Basic–Alimentary TractCyclooxygenase-2–derived lipoxin A4 increases gastric resistance to aspirin-induced damage*,**,*
Section snippets
Material and methods
Male Wistar rats weighing 200–300 g were obtained from Charles River (Montreal, Canada, or Monza, Italy). All experimental procedures described below were approved by our institutional animal research committees and were in accordance with nationally approved guidelines for the treatment of laboratory animals.
Suppression of COX-1 and COX-2 by aspirin
Preliminary dose-response studies indicated that doses of aspirin of >30 mg/kg produced significant gastric damage. We chose to use a dose of 50 mg/kg of aspirin for the studies described below. At this dosage, aspirin significantly suppressed COX-1 and COX-2. In the carrageenan-airpouch model, aspirin inhibited COX-2-derived PGE2 synthesis by 71% (reduced from 1.24 ± 0.21 ng/mL in the vehicle-treated group to 0.36 ± 0.23 ng/mL; P < 0.05) and suppressed COX-1 activity (whole-blood thromboxane
Discussion
Clinical trials suggest that selective COX-2 inhibitors produce severe gastrointestinal ulcer complications at about half the rate of conventional NSAIDs.22, 23 However, such a safety advantage may be significantly abrogated if the patient treated with a selective COX-2 inhibitor is also using low-dose aspirin, such as for cardioprotection.23 The results of the present study clearly show that selective inhibition of COX-2, with either celecoxib or rofecoxib, can lead to an exacerbation of the
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Address requests for reprints to: John L. Wallace, Ph.D., Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. e-mail: [email protected]; fax: (403) 270-3353.
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Supported by a grant from the Canadian Institutes of Health Research.
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Dr. Wallace is an Alberta Heritage Foundation for Medical Research Senior Scientist.