NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2

Gastroenterology. 2000 Sep;119(3):706-14. doi: 10.1053/gast.2000.16510.


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 E(2) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Celecoxib
  • Cell Adhesion / drug effects
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • Gastric Mucosa / metabolism
  • Isoenzymes / antagonists & inhibitors*
  • Ketorolac / pharmacology
  • Leukocytes / physiology
  • Male
  • Membrane Proteins
  • Prostaglandin-Endoperoxide Synthases
  • Prostaglandins / biosynthesis
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Wistar
  • Regional Blood Flow / drug effects
  • Stomach / blood supply
  • Stomach / drug effects*
  • Stomach / pathology*
  • Sulfonamides / pharmacology
  • Thiophenes / pharmacology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Prostaglandins
  • Pyrazoles
  • SC 560
  • Sulfonamides
  • Thiophenes
  • DuP 697
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, rat
  • Celecoxib
  • Ketorolac