title: Gastric mucosal protection against ethanol by EP2 and EP4 signaling through the inhibition of leukotriene C4 production.
abstract: Prostaglandin (PG)E derivatives are widely used for treating gastric mucosal injury. PGE receptors are classified into four subtypes, EP(1), EP(2), EP(3), and EP(4). We have tested which EP receptor subtypes participate in gastric mucosal protection against ethanol-induced gastric mucosal injury and clarified the mechanisms of such protection. The gastric mucosa of anesthetized rats was perfused at 2 ml/min with physiological saline, agonists for EP(1), EP(2), EP(3), and EP(4), or 50% ethanol, using a constant-rate pump connected to a cannula placed in the esophagus. The gastric microcirculation of the mucosal base of anesthetized rats was observed by transillumination through a window made by removal of the adventitia and muscularis externa. PGE(2) and subtype-specific EP agonists were applied to the muscularis mucosae at the window. Application of 50% ethanol dilated the mucosal arterioles and constricted the collecting venules. Collecting venule constriction by ethanol was completely inhibited by PGE(2) and by EP(2) and EP(4) agonists (100 nM) but not by an EP(1) or an EP(3) agonist. Ethanol-induced mucosal injury was also inhibited by EP(2) and EP(4) agonists. When leukotriene (LT)C(4) levels in the perfusate of the gastric mucosa were determined by ELISA, intragastric ethanol administration elevated the LTC(4) levels sixfold from the basal levels. These elevated levels were significantly (60%) reduced by both EP(2) and EP(4) agonists but not by other EP agonists. Since LTC(4) application at the window constricted collecting venules strongly, and an LTC antagonist reduced ethanol-induced mucosal injury, reductions in LTC(4) generation in response to EP(2) and EP(4) receptor signaling may be relevant to the protective action of PGE(2). The present results indicate that EP(2) and EP(4) receptor signaling inhibits ethanol-induced gastric mucosal injury through cancellation of collecting venule constriction by reducing LTC(4) production.
authors.affiliation: Dept. of Pharmacology, Kitasato Univ. School of Medicine, Sagamihara, Kanagawa 228-8555, Japan.
authors.forename: Youichiro
authors.initials: Y
authors.lastname: Hattori
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohno
authors.forename: Takako
authors.initials: T
authors.lastname: Ae
authors.forename: Takeo
authors.initials: T
authors.lastname: Saeki
authors.forename: Katsuharu
authors.initials: K
authors.lastname: Arai
authors.forename: Sumito
authors.initials: S
authors.lastname: Mizuguchi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Saigenji
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000633:toxicity*; D014699:Venules / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D002867:Chromones; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014662:Vasoconstrictor Agents; D017997:Leukotriene C4; D000431:Ethanol; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D001094:Arachidonate 5-Lipoxygenase; D015232:Dinoprostone; C047681:pranlukast