Caves Rachel E, Carpenter Alexander, Choisy Stéphanie C, Clennell Ben, Cheng Hongwei, McNiff Cameron, Mann Brendan, Milnes James T, Hancox Jules C, James Andrew F
School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, United Kingdom.
Xention Ltd, Cambridge, United Kingdom.
Heart Rhythm O2. 2020 Aug;1(3):206-214. doi: 10.1016/j.hroo.2020.05.006.
Atrial-ventricular differences in voltage-gated Na currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative antiarrhythmic drug with properties similar to the prototypical atrial-selective Na channel blocker ranolazine that has been shown to be safe and well tolerated in patients.
The present study investigated atrial-ventricular differences in the biophysical properties and inhibition by eleclazine of voltage-gated Na currents.
The fast and late components of whole-cell voltage-gated Na currents (respectively, and ) were recorded at room temperature (∼22°C) from rat isolated atrial and ventricular myocytes.
Atrial activated at command potentials ∼5.5 mV more negative and inactivated at conditioning potentials ∼7 mV more negative than ventricular . There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of activated by 3 nM ATX-II (ICs ∼200 nM). Eleclazine (10 μM) inhibited in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of from inactivation in both cell types.
Differences exist between rat atrial and ventricular myocytes in the biophysical properties of . The more negative voltage dependence of activation/inactivation in atrial myocytes underlies differences between the 2 cell types in the voltage dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective antiarrhythmic drug.
电压门控钠电流的房室差异可能有助于开发心房选择性抗心律失常药物，以抑制心房颤动而无室性快速心律失常风险。依来卡嗪（GS - 6615）是一种假定的抗心律失常药物，其特性类似于原型心房选择性钠通道阻滞剂雷诺嗪，已证明在患者中安全且耐受性良好。
本研究调查了依来卡嗪对电压门控钠电流的生物物理特性及抑制作用的房室差异。
在室温（约22°C）下，从大鼠分离的心房和心室肌细胞记录全细胞电压门控钠电流的快速和晚期成分（分别为 和 ）。
心房 的激活电位比心室 的负约5.5 mV，失活电位比心室 的负约7 mV。在3 nM ATX - II激活的 （IC50约200 nM）的依来卡嗪抑制方面，心房和心室肌细胞之间没有差异。依来卡嗪（10 μM）以与优先激活状态阻滞一致的使用依赖性方式抑制心房和心室肌细胞中的 。依来卡嗪在心房和心室肌细胞中产生电压依赖性瞬时抑制；它导致半最大失活电压负移，并减慢了两种细胞类型中 从失活状态的恢复。
大鼠心房和心室肌细胞在 的生物物理特性方面存在差异。心房肌细胞中 激活/失活的电压依赖性更负是两种细胞类型在依来卡嗪瞬时抑制电压依赖性方面存在差异的基础。依来卡嗪作为一种心房选择性抗心律失常药物值得进一步研究。
