Contribution of late sodium current (INa-L) to rate adaptation of ventricular repolarization and reverse use-dependence of QT-prolonging agents
Contribution of late sodium current (INa-L) to rate adaptation of ventricular repolarization and reverse use-dependence of QT-prolonging agents
复制标题
晚钠电流 (INa-L) 对心室复极速率适应和逆转 QT 延长药物的使用依赖性的贡献
DOI：
10.1016/j.hrthm.2010.12.026
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发表时间：
2011-05-01
期刊：
影响因子：
5.5
通讯作者：
Yan, Gan-Xin
中科院分区：
文献类型：
--
作者：
Guo, Donglin;Lian, Jianfang;Yan, Gan-Xin
背景：心室复极率适应异常是致心律失常的。关于复极化中速率相关变化的潜在离子机制存在争议。目的探讨晚期钠电流（INa-L）在心室复极正常速率依赖性和qt延长剂反向使用依赖性中的作用。方法在离体兔心室角和单个肌细胞中观察INa-L阻断、INa-L增强、I-Kr阻断和细胞外钾浓度（[K+](o)）变化对QT间期和动作电位持续时间（APD）速率适应的影响。使用全细胞电压钳技术测定了INa-L、延迟整流钾电流（I-K）和l型钙电流（I-Ca）的速率依赖性。结果在对照组，当[K+](o)保持不变时，APD在多细胞制剂和分离的单心室肌细胞中表现出速率依赖性变化。[K+](o)从4 mM减少到1 mM或INa-L增强可显著增强APD的速率依赖性，但选择性钠通道阻滞剂河豚毒素可显著减弱APD的速率依赖性。I-Kr阻滞剂dofetilide （3 nM）使QT与基本周期长度斜率增大（71.2 +/- 13.1 ms/s vs 35.1 +/- 8.8 ms/s, n = 4, P < 0.05）。5 μ M河豚毒素（11.4 +/- 4.3 ms/s, n = 4, P < 0.01）消除了这种反向使用依赖。在2000到500 ms的基本周期长度范围内，I-Ca和I-K没有显著差异。然而，INa-L表现出显著的速率依赖性降低。结论INa-L因其失活和恢复缓慢，对APD/QT速率变化敏感，在APD/QT速率依赖和某些APD/QT延长药物的反向使用依赖中起核心作用。
BACKGROUND Abnormal rate adaptation of ventricular repolarization is arrhythmogenic. There is controversy on the underlying ionic mechanisms for rate-dependent change in repolarization.OBJECTIVE The purpose of this study was to examine the role of the late sodium current (INa-L) in normal rate-dependence of ventricular repolarization and reverse use-dependence of QT-prolonging agents.METHODS The effects of INa-L blockade, INa-L enhancement, I-Kr blockade, and changes in extracellular potassium concentration ([K+](o)) on rate adaptation of the QT interval and action potential duration (APD) were examined in isolated rabbit ventricular wedges and single myocytes. Rate dependence of INa-L, delayed rectifier potassium current (I-K), and L-type calcium current (I-Ca) was determined using a whole-cell, voltage clamp technique.RESULTS At control, APD exhibited rate-dependent changes in the multicellular preparations as well as in the isolated single ventricular myocytes when [K+](o) remained constant. The rate dependence of APD was significantly enhanced by reduction of [K+](o) from 4 to 1 mM or by INa-L enhancement but was markedly blunted by the selective sodium channel blocker tetrodotoxin. The I-Kr blocker dofetilide (3 nM) amplified the QT to basic cycle length slope (71.2 +/- 13.1 ms/s vs 35.1 +/- 8.8 ms/s in control, n = 4, P < .05). This reverse use-dependence was abolished by tetrodotoxin at 5 mu M (11.4 +/- 4.3 ms/s, n = 4, P < .01). There were no significant differences in I-Ca or I-K over the range of basic cycle lengths from 2,000 to 500 ms. However, INa-L exhibited a significant rate-dependent reduction.CONCLUSION INa-L is sensitive to rate change due to its slow inactivation and recovery kinetics and plays a central role in the rate dependence of APD/QT and in the reverse use-dependence of select APD/QT-prolonging agents.