occult bleeding showed a close relations hip with severity of colitis. These findings suggest that there may ex ist a balance between NO protective and aggressive effects. In TNB-ind uced colitis, antagonism of endogenous NO generation was intensified, whereas slight inhibition of NO synthesis reduced lesions. Variations in responses, related to timing or dose changes in L-NAME, may reflect the differences in inducible vs constitutive NO synthase isoforms.