Suppression of acute experimental colitis by a highly selective inducible nitric-oxide synthase inhibitor, N-[3-(aminomethyl)benzyl]acetamidine

High concentrations of nitric oxide (NO) produced by the inducible nitric-o xide synthase (iNOS) are associated with ulcerative inflammation and diseas e activity in colitis. Therefore, inhibition of NOS serves as a novel exper imental approach to treat gut inflammation. The aim of the present study wa s to investigate the effects of a novel highly selective NOS inhibitor, N-[ 3-(aminomethyl)benzyl]acetamidine (1400W), as compared with a nonselective NOS inhibitor, N(G)-nitro-L-arginine-methylester (L-NAME), in 2,4,6-trinitr obenzenesulfonic acid (TNBS)-induced acute colitis in the rat. Increased ex pression of NOS protein and mRNA was found in acute TNBS-induced colitis al ong with neutrophil infiltration, inflammatory edema, and tissue damage. In a 24-h model of acute colitis, subcutaneous injections of 1400W (5 or 10 m g/kg t.i.d.) produced a 56 and 95% reduction in inflammatory edema formatio n, a 68 and 63% reduction in neutrophil infiltration (measured as myelopero xidase activity), and a 19 and 26% decrease in the size of mucosal lesions as compared with vehicle treatment. Administration Of L-NAME (35 mg/kg) fai led to produce any significant beneficial effects as compared with vehicle treatment in this experimental model of acute colitis. Treatment with 1400W , a highly selective inhibitor of NOS, reduced formation of edema, neutroph il infiltration, and macroscopic inflammatory damage in experimentally indu ced acute colitis in the rat. In contrast, nonselective nitric-oxide syntha se inhibition with L-NAME provided no benefit. These results support the id ea that selective NOS inhibitors have a promise in the treatment of colitis .