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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Rofecoxib Produces Intestinal but Not Gastric Damage in the Presence of a Low Dose of Indomethacin in Rats

Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan

Indomethacin in small doses is known to inhibit prostaglandin (PG) production, yet it does not damage the gastrointestinal mucosa. We examined whether a cyclooxygenase (COX)-2 inhibitor induces gastrointestinal damage in the presence of a low dose of indomethacin and investigated the ulcerogenic mechanism in relation to COX-2 expression. Rats with or without 18-h fasting were administered rofecoxib (a selective COX-2 inhibitor; 10 or 30 mg/kg p.o.) in the absence or presence of indomethacin (3 mg/kg p.o.), and the gastric or intestinal mucosa was examined 8 and 24 h later, respectively. Neither indomethacin nor rofecoxib alone caused damage in the stomach or small intestine. However, indomethacin damaged the small intestine in the presence of rofecoxib, yet the same treatment did not damage the stomach. Indomethacin reduced the mucosal PGE₂ content in both tissues, whereas rofecoxib did not. The COX-2 mRNA was up-regulated in the intestine but not the stomach after indomethacin treatment, and the reduced PGE₂ content was significantly recovered later only in the small intestine, in a rofecoxib-inhibitable manner. Indomethacin produced hypermotility in the small intestine but not the stomach, whereas rofecoxib had no effect. These results suggest that the PG deficiency caused by a low dose of indomethacin produces hypermotility and COX-2 expression in the small intestine but not the stomach, resulting in damage when COX-2 is inhibited. It is assumed that the hypermotility response is a key event in the expression of COX-2 and thereby important in the development of mucosal damage in the gastrointestinal tract.

Address correspondence to: Dr. Koji Takeuchi, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607, Japan. E-mail: takeuchi{at}mb.kyoto-phu.ac.jp