Distinctive property and pharmacology of voltage-gated sodium current in rat atrial vs ventricular myocytes

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• 作者：Kui-Hao Chen ; MD ; PhD^* ; ^&dagger ; ; Xiao-Hui Xu ; MD ; PhD^&dagger ; ; Hai-Ying Sun ; MSc^* ; Xin-Ling Du ; MD ; PhD^&Dagger ; ; Hui Liu ; MD ; PhD^* ; ^&dagger ; ; Lei Yang ; MD^* ; ^§ ; ; Guo-Sheng Xiao ; MD ; PhD^¶ ; ; Yan Wang ; MD ; PhD^¶ ; ; Man-Wen Jin ; PhD^&dagger ; ; ^{mwjin@mail.tjmu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Gui-Rong Li ; PhD^* ; ^¶ ; ; ^{grli8@outlook.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：INa ; voltage-gated sodium current ; NaV ; voltage-gated sodium channel ; qPCR ; quantity real-time polymerase chain reaction ; RT-PCR ; reverse transcription polymerase chain reaction
• 刊名：Heart Rhythm
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：13
• 期：3
• 页码：762-770
• 全文大小：1771 K

文摘

Several mammalian species display distinct biophysical properties between atrial and ventricular voltage-gated sodium current (I_Na); however, the potential mechanism behind this phenomenon is unknown.

Objective

The purpose of this study was to investigate the potential molecular identities of the different I_Na in atrial and ventricular myocytes of rat hearts.

Methods

Whole-cell patch voltage-clamp and molecular biology techniques were used in the study.

Results

Ventricular I_Na exhibited a slower inactivation, more positive potential of inactivation, and quicker recovery from inactivation compared to atrial I_Na. Real-time polymerase chain reaction and western blot analysis revealed that mRNA and protein levels of Na_Vβ2 and Na_Vβ4 subunits, but not Na_V1.5, were greater in ventricular myocytes than in atrial myocytes. I_Na in heterologous HEK 293 cell expression system with coexpressing hNa_V1.5 and hNa_Vβ2/hNa_Vβ4 showed similar biophysical properties to ventricular I_Na. Greater protein expression of Na_Vβ2 and Na_Vβ4 subunits was also observed in human ventricles. Interestingly, pharmacologic study revealed that the antiarrhythmic drug dronedarone (10 μM) inhibited atrial I_Na more (by 73%) than ventricular I_Na (by 42%), and shifted its inactivation to more negative voltages (–4.6 mV) compared to ventricular I_Na.

Conclusion

The results of this study demonstrate the novel information that the distinctive biophysical properties of I_Na in atrial and ventricular myocytes can be attributed to inhomogeneous expression of Na_Vβ2 and Na_Vβ4 subunits, and that atrial I_Na is more sensitive to inhibition by dronedarone.