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-oxide synthase (iNOS) are associated with ulcerative inflammation and disease activity in colitis. Therefore, inhibition of iNOS serves as a novel experimental approach to treat gut inflammation. The aim of the present study was to investigate the effects of a novel highly selective iNOS inhibitor, N-[3-(aminomethyl)benzyl]acetamidine (1400W), as compared with a nonselective NOS inhibitor, N(G)-nitro-L-arginine-methyl-ester (L-NAME), in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute colitis in the rat. Increased expression of iNOS protein and mRNA was found in acute TNBS-induced colitis along with neutrophil infiltration, inflammatory edema, and tissue damage. In a 24-h model of acute colitis, subcutaneous injections of 1400W (5 or 10 mg/kg t.i.d.) produced a 56 and 95% reduction in inflammatory edema formation, a 68 and 63% reduction in neutrophil infiltration (measured as myeloperoxidase 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) failed 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 iNOS, reduced formation of edema, neutrophil infiltration, and macroscopic inflammatory damage in experimentally induced acute colitis in the rat. In contrast, nonselective nitric-oxide synthase inhibition with L-NAME provided no benefit. These results support the idea that selective iNOS inhibitors have a promise in the treatment of colitis.
Kankuri
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E
Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland. esko.kankuri@helsinki.fi
Vaali
K
K
Knowles
R G
RG
Lähde
M
M
Korpela
R
R
Vapaatalo
H
H
Moilanen
E
E
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D015153:Blotting, Western; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009929:Organ Size / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid
D000578:Amidines; D000893:Anti-Inflammatory Agents; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D012333:RNA, Messenger; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat