Induction of intestinal damage by rofecoxib, the selective COX-2 inhibitor, under inhibition of nitric oxide production in rats

We examined whether intestinal damage is provoked in rats under inhibition of both cNOS and COX-2. SC-560, rofecoxib or L-NAME was given either alone or in combination, and the animals were killed 24 h later. Neither SC-560 nor rofecoxib alone provoked damage in the small intestinal mucosa. However, SC-560 produced gross lesions when administered together with rofecoxib. Likewise, L-NAME alone did not cause damage, but this agent provoked gross lesions when administered together with rofecoxib. Mucosal PGE₂ content was decreased by SC-560 but not by rofecoxib and L-NAME. The expression of COX-2 was upregulated by L-NAME as well as by SC-560. Both L-NAME and SC-560 enhanced intestinal motility, decreased mucus secretion, and increased the enterobacterial number in the mucosa. We conclude that inhibition of both cNOS and COX-2 provokes intestinal damage. Inhibition of cNOS up-regulates COX-2 expression, and this may be a key to occurrence of intestinal damage associated with COX-2 inhibition.