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This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/G80    most recent 00292.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hattori, Y. Articles by Majima, M. Search for Related Content PubMed PubMed Citation Articles by Hattori, Y. Articles by Majima, M.

MUCOSAL BIOLOGY

Gastric mucosal protection against ethanol by EP₂ and EP₄ signaling through the inhibition of leukotriene C₄ production

Departments of ¹Pharmacology and ²Gastroenterology, Kitasato University School of Medicine; ³Department of Molecular Pharmacology, Kitasato University Graduate School of Medical Sciences, Sagamihara; and ⁴Department of Internal Medicine, Isehara Kyodo Hospital, Isehara, Kanagawa, Japan

Submitted 27 June 2007 ; accepted in final form 1 October 2007

Prostaglandin (PG)E derivatives are widely used for treating gastric mucosal injury. PGE receptors are classified into four subtypes, EP₁, EP₂, EP₃, and EP₄. 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 EP₁, EP₂, EP₃, and EP₄, 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. PGE₂ 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 PGE₂ and by EP₂ and EP₄ agonists (100 nM) but not by an EP₁ or an EP₃ agonist. Ethanol-induced mucosal injury was also inhibited by EP₂ and EP₄ agonists. When leukotriene (LT)C₄ levels in the perfusate of the gastric mucosa were determined by ELISA, intragastric ethanol administration elevated the LTC₄ levels sixfold from the basal levels. These elevated levels were significantly (60%) reduced by both EP₂ and EP₄ agonists but not by other EP agonists. Since LTC₄ application at the window constricted collecting venules strongly, and an LTC antagonist reduced ethanol-induced mucosal injury, reductions in LTC₄ generation in response to EP₂ and EP₄ receptor signaling may be relevant to the protective action of PGE₂. The present results indicate that EP₂ and EP₄ receptor signaling inhibits ethanol-induced gastric mucosal injury through cancellation of collecting venule constriction by reducing LTC₄ production.

prostaglandin E₂; EP receptor; gastric microcirculation; gastric perfusion