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 PGE₂had 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.

Prostaglandin EP Receptors Involved in Modulating Gastrointestinal Mucosal Integrity

“…These biphasic effects were mimicked by 17-phenyl PGE 2 and significantly antagonized by the EP1 antagonist ONO-8711, while other PGE derivatives, including EP2, EP3, and EP4 agonists, had no effect. PGE 2 and 17-phenyl PGE 2 had no effect on acid secretion but significantly increased pepsin secretion, in an EP1 antagonist-sensitive manner (16). These results indicate that PGE 2 has a biphasic effect on acid reflux esophagitis depending on the dose: a protective effect at lower doses and an aggravating effect at high doses, both mediated by EP1 receptors.…”

Prolonged Esophagitis After Primary Dysfunction of the Pyloric Sphincter in the Rat and Therapeutic Potential of the Gastric Pentadecapeptide BPC 157

“…BPC 157-reduction of acute alcohol-, indomethacin-, aspirin-lesions (5 -7, 29, 30, 38), or chronic alcohol drinking-(31), acetic acid- (16,43) lesions is likely relevant for its effect on endogenous prostaglandin (PG) in esophagitis and chronic esophagitis attenuation. Indeed, it was recently reported that the acid reflux esophagitis was prevented or aggravated by prior administration of PGE 2 or indomethacin, respectively (44). However, various PGs differently affect lower esophageal sphincter, pyloric sphincter, and ileocaecal sphincter, while pyloric sphincter is not responsive to PGs treatment (45).…”

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…EP 1 receptors are essential for HCO 3 Ϫ secretion in response to mucosal acidification in the stomach . A dual role for EP 1 receptors in esophagitis is clearer, whereby PGE 2 has a protective effect at low doses and a deleterious effect at high doses (Yamato et al, 2005). In the kidney, PGE 2 activates EP 1 receptors to inhibit Na ϩ absorption by the renal collecting duct (Guan et al, 1998).…”