title: Biphasic effect of prostaglandin E2 in a rat model of esophagitis mediated by EP1 receptors: relation to pepsin secretion.
abstract: We investigated the roles of prostaglandin (PG) E2 and cyclooxygenase (COX) isoenzymes in the mucosal defense of the esophagus, using subtype-selective EP agonists and antagonists as well as various COX inhibitors, in an acute rat esophagitis model. The animals were used after fasting for 18 h. Acid reflux esophagitis was induced by ligating both the pylorus and the transitional region between the forestomach and the glandular portion under ether anesthesia, and the damage was examined 3 or 4 h later. The esophageal lesions were significantly aggravated by prior administration of indomethacin and SC-560 (a selective COX-1 inhibitor) but not rofecoxib (a selective COX-2 inhibitor). PGE2 prevented these lesions at lower doses, yet the protective effect disappeared at a high dose. This biphasic effect was mimicked by 17-phenyl PGE2 (EP1 agonist) and antagonized by ONO-AE-829 (EP1 antagonist), while neither EP2, EP3, nor EP4 agonists had any effect on the esophageal lesions. PGE2 and 17-phenyl PGE2 had no effect on the acid secretion, but significantly increased the pepsin secretion, in a dose-dependent manner. The development of the esophageal lesions was totally prevented by pepstatin, a specific inhibitor of pepsin, and markedly aggravated by exogenous pepsin. We conclude that endogenous PGs derived from COX-1 are involved in the mucosal defense of the esophagus and that PGE2 has a biphasic influence on esophageal injury, depending on the dose: a protective effect at low doses and a deleterious effect at high doses, both mediated by EP1 receptors--the latter effect of PGE2 may be brought about by stimulation of the pepsin secretion.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yamato
authors.forename: Kenji
authors.initials: K
authors.lastname: Nagahama
authors.forename: Tohru
authors.initials: T
authors.lastname: Kotani
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kato
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D019610:Cytoprotection / Q000502:physiology; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004941:Esophagitis / Q000188:drug therapy*; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D007213:Indomethacin / Q000633:toxicity; D008297:Male; D010434:Pepsin A / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000502:physiology*; D058306:Receptors, Prostaglandin E, EP1 Subtype
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; C545637:Ptger1 protein, rat; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D010434:Pepsin A; D015232:Dinoprostone; D007213:Indomethacin