Coleman R A, Grix S P, Head S A, Louttit J B, Mallett A, Sheldrick R L
Department of Cardiovascular and Respiratory Pharmacology, Glaxo Group Research Ltd., Ware, Herts, U.K.
Prostaglandins. 1994 Feb;47(2):151-68. doi: 10.1016/0090-6980(94)90084-1.
A range of prostanoid agonists were tested for activity on isolated ring preparations of piglet saphenous vein. The selective TxA2-mimetic (TP-receptor agonist), U-46619, contracted the preparation in a concentration-related fashion. These contractions were inhibited by the TP-receptor blocking drug, GR32191B, producing a pA2 of 7.8 (slope = 1.6). Prostanoid-induced relaxant responses were studied on preparations which had been pre-contracted using an EC60 concentration of phenylephrine (mean EC60 = 0.97 microM), in the presence of GR32191B (1 microM), to block contractile TP-receptors. Under these conditions, PGD2, PGE2, PGF2 alpha, PGI2, and U-46619, all caused concentration-related relaxation. PGE2 was the most potent agonist (EC50 = 0.23nM), whereas, all of the other agonists were at least 1,000-fold weaker, providing strong evidence for the presence of inhibitory EP-receptors. The selective synthetic EP-agonists, sulprostone (EP1/EP3) and AH13205X (EP2), were next tested for relaxant activity. While both compounds caused concentration-related relaxant activity, they were respectively 6,000 and 11,000-fold less potent than PGE2. The potent TP-receptor blocking drugs, AH22921X and AH23848B, were both weak antagonists of PGE2 but not isoproterenol-induced relaxant responses of piglet saphenous vein in a concentration-related fashion. These two compounds had pA2 values against PGE2 of 5.3 and 5.4 respectively, with regression slopes not significantly different from unity. In contrast, neither compound at a concentration of 30 microM had any antagonist activity against prostanoid-induced effects on guinea-pig fundus (EP1), rabbit ear artery (EP2) or guinea-pig vas deferens (EP3). In conclusion, the piglet saphenous vein contains TP-receptors mediating smooth muscle contraction, and a PGE2-specific (EP) receptor mediating relaxation. The inhibitory EP-receptor does not appear to be of the EP1, EP2 or EP3-subtypes, and appears therefore to be a novel subtype which we tentatively term EP4, and the potent TP-receptor blocking drugs, AH22921X and AH23848B, appear to be weak, but specific EP4-receptor blocking drugs.
对一系列前列腺素类激动剂进行了测试，以观察它们对仔猪隐静脉离体环制剂的活性。选择性血栓素A2模拟物（TP受体激动剂）U-46619以浓度相关的方式使该制剂收缩。这些收缩被TP受体阻断药物GR32191B抑制，其pA2值为7.8（斜率 = 1.6）。在已使用苯肾上腺素的EC60浓度（平均EC60 = 0.97 microM）预收缩的制剂上，在GR32191B（1 microM）存在下以阻断收缩性TP受体，研究前列腺素诱导的舒张反应。在这些条件下，前列腺素D2、前列腺素E2、前列腺素F2α、前列环素和U-46619均引起浓度相关的舒张。前列腺素E2是最有效的激动剂（EC50 = 0.23 nM），而所有其他激动剂的效力至少弱1000倍，这为存在抑制性EP受体提供了有力证据。接下来测试了选择性合成的EP激动剂舒前列素（EP1/EP3）和AH13205X（EP2）的舒张活性。虽然这两种化合物都引起浓度相关的舒张活性，但它们的效力分别比前列腺素E2低6000倍和11000倍。强效的TP受体阻断药物AH22921X和AH23848B均为前列腺素E2的弱拮抗剂，但对异丙肾上腺素诱导的仔猪隐静脉舒张反应无浓度相关的拮抗作用。这两种化合物对前列腺素E2的pA2值分别为5.3和5.4，回归斜率与1无显著差异。相比之下，浓度为30 microM时，这两种化合物对前列腺素类对豚鼠胃底（EP1）、兔耳动脉（EP2）或豚鼠输精管（EP3）的作用均无拮抗活性。总之，仔猪隐静脉含有介导平滑肌收缩的TP受体和介导舒张的前列腺素E2特异性（EP）受体。抑制性EP受体似乎不是EP1、EP2或EP3亚型，因此似乎是一种新型亚型，我们暂时将其命名为EP4，而强效的TP受体阻断药物AH22921X和AH23848B似乎是弱但特异性的EP4受体阻断药物。
