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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Therapeutic Administration of a Selective Inhibitor of Nitric Oxide Synthase Does Not Ameliorate the Chronic Inflammation and Tissue Damage Associated with Adjuvant-Induced Arthritis in Rats

Daniel S. Fletcher, W. Richard Widmer, Silvi Luell, Amy Christen, Chad Orevillo, Shrenik Shah and Denise Visco
Journal of Pharmacology and Experimental Therapeutics February 1998, 284 (2) 714-721;
Daniel S. Fletcher
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W. Richard Widmer
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Silvi Luell
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Amy Christen
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Chad Orevillo
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Shrenik Shah
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Denise Visco
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Abstract

Up-regulation of the inducible isoform of nitric oxide synthase (iNOS) was determined during the development of adjuvant-induced arthritis in the rat. iNOS enzymatic activity, measured in spleen tissue, appeared and increased coincidentally with the appearance and degree of paw swelling and joint destruction in this arthritis model, when measured on days 0 through 21 subsequent to inoculation of the rats with adjuvant. The increase in enzymatic activity was paralleled by an increase in the plasma nitrite/nitrate (NOx) level and the appearance of immunoreactive iNOS, as measured by Western immunoblot, in the spleens of these rats. Prophylactic administration of N-iminoethyl-l-lysine (l-NIL) completely abolished iNOS activity (plasma NOx elevation) and effectively reduced both the swelling and radiographic changes in the joint tissues of the noninjected paw measured on day 21. However, therapeutic administration of l-NIL beginning on day 14 had no effect on the inflammatory or arthritic changes measured on day 21, even though plasma NOx levels were reduced to that of the naive controls. These results suggest that iNOS may be involved with the initial stages of the immune response to adjuvant injection, but its product, NO, does not mediate the chronic inflammation and joint destruction which occur during the later phase in this model.

Footnotes

  • Send reprint requests to: Daniel S. Fletcher, R80Y-150, Merck & Co., P.O. Box 2000, Rahway, NJ 07065.

  • ↵1 Current address: Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN 47907-1248.

  • Abbreviations:
    NO
    nitric oxide
    NOS
    nitric oxide synthase
    NOx
    total nitrite/nitrate
    l- or d-NIL
    N-iminoethyl-(l or d)-lysine
    l-NAME
    NG-nitro-l-arginine methyl ester
    l-NMMA
    NG-monomethyl-l-arginine
    RAD
    radiographic
    DTT
    dithiothreitol
    FAD
    flavin-adenine-dinucleotide
    FMN
    flavin-mononucleotide
    NADPH
    β-nicotinamide adenine dinucleotide phosphate
    COX
    cyclooxygenase
    PAGE
    polyacrylamide gel electrophoresis
    EDTA
    ethylenediaminetetraacetic acid
    LPS
    lipopolysaccharide
    • Received May 13, 1997.
    • Accepted October 22, 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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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Therapeutic Administration of a Selective Inhibitor of Nitric Oxide Synthase Does Not Ameliorate the Chronic Inflammation and Tissue Damage Associated with Adjuvant-Induced Arthritis in Rats

Daniel S. Fletcher, W. Richard Widmer, Silvi Luell, Amy Christen, Chad Orevillo, Shrenik Shah and Denise Visco
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 714-721;

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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Therapeutic Administration of a Selective Inhibitor of Nitric Oxide Synthase Does Not Ameliorate the Chronic Inflammation and Tissue Damage Associated with Adjuvant-Induced Arthritis in Rats

Daniel S. Fletcher, W. Richard Widmer, Silvi Luell, Amy Christen, Chad Orevillo, Shrenik Shah and Denise Visco
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 714-721;
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