Blockade of HERG cardiac K+ current by antifungal drug miconazole
Blockade of HERG cardiac K+ current by antifungal drug miconazole
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DOI：
10.1038/sj.bjp.0706095
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发表时间：
2005-03-01
影响因子：
7.3
通讯作者：
Nakashima, Y
中科院分区：
文献类型：
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作者：
Kikuchi, K;Nagatomo, T;Nakashima, Y
1 咪康唑是一种咪唑抗真菌药，与获得性长 QT 综合征和室性心律失常有关。咪康唑通过抑制肝细胞色素 P450 代谢途径来增加 QT 延长药物的血浆浓度，但是否对心脏离子通道有直接影响尚未阐明。2 为了确定这些临床发现的机制，我们研究了咪康唑对人 ether-a-go-go 相关基因 (HERG) K+ 通道的影响。3 HERG 通道在人胚胎肾 293 (HEK293) 细胞中异源表达，并且使用膜片钳技术（23°C）记录全细胞电流。4达克宁以浓度依赖性方式（0.4-40μM）抑制HERG峰值尾电流，IC50为2.1μM（每个浓度下n = 3-5个细胞，希尔系数1.2）。 HERG 阻滞不依赖于频率。它需要通道激活，发生迅速，并且具有非常缓慢的解离特性。5 激活曲线向负方向移动（V-1/2：对照中为 -9.5+/-2.3 mV，4 μM 咪康唑后为 -15.3+/-2.4 mV，P
1 Miconazole, an imidazole antifungal agent, is associated with acquired long QT syndrome and ventricular arrhythmias. Miconazole increases the plasma concentration of QT-prolonging drugs by inhibiting the hepatic cytochrome P450 metabolic pathway, but whether it has direct effects on cardiac ion channels has not been elucidated.2 To determine the mechanism underlying these clinical findings, we investigated the effect of miconazole on human ether-a-go-go-related gene (HERG) K+ channels.3 HERG channels were heterologously expressed in human embryonic kidney 293 (HEK293) cells and whole-cell currents were recorded using a patch-clamp technique (23 degrees C).4 Miconazole inhibited HERG peak tail current in a concentration-dependent manner (0.4-40 mu M) with an IC50 of 2.1 mu M (n=3-5 cells at each concentration, Hill coefficient 1.2). HERG block was not frequency-dependent. It required channel activation, occurred rapidly, and had very slow dissociation properties.5 The activation curve was shifted in a negative direction (V-1/2: -9.5+/-2.3 mV in controls and -15.3+/-2.4 mV after 4 mu M miconazole, P