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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Ulcerogenic Influence of Selective Cyclooxygenase-2 Inhibitors in the Rat Stomach with Adjuvant-Induced Arthritis

Shinichi Kato, Yoshihiro Ogawa, Kenji Kanatsu, Mitsuaki Okayama, Toshio Watanabe, Tetsuo Arakawa and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 503-509; DOI: https://doi.org/10.1124/jpet.102.040659
Shinichi Kato
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Yoshihiro Ogawa
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Kenji Kanatsu
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Mitsuaki Okayama
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Toshio Watanabe
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Tetsuo Arakawa
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Koji Takeuchi
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Abstract

Cyclooxygenase (COX)-2 inhibitors have been developed as new gastric sparing anti-inflammatory drugs. We previously reported that the ulcerogenic response to conventional nonselective COX inhibitors, such as indomethacin and aspirin, was markedly increased in arthritic rats. The ulcerogenic effect of selective COX-2 inhibitors in arthritic animals, however, remains unknown. The present study was designed to examine the influence of selective COX-2 inhibitors, such as rofecoxib and celecoxib, on gastric mucosal integrity in rats with adjuvant-induced arthritis. Arthritis was induced in male dark Agouti rats by injection of Freund's complete adjuvant into the right hind paw. Two weeks after the injection, the animals were fasted for 18 h, various COX inhibitors were administered orally, and the mucosa was examined for lesions 4 h later. Oral administration of indomethacin caused hemorrhagic gastric lesions in both normal and arthritic rats, although the severity of lesions was significantly greater in the latter group. In contrast, neither rofecoxib nor celecoxib caused any gastric damage in normal rats, but both drugs provoked hemorrhagic gastric lesions in arthritic rats. The expression of COX-2 mRNA and immuno-positive cells was observed in the gastric mucosa of arthritic but not normal rats. The gastric mucosal prostaglandin (PG) E2 content was significantly elevated in arthritic rats in a rofecoxib-sensitive manner. In conclusion, COX-2 inhibitors produce gastric lesions in arthritic rats, similar to the nonselective COX-inhibitors. COX-2 is up-regulated in the stomach of arthritic rats, and PGs produced by COX-2 play a role in maintaining the integrity of the gastric mucosa.

Footnotes

  • DOI: 10.1124/jpet.102.040659

  • Abbreviations:
    NSAID
    nonsteroidal anti-inflammatory drug
    PG
    prostaglandin
    COX
    cyclooxygenase
    FCA
    Freund's complete adjuvant
    bp
    base pair
    PCR
    polymerase chain reaction
    PBS
    phosphate-buffered saline
    NS-398
    N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methanesulfonamide
    • Received June 25, 2002.
    • Accepted June 27, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Ulcerogenic Influence of Selective Cyclooxygenase-2 Inhibitors in the Rat Stomach with Adjuvant-Induced Arthritis

Shinichi Kato, Yoshihiro Ogawa, Kenji Kanatsu, Mitsuaki Okayama, Toshio Watanabe, Tetsuo Arakawa and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 503-509; DOI: https://doi.org/10.1124/jpet.102.040659

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Ulcerogenic Influence of Selective Cyclooxygenase-2 Inhibitors in the Rat Stomach with Adjuvant-Induced Arthritis

Shinichi Kato, Yoshihiro Ogawa, Kenji Kanatsu, Mitsuaki Okayama, Toshio Watanabe, Tetsuo Arakawa and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 503-509; DOI: https://doi.org/10.1124/jpet.102.040659
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