Characterization of the EP receptor types that mediate longitudinal smooth muscle contraction of human colon, mouse colon and mouse ileum

Authors


Address for Correspondence
Sian E Fairbrother, Novartis Pharmaceuticals UK Limited, PH, GI-DA, GBHO, 38B09/23, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK.
Tel: +44 0140 332 3334; fax: +44 0140 332 3054;
e-mail: sian.carr@novartis.com

Abstract

Background  Prostaglandin E2 (PGE2) is an inflammatory mediator implicated in several gastrointestinal pathologies that affect normal intestinal transit. The aim was to establish the contribution of the four EP receptor types (EP1–4), in human colon, that mediate PGE2-induced longitudinal smooth muscle contraction.

Methods  Changes in isometric muscle tension of human colon, mouse colon and mouse ileum were measured in organ baths in response to receptor-specific agonists and antagonists. In addition, lidocaine was used to block neurogenic activity to investigate whether EP receptors were pre- or post-junctional.

Key Results  PGE2 contracted longitudinal muscle from human and mouse colon and mouse ileum. These contractions were inhibited by the EP1 receptor antagonist, EP1A in human colon, whereas a combination of EP1A and the EP3 antagonist, L798106 inhibited agonist responses in both mouse preparations. The EP3 agonist, sulprostone also increased muscle tension in both mouse tissues, and these responses were inhibited by lidocaine in the colon but not in the ileum. Although PGE2 consistently contracted all three muscle preparations, butaprost decreased tension by activating smooth muscle EP2 receptors in both colonic tissues. Alternatively, in mouse ileum, butaprost responses were lidocaine-sensitive, suggesting that it was activating prejunctional EP2 receptors on inhibitory motor neurons. Conversely, EP4 receptors were not functional in all the intestinal muscle preparations tested.

Conclusions & Inferences  PGE2-induced contraction of longitudinal smooth muscle is mediated by EP1 receptors in human colon and by a combination of EP1 and EP3 receptors in mouse intestine, whereas EP2 receptors modulate relaxation in all three preparations.

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