title: Adaptive gastric cytoprotection is mediated by prostaglandin EP1 receptors: a study using rats and knockout mice.
abstract: Endogenous prostaglandins (PGs) play a central role in adaptive cytoprotection induced in the stomach by mild irritants. In the present study, we used taurocholate (TC) as a mild irritant in both rats and EP-receptor knockout mice, and examined which EP receptor is responsible for the adaptive gastric cytoprotection. Gastric lesions were induced by p.o. administration of HCl/ethanol (60% ethanol in 150 mM HCl). TC (5-20 mM) or PGE2 was administered p.o. 30 min before HCl/ethanol. HCl/ethanol-induced gastric lesions were dose dependently prevented by TC, and the effect at 20 mM was equivalent to that induced by PGE2 at 0.3 mg/kg. The protective effect of TC was significantly attenuated by indomethacin as well as ONO-AE-829, the EP1 antagonist, but not by either NS-398, the selective cyclooxygenase (COX)-2 inhibitor, or chemical ablation of capsaicin-sensitive sensory neurons. Likewise, the protective action of PGE2 was also antagonized by ONO-AE-829 but not chemical deafferentation. TC significantly increased PGE2 contents in the stomach, with or without chemical deafferentation, and this effect was blocked in the presence of indomethacin but not NS-398 or ONO-AE-829. TC increased the mucosal PGE2 contents similarly in both wild-type and knockout mice lacking EP1 or EP3 receptors, yet the protective action of TC against HCl/ethanol was observed in both wild-type and EP3 receptor knockout mice, but not in mice lacking EP1 receptors. The present findings confirmed a role for endogenous PGE2 produced by COX-1 in adaptive gastric cytoprotection and suggested that this action is mediated by activation of EP1-receptors but not associated with capsaicin-sensitive afferent neurons.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan. takeuchi@mb.kyoto-phu.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.forename: H
authors.initials: H
authors.lastname: Araki
authors.forename: M
authors.initials: M
authors.lastname: Umeda
authors.forename: Y
authors.initials: Y
authors.lastname: Komoike
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D051546:Cyclooxygenase 2; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D015232:Dinoprostone / Q000008:administration & dosage / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D006851:Hydrochloric Acid; D007213:Indomethacin / Q000008:administration & dosage; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009578:Nitrobenzenes / Q000008:administration & dosage; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013276:Stomach Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D013449:Sulfonamides / Q000008:administration & dosage; D013656:Taurocholic Acid / Q000008:administration & dosage
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D009578:Nitrobenzenes; C545636:Ptger1 protein, mouse; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000431:Ethanol; D013656:Taurocholic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D006851:Hydrochloric Acid; D007213:Indomethacin