Shuraih Mossaab, Ai Tomohiko, Vatta Matteo, Sohma Yoshiro, Merkle Eileen M, Taylor Erica, Li Zhaohui, Xi Yutao, Razavi Mehdi, Towbin Jeffrey A, Cheng Jie
Electrophysiology Research Laboratory, Texas Heart Institute/St. Luke's Episcopal Hospital, Houston, Texas 77030, USA.
J Cardiovasc Electrophysiol. 2007 Apr;18(4):434-40. doi: 10.1111/j.1540-8167.2007.00777.x. Epub 2007 Jan 10.
The potential pathophysiological role of common SCN5A polymorphisms in cardiac arrhythmias has been increasingly recognized. However, little is known about the impact of those polymorphisms on the pharmocological response of hNav1.5 to various antiarrhythmic agents.
The known SCN5A polymorphism, S524Y, was studied in comparison with the wild type (WT) in [corrected] the SCN5A-Q1077del variant. The ion channel gating kinetics and pharmacology were evaluated using whole-cell patch-clamp methods in HEK-293 cells. Consistent with a previous report, the basal ion channel gating kinetics of S524Y were indistinguishable from the WT. Quinidine (20 microM) caused similar extent of tonic block reduction of sodium currents at -120 mV in WT and S524Y. Surprisingly, quinidine (20 microM) exerted a more use-dependent block by a 10 Hz pulse train in S524Y than in WT at 22 degrees C (Ki: WT, 51.3 microM; S524Y, 20.3 microM). S524Y significantly delayed recovery from the use-dependent block, compared with the WT (tau= 88.6 +/- 7.9 s vs 41.9 +/- 6.6 s, P < 0.005). Under more physiological conditions using a 2 Hz pulse train at 37 degrees C, S524Y similarly enhanced the use-dependent block by quinidine. In addition, S524Y enhanced the use-dependent block by flecainide (12.5 microM), but not by mexiletine (100 microM).
A common SCN5A polymorphism, S524Y, can enhance a use-dependent block by class Ia and Ic antiarrhythmic agents. Our findings may have clinical implications in pharmacological management of cardiac arrhythmias since this common SCN5A polymorphism might be a contributing factor to the variable antiarrhythmic response.
常见的SCN5A基因多态性在心律失常中的潜在病理生理作用已得到越来越多的认识。然而，关于这些多态性对hNav1.5对各种抗心律失常药物的药理反应的影响却知之甚少。
将已知的SCN5A基因多态性S524Y与野生型（WT）以及SCN5A-Q1077del变体进行比较研究。在HEK-293细胞中使用全细胞膜片钳方法评估离子通道门控动力学和药理学特性。与先前的报告一致，S524Y的基础离子通道门控动力学与野生型无明显差异。奎尼丁（20μM）在野生型和S524Y中，在-120mV时引起的钠电流强直阻滞减少程度相似。令人惊讶的是，在22℃时，奎尼丁（20μM）在S524Y中通过10Hz脉冲串产生的使用依赖性阻滞比在野生型中更强（抑制常数：野生型，51.3μM；S524Y，20.3μM）。与野生型相比，S524Y从使用依赖性阻滞中的恢复明显延迟（恢复时间常数=88.6±7.9秒对41.9±6.6秒，P<0.005）。在37℃使用2Hz脉冲串的更生理条件下，S524Y同样增强了奎尼丁的使用依赖性阻滞。此外，S524Y增强了氟卡尼（12.5μM）的使用依赖性阻滞，但对美西律（100μM）没有影响。
常见的SCN5A基因多态性S524Y可增强I类a和I类c抗心律失常药物的使用依赖性阻滞。我们的发现可能对心律失常的药物治疗具有临床意义，因为这种常见的SCN5A基因多态性可能是抗心律失常反应变异性的一个促成因素。
