Ulcerogenic influence of selective cyclooxygenase-2 inhibitors in the rat stomach with adjuvant-induced arthritis.
Cyclooxygenase (COX)-2 inhibitors have been developed as new gastric sparing anti-inflammatory drugs. We previously reported that the ulcerogenic response to conventional nonselective COX inhibitors, such as indomethacin and aspirin, was markedly increased in arthritic rats. The ulcerogenic effect of selective COX-2 inhibitors in arthritic animals, however, remains unknown. The present study was designed to examine the influence of selective COX-2 inhibitors, such as rofecoxib and celecoxib, on gastric mucosal integrity in rats with adjuvant-induced arthritis. Arthritis was induced in male dark Agouti rats by injection of Freund's complete adjuvant into the right hind paw. Two weeks after the injection, the animals were fasted for 18 h, various COX inhibitors were administered orally, and the mucosa was examined for lesions 4 h later. Oral administration of indomethacin caused hemorrhagic gastric lesions in both normal and arthritic rats, although the severity of lesions was significantly greater in the latter group. In contrast, neither rofecoxib nor celecoxib caused any gastric damage in normal rats, but both drugs provoked hemorrhagic gastric lesions in arthritic rats. The expression of COX-2 mRNA and immuno-positive cells was observed in the gastric mucosa of arthritic but not normal rats. The gastric mucosal prostaglandin (PG) E(2) content was significantly elevated in arthritic rats in a rofecoxib-sensitive manner. In conclusion, COX-2 inhibitors produce gastric lesions in arthritic rats, similar to the nonselective COX-inhibitors. COX-2 is up-regulated in the stomach of arthritic rats, and PGs produced by COX-2 play a role in maintaining the integrity of the gastric mucosa.
Kato
Shinichi
S
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan. skato@mb.kyoto-phu.ac.jp
Ogawa
Yoshihiro
Y
Kanatsu
Kenji
K
Okayama
Mitsuaki
M
Watanabe
Toshio
T
Arakawa
Tetsuo
T
Takeuchi
Koji
K
D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology*; D002199:Capillary Permeability / Q000187:drug effects; D000068579:Celecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D015232:Dinoprostone / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007213:Indomethacin / Q000633:toxicity; D007527:Isoenzymes / Q000378:metabolism*; D007783:Lactones / Q000633:toxicity*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000633:toxicity*; D013450:Sulfones
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D000068579:Celecoxib; D015232:Dinoprostone; D007213:Indomethacin