Aim: To investigate the EP receptor subtype involved in the gastroprotective action of prostaglandin (PG) E 2 using various EP receptor agonists in rats, and using knockout mice lacking EP 1 or EP 3 receptors. Methods: Male SD rats and C57BL/6 mice were used after an 18-h fast. Gastric lesions were induced by oral administration of HCl/ethanol (150 mM HCl in 60% ethanol). Rats were given various EP agonists i.v. 10 min before HCl/ethanol: PGE 2 , sulprostone (EP 1 /EP 3 agonist), butaprost (EP 2 agonist), 17-phenyl-wtrinorPGE 2 (17-phenylPGE 2 : EP 1 agonist), ONO-NT012 (EP 3 agonist) and 11-deoxyPGE 1 (EP 3 /EP 4 agonist). In a separate study, the effect of PGE 2 on HCl/ethanol lesions was examined in EP 1 -and EP 3 -receptor knockout mice. Results: Gastric lesions induced by HCl/ethanol were dose dependently prevented by PGE 2 ; this effect was mimicked by sulprostone and 17-phenylPGE 2 and was signi®cantly antagonized by ONO-AE-829, an EP 1 antagonist. Neither butaprost, ONO-NT012 nor 11-deoxyPGE 1 exhibited any protective activity against HCl/ethanol-induced gastric lesions. PGE 2 caused an inhibition of gastric motility as well as an increase of mucosal blood¯ow and mucus secretion, the effects being mimicked by prostanoids activating EP 1 receptors, EP 2 /EP 3 /EP 4 receptors and EP 4 receptors, respectively. On the other hand, although HCl/ethanol caused similar damage in both wild-type mice and knockout mice lacking EP 1 or EP 3 receptors, the cytoprotective action of PGE 2 observed in wild-type and EP 3 -receptor knockout mice totally disappeared in mice lacking EP 1 receptors. Conclusion:The gastric cytoprotective action of PGE 2 is mediated by activation of EP 1 receptors. This effect may be functionally associated with inhibition of gastric motility but not with increased mucosal blood¯ow or mucus secretion.
1 We examined the e ects of selective and nonselective cyclo-oxygenase (COX) inhibitors on various functional changes in the rat stomach induced by topical application of taurocholate (TC) and investigated the preferential role of COX isozymes in these responses. 2 Rat stomachs mounted in ex vivo chambers were perfused with 50 mM HCl and transmucosal potential di erence (p.d.), mucosal blood¯ow (GMBF), luminal acid loss and luminal levels of prostaglandin E 2 (PGE 2 ) were measured before, during and after exposure to 20 mM TC. 3 Mucosal application of TC in control rats caused a reduction in p.d., followed by an increase of luminal acid loss and GMBF, and produced only minimal damage in the mucosa 2 h later. Pretreatment with indomethacin (10 mg kg 71 , s.c.), a nonselective COX-1 and COX-2 inhibitor, attenuated the gastric hyperaemic response caused by TC without a ecting p.d. and acid loss, resulting in haemorrhagic lesions in the mucosa. In contrast, selective COX-2 inhibitors, such as NS-398 and nimesulide (10 mg kg 71 , s.c.), had no e ect on any of the responses induced by TC and did not cause gross damage in the mucosa. 4 Luminal PGE 2 levels were markedly increased during and after exposure to TC and this response was signi®cantly inhibited by indomethacin but not by either NS-398 or nimesulide. The expression of COX-1-mRNA was consistently detected in the gastric mucosa before and after TC treatment, while a faint expression of COX-2-mRNA was detected only 2 h after TC treatment. 5 Both NS-398 and nimesulide signi®cantly suppressed carrageenan-induced rat paw oedema, similar to indomethacin. 6 These results con®rmed a mediator role for prostaglandins in the gastric hyperaemic response following TC-induced barrier disruption, and suggest that COX-1 but not COX-2 is a key enzyme in maintaining`housekeeping' functions in the gastric mucosa under both normal and adverse conditions.
Background/aims: Endogenous prostaglandins (PGs) are considered to play a pivotal role in maintaining the mucosal integrity of the stomach after injury. In the present study, we evaluated the mucosal ulcerogenic and mucosal blood flow (GMBF) responses in the stomach after damage by taurocholate (TC) in knockout mice lacking EP1 or EP3 receptors. Methods: Under urethane anaesthesia, a mouse stomach was mounted in an ex vivo chamber, exposed to 20 mmol/L TC for 20 min and treated with 20 mmol/L HCl before and after TC. GMBF was measured with a laser Doppler flowmeter. Results: Mucosal exposure to TC in wild‐type mice caused a marked decrease in potential difference (PD), followed by an increase in H+ loss and GMBF. The decreased PD was gradually normalized after removal of TC from the chamber, with minimal damage in the mucosa 1 h after TC treatment. This hyperaemic response was inhibited by indomethacin, resulting in severe lesions in the mucosa without any change in PD or H+ loss. None of these responses induced by TC were altered in EP3−/− mice. However, in mice lacking EP1 receptors, TC treatment did not increase GMBF, despite causing PD reduction and acid loss, and resulted in severe damage in the mucosa. These responses were closely similar to those observed in animals pretreated with ONO‐8711, a EP1 receptor antagonist. Mucosal PGE2 content was significantly increased after TC, similarly in all groups of mice. Conclusion: These results confirm a mediator role for PGE2 in gastric hyperaemic response following mucosal exposure to TC and suggest that endogenous PGs may contribute to maintaining mucosal integrity after barrier disruption, mainly through activation of the EP1 receptor subtype.
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