EP2 and EP4 receptors mediate PGE2 induced relaxation in murine colonic circular muscle: Pharmacological characterization

Background: Prostaglandin E-2 (PGE(2)) is a regulator of gastrointestinal motility that might be involved in impaired motor function associated to gut inflammation. The aim of the present work is to pharmacologically characterize responses to exogenous and endogenous PGE(2) in the mouse colon targeting EP2 and EP4 receptors. Methods: Wild type (WT) and EP2 receptor knockout (EP2-KO) mice were used to characterize PGE(2) and butaprost (EP2 receptor agonist) effects on smooth muscle resting membrane potential and myogenic contractility in circularly oriented colonic preparations. Results: In WT animals, PGE(2) and butaprost concentration-dependently inhibited spontaneous contractions and hyperpolarized smooth muscle cells. Combination of both EP2 (PF-04418948 0.1 mu M) and EP4 receptor antagonists (L-161,982 10 mu M) was needed to block both electrical and mechanical PGE(2) responses. Butaprost inhibitory responses (both electrical and mechanical) were totally abolished by PF-04418948 0.1 mu M. In EP2-KO mice, PGE(2) (but not butaprost) concentration-dependently inhibited spontaneous contractions and hyperpolarized smooth muscle cells. In EP2-KO mice, PGE(2) inhibition of spontaneous contractility and hyperpolarization was fully antagonized by L-161,982 10 mu M. In WT animals, EP2 and EP4 receptor antagonists caused a smooth muscle depolarization and an increase in spontaneous mechanical activity. Conclusions: PGE(2) responses in murine circular colonic layer are mediated by post-junctional EP2 and ER4 receptors. PF-04418948 and L-161,982 are selective EP2 and EP4 receptor antagonists that inhibit PGE(2) responses. These antagonists might be useful pharmacological tools to limit prostaglandin effects associated to dismotility in gut inflammatory processes. (C) 2014 Elsevier Ltd. All rights reserved.