Abstract
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.
Footnotes
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This research was supported in part by Kyoto Pharmaceutical University 21st Century COE Program and Open Research Program from the Ministry of Education, Science and Culture of Japan.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.084962.
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ABBREVIATIONS: NSAID, nonsteroidal antiinflammatory drug; PG, prostaglandin; COX, cyclooxygenase; SC-560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; iNOS, inducible nitric-oxide synthase; PCR, polymerase chain reaction; bp, base pair(s); G3PDH, glyceraldehyde-3-phosphate dehydrogenase; CFU, colony-forming unit(s).
- Received February 14, 2005.
- Accepted April 4, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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