Background: A recent study demonstrated that inhibition of both cyclooxygenase (COX)‐1 and COX‐2 is required for the development of nonsteroidal anti‐inflammatory drug (NSAID)‐induced gastric lesions. However, the role of COX‐1 or COX‐2 inhibition in the pathogenisis of these lesions remains unclear. Aim: To examine the gastric ulcerogenic properties of selective COX‐1 and COX‐2 inhibitors in rats and to investigate further the relationship of COX inhibition to various events involved in the process of NSAID‐induced gastric lesions. Methods: Animals were given various COX inhibitors p.o., either alone or in combination, and killed 8 h later. Under the treatment, gastric damage, prostaglandin (PG) E2 content, mucosal permeability, myeloperoxidase (MPO) activity as well as gastric motility were examined. Results: The nonselective COX inhibitor indomethacin inhibited PGE2 production, enhanced gastric motility, and provoked severe lesions in the stomach, with an increase in mucosal permeability and MPO activity. In contrast, the selective COX‐2 inhibitor rofecoxib did not induce any damage in the stomach and had no effect on mucosal PGE2 content. Similarly, the selective COX‐1 inhibitor SC‐560 also caused no gastric damage, despite inhibiting PGE2 production. The combined administration of SC‐560 and rofecoxib, however, provoked gross damage in the gastric mucosa, in a dose‐dependent manner for each drug. SC‐560, but not rofecoxib, caused marked gastric hypermotility and an increase in mucosal permeability, although an increase in MPO activity was observed only when rofecoxib was coadministered. The normal gastric mucosa expressed COX‐1 mRNA and not COX‐2 mRNA, but COX‐2 mRNA was expressed in the stomach after administration of SC‐560 as well as indomethacin but not rofecoxib. Conclusion: These results suggest that the gastric ulcerogenic properties of NSAIDs are not accounted for solely by COX‐1 inhibition, but require the inhibition of both COX‐1 and COX‐2. The inhibition of COX‐1 up‐ regulates COX‐2 expression, and COX‐2/PGs may, in turn, counteract the deleterious affects of gastric hypermotility due to COX‐1 inhibition.

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Background/Aim: Studies have demonstrated an important role for endogenous PG and NO in the healing of chronic gastric ulcers. We investigated the effects of COX and NOS inhibitors on the healing of duodenal ulcers, in comparison with gastric ulcers, in rats. Methods: Gastric and duodenal ulcers were induced by serosal application of acetic acid (0.1 ml of 100% acetic acid) for 60 and 20 s, respectively. Indomethacin (a nonselective COX inhibitor) or rofecoxib (a selective COX-2 inhibitor) was given p.o. once daily for 14 days from 3 days after ulcer induction, while N^G-nitro-L-arginine methyl ester (L-NAME: a nonselective NOS inhibitor) or aminoguanidine (a relatively selective iNOS inhibitor) was given s.c. twice daily during this period. Results: Both gastric and duodenal ulcers induced by acetic acid healed spontaneously within 17 days to a minimal size. Daily administration of indomethacin or rofecoxib significantly delayed the healing of gastric but not duodenal ulcers. In contrast, the healing of both gastric and duodenal ulcers was delayed by repeated administration of either L-NAME or aminoguanidine. Ulceration markedly increased the PGE₂ content of the ulcerated mucosa in both the stomach and duodenum, and the increased PG biosynthetic response was inhibited by either indomethacin or rofecoxib in both tissues. The expression of both COX-2 and iNOS mRNAs was upregulated in the ulcerated mucosa of the stomach and duodenum. Conclusion: These results suggest that COX-2/PG is actively involved in the healing of gastric but not duodenal ulcers, although the mRNA for COX-2 is expressed in the duodenal mucosa after ulceration, as potently as in the gastric mucosa. In contrast, NO produced by both cNOS and iNOS plays a role in the healing of both gastric and duodenal ulcers.

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