Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels.
Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels.
复制标题
卡维地洛针对人类 K2P 3.1 (TASK1) K 泄漏通道。
DOI：
10.1111/j.1476-5381.2011.01319.x
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发表时间：
2011
影响因子：
7.3
通讯作者：
Thomas,D
中科院分区：
文献类型：
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作者：
Staudacher,K;Staudacher,I;Ficker,E;Seyler,C;Gierten,J;Kisselbach,J;Rahm,A-K;Trappe,K;Schweizer,PA;Becker,R;Katus,HA;Thomas,D
背景和结论人K2P3.1（TASK 1）通道代表了房颤药物治疗的潜在靶点。K2 P通道通过稳定膜电位和加速复极化来控制兴奋性。在心脏中，III类抗心律失常药物抑制K2 P电流导致动作电位延长和电自律性抑制。卡维地洛具有抗心律失常活性，并抑制心脏手术或心脏复律后的房颤。本研究的目的是研究卡维地洛对人K2P3.1的急性作用。实验方法使用双电极电压钳和全细胞膜片钳电生理学记录来自异种卵母细胞的hK2P3.1电流，中国仓鼠卵巢细胞（CHO）和人肺动脉平滑肌细胞（hPASMC）。关键词卡维地洛浓度依赖性地抑制异种卵母细胞（IC 50 = 3.8 µM）和哺乳动物CHO细胞（IC 50 = 0.83 µM）。此外，在hPASMC中证实了天然IK2P3.1对卡维地洛的敏感性。通道以频率依赖性方式在开放和闭合状态下被阻断，导致静息膜电位去极化7.7 mV。 卡维地洛使电流-电压（I-V）关系向超极化电位移动了−6.9 mV。 开放整流，K2 P电流的特点，没有受到影响。结论和IMPLICATIONS的抗肿瘤药物卡维地洛的目标hK2P3.1背景通道。我们认为，心脏hK2P3.1电流阻滞可能会抑制电自律性，延长心房不应期，并有助于III类抗心律失常作用的患者与药物治疗。
BACKGROUND AND PURPOSEHuman K2P3.1 (TASK1) channels represent potential targets for pharmacological management of atrial fibrillation. K2Pchannels control excitability by stabilizing membrane potential and by expediting repolarization. In the heart, inhibition of K2Pcurrents by class III antiarrhythmic drugs results in action potential prolongation and suppression of electrical automaticity. Carvedilol exerts antiarrhythmic activity and suppresses atrial fibrillation following cardiac surgery or cardioversion. The objective of this study was to investigate acute effects of carvedilol on human K2P3.1 (hK2P3.1) channels.EXPERIMENTAL APPROACHTwo‐electrode voltage clamp and whole‐cell patch clamp electrophysiology was used to record hK2P3.1 currents fromXenopusoocytes, Chinese hamster ovary (CHO) cells and human pulmonary artery smooth muscle cells (hPASMC).KEY RESULTSCarvedilol concentration‐dependently inhibited hK2P3.1 currents inXenopusoocytes (IC50= 3.8 µM) and in mammalian CHO cells (IC50= 0.83 µM). In addition, carvedilol sensitivity of nativeIK2P3.1was demonstrated in hPASMC. Channels were blocked in open and closed states in frequency‐dependent fashion, resulting in resting membrane potential depolarization by 7.7 mV. Carvedilol shifted the current–voltage (I–V) relationship by −6.9 mV towards hyperpolarized potentials. Open rectification, characteristic of K2Pcurrents, was not affected.CONCLUSIONS AND IMPLICATIONSThe antiarrhythmic drug carvedilol targets hK2P3.1 background channels. We propose that cardiac hK2P3.1 current blockade may suppress electrical automaticity, prolong atrial refractoriness and contribute to the class III antiarrhythmic action in patients treated with the drug.