Piglet saphenous vein contains multiple relaxatory prostanoid receptors: Evidence for EP 4, EP 2, DP and IP receptor subtypes

Abstract

1 Prostaglandin E 2 produced endothelium-independent relaxation of phenylephrine- and 5-HT-contracted piglet saphenous vein (PSV; pEC 50 = 8.6±0.2; n = 6). 2 The prostanoid EP 4 receptor antagonist GW627368X (30-300 nM) produced parallel rightward displacement of PGE 2 concentration-effect (E/[A]) curves (pK b = 9.2±0.2; slope = 1). Higher concentrations of GW627368X did not produce further rightward shifts, revealing the presence of non-EP 4 prostanoid receptors. 3 In all, 18 other prostanoid receptor agonists relaxed PSV in a concentration-related manner. Relative potencies of agonists most sensitive to 10 μM GW627368X (and therefore predominantly activating EP 4 receptors) correlated well with those at human recombinant EP 4 receptors in human embryonic kidney (HEK-293) cells (r 2 = 0.74). 4 In the presence of 10 μM GW627368X, the rank order of agonist relative potency matched that of the human recombinant EP 2 receptor in Chinese hamster ovary cells (r 2 = 0.72). 5 Iloprost, cicaprost and PGI 2 relaxed PSV maximally and were antagonised by 10 μM GW627368X, demonstrating that they were full EP 4 receptor agonists. Residual responses to these compounds in the presence of GW627368X suggested the presence of IP receptors. 6 BW245C relaxed PSV maximally (pEC 50 = 6.8±0.1). In the presence of 10 μM GW627368X, BW245C produced biphasic E/[A] curves (phase one pEC 50 = 6.6; α = 24%; phase two pEC 50 = 5.1; α = 112%). Phase two was antagonised by the DP receptor antagonist BW A868C (1 μM), demonstrating that BW245C is an agonist at DP and EP4 receptors. 7 We conclude that PSV contains EP 4, EP 2, DP and IP receptors; IP receptor agonists are also porcine EP 4 receptor agonists. © 2005 Nature Publishing Group All rights reserved.