Lankenau Institute for Medical Research and Main Line Health Heart Center, Wynnewood, Pennsylvania 19096, USA.
Heart Rhythm. 2011 May;8(5):762-9. doi: 10.1016/j.hrthm.2010.12.026. Epub 2010 Dec 22.
Abnormal rate adaptation of ventricular repolarization is arrhythmogenic. There is controversy on the underlying ionic mechanisms for rate-dependent change in repolarization.
The purpose of this study was to examine the role of the late sodium current (I(Na-L)) in normal rate-dependence of ventricular repolarization and reverse use-dependence of QT-prolonging agents.
The effects of I(Na-L) blockade, I(Na-L) enhancement, I(Kr) blockade, and changes in extracellular potassium concentration (K(+)) 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 I(Na-L), delayed rectifier potassium current (I(K)), and L-type calcium current (I(Ca)) was determined using a whole-cell, voltage clamp technique.
At control, APD exhibited rate-dependent changes in the multicellular preparations as well as in the isolated single ventricular myocytes when K(+) remained constant. The rate dependence of APD was significantly enhanced by reduction of K(+) from 4 to 1 mM or by I(Na-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 μM (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, I(Na-L) exhibited a significant rate-dependent reduction.
I(Na-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.
心室复极的异常率适应性是致心律失常的。对于复极时的这种变化，其潜在的离子机制仍存在争议。
本研究旨在探讨晚期钠电流（I(Na-L)）在心室复极正常率依赖性以及 QT 延长药物的反向使用依赖性中的作用。
采用兔心室楔形组织和单个心肌细胞，检测 I(Na-L)阻断、I(Na-L)增强、I(Kr)阻断以及细胞外钾浓度K(+)改变对 QT 间期和动作电位时程（APD）的影响。使用全细胞膜片钳技术测定 I(Na-L)、延迟整流钾电流（I(K))和 L 型钙电流（I(Ca))的速率依赖性。
在对照条件下，当K(+)保持不变时，多细胞标本和分离的单个心室肌细胞均表现出 APD 的速率依赖性变化。当K(+)从 4 降至 1 mM 或 I(Na-L)增强时，APD 的速率依赖性显著增强，但选择性钠通道阻滞剂河豚毒素则明显减弱。I(Kr)阻滞剂地尔硫卓（3 nM）使 QT 至基本心动周期长度斜率增大（71.2±13.1 ms/s 比对照时的 35.1±8.8 ms/s，n=4，P<.05）。这种反向使用依赖性在 5 μM 时被河豚毒素消除（11.4±4.3 ms/s，n=4，P<.01）。在 2000 至 500 ms 的基本心动周期长度范围内，I(Ca)或 I(K)均无显著差异。然而，I(Na-L)表现出明显的速率依赖性减少。
由于 I(Na-L)的慢失活和恢复动力学，它对速率变化很敏感，在 APD/QT 的速率依赖性以及选择性 APD/QT 延长药物的反向使用依赖性中发挥着核心作用。
