Gastric Cytoprotection by prostaglandin E2 -: Relation to EP receptor subtypes

This article overviews our recent studies on the relation between EP receptor subtypes and gastric cytoprotection afforded by endogenous and exogenous PGE2, using rats and EP-receptor knockout mice. Exogenous PGE2 dose-dependently reduced the severity of HCl/ethanol-induced gastric lesions. This action of PGE2 was mimicked by another E type prostanoids such as sulprostone (EP1/EP3) and 17-phenyl PGE2 (EP 1) but not by butaprost (EP2), ONO-NT-012 (EP3) or 11-deoxy PGE1 (EP3/EP4), and significantly attenuated by ONO-AE-829 the selective EP I antagonist. Similar results were obtained in EP-receptor knockout mice, and PGE2 inhibited these lesions in both wild type and EP3-receptor knockout mice but not in the animals lacking EP1-receptors. HCl/ethanol-induced gastric lesions were also prevented by mild irritants such 20 mM taurocholate (TC). This effect was accompanied by an increase of mucosal PGE2 production, attenuated by indomethacin as well as ONO-AE-829, and disappeared in EP I-receptor knockout mice. On the other hand, capsaicin also protected the stomach against HCl/ethanol, without increase of mucosal PGE2 production. This action was totally attenuated by chemical ablation of afferent neurons, partially mitigated by indomethacin but not by ONO-AE-829. Attenuation by indomethacin of the capsaicin protection was recoverd in the presence of butaprost but not other EP agonists. In addition, capsaicin exihibited gastric protection in knockout mice lacking EP1- and EP3-receptors but not in IP-receptor knockout mice. We conclude that 1) PGE2, either generated endogenously or administered exogenously, exhibit gastric cytoprotection directly through EP 1 receptors, 2) this action may be functionally associated with inhibition of gastric motility but not with increase of gastric mucosal blood flow or mucus secretion, and 3) endogenous PGs also contribute to the mucosal protection induced by capsaicin by sensitizing sensory neurons, probably through EP2- and IP-receptors.