Department of Biology, Gilead Sciences, Fremont, California.
Am J Physiol Heart Circ Physiol. 2018 Feb 1;314(2):H236-H245. doi: 10.1152/ajpheart.00071.2017. Epub 2017 Sep 29.
The physiological role of cardiac late Na current ( I) has not been well described. In this study, we tested the hypothesis that selective inhibition of physiological late I 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). The effects of GS-458967 (GS967) on the physiological late I 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 with IC values of 0.5 and 1.9 µM, respectively, and significantly shortened the APD measured at 90% repolarization (APD). A strong correlation between inhibition of the physiological late I and shortening of APD by GS967 or tetrodotoxin ( R of 0.96 and 0.97, respectively) was observed. Pretreatment of isolated myocytes or hearts with GS967 (1 µM) significantly shortened APD and monophasic APD and prevented the prolongation and associated arrhythmias caused by the I inhibitor E4031 (1 µM). In conclusion, selective inhibition of physiological late I shortens the APD, stabilizes ventricular repolarization, and decreases the proarrhythmic potential of pharmacological agents that slow ventricular repolarization. Thus, selective inhibition of late I 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.
心脏晚期钠电流（I）的生理作用尚未得到很好的描述。在这项研究中，我们检验了以下假设，即选择性抑制生理晚期 I 可缩短正常动作电位（AP）时程（APD），并对抗由抑制延迟整流钾电流（I）引起的 APD 延长和心律失常活动。测定了 GS-458967（GS967）对兔离体心室肌细胞生理晚期 I 和 APs 的影响，以及对兔离体灌流心脏单相 APs 和心律失常的影响。在心室肌细胞中，GS967 与比较剂河豚毒素浓度依赖性地减少生理晚期 I，IC 值分别为 0.5 和 1.9 μM，显著缩短 90%复极化时的 APD（APD）。观察到 GS967 或河豚毒素抑制生理晚期 I 与缩短 APD 之间存在很强的相关性（R 值分别为 0.96 和 0.97）。GS967（1 μM）预处理分离的心肌细胞或心脏可显著缩短 APD 和单相 APD，并预防 I 抑制剂 E4031（1 μM）引起的延长和相关心律失常。结论：选择性抑制生理晚期 I 可缩短 APD，稳定心室复极，降低减慢心室复极的药物的致心律失常潜能。因此，选择性抑制晚期 I 可能成为稳定心室复极和抑制与 AP 或 QT 间期延长相关的心律失常的普遍方法。
评估了生理晚期钠电流对兔心肌细胞动作电位时程（APD）的贡献。抑制这种电流可防止兔心肌细胞的 APD 延长，防止由延迟整流钾电流抑制引起的兔离体心脏单相 APD 延长和心律失常的发生。
