Abstract
The effect of mercaptoethylguanidine (MEG), a selective inhibitor of the inducible nitric oxide synthase and peroxynitrite scavenger, was evaluated in a rat model of colonic injury. A single intracolonic administration of trinitrobenzene sulfonic acid (TNBS, 20 mg/kg) dissolved in ethanol induced a severe colitis in male rats. Rats experienced bloody diarrhea and a significant loss of body weight. At 4 days after TNBS administration, the colon damage was characterized by areas of mucosal necrosis. Activity of myeloperoxidase, a marker of neutrophil infiltration, and levels of the 6-keto-prostaglandin F1α, were also markedly increased, whereas colonic ATP levels were reduced into the damaged tissue. Immunohistochemistry for the inducible nitric oxide synthase and nitrotyrosine, an index of nitrosative stress, showed an intense staining in the inflamed colon. Treatment with MEG (10 mg/kg i.v. b.i.d.) significantly reduced the appearance of diarrhea and the loss of body weight. This was associated with a remarkable amelioration of the disruption of the colonic architecture and suppression of the energetic failure, as well as a significant reduction of colonic myeloperoxidase activity and 6-keto-prostaglandin F1α levels. MEG also reduced the appearance of iNOS and nitrotyrosine immunoreactivity in the colon. The results of this study suggested that administration of MEG may be beneficial for the treatment of inflammatory bowel diseases.
Footnotes
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Send reprint requests to: Basilia Zingarelli, MD, PhD, Children’s Hospital Medical Center, Division of Critical Care, 3333 Burnet Ave, Cincinnati, OH 45229.
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↵1 Funding for this study was provided in part by National Institutes of Health Grant 1R01-HL59352–01 to Dr. Andrew L. Salzman.
- Abbreviations:
- NO
- nitric oxide
- cNOS
- constitutive nitric oxide synthase
- iNOS
- inducible nitric oxide synthase
- TNBS
- 2,4,6-trinitrobenzene sulfonic acid
- MEG
- mercaptoethylguanidine
- IBD
- inflammatory bowel disease
- 6-keto-PGF1α
- 6-keto-prostaglandin F1α
- ANOVA
- analysis of variance
- Received March 19, 1998.
- Accepted July 9, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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