title: Inhibition of both COX-1 and COX-2 is required for development of gastric damage in response to nonsteroidal antiinflammatory drugs.
abstract: We examined the gastric ulcerogenic property of selective COX-1 and/or COX-2 inhibitors in rats, and investigated whether COX-1 inhibition is by itself sufficient for induction of gastric damage. Animals fasted for 18 h were given various COX inhibitors p.o., either alone or in combination, and they were killed 8 h later. The nonselective COX inhibitors such as indomethacin, naproxen and dicrofenac inhibited PG production, increased gastric motility, and provoked severe gastric lesions. In contrast, the selective COX-2 inhibitor rofecoxib did not induce any damage in the stomach, with no effect on the mucosal PGE(2) contents and gastric motility. Likewise, the selective COX-1 inhibitor SC-560 also did not cause gastric damage, despite causing a significant decrease in PGE(2) contents. The combined administration of SC-560 and rofecoxib, however, provoked gross damage in the gastric mucosa, in a dose-dependent manner. SC-560 also caused a marked gastric hypermotility, whereas rofecoxib had no effect on basal gastric motor activity. On the other hand, the COX-2 mRNA was expressed in the stomach after administration of SC-560, while the normal gastric mucosa expressed only COX-1 mRNA but not COX-2 mRNA. These results suggest that the gastric ulcerogenic property of conventional NSAIDs is not accounted for solely by COX-1 inhibition and requires the inhibition of both COX-1 and COX-2. The inhibition of COX-1 up-regulates the COX-2 expression, and this may counteract the deleterious influences, such as gastric hypermotility and the subsequent events, due to a PG deficiency caused by COX-1 inhibition.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Araki
authors.forename: Y
authors.initials: Y
authors.lastname: Komoike
authors.forename: S
authors.initials: S
authors.lastname: Hase
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D005769:Gastrointestinal Motility / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D007783:Lactones / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D011720:Pyrazoles; C115461:SC 560; D013450:Sulfones; C116926:rofecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D007213:Indomethacin