Development of intestinal, but not gastric damage caused by a low dose of indomethacin in the presence of rofecoxib.
The ulcerogenic effect of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on the gastrointestinal mucosa was investigated in the presence of a low dose of indomethacin. Indomethacin at 3 mg/kg did not cause any damage in both the stomach and small intestine, despite inhibiting prostaglandin (PG) production. Rofecoxib had no effect on PG production and did not cause any damage in these tissues. In the presence of indomethacin, however, rofecoxib provoked damage in the small intestine but not the stomach. Indomethacin at 3 mg/kg induced hypermotility and COX-2 expression in the intestine but not in the stomach, both in an atropine-sensitive manner. These results suggest that a low dose of indomethacin produces damage in the small intestine but not in the stomach when administered together with rofecoxib. The PG deficiency caused by a low dose of indomethacin produces hypermotility and COX-2 expression in the small intestine, and results 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.
Yokota
Aya
A
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
Taniguchi
Masaki
M
Tanaka
Akiko
A
Takeuchi
Koji
K
D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000633:toxicity; D001285:Atropine / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000172:deficiency / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005769:Gastrointestinal Motility / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology* / Q000633:toxicity; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013450:Sulfones / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D006146:Guanidines; D007783:Lactones; D011720:Pyrazoles; C115461:SC 560; D013450:Sulfones; C116926:rofecoxib; D001285:Atropine; D000667:Ampicillin; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C004479:pimagedine; D007213:Indomethacin