Abstract
GI inflammation is associated with an increase in nitric oxide production and expression of the inducible isoform of nitric oxide synthase (iNOS). Using a spontaneous model of chronic colonic inflammation in rhesus monkeys, which shares morphological and clinical features with ulcerative colitis, we assessed the therapeutic benefit of administration of iNOS inhibitors. Sixteen colitic rhesus monkeys underwent an endoscopy procedure before commencement of the trial, and biopsies from three sites of the colon and plasma were collected. Monkeys were randomly assigned to three treatment groups and were administered by oral bolus 60 mg/kg/day l-N6-(1-Iminoethyl) lysine, 60 mg/kg/day aminoguanidine or a placebo (0.9% NaCl) twice daily. Monkeys were sacrificed after 10 days, colonic tissue from multiple sites was dissected and processed for histological and biochemical analysis. In rhesus colitis, diarrhea was characterized by a significant increase in fecal water content and daily fecal output. iNOS was localized immunohistochemically in plasma cells and neutrophils in the colonic mucosa and lamina propria, paralleled by enhanced iNOS gene expression determined by reverse-transcriptase polymerase chain reaction. Only l-N6-(1-imineothyl) lysine administration resulted in a significant reduction in systemic nitric oxide production, and neither of the iNOS inhibitors significantly reduced the histological inflammatory score nor ameliorated diarrheal symptoms. From these findings, we conclude that in this chronic, spontaneous model of colonic inflammation, administering iNOS inhibitors with this treatment regimen did not provide any major therapeutic benefit.
Footnotes
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Send reprint requests to: Dr. Mark J. S. Miller, Department of Pediatrics, Louisiana State University Medical Center, 1542 Tulane Avenue, New Orleans, LA 70112.
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↵1 Funding for this work was provided by G. D. Searle. Studies performed at the California Regional Primate Research Center were in part funded by NIH 2P51-RR-AG00169—“California Regional Primate Research Center.” Studies performed at the Tulane Regional Primate Research Center were funded in part by FDA contract 223-94-1100—“Breed and maintain Macaca mullata monkeys in a coral environment” and by NIH 5P51-RR00164—“Support for Regional Primate Research Center.”
- Abbreviations:
- iNOS
- inducible nitric oxide synthase
- NO
- nitric oxide
- l-NIL
- l-N6-(1-Iminoethyl)lysine
- AG
- aminoguanidine
- l-NAME
- N-nitro-l-arginine methyl ester
- RNI
- reactive nitrogen intermediates
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- RT-PCR
- reverse-transcriptase polymerase chain reaction
- VIP
- vasoactive intestinal peptide
- SP
- substance P
- IL-1
- interlukin-1
- TNFα
- tumor necrosis factor α
- TNBS
- trinitrobenzene sulfonic acid
- Received March 28, 1996.
- Accepted October 21, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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