This article reviews our recent observations on NSAID-induced gastric mucosal lesions, especially on the role of COX inhibition. The nonselective COX inhibitors tested (conventional NSAIDs) caused hemorrhagic lesions in the stomach, with a marked gastric hypermotility and a decrease of mucosal PGE2 contents. On the other hand, the selective COX-2 inhibitor rofecoxib did not induce any damage in the stomach, with no effect on the mucosal PGE2 contents. Likewise, the selective COX-1 inhibitor SC-560 also did not cause gastric damage, despite causing a significant decrease in PG2 contents. However, the combined administration of SC-560 and rofecoxib provoked gross damage in the gastric mucosa, in a dose-dependent manner. Indomethacin enhanced gastric motility with an increase of mucosal permeability and MPO activity before the occurrence of gastric damage. SC-560, but not rofecoxib, caused a marked gastric hypermotility and an increase of mucosal permeability, although the MPO activity increased only when rofecoxib was co-administered. The normal gastric mucosa expressed only COX-1 mRNA but not COX-2 mRNA, while the COX-2 mRNA was expressed in the stomach after administration of SC-560 as well as indomethacin but not rofecoxib. The up-regulation of COX-2 induced by indomethacin was prevented by atropine at the dose that inhibited gastric hypermotility but not by omeprazole at the antisecretory dose. We conclude that 1)gastric ulcerogenic properties of NSAID are not accounted for solely by COX-1 inhibition and require the inhibition of both COX-1 and COX-2, 2) the inhibition of COX-1 up-regulates the COX-2 expression, and the COX-2/PGs may counteract the deleterious influences caused by COX-1 inhibition, and 3) the expression of COX-2 may be associated with gastric hypermotility response induced by COX-1 inhibition.
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