The effects of A-803467 on cardiac Nav1.5 channels.
The effects of A-803467 on cardiac Nav1.5 channels.
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DOI：
10.1016/j.ejphar.2015.02.019
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发表时间：
2015-05
影响因子：
5
通讯作者：
Zhonglin Han;Yu Jiang;Feng Xiao;K. Cao;Dao-wu Wang
中科院分区：
文献类型：
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作者：
Zhonglin Han;Yu Jiang;Feng Xiao;K. Cao;Dao-wu Wang
A-803467是一种选择性Nav1.8阻滞剂，但其对心脏钠通道的作用机制尚不确定。因此，我们研究了A-803467对分离的小鼠心室肌细胞和瞬时表达Nav1.5/SCN 5A（主要心脏钠通道）的人胚肾293（HEK 293）细胞系中心脏钠通道的机制作用。在0.3 μM及以上浓度下，A-803467以剂量依赖性方式阻断心室肌细胞和inSCN 5A表达HEK 293细胞系中的心脏钠电流。在这两种模型中，药物在电导电压关系中点引起显着的去极化转变，电压依赖性通道失活的超极化转变，失活恢复较慢。此外，药物以频率依赖性方式降低钠电流幅度，并阻断晚期钠电流，加速失活，并增强中间失活状态。我们的研究结果提供了强有力的证据，表明A-803467影响经典心脏Nav1.5通道的多种生物物理特性，我们的数据可用于研究A-803467作为抗心律失常药物的潜在应用。
A-803467 is a selective Nav1.8 blocker, but its mechanism of action at cardiac sodium channels is uncertain. Thus, we investigated the mechanistic effects of A-803467 on cardiac sodium channels in isolated mouse ventricular myocytes and in human embryonic kidney 293 (HEK293) cell lines that transiently expressed Nav1.5/SCN5A, the predominant cardiac sodium channel. At 0.3 μM and greater, A-803467 blocked cardiac sodium currents in a dose-dependent manner in both ventricular myocytes and inSCN5A-expressing HEK293 cell lines. In both models, the drug caused significant depolarizing shifts at the conductance voltage relationship midpoint, hyperpolarizing shifts in voltage-dependent channel inactivation, and slower recovery from inactivation. Also, the drug reduced sodium current amplitude in a frequency-dependent manner, and blocked late sodium currents, accelerated inactivation, and enhanced the intermediate inactivation state. Our results provide strong evidence that A-803467 affects multiple biophysical characteristics of the canonical cardiac Nav1.5 channel and our data can be used to study potential applications of A-803467 as an antiarrhythmic drug.