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We investigated the role that prostaglandins (PGs) and EP receptors play in facilitating the gastroprotective action of capsaicin against HCl/ethanol in rats and mice. Male SpragueDawley rats and C57BL/6 mice were used after 18 h of fasting. The animals were given HCl/ethanol (60% in 150 mM HCl) p.o. and killed 1 h later. Capsaicin or various EP agonists were given p.o. 30 min or i.v. 10 min before HCl/ethanol. In some cases, indomethacin or various EP agonists were given s.c. 30 min or i.v 10 min before capsaicin, respectively. Gastric lesions induced by HCl/ethanol were significantly inhibited by PGE 2 as well as capsaicin. The effect of PGE 2 was antagonized by ONO-AE-829 (EP1 antagonist), whereas the capsaicin action was mitigated by indomethacin as well as sensory deafferentation but not by ONO-AE-829. The generation of mucosal PGE 2 was not affected by either capsaicin or sensory deafferentation, but was significantly inhibited by indomethacin. Although neither butaprost (EP2), ONO-NT-012 (EP3), nor 11-deoxy PGE1 (EP4) alone had any effect on HCl/ethanolinduced gastric lesions, only butaprost restored the protective action of capsaicin in the presence of indomethacin. Capsaicin provided a protective action against HCl/ethanol-induced gastric lesions in wild-type (ϩ/ϩ) mice in an indomethacin-sensitive manner, and this action was similarly observed in EP1 (Ϫ/Ϫ) and EP3 (Ϫ/Ϫ) mice but not in the animals lacking IP receptors. These results suggest that capsaicin exhibits gastric cytoprotection, essentially by stimulating sensory neurons, and this action is facilitated by endogenous PGs through EP2/IP receptors, probably sensitizing the sensory neurons to capsaicin.

We investigated the preferential role of cyclooxygenase (COX) isozymes in various functional changes of the rat stomach after exposure to taurocholate (TC) as a mild irritant. Under urethane anesthesia, a rat stomach mounted in an ex vivo chamber was perfused with saline or acid (50 mM HCl), and transmucosal potential difference (PD), gastric mucosal blood flow (GMBF), and acid secretion were measured before and after exposure of the stomach to 20 mM TC for 30 min. Indomethacin, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (a selective COX-1 inhibitor), or rofecoxib (a selective COX-2 inhibitor) was given intraduodenally 30 min before the TC treatment. Mucosal application of TC caused a marked reduction in PD, followed by a decrease of acid secretion and an increase of GMBF. Previous administration of indomethacin did not affect the reduction in PD but significantly mitigated the two other responses induced by TC, resulting in a delay in the recovery in PD. These effects were mimicked by SC-560 but not rofecoxib, although neither of these drugs had any effect on the reduction in PD. Perfusion of TC-treated stomachs with 50 mM HCl caused only minimal damage, yet this treatment produced gross lesions in the presence of indomethacin or SC-560. Mucosal exposure to TC increased prostaglandin E 2 production, but the response was inhibited by both indomethacin and SC-560 but not rofecoxib. These results suggested that COX-1 but not COX-2 is a key enzyme for regulating the functional alterations of the stomach and for maintaining the mucosal integrity after barrier disruption.In the gastrointestinal tract tissues, prostaglandins (PGs) are involved in a variety of physiological processes, including gastric secretion, production of mucus, mucosal blood flow, and maintenance of mucosal integrity (Robert and Ruwart, 1982). The key enzyme in the pathway for PG synthesis, cyclooxygenase (COX

Nonsteroidal antiinflammatory drugs (NSAIDs) produce gastric damage in experimental animals, irrespective of the route of administration. However, aspirin (ASA) causes damage only when it is given orally. In the present study, we examined the gastric ulcerogenic effect of subcutaneously administered ASA in rats, in comparison with various NSAIDs, and investigated the reason why ASA does not cause damage in the stomach, in relation to its metabolite salicylic acid (SA). Since the antiinflammatory action of SA is known to be mediated, partly, by endogenous adenosine (AD), we also examined the possible involvement of AD in the protective action of SA. Various NSAIDs (indomethacin, flurbiprofen, naproxen, diclrofenac, ASA, SA) were administered subcutaneously, and the gastric mucosa was examined macroscopically 4 hr later. All NSAIDs tested, except ASA and SA, caused hemorrhagic lesions in the stomach, with a marked gastric hypermotility and a decrease of mucosal PGE2 contents. These ulcerogenic and motility responses caused by NSAIDs were blocked by pretreatment with atropine or PGE2. ASA, although inhibiting PGE2 generation, caused neither hypermotility nor damage in the stomach. On the other hand, SA alone inhibited basal gastric motility without any effect on mucosal PGE2 contents, and this agent, when given together with indomethacin, prevented gastric hypermotility and lesion formation in response to indomethacin, without affecting the reduced PGE2 contents. Likewise, ASA inhibited these responses to indomethacin, yet the effects appeared later than those of SA. Following administration of ASA, the blood SA levels reached a peak within 30 min and remained elevated for 4 hr. In addition, the protective effect of SA was not significantly influenced by either the AD deaminase or the AD-receptor antagonists. These results suggest that the failure of parenteral ASA to induce gastric damage may be explained by a protective action of SA metabolized from ASA. SA has a cytoprotective action against NSAID-induced gastric lesions, and this action is not mediated by endogenous AD but may be functionally associated with inhibition of the gastric motility response.