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.

延迟的整流器KII D1+IE D1电流（II D2KIY D2）是负责心脏作用潜力重极化的最重要的电流之一。 II D2KIY D2由两个不同的组成部分组成：快速激活的成分II D2KRIY D2和一个缓慢的激活成分II D2KSIE D2。目前使用的大多数III类药物，例如D-索洛尔，多菲替二，半解酯和MS-551优先块II D2KRIE D2。编码II D2KRIE D2和II D2KSIE D2的钾通道基因分别是HERG和KVLQT1/Mink。在这项研究中，我们检查了对HERG和KVLQT1/Mink Currents上各种III级抗心律失常药物的调节。我们先前表明，心脏毒素剂Vesnarinone在Rabbit cortricular Myocycytes中产生了动作电位持续时间（APD）的频率依赖性延长。其他III级药物尚未报告作为III类抗心律失常剂的这种有利性能。为了阐明基本机制，我们研究了vensnarinone对HERG通道的影响，而Xenopus卵母细胞中的KVLQT1/Mink通道。 Vesnarinone对HERG电流提供了浓度依赖性抑制，ICII D250 D2为58.7±9.3μm + 50mV（n = 5）。在 +10mV时，HERG块的发作是178±15毫秒（n = 3）开发的。 vesnarinone在300 m处产生的KVLQT1/Mink电流最少。这些结果表明，1）vesnarinone在APD中的延长是由HERG的阻滞引起的，但不是KVLQT1/Mink通道，2）vesnarinone对APD的频率依赖性延长引起的，vesnarinone的频率依赖性依赖电压依赖性依赖性依赖性依赖性的结合，而不是在impriant的impriant of to nom nom nom nom nom nom nibers imbrentive and imbrentive nibers Intrend contrient contrient contrient otferemant，3）与中等时间的插入，3）电压改变了。

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。

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。

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。

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)。

LEE Jong-KooK, NISHIYAMA Atsushi, KAMBE Fukushi, SEO, Hisao, TAKEUCHI Susumu, KAMIYA Kaichiro, KODAMA Itsuo, TOYAMA Junji: "Downregulation of voltage-gated K+ channels in rat heart with right ventricular hypertrophy"American Journal of Physiology 277 (Hea

LEE Jong-KooK、NISHIYAMA Atsushi、KAMBE Fukushi、SEO、Hisao、TAKEUCHI Susumu、KAMIYA Kaichiro、KODAMA Ituo、TOYAMA Junji：“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 277（Hea