Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel - Open-channel block by methanesulfonanilides
Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel - Open-channel block by methanesulfonanilides
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DOI：
10.1161/01.res.78.3.499
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发表时间：
1996-03-01
影响因子：
20.1
通讯作者：
Sanguinetti, MC
中科院分区：
文献类型：
--
作者：
Spector, PS;Curran, ME;Sanguinetti, MC
我们最近报道了钾通道基因HERG的突变导致长QT综合征。HERG在非洲爪蟾卵母细胞中的异源表达表明，该通道具有与心脏延迟整流钾电流（I-Kr）几乎相同的生物物理特性，但具有不同的药理学特性。III类抗心律失常药物如E-4031和MK-499是心肌细胞中I-Kr的有效和特异性阻断剂。我们的初步研究表明，这些化合物在1 μ mol/L浓度下不阻断HERG。在本研究中，我们使用标准的双微电极电压钳技术，以进一步表征这些药物对卵母细胞中表达的HERO通道的影响。与初始结果一致，当卵母细胞在负电位下进行电压钳位且在与药物平衡期间不进行脉冲时，1 μ mol/L MK-499和E-4031对HERO无影响。然而，MK-499阻断HERG电流，如果卵母细胞被反复脉冲，或钳位在一个电压正的阈值电位通道激活。这一发现与以前的研究相反，以前的研究表明，即使在没有脉冲的情况下，类似的药物也能显著阻断分离的肌细胞中的I-Kr。这种明显的差异可能是由于通道特性（HERG与豚鼠和小鼠I-Kr）、组织（卵母细胞与肌细胞）或特定药物的差异。在稳态条件下，MK-499对HERO的阻断作用在123+/-12 nmol/L和-20 mV试验电位下达到最大值的一半。MK-499（150 nmol/L）不影响激活和整流的电压依赖性，也不影响HERG的激活和失活动力学。这些数据表明MK-499优先阻断开放的HERG通道，并进一步支持HERG亚基在心肌细胞中形成I-Kr通道的结论。
We recently reported that mutations in HERG, a potassium channel gene, cause long QT syndrome. Heterologous expression of HERG in Xenopus oocytes revealed that this channel had biophysical properties nearly identical to a cardiac delayed rectifier K+ current, I-Kr, but had dissimilar pharmacological properties. Class III antiarrhythmic drugs such as E-4031 and MK-499 are potent and specific blockers of I-Kr in cardiac myocytes. Our initial studies indicated that these compounds did not block HERG at a concentration of 1 mu mol/L. In the present study, we used standard two-microelectrode voltage-clamp techniques to further characterize the effects of these drugs on HERO channels expressed in oocytes. Consistent with initial findings, 1 mu mol/L MK-499 and E-4031 had no effect on HERO when oocytes were voltage clamped at a negative potential and not pulsed during equilibration with the drug. However, MK-499 did block HERG current if oocytes were repetitively pulsed, or clamped at a voltage positive to the threshold potential for channel activation. This finding is in contrast to previous studies that showed significant block of I-Kr in isolated myocytes by similar drugs, even in the absence of pulsing. This apparent discrepancy may be due to differences in channel characteristics (HERG versus guinea pig and mouse I-Kr), tissue (oocytes versus myocytes), or specific drugs. Under steady state conditions, block of HERO by MK-499 was half maximal at 123+/-12 nmol/L at a test potential of -20 mV. MK-499 (150 nmol/L) did not affect the voltage dependence of activation and rectification nor the kinetics of activation and deactivation of HERG. These data indicate that MK-499 preferentially blocks open HERG channels and further support the conclusion that HERG subunits form I-Kr channels in cardiac myocytes.