Thomas Dierk, Wimmer Anna-Britt, Wu Kezhong, Hammerling Bettina C, Ficker Eckhard K, Kuryshev Yuri A, Kiehn Johann, Katus Hugo A, Schoels Wolfgang, Karle Christoph A
Department of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, 69115, Heidelberg, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2004 May;369(5):462-72. doi: 10.1007/s00210-004-0931-8. Epub 2004 Apr 20.
Human ether-a-go-go-related gene (HERG) potassium channels are expressed in multiple tissues including the heart and adenocarcinomas. In cardiomyocytes, HERG encodes the alpha-subunit underlying the rapid component of the delayed rectifier potassium current, I(Kr), and pharmacological reduction of HERG currents may cause acquired long QT syndrome. In addition, HERG currents have been shown to be involved in the regulation of cell proliferation and apoptosis. Selective alpha 1-adrenoceptor antagonists are commonly used in the treatment of hypertension and benign prostatic hyperplasia. Recently, doxazosin has been associated with an increased risk of heart failure. Moreover, quinazoline-derived alpha 1-inhibitors induce apoptosis in cardiomyocytes and prostate tumor cells independently of alpha1-adrenoceptor blockade. To assess the action of the effects of prazosin, doxazosin, and terazosin on HERG currents, we investigated their acute electrophysiological effects on cloned HERG potassium channels heterologously expressed in Xenopus oocytes and HEK 293 cells.Prazosin, doxazosin, and terazosin blocked HERG currents in Xenopus oocytes with IC(50) values of 10.1, 18.2, and 113.2 microM respectively, whereas the IC(50) values for HERG channel inhibition in human HEK 293 cells were 1.57 microM, 585.1 nM, and 17.7 microM. Detailed biophysical studies revealed that inhibition by the prototype alpha 1-blocker prazosin occurred in closed, open, and inactivated channels. Analysis of the voltage-dependence of block displayed a reduction of inhibition at positive membrane potentials. Frequency-dependence was not observed. Prazosin caused a negative shift in the voltage-dependence of both activation (-3.8 mV) and inactivation (-9.4 mV). The S6 mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) HERG current blockade, indicating that prazosin binds to a common drug receptor within the pore-S6 region. In conclusion, this study demonstrates that HERG potassium channels are blocked by prazosin, doxazosin, and terazosin. These data may provide a hypothetical molecular explanation for the apoptotic effect of quinazoline-derived alpha1-adrenoceptor antagonists.
人类醚 - 去极化相关基因（HERG）钾通道在包括心脏和腺癌在内的多种组织中表达。在心肌细胞中，HERG编码延迟整流钾电流I(Kr)快速成分的α亚基，HERG电流的药理学降低可能导致获得性长QT综合征。此外，已表明HERG电流参与细胞增殖和凋亡的调节。选择性α1 - 肾上腺素能受体拮抗剂常用于治疗高血压和良性前列腺增生。最近，多沙唑嗪与心力衰竭风险增加有关。此外，喹唑啉衍生的α1抑制剂可独立于α1 - 肾上腺素能受体阻断作用诱导心肌细胞和前列腺肿瘤细胞凋亡。为了评估哌唑嗪、多沙唑嗪和特拉唑嗪对HERG电流的作用，我们研究了它们对非洲爪蟾卵母细胞和HEK 293细胞中异源表达的克隆HERG钾通道的急性电生理效应。哌唑嗪、多沙唑嗪和特拉唑嗪在非洲爪蟾卵母细胞中阻断HERG电流，IC(50)值分别为10.1、18.2和113.2微摩尔，而在人HEK 293细胞中HERG通道抑制的IC(50)值分别为1.57微摩尔、585.1纳摩尔和17.7微摩尔。详细的生物物理研究表明，原型α1阻滞剂哌唑嗪对关闭、开放和失活通道均有抑制作用。对阻断电压依赖性的分析显示，在正膜电位下抑制作用减弱。未观察到频率依赖性。哌唑嗪使激活（-3.8毫伏）和失活（-9.4毫伏）的电压依赖性发生负向偏移。S6突变Y652A和F656A部分减弱（Y652A）或消除（F656A）了HERG电流阻断，表明哌唑嗪与孔道 - S6区域内的共同药物受体结合。总之，本研究表明HERG钾通道被哌唑嗪、多沙唑嗪和特拉唑嗪阻断。这些数据可能为喹唑啉衍生的α1 - 肾上腺素能受体拮抗剂的凋亡作用提供一个假设的分子解释。
