Drug design for cardiac treatment by control of K channel

通过控制 K 通道进行心脏治疗的药物设计

• 批准号: 10044259
• 负责人: KAMIYA Kaichiro
• 金额: $ 3.26万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10044259/
• 关键词: ion channels; antiarrhythmic drugs; K channel blocker; 突然死; QT延長症候群

The delayed rectifier KィイD1+ィエD1 current (IィイD2KィエD2) is one of the most important currents responsible for repolarization of cardiac action potential. IィイD2KィエD2 is composed of two distinctive components : a rapidly activating component, IィイD2KrィエD2, and a slowly activating component, IィイD2KsィエD2. Most of the Class III drugs currently used, such as d-sotalol, dofetilide, sematilide and MS-551 preferentially block IィイD2KrィエD2. Potassium channel genes which encode IィイD2KrィエD2 and IィイD2KsィエD2, are HERG and KVLQT1/minK, respectively. In this study, we examined the modulation of various class III antiarrhythmic drugs on HERG and KVLQT1/minK currents.We have previously shown that vesnarinone, a cardiotonic agent, produced a frequency-dependent prolongation of action potential duration (APD) in rabbit ventricular myocytes. This favorable property as a class III antiarrhythmic agent has not been reported with other class III drugs. To elucidate the underlying mechanisms, we studied the effects of vesnarinone on HERG channels, and KVLQT1/minK channels in Xenopus oocytes. Vesnarinone provided a concentration-dependent inhibition on HERG current with an ICィイD250ィエD2 of 58.7±9.3 μM + 50mV (n=5). The onset of HERG block by 100μM vesnarinone at +10mV developed with a time constant of 178±15 msec (n=3). Vesnarinone at 300 M produced a minimal reduction in KVLQT1/minK current. These results suggest that 1) the prolongation in APD by vesnarinone is caused by block of HERG, but not KVLQT1/minK channels, 2) frequency-dependent prolongation of APD by vesnarinone results from the voltage-dependent binding and unbinding of the drug to HERG channels with moderate time constants, 3) inactivation gate may not interfere neither the drug binding nor unbinding when membrane voltage was altered.

延迟整流钾通道（延迟整流钾通道D1+钾通道D1）电流（I钾通道D2 K钾通道D2）是心脏动作电位复极过程中最重要的电流之一。I κ D2 K κ D2由两种不同的组分组成：快速活化组分I κ D2 Kr κ D2和缓慢活化组分I κ D2 Ks κ D2。目前使用的大多数III类药物，如d-索他洛尔、多非利特、司马利特和MS-551优先阻断I型受体D2 Kr型受体D2。钾离子通道基因编码I κ D2 Kr κ D2和I κ D2 Ks κ D2，分别为HERG和KVLQT 1/minK。在这项研究中，我们研究了各种III类抗心律失常药物对HERG和KVLQT 1/minK电流的调制，我们以前已经表明，vesnarinone，一种强心剂，在兔心室肌细胞中产生了频率依赖性的动作电位时程（APD）延长。这种作为III类抗肿瘤药物的有利性质尚未报道与其他III类药物。为了阐明潜在的机制，我们研究了维司力农对爪蟾卵母细胞HERG通道和KVLQT 1/minK通道的影响。Vesnarinone对HERG电流具有浓度依赖性抑制作用，IC_（250）mV_（D2）为58.7±9.3 μM +50 mV（n=5）。100μM维司力农在+10 mV时开始HERG阻滞，时间常数为178±15 msec（n=3）。300 M的维司力农对KVLQT 1/minK电流产生最小的降低。这些结果表明：1）维司力农延长APD是通过阻断HERG而不是KVLQT 1/minK通道引起的; 2）维司力农延长APD的频率依赖性是由于药物与HERG通道的电压依赖性结合和去结合，时间常数适中; 3）失活门在膜电压改变时不干扰药物的结合和去结合。

项目成果

LEE Jong-Kook,NISHIYAMA Atsushi,KAMBE Fukushi,SEO Hisao,TAKEUCHI Susumu,KAMIYA Kaichiro: "Downregulation of voltage-gated K+ channels in rat heart with right ventricular hypertrophy"American Journal of Physiology. 277. 1725-1731 (1999)

LEE Jong-Kook、NISHIYAMA Atsushi、KAMBE Fukushi、SEO Hisao、TAKEUCHI Susumu、KAMIYA Kaichiro：“右心室肥大大鼠心脏电压门控 K 通道的下调”美国生理学杂志。

LEE Jong-Kook, NISHIYAMA Atsushi, KAMBE Fukushi, SEO Hisato, TAKEUCHI Susumu, KAMIYA Kaichiro: "Downregulation of voltage-gated K+ channels in rat heart with right ventricular hypertrophy"American Journal of Physiology. 277. 1725-1731 (1999)

LEE Jong-Kook、NISHIYAMA Atsushi、KAMBE Fukushi、SEO Hisato、TAKEUCHI Susumu、KAMIYA Kaichiro：“右心室肥大大鼠心脏中电压门控 K 通道的下调”美国生理学杂志。

KADA Kenji, YASUI Kenji, NARUSE Kenji, KAMIYA Kaichiro, et al.: "Orientation change change of cardiocytes induced by cyclic stretch stimulation : Time dependency and involvement of protein kinases"Journal of Molecular and Cellular Cardiology. 31. 247-259

KADA Kenji、YASUI Kenji、NARUSE Kenji、KAMIYA Kaichiro 等人：“循环拉伸刺激诱导的心肌细胞的方向变化：时间依赖性和蛋白激酶的参与”分子和细胞心脏病学杂志。

神谷 香一郎: "循環器病への挑戦シリーズXIII,「心房細動の最近の話題」"ライフメディコム. 13 (1999)

Koichiro Kamiya：“挑战心血管疾病系列 XIII，‘心房颤动的最新话题’”Life Medicom 13 (1999)。

CHENG Jianhua, KAMIYA Kaichiro, LIU Weiran, TSUJI Yukiomi, et al.: "Heterogeneous distribution of the two components of delayed rectifier K+ current : a potential mechanism of the proarrhythmic effects of methanesulfonanilide class III agents"Cardiovascul

程建华，KAMIYA Kaichiro，刘蔚然，TSUJI Yukiomi，等：“延迟整流K电流两个分量的异质分布：甲磺酰苯胺III类药物致心律失常作用的潜在机制”心血管