title: Rofecoxib produces intestinal but not gastric damage in the presence of a low dose of indomethacin in rats.
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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yokota
authors.forename: Masaki
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Takahira
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001285:Atropine / Q000494:pharmacology; D015169:Colony Count, Microbial; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004755:Enterobacteriaceae; D005753:Gastric Mucosa / Q000382:microbiology / Q000473:pathology; D005769:Gastrointestinal Motility / Q000187:drug effects; D007213:Indomethacin; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000382:microbiology / Q000473:pathology; D007413:Intestinal Mucosa / Q000382:microbiology / Q000473:pathology; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000382:microbiology / Q000473:pathology; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D008565:Membrane Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; C115461:SC 560; D013450:Sulfones; C116926:rofecoxib; D001285:Atropine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone; D007213:Indomethacin