Pulmonary vasoconstrictor action of KCNQ potassium channel blockers
Pulmonary vasoconstrictor action of KCNQ potassium channel blockers
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DOI：
10.1186/1465-9921-7-31
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发表时间：
2006-02-20
影响因子：
5.8
通讯作者：
Gurney, AM
中科院分区：
文献类型：
--
作者：
Joshi, S;Balan, P;Gurney, AM
背景：KCNQ通道在神经系统、心脏和内耳中已被广泛研究，它们具有重要的生理功能。最近的报告表明，KCNQ 通道也可能在门静脉中表达，表明它们会影响自发收缩活动。 KCNQ 通道介导的 K+ 电流的生物物理特性类似于肺动脉平滑肌细胞静息 K+ 电导和静息电位下的电流。因此，我们通过测定选择性 KCNQ 通道阻滞剂利诺吡啶和 XE991 促进肺血管收缩的能力，研究了 KCNQ 通道在调节肺动脉功能中的可能作用。方法：使用小血管肌动描记法测量大鼠和小鼠肺内或肠系膜动脉产生的张力。在完整血管和内皮剥脱血管中测量对利诺吡啶和 XE991 的收缩反应。还在阻止神经释放的去甲肾上腺素或ATP的收缩作用，或阻断各种Ca2+流入途径的条件下进行实验，以研究收缩的机制。结果：利诺吡啶和XE991均使大鼠和小鼠肺动脉收缩，但对肠系膜动脉影响很小。在每种情况下，最大收缩几乎与对 50 mM K+ 的反应一样大。 Linopirdine 的 EC50 约为 1 μM，而 XE991 的效力几乎高出 10 倍。去除内皮或暴露于酚妥拉明或α,β-亚甲基ATP（分别阻断α(1)-肾上腺素受体或P2X受体）均不会影响收缩。在无 Ca2+ 溶液和 1 μM 硝苯地平或 10 μM levcromakalim 存在下，收缩被消除。结论：KCNQ 通道阻滞剂是有效且有力的肺动脉收缩剂。这种作用对于肺循环可能是选择性的，因为肠系膜动脉几乎没有反应。结果表明，药物直接作用于平滑肌细胞，收缩需要电压依赖性 Ca2+ 流入。结论是，该药物可能通过阻断肺动脉肌细胞中的KCNQ通道，导致膜去极化和Ca2+通过L型Ca2+通道流入而发挥作用。这意味着 KCNQ 通道在调节肺动脉肌细胞静息膜电位方面发挥着功能作用。
Background: KCNQ channels have been widely studied in the nervous system, heart and inner ear, where they have important physiological functions. Recent reports indicate that KCNQ channels may also be expressed in portal vein where they are suggested to influence spontaneous contractile activity. The biophysical properties of K+ currents mediated by KCNQ channels resemble a current underlying the resting K+ conductance and resting potential of pulmonary artery smooth muscle cells. We therefore investigated a possible role of KCNQ channels in regulating the function of pulmonary arteries by determining the ability of the selective KCNQ channel blockers, linopirdine and XE991, to promote pulmonary vasoconstriction.Methods: The tension developed by rat and mouse intrapulmonary or mesenteric arteries was measured using small vessel myography. Contractile responses to linopirdine and XE991 were measured in intact and endothelium denuded vessels. Experiments were also carried out under conditions that prevent the contractile effects of nerve released noradrenaline or ATP, or block various Ca2+ influx pathways, in order to investigate the mechanisms underlying contraction.Results: Linopirdine and XE991 both contracted rat and mouse pulmonary arteries but had little effect on mesenteric arteries. In each case the maximum contraction was almost as large as the response to 50 mM K+. Linopirdine had an EC50 of around 1 mu M and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or alpha,beta-methylene ATP, to block alpha(1)-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca2+-free solution and in the presence of 1 mu M nifedipine or 10 mu M levcromakalim. Conclusion: The KCNQ channel blockers are potent and powerful constrictors of pulmonary arteries. This action may be selective for the pulmonary circulation as mesenteric arteries showed little response. The results imply that the drugs act directly on smooth muscle cells and contraction requires voltage-dependent Ca2+ influx. It is concluded that the drugs probably act by blocking KCNQ channels in pulmonary artery myocytes, leading to membrane depolarization and Ca2+ influx through L-type Ca2+ channels. This implies a functional role for KCNQ channels in regulating the resting membrane potential of pulmonary artery myocytes.