Aya Yokota

Factors involved in upregulation of inducible nitric oxide synthase in rat small intestine following administration of nonsteroidal anti-inflammatory drugs.

We investigated the functional mechanisms underlying the expression of inducible nitric oxide (NO) synthase (iNOS) in the rat small intestine following the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and found a correlation with the intestinal ulcerogenic properties of NSAIDs. Conventional NSAIDs (indomethacin, dicrofenac, naproxen, and flurbiprophen), a selective cyclooxygenase (COX)-1 inhibitor (SC-560) and a selective COX-2 inhibitor (rofecoxib) were administered p.o., and the intestinal mucosa was examined 24 hours later. Indomethacin decreased prostaglandin E2 (PGE2) production in the intestinal mucosa and caused intestinal hypermotility and bacterial invasion as well as the upregulation of iNOS expression and NO production, resulting in hemorrhagic lesions. Other NSAIDs similarly inhibited PGE2 production and caused hemorrhagic lesions with intestinal hypermotility as well as iNOS expression. Hypermotility in response to indomethacin was prevented by both PGE2 and atropine but not ampicillin, yet all these agents inhibited not only bacterial invasion but also expression of iNOS as well, resulting in prevention of intestinal lesions. SC-560, but not rofecoxib, caused a decrease in PGE2 production, intestinal hypermotility, bacterial invasion, and iNOS expression, yet this agent neither increased iNOS activity nor provoked intestinal damage because of the recovery of PGE2 production owing to COX-2 expression. Food deprivation totally attenuated both iNOS expression and lesion formation in response to indomethacin. In conclusion, the expression of iNOS in the small intestine following administration of NSAIDs results from COX-1 inhibition and is functionally associated with intestinal hypermotility and bacterial invasion. This process plays a major pathogenic role in the intestinal ulcerogenic response to NSAIDs.

COX Inhibition and NSAID-Induced Gastric Damage - Roles in Various Pathogenic Events

This article reviews our recent studies on NSAID-induced gastric damage, focusing on the relation between COX inhibition and pathogenic events. Conventional NSAIDs such as indomethacin, at a dose that inhibits PG production, enhance gastric motility, resulting in an increase in mucosal permeability and MPO activity, and eventually, gastric lesions. The development of these lesions can be prevented by administering PGE2 or antisecretory drugs, and also via an atropine-sensitive mechanism, not related to any antisecretory action. The selective COX-2 inhibitor rofecoxib has no effect on PG production and does not induce damage in the stomach. The selective COX-1 inhibitor SC-560 also does not cause damage, despite evoking a decrease in the PGE2 level. The combined administration of SC-560 and rofecoxib, however, provokes the formation of gastric lesions. SC-560, but not rofecoxib, causes gastric hypermotility and an increase in mucosal permeability, although the level of MPO activity increases only when rofecoxib is co-administered. COX-2 mRNA is expressed in the stomach after administration of SC-560 and indomethacin but not rofecoxib. The up-regulation of COX-2 expression in response to indomethacin is prevented by atropine at a dose that inhibits gastric hypermotility but not by omeprazole at an antisecretory dose. We conclude that the gastric ulcerogenic properties of NSAIDs are not accounted for solely by the inhibition of COX-1 and require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 up-regulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious influences of the COX-1 inhibition.

Oral but Not Parenteral Aspirin Upregulates COX-2 Expression in Rat Stomachs

Aim: We compared the ulcerogenic effects of aspirin (ASA) and indomethacin in the rat gastric mucosa depending on the route of administration, together with the expression of COX-2. Methods: Animals fasted for 18 h were given ASA or indomethacin, either p.o. or s.c., and the stomach was examined 4 h later. Results: Indomethacin decreased mucosal PGE2 level, increased gastric motility, and caused gastric lesions with the up-regulation of COX-2 expression, irrespective of the route of administration. ASA induced both damage and COX-2 expression in the stomach when given p.o. but not s.c., despite decreasing the PGE2 level similarly via either route of administration. Gastric motility was temporarily increased and gastric potential difference (PD) was markedly decreased by ASA given p.o. PGE2 and atropine, although preventing ASA-induced gastric lesions as well as hypermotility, affected neither the COX-2 expression nor PD reduction induced by p.o. ASA. By contrast, the COX-2 expression induced by indomethacin was prevented by both PGE2 and atropine. Conclusion: ASA given p.o. caused damage in the stomach, together with the up-regulation of COX-2 expression, and this expression may be due to the topical irritative action, rather than being a result of PG deficiency. The expression of COX-2 after indomethacin is associated with gastric hypermotility due to PG deficiency.

Development of intestinal, but not gastric damage caused by a low dose of indomethacin in the presence of rofecoxib

The ulcerogenic effect of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on the gastrointestinal mucosa was investigated in the presence of a low dose of indomethacin. Indomethacin at 3 mg/kg did not cause any damage in both the stomach and small intestine, despite inhibiting prostaglandin (PG) production. Rofecoxib had no effect on PG production and did not cause any damage in these tissues. In the presence of indomethacin, however, rofecoxib provoked damage in the small intestine but not the stomach. Indomethacin at 3 mg/kg induced hypermotility and COX-2 expression in the intestine but not in the stomach, both in an atropine-sensitive manner. These results suggest that a low dose of indomethacin produces damage in the small intestine but not in the stomach when administered together with rofecoxib. The PG deficiency caused by a low dose of indomethacin produces hypermotility and COX-2 expression in the small intestine, and results in damage when COX-2 is inhibited. It is assumed that the hypermotility response is a key event in the expression of COX-2 and thereby important in the development of mucosal damage in the gastrointestinal tract.

Prostaglandin EP receptor subtypes and gastric cytoprotection

This article reviews recent studies dealing with the relationship between the cytoprotective action of PGE2 and the EP receptor subtypes in the gastric mucosa. Gastric cytoprotection afforded by PGE2 was mimicked by EP1 agonists and attenuated by the EP1 antagonist. Likewise, the adaptive cytoprotection induced by a mild irritant was attenuated by the EP1 antagonist and indomethacin. By contrast, capsaicin-induced protection was mitigated by indomethacin as well as sensory deafferentation but not by the EP1 antagonist. PGE2 failed to provide both direct and adaptive cytoprotection in EP1-receptor knockout mice, while capsaicin-induced protection was observed in the animals lacking either EP1 or EP3 receptors but disappeared in IP receptor knockout mice. We conclude that PGs, either generated endogenously or administered exogenously, exhibit gastric cytoprotection directly through activation of EP1 receptors, and endogenous PGs also contribute to the mucosal protection induced by capsaicin by sensitizing sensory neurons, probably through IP receptors.