Piglet saphenous vein contains multiple relaxatory prostanoid receptors: evidence for EP4 EP2 DP and IP receptor subtypes

摘要

class="enumerated" style="list-style-type:decimal">Prostaglandin E2 produced endothelium-independent relaxation of phenylephrine- and 5-HT-contracted piglet saphenous vein (PSV; pEC50=8.6±0.2; n=6).The prostanoid EP4 receptor antagonist GW627368X (30–300 nM) produced parallel rightward displacement of PGE2 concentration–effect (E/[A]) curves (pKb=9.2±0.2; slope=1). Higher concentrations of GW627368X did not produce further rightward shifts, revealing the presence of non-EP4 prostanoid receptors.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 EP4 receptors) correlated well with those at human recombinant EP4 receptors in human embryonic kidney (HEK-293) cells (r²=0.74).In the presence of 10 μM GW627368X, the rank order of agonist relative potency matched that of the human recombinant EP2 receptor in Chinese hamster ovary cells (r²=0.72).Iloprost, cicaprost and PGI2 relaxed PSV maximally and were antagonised by 10 μM GW627368X, demonstrating that they were full EP4 receptor agonists. Residual responses to these compounds in the presence of GW627368X suggested the presence of IP receptors.BW245C relaxed PSV maximally (pEC50=6.8±0.1). In the presence of 10 μM GW627368X, BW245C produced biphasic E/[A] curves (phase one pEC50=6.6; α=24%; phase two pEC50=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.We conclude that PSV contains EP4, EP2, DP and IP receptors; IP receptor agonists are also porcine EP₄ receptor agonists.