Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKr blockade
Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKr blockade
复制标题
ATX-II 和雷诺嗪对晚钠电流的调节影响 IKr 阻断的反向使用依赖性和促心律失常倾向
DOI：
10.1111/j.1476-5381.2010.01181.x
复制
发表时间：
2011-09-01
影响因子：
7.3
通讯作者：
Yan, Gan-Xin
中科院分区：
文献类型：
--
作者：
Jia, Shaobin;Lian, Jiangfan;Yan, Gan-Xin
药物诱导的尖端扭转型室性心动过速（TdP）常发生在心动过缓时，这是由于药物的反向使用依赖性。我们检验了抑制或增强晚钠电流（I-Na，I-L）可以调节药物诱导的QT和Tp-e（复极离散指数）的反向使用依赖性，从而调节对TdP的倾向性的假设。同时记录来自内皮细胞的动作电位和透壁ECG。单独或联合检测了槽纹银莲花毒素（ATX-II）（一种I-Na、I-L增强剂）、d，l-索他洛尔、克拉霉素和雷诺嗪（一种I-Na、I-L阻滞剂）对QT、Tp-e和促心律失常事件的心率依赖性变化的影响。在对照组和药物输注过程中计算心率依赖性QT和Tp-e斜率和TdP评分（TdP倾向的综合指数）。关键的TSATX-II（30 nM）和索他洛尔（300 μ M）引起QT和Tp-e间期显著增加，QT-基本周期长度（BCL）和Tp-e-BCL斜率（即反向使用依赖性）和TdP显著增加。在ATX-Ⅱ或索他洛尔中加入雷诺嗪（15 μ M）可显著减弱QT-BCL、Tp-e-BCL斜率和增加TdP评分。相比之下，克拉霉素（100 μ M）适度延长QT和Tp-e，而不引起R-on-T期外收缩或TdP，但在克拉霉素中加入ATX-II（1 nM）显著放大了QT-BCL和Tp-e-BCL斜率，并进一步增加了TdP评分。I-L可显著降低延长QT间期药物的TdP倾向。
BACKGROUND AND PURPOSEDrug-induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use-dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (I-Na,I-L) could modulate the drug-induced reverse use-dependence in QT and Tp-e (an index of dispersion of repolarization), and therefore the liability for TdP.EXPERIMENTAL APPROACHArterially perfused rabbit left ventricular wedge preparations were used. Action potentials from the endocardium were recorded simultaneously with a transmural ECG. The effects of Anemonia sulcata toxin (ATX-II) (an I-Na,I-L enhancer), d,l-sotalol, clarithromycin and ranolazine (an I-Na,I-L blocker) on rate-dependent changes in QT, Tp-e and proarrhythmic events were tested, either alone or in combination. Rate-dependent QT and Tp-e slopes and TdP score (a combined index of TdP liability) were calculated at control and during drug infusion.KEY RESULTSATX-II (30 nM) and sotalol (300 mu M) caused a marked increase in QT and Tp-e intervals, steeper QT-basic cycle length (BCL) and Tp-e-BCL slopes (i.e. reverse use-dependence), and TdP. Addition of ranolazine (15 mu M) to ATX-II or sotalol significantly attenuated QT-BCL, Tp-e-BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 mu M) moderately prolonged QT and Tp-e without causing R-on-T extrasystole or TdP, but addition of ATX-II (1 nM) to clarithromycin markedly amplified the QT-BCL and Tp-e-BCL slopes and further increased TdP score.CONCLUSION AND IMPLICATIONSModulation of I-Na,I-L altered drug-induced reverse use-dependence related to QT as well as Tp-e, indicating that inhibition of I-Na,I-L can markedly reduce the TdP liability of agents that prolong QT intervals.