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The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E 2 in rat stomach
Author(s) -
Araki H.,
Ukawa H.,
Sugawa Y.,
Yagi K.,
Suzuki K.,
Takeuchi K.
Publication year - 2000
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1046/j.1365-2036.2000.014s1116.x
Subject(s) - prostaglandin e2 receptor , agonist , receptor , prostaglandin e , prostaglandin e2 , medicine , endocrinology , prostaglandin , knockout mouse , pharmacology , chemistry , receptor antagonist , antagonist
Summary 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 m m 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‐ω‐trinorPGE 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 significantly 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 flow 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 flow or mucus secretion.