The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E2 in rat stomach

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 EP1 or EP3 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 (EP1/EP3 agonist), butaprost (EP2 agonist), 17-phenyl-omega-trinorPGE(2) (17-phenylPGE(2): EP1 agonist), ONO-NT012 (EP3 agonist) and 11-deoxyPGE(1) (EP3/EP4 agonist). In a separate study, the effect of PGE(2) on HCl/ethanol lesions was examined in EP1- and EP3-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 significantly antagonized by ONO-AE-829, an EP1 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 flow and mucus secretion, the effects being mimicked by prostanoids activating EP1 receptors, EP2/EP3/EP4 receptors and EP4 receptors, respectively. On the other hand, although HCl/ethanol caused similar damage in both wild-type mice and knockout mice lacking EP1 or EP3 receptors, the cytoprotective action of PGE(2) observed in wild-type and EP3-receptor knockout mice totally disappeared in mice lacking EP1 receptors. Conclusion: The gastric cytoprotective action of PGE(2) is mediated by activation of EP1 receptors. This effect may be functionally associated with inhibition of gastric motility but not with increased mucosal blood flow or mucus secretion.