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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Hiroshi Satoh, Kikuko Amagase and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 270-277; DOI: https://doi.org/10.1124/jpet.112.197475
Hiroshi Satoh
Department of Pharmacology and Experimental Therapeutics, Division of Pathological Science, Kyoto Pharmaceutical University, Kyoto, Japan
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Kikuko Amagase
Department of Pharmacology and Experimental Therapeutics, Division of Pathological Science, Kyoto Pharmaceutical University, Kyoto, Japan
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Koji Takeuchi
Department of Pharmacology and Experimental Therapeutics, Division of Pathological Science, Kyoto Pharmaceutical University, Kyoto, Japan
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Abstract

Antisecretory drugs such as histamine H2-receptor antagonists (H2-RAs) and proton pump inhibitors (PPIs) are commonly used for the treatment of gastric and duodenal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). However, the effects of these drugs on NSAID-induced small intestinal ulcers are not fully understood. The effects of H2-RAs and PPIs on NSAID-induced gastrointestinal lesions and small intestinal motility were examined in rats. Male Wistar rats (180–220 g) were used. Indomethacin (10 mg/kg) was administered orally in fasted or fed rats, and gastrointestinal lesions were examined 24 h after indomethacin administration. Intestinal motility was measured by using a balloon method under urethane anesthesia. Indomethacin produced multiple lesions in the gastric corpus in fasted rats and in the small intestine in fed rats: 1) H2-RAs (cimetidine, ranitidine, and famotidine) and PPIs (omeprazole, lansoprazole, and rabeprazole) markedly inhibited the formation of gastric lesions. 2) The drugs, except for lansoprazole, increased intestinal lesions. 3) H2-RAs augmented the increase in intestinal motility caused by indomethacin, and the effects of H2-RAs on motility and intestinal lesions were markedly inhibited by atropine. 4) Lansoprazole inhibited the formation of intestinal lesions, and the effect was prevented by both pharmacological ablation of capsaicin-sensitive sensory neurons and pretreatment with N-nitro-l-arginine methyl ester, a selective inhibitor of nitric-oxide synthesis. The results suggest that: 1) inhibition of acid secretion by antisecretory drugs may exacerbate NSAID-induced intestinal lesions, 2) H2-RAs further aggravate lesions by increasing intestinal motility via the activation of cholinergic pathways, and 3) lansoprazole protects the intestinal mucosa against NSAID-related ulcerative stimuli.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.197475.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    NSAID
    nonsteroidal anti-inflammatory drug
    ACh
    acetylcholine
    ATR
    atropine
    CAP
    capsaicin
    CIM
    cimetidine
    CSSN
    capsaicin-sensitive sensory neuron
    DIC
    diclofenac
    FAM
    famotidine
    H2-RA
    histamine H2-receptor antagonist
    IND
    indomethacin
    LI
    lesion index
    l-NAME
    N-nitro-l-arginine methyl ester
    LPZ
    lansoprazole
    NO
    nitric oxide
    OPZ
    omeprazole
    PGE2
    prostaglandin E2
    PPI
    proton pump inhibitor
    RAN
    ranitidine
    RPZ
    rabeprazole
    SNP
    sodium nitroprusside
    VEH
    vehicle.

  • Received June 14, 2012.
  • Accepted July 31, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Exacerbation of Intestinal Ulcer by Antisecretory Drugs

Hiroshi Satoh, Kikuko Amagase and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 270-277; DOI: https://doi.org/10.1124/jpet.112.197475

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Exacerbation of Intestinal Ulcer by Antisecretory Drugs

Hiroshi Satoh, Kikuko Amagase and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 270-277; DOI: https://doi.org/10.1124/jpet.112.197475
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