Similarities in the Mechanism of Action of Two New Vasodilator Drugs: Pinacidil and BRL 34915
Similarities in the Mechanism of Action of Two New Vasodilator Drugs: Pinacidil and BRL 34915
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两种新型血管扩张药物作用机制的相似之处：吡那地尔和 BRL 34915
DOI：
10.1097/00005344-198801000-00014
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发表时间：
1988
影响因子：
3
通讯作者：
C. Pally
中科院分区：
文献类型：
--
作者：
N. Cook;U. Quast;R. Hof;Y. Baumlin;C. Pally
摘要：本研究比较了pinacidil与另一种新型血管扩张剂BRL 34915的体内和体外活性，BRL 34915被认为是通过打开血管平滑肌中的K+通道起作用。在兔主动脉中，BRL 34915和pinacidil引起KCl浓度-反应曲线右移和非竞争性拮抗血管紧张素II收缩，IC50分别为5 μM和10 μM。在加载86Rb的豚鼠门静脉中，BRL 34915和pinacidil均刺激86Rb+流出，浓度范围在0.3 ~ 30 μM。在饱和浓度下，pinacidil引起的最大外排仅为BRL 34915的三分之一。brl34915和pinacidil同时抑制同一血管的自发活性，IC50分别为12和32 n M。因此，在药物浓度低于刺激86Rb+外排所需浓度100倍时，观察到对机械活性的影响。在麻醉的大鼠中，这两种化合物都能迅速降低血压，BRL 34915在这方面的效果是pinacidil的三倍。brl34915治疗后心动过速比pinacidil治疗后更为明显。在大鼠中，这两种血管扩张剂对血管紧张素II加压反应的拮抗作用很差，这与同等有效降压剂量的Ca2+拮抗剂对这些反应的有效作用形成鲜明对比。我们得出结论，pinacidil与brl34915一样，是一种有效的抗高血压药物，能够增强血管平滑肌的K+通透性。这两种药物的相似之处表明它们具有共同的作用机制。然而，刺激86Rb外排所需的药物浓度与门静脉中看到的机械效应之间的差异，并不排除其他作用可能有助于其血管舒张活性的可能性。
Summary: The present study compares the in vitro and in vivo activities of pinacidil with another new vasodilator drug, BRL 34915, claimed to act via the opening of K+channels in vascular smooth muscle. In the rabbit aorta, BRL 34915 and pinacidil caused rightward shifts of the KCl concentration–response curve and noncompetitively antagonized angiotensin II contractions, yielding an IC50 of 5 and 10 μM, respectively. In 86Rb-loaded guinea pig portal veins, both BRL 34915 and pinacidil stimulated 86Rb+ efflux over the concentration range 0.3–30 μM. At saturating concentrations, the maximum efflux elicited by pinacidil was only one-third that of BRL 34915. Spontaneous activity measured simultaneously from the same vessels was inhibited by BRL 34915 and pinacidil with an IC50 of 12 and 32 n M, respectively. Effects on mechanical activity were thus observed at drug concentrations 100-fold lower than those required to stimulate 86Rb+ efflux. In anesthetized rats, both compounds rapidly lowered blood pressure, with BRL 34915 being threefold more potent than pinacidil in this respect. Tachycardia was more pronounced after BRL 34915 than after pinacidil. Angiotensin II pressor responses were poorly antagonized by these two vasodilators in rats, in marked contrast to the potent effects of Ca2+ antagonists on these responses at equieffective hypotensive doses. We conclude the pinacidil, like BRL 34915, is a potent antihypertensive that is able to enhance the K+ permeability of vascular smooth muscle. The similarities between these two drugs suggest they have a common mechanism of action. However, the discrepancy between the concentrations of these drugs necessary to stimulate 86Rb efflux, and those at which mechanical effects are seen in the portal vein, do not rule out the possibility that other actions may contribute to their vasodilator activities.