Distinction between relaxations induced via prostanoid EP4 and IP1 receptors in pig and rabbit blood vessels

1 Our study shows that the prostacyclin analogues AFP-07 and cicaprost are moderately potent agonists for prostanoid EP4 receptors, in addition to being highly potent IP1 receptor agonists. Both activities were demonstrated on piglet and rabbit saphenous veins, which are established EP4 preparations. 2 On piglet saphenous vein, PGE(2) was 6.1, 24, 96, 138, 168 and 285 times respectively more potent than AFP-07, cicaprost, PGI(2), iloprost, carbacyclin and TEI-9063 in causing relaxation. Another prostacyclin analogue taprostene did not induce maximum relaxation (21-74%), and did not oppose the action of PGE(2). The EP4 receptor antagonist AH 23848 (30 muM) blocked relaxant responses to PGE(2) (dose ratio = 8.6 +/- 1.3, s.e.mean) to a greater extent than cicaprost (4.9 +/- 0.7) and AFP-07 (3.8 +/- 0.8), had variable effects on TEI-9063 -induced relaxation (3.7 +/- 1.5), and had no effect on taprostene responses (<2.0). 3 On rabbit saphenous vein, AH 23848 blocked the relaxant actions of PGE(2), AFP-07, cicaprost, iloprost and carbacyclin to similar extents. 4 AFP-07, cicaprost and TEI-9063 showed high IP1 relaxant potency on piglet carotid artery, rabbit mesenteric artery and guinea-pig aorta, with AFP-07 confirmed as the most potent IP1 agonist reported to date. AH 23848 did not block cicaprost-induced relaxation of piglet carotid artery. EP3 contractile systems in these preparations can confound IP1 agonist potency estimations. 5 Caution is urged when using AFP-07 and cicaprost to characterize IP1 receptors in the presence of EP4 receptors. Taprostene may be a lead to a highly selective IP1 receptor agonist.