Effect of Azelastine on Cardiac Repolarization of Guinea-Pig Cardiomyocytes, hERG K+ Channel, and Human L-type and T-type Ca2+ Channel
Effect of Azelastine on Cardiac Repolarization of Guinea-Pig Cardiomyocytes, hERG K+ Channel, and Human L-type and T-type Ca2+ Channel
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DOI：
10.1254/jphs.12239fp
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发表时间：
2013-09-01
影响因子：
3.5
通讯作者：
Jo, Su-Hyun
中科院分区：
文献类型：
--
作者：
Park, Mi-Hyeong;Lee, Seung Ho;Jo, Su-Hyun
氮卓斯汀是第二代组胺HI受体拮抗剂，用作抗哮喘和抗过敏药物，可诱导QT间期延长和尖端扭转型室性心动过速。我们研究了氮卓斯汀对人ether-a-go-go-related基因（hERG）通道、动作电位时程（APD）、L型（I-Ca，I-L）和T型钙电流（I-Ca，I-T）的急性效应，以确定其促肾上腺皮质激素作用的电生理学基础。氮卓斯汀浓度依赖性地增加90%复极时的APD，在豚鼠心室肌细胞中的IC 50为1.08 nM。我们使用双微电极电压钳和膜片钳技术检测了氮卓斯汀对爪蟾卵母细胞和HEK 293细胞中表达的hERG通道的影响。在电压阶跃和尾电流结束时，氮卓斯汀诱导hERG电流振幅呈浓度依赖性降低。氮卓斯汀诱导阻断HEK 293细胞中表达的hERG电流的IC 50为11.43 nM，而药物抑制I-Ca，I-L和I-Ca，I-T，IC 50值分别为7.60和26.21 μ M。S6结构域突变Y 652 A部分减弱hERG电流阻滞，F656 A消除hERG电流阻滞。这些结果表明，氮卓斯汀是hERG通道的强效阻滞剂，而不是I-Ca，I-L或I-Ca，I-T，为氮卓斯汀临床给药期间的致瘤性副作用提供了分子机制。
Azelastine is a second generation histamine HI receptor antagonist used as an anti-asthmatic and anti-allergic drug that can induce QT prolongation and torsades de pointes. We investigated the acute effects of azelastine on human ether-a-go-go-related gene (hERG) channels, action potential duration (APD), and L-type (I-Ca,I-L) and T-type Ca2+ current (I-Ca,I-T) to determine the electrophysiological basis for its proarrhythmic potential. Azelastine increased the APD at 90% of repolarization concentration dependently, with an IC50 of 1.08 nM in guinea-pig ventricular myocytes. We examined the effects of azelastine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Azelastine induced a concentration-dependent decrease of the hERG current amplitude at the end of the voltage steps and tail currents. The IC50 for the azelastine-induced block of the hERG currents expressed in HEK293 cells was 11.43 nM, while the drug inhibited I-Ca,I-L and I-Ca,I-T with IC50 values of 7.60 and 26.21 mu M, respectively. The S6 domain mutations, Y652A partially attenuated and F656A abolished hERG current block. These results suggest that azelastine is a potent blocker of hERG channels rather than I-Ca,I-L or I-Ca,I-T, providing molecular mechanisms for the arrhythmogenic side effects during the clinical administration of azelastine.