Na_v1.5-derived Na⁺ current (I_Na) exerts a pivotal role in the depolarization phase of cardiomyocytes’ action potential, and, therefore, changes in I_Na can contribute to fatal arrhythmias. Na_v1.5 displays naturally occurring ethnicity-related polymorphisms, which might alter the functioning and pharmacology of the channel. Some studies have shown how single-nucleotide polymorphism can change the response to antiarrhythmic drugs. Investigations on the role of Na_v1.5 in arrhythmogenesis associated with its functional polymorphisms are currently growing as well as the possible variability in the antiarrhythmic pharmacotherapy among ethnic groups. The influence of the ethnicity-related polymorphisms (S524Y, S1103Y, R1193Q, V1951L) on the responsiveness, selectivity, and pharmacological efficacy of the clinically used antiarrhythmic amiodarone (AMIO) is not completely known. Our objectives were to analyze biophysical and pharmacological aspects of four ethnicity-related polymorphisms before and after exposure to AMIO. Polymorphisms caused reduced AMIO potency compared with wild type (WT), which can vary by up to 4× between them. AMIO shifted the voltage dependency for current inactivation without significant effect in voltage-dependent activation to a similar extent in WT and polymorphisms. The recovery from inactivation was altered between the polymorphisms when compared with WT. Finally, the use dependency of AMIO differed between studied groups, especially at a more depolarized cell membrane. Thus, our work may guide future studies focusing on the efficiency of AMIO in treating different arrhythmias and establish more individualized guidelines for its use depending on the Na_v1.5 polymorphism after validating our findings using in vivo studies.

中文翻译：

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民族相关钠电压门控通道α亚基 5 多态性塑造胺碘酮对 Nav1.5 的体外药理作用

Na _v 1.5 衍生的 Na ⁺电流 (I _Na ) 在心肌细胞动作电位的去极化阶段发挥关键作用，因此， I _{Na 的}变化可导致致命的心律失常。Na _v 1.5 显示自然发生的种族相关的多态性，这可能会改变通道的功能和药理学。一些研究表明单核苷酸多态性如何改变对抗心律失常药物的反应。Na _v作用的调查1.5 在与其功能多态性相关的心律失常发生中，以及种族群体中抗心律失常药物疗法的可能变异性目前正在增长。种族相关的多态性（S524Y、S1103Y、R1193Q、V1951L）对临床使用的抗心律失常药胺碘酮 (AMIO) 的反应性、选择性和药理疗效的影响尚不完全清楚。我们的目标是分析暴露于 AMIO 之前和之后的四种种族相关多态性的生物物理和药理学方面。与野生型 (WT) 相比，多态性导致 AMIO 效力降低，它们之间的差异可达 4 倍。AMIO 改变了电流失活的电压依赖性，而在 WT 和多态性中对电压依赖性激活没有显着影响。与WT相比，多态性之间的失活恢复发生了改变。最后，研究组之间对 AMIO 的使用依赖性不同，尤其是在去极化程度更高的细胞膜上。因此，我们的工作可以指导未来的研究，重点关注 AMIO 治疗不同心律失常的效率，并根据 Na_v 1.5 使用体内研究验证我们的发现后的多态性。