Inhibition of nitric oxide synthesis by aminoguanidine increases intestinal damage in the acute phase of rat TNB-colitis.
The role of nitric oxide (NO) in the pathophysiology of inflammatory bowel diseases (IBD) is controversially discussed. The aim of the present study was to investigate the role of NO inhibition in the acute phase of rat 2,4,6-trinitrobenzenesulphonic acid (TNB)-colitis. To inhibit NO synthesis we used aminoguanidine (AG) as a selective inhibitor of inducible nitric oxide synthase (iNOS). TNB-colitis was induced in rats with and without pretreatment with AG (200 mg kg-1 body weight in the drinking water). The severity of colitis was observed over a period of 7 days. On days 1 and 2, AG reduced concentrations of plasma nitrate and nitrite as well as of portal 6-keto-prostaglandin 1alpha. AG pretreatment increased colonic damage and inflammatory response, assessed by colonic myeloperoxidase and serum lactate dehydrogenase activity, macroscopic damage score, tumour necrosis factor-alpha concentration in stool and colonic glutathione content. The AG-treated group showed a higher and prolonged nuclear factor kappaB (NF-kappaB)/Rel binding activity in the colon. We conclude that NOS inhibition by AG is not beneficial in acute intestinal inflammation. With regard to appropriate therapeutic strategies, NF-kappaB/Rel activation might be a more suitable target.
Department of Internal Medicine I, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany. nektarios.dikopoulos@medizin.uni-ulm.de
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N
Dikopoulos
A K
AK
Nüssler
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S
Liptay
M
M
Bachem
M
M
Reinshagen
M
M
Stiegler
R M
RM
Schmid
G
G
Adler
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H
Weidenbach
D000208:Acute Disease; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006146:Guanidines / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D015854:Up-Regulation / Q000187:drug effects
D006146:Guanidines; D016328:NF-kappa B; D011453:Prostaglandins; D011518:Proto-Oncogene Proteins; C497595:Relb protein, rat; D014157:Transcription Factors; D051841:Transcription Factor RelB; D009569:Nitric Oxide; D014302:Trinitrobenzenesulfonic Acid; C004479:pimagedine