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OtherGASTROINTESTINAL PHARMACOLOGY

Effects of Nitric Oxide Synthase Inhibition or Sulfasalazine on the Spontaneous Colitis Observed in HLA-B27 Transgenic Rats

Satoshi Aiko, John Fuseler and Matthew B. Grisham
Journal of Pharmacology and Experimental Therapeutics February 1998, 284 (2) 722-727;
Satoshi Aiko
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John Fuseler
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Matthew B. Grisham
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Abstract

The objective of this study was to determine the effects that certain nitric oxide synthase inhibitors have on the spontaneous intestinal and colonic inflammation that develops in HLA-B27 transgenic rats and compare these data to those obtained using sulfasalazine (SZ). In an attempt to more closely mimic the clinical situation, drug treatment was begun after the onset of colitis. HLA-B27 male rats that developed clinical signs of colitis (diarrhea/loose stools) at 17 wk of age were randomized into fours groups consisting of one untreated colitic group and three treatment groups that received either aminoguanidine (AG; 52 μmol/kg/day), NG-nitro-l-arginine methyl ester (L-NAME; 45 μmol/kg/day) or SZ (130 mg/kg/day) in their drinking water for 14 days. Aged-matched Fisher 344 male rats were used as healthy controls. After 3 wk of treatment, ileal and colonic mucosal permeabilities, granulocyte infiltration and nitric oxide were quantified using blood-to-lumen clearance of 51Cr-EDTA, tissue myeloperoxidase activity, and plasma levels of nitrate and nitrite, respectively. We found that both AG and L-NAME but not SZ significantly attenuated the increases in plasma nitrate and nitrite levels. Interestingly, all three drugs were effective at significantly attenuating the increases in myeloperoxidase activity in the distal colon. Treatment with AG and SZ but not L-NAME were effective at significantly attenuating the increase in ileal and colonic permeabilities. Quantitative histological analysis revealed that AG and L-NAME but not SZ significantly attenuated the increase in the mucosal thickness and crypt depth in the distal colon compared to untreated colitis. Taken together, these data demonstrate that oral administration of certain nitric oxide synthase inhibitors or SZ to animals with active colitis attenuates the colonic inflammation by at least two different mechanisms. One mechanism appears to be dependent on inhibition of NO production whereas the other mechanism does not.

Footnotes

  • Send reprint requests to: Dr. Matthew B. Grisham, Department of Molecular and Cellular Physiology, LSU Medical Center, P.O. Box 33932, Shreveport, LA 71130-3932.

  • ↵1 This work was supported by DK 47663 and the Morphology Core of DK PO1 43785.

  • Abbreviations:
    NO
    nitric oxide
    NOS
    nitric oxide synthase
    MPO
    myeloperoxidase
    EDTA
    ethylenediaminetetraacetic acid
    IBD
    inflammatory bowel disease
    L-NAME
    NG-nitro-l-arginine
    AG
    aminoguanidine
    PG/PS
    peptidoglycan-polysaccharide
    SZ
    sulfasalazine
    iNOS
    inducible isoform of NOS
    5ASA
    5-aminosalicylate
    • Received June 9, 1997.
    • Accepted October 1, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 2
1 Feb 1998
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OtherGASTROINTESTINAL PHARMACOLOGY

Effects of Nitric Oxide Synthase Inhibition or Sulfasalazine on the Spontaneous Colitis Observed in HLA-B27 Transgenic Rats

Satoshi Aiko, John Fuseler and Matthew B. Grisham
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 722-727;

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OtherGASTROINTESTINAL PHARMACOLOGY

Effects of Nitric Oxide Synthase Inhibition or Sulfasalazine on the Spontaneous Colitis Observed in HLA-B27 Transgenic Rats

Satoshi Aiko, John Fuseler and Matthew B. Grisham
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 722-727;
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