Selective inhibition of physiological late Na+ current stabilizes ventricular repolarization
Selective inhibition of physiological late Na+ current stabilizes ventricular repolarization
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DOI：
10.1152/ajpheart.00071.2017
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发表时间：
2018-02-01
影响因子：
4.8
通讯作者：
Belardinelli, Luiz
中科院分区：
文献类型：
--
作者：
El-Bizri, Nesrine;Li, Cindy Hong;Belardinelli, Luiz
心脏晚Na+电流（I-Na）的生理作用尚未得到很好的描述。在本研究中，我们验证了这样一个假设，即选择性抑制生理性晚期I-Na延长了正常动作电位（AP）时程（APD），并抵消了由抑制延迟整流钾电流（I-Kr）引起的APD和突触活动的延长。本文观察了GS-458967（GS 967）对家兔离体心室肌细胞生理性晚期I-Na和AP的影响，以及对家兔离体灌流心脏单相AP和心律失常的影响。在心室肌细胞中，GS 967和河豚毒素浓度依赖性地降低生理性晚期I-Na，IC 50值分别为0.5和1.9 μ M，并显著缩短在90%复极化时测量的APD（APD（90））。GS 967或河豚毒素（R-2分别为0.96和0.97）对生理性晚期I-Na的抑制与APD缩短之间存在较强的相关性。用GS 967（1 μ M）预处理离体心肌细胞或心脏可显著缩短APD（90）和单相APD（90），并防止I-Kr抑制剂E4031（1 μ M）引起的延长和相关心律失常。总之，选择性抑制生理性晚期I-Na可缩短APD，稳定心室复极，并降低减慢心室复极的药物的促心律失常潜力。因此，晚I-Na的选择性抑制可能构成一个可推广的方法来稳定心室复极和抑制与AP或QT间期延长的条件相关的acromogenicity。新&值得注意的是生理晚Na+电流的贡献在动作电位时程（APD）的兔心肌细胞进行了估计。抑制该电流可防止延迟整流钾电流抑制引起的兔心肌细胞动作电位时程延长、单相动作电位时程延长及兔离体心脏心律失常的发生。
The physiological role of cardiac late Na+ current (I-Na) has not been well described. In this study, we tested the hypothesis that selective inhibition of physiological late I-Na abbreviates the normal action potential (AP) duration (APD) and counteracts the prolongation of APD and arrhythmic activities caused by inhibition of the delayed rectifier K+ current (I-Kr). The effects of GS-458967 (GS967) on the physiological late I-Na and APs in rabbit isolated ventricular myocytes and on the monophasic APs and arrhythmias in rabbit isolated perfused hearts were determined. In ventricular myocytes, GS967 and, for comparison, tetrodotoxin concentration dependently decreased the physiological late I-Na with IC50 values of 0.5 and 1.9 mu M, respectively, and significantly shortened the APD measured at 90% repolarization (APD(90)). A strong correlation between inhibition of the physiological late I-Na and shortening of APD by GS967 or tetrodotoxin (R-2 of 0.96 and 0.97, respectively) was observed. Pretreatment of isolated myocytes or hearts with GS967 (1 mu M) significantly shortened APD(90) and monophasic APD(90) and prevented the prolongation and associated arrhythmias caused by the I-Kr inhibitor E4031 (1 mu M). In conclusion, selective inhibition of physiological late I-Na shortens the APD, stabilizes ventricular repolarization, and decreases the proarrhythmic potential of pharmacological agents that slow ventricular repolarization. Thus, selective inhibition of late I-Na may constitute a generalizable approach to stabilize ventricular repolarization and suppress arrhythmogenicity associated with conditions whereby AP or QT intervals are prolonged.NEW & NOTEWORTHY The contribution of physiological late Na+ current in action potential duration (APD) of rabbit cardiac myocytes was estimated. The inhibition of this current prevented the prolongation of APD in rabbit cardiac myocytes, the prolongation of monophasic APD, and generation of arrhythmias in rabbit isolated hearts caused by delayed rectifier K+ current inhibition.