Gastroenterology

Gastroenterology

Volume 119, Issue 3, September 2000, Pages 706-714
Gastroenterology

Alimentary Tract
NSAID-induced gastric damage in rats: Requirement for inhibition of both cyclooxygenase 1 and 2,☆☆,

https://doi.org/10.1053/gast.2000.16510Get rights and content

Abstract

Background & Aims: Selective cyclooxygenase (COX)-2 inhibitors produce less gastric damage than conventional nonsteroidal anti-inflammatory drugs (NSAIDs), suggesting that NSAIDs cause damage by inhibiting COX-1. We tested this hypothesis in rats by using a selective COX-1 inhibitor (SC-560). Methods: The effects of SC-560, celecoxib (selective COX-2 inhibitor), or a combination of both inhibitors on gastric damage and prostaglandin synthesis were determined. Selectivity of the drugs for COX-1 vs. COX-2 was assessed in the carrageenan-airpouch model. A COX-1–preferential inhibitor, ketorolac, was also evaluated. The effects of these inhibitors on leukocyte adherence to vascular endothelium and on gastric blood flow were assessed. Results: SC-560 markedly reduced gastric prostaglandin synthesis and platelet COX-1 activity, but spared COX-2 and did not cause gastric damage. Celecoxib did not affect gastric prostaglandin E2 synthesis and did not cause gastric damage. However, the combination of SC-560 and celecoxib invariably caused hemorrhagic erosion formation, comparable to that seen with indomethacin. Ketorolac caused damage only at doses that inhibited both COX isoforms, or when given with a COX-2 inhibitor. Celecoxib, but not SC-560, significantly increased leukocyte adherence, whereas SC-560, but not celecoxib, reduced gastric blood flow. Conclusions: Inhibition of both COX-1 and COX-2 is required for NSAID-induced gastric injury in the rat.

GASTROENTEROLOGY 2000;119:706-714

Section snippets

Animals

Male Wistar rats weighing 175–200 g were obtained from Charles River Breeding Farms (Montreal, Quebec, Canada) and were housed in the Animal Care Facility at the University of Calgary. The rats were fed standard laboratory chow and tap water ad libitum. The rats were deprived of food, but not water, for 18–20 hours before an experiment. All experiments described below received prior approval from the Animal Care Committee of the University of Calgary and were performed in accordance with the

Selectivity of the inhibitors

In the carrageenan-airpouch model, celecoxib inhibited PGE2 synthesis by 97% but had no effect on whole blood TX synthesis (Figure 1).

. Effects of celecoxib (15 mg/kg) and SC-560 (40 mg/kg) on inflammatory PGE2 synthesis (index of COX-2 activity; A) and whole blood TX synthesis (index of COX-1 activity; B). Celecoxib inhibited COX-2 but not COX-1. SC-560 inhibited COX-1 but not COX-2. The combination of celecoxib and SC-560 inhibited both COX-1 and COX-2. Indomethacin (5 mg/kg) inhibited COX-1

Discussion

Selective inhibition of COX-2 has been shown to be associated with significantly less gastric erosion formation than that seen with anti-inflammatory doses of conventional NSAIDs, both in animals1, 2 and humans.4, 25 Such data are consistent with the notion that the suppression of COX-1 by conventional NSAIDs underlies their ability to cause gastric damage. However, it is a presumption that blockade of COX-1 is all that is needed for erosions to develop, because before the present study, 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.

    ☆☆

    Supported by a grant from the Medical Research Council of Canada (MRC) and by an MRC/AstraZeneca/Canadian Association of Gastroenterology Research Fellowship and an AHFMR Fellowship (to N.V.).

    Dr. Wallace is an MRC Senior Scientist and an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Scientist.

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