Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Department of Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Int J Mol Sci. 2023 Jan 18;24(3):1904. doi: 10.3390/ijms24031904.
A considerable amount of literature has been published on antidepressants and cardiac ion channel dysfunction. The antidepressant paroxetine has been associated with Brugada syndrome and long QT syndrome, albeit on the basis of conflicting findings. The cardiac voltage-gated sodium channel (Na1.5) is related to both of these syndromes, suggesting that paroxetine may have an effect on this channel. In the present study, we therefore carried out patch clamp experiments to examine the effect of paroxetine on human Na1.5 channels stably expressed in human embryonic kidney 293 (HEK-293) cells as well as on action potentials of isolated rabbit left ventricular cardiomyocytes. Additionally, computer simulations were conducted to test the functional effects of the experimentally observed paroxetine-induced changes in the Na1.5 current. We found that paroxetine led to a decrease in peak Na1.5 current in a concentration-dependent manner with an IC of 6.8 ± 1.1 µM. In addition, paroxetine caused a significant hyperpolarizing shift in the steady-state inactivation of the Na1.5 current as well as a significant increase in its rate of inactivation. Paroxetine (3 µM) affected the action potential of the left ventricular cardiomyocytes, significantly decreasing its maximum upstroke velocity and amplitude, both of which are mainly regulated by the Na1.5 current. Our computer simulations demonstrated that paroxetine substantially reduces the fast sodium current of human left ventricular cardiomyocytes, thereby slowing conduction and reducing excitability in strands of cells, in particular if conduction and excitability are already inhibited by a loss-of-function mutation in the Na1.5 encoding gene. In conclusion, paroxetine acts as an inhibitor of Na1.5 channels, which may enhance the effects of loss-of-function mutations in .
已有大量文献报道了抗抑郁药与心脏离子通道功能障碍之间的关系。尽管研究结果相互矛盾，但抗抑郁药帕罗西汀与 Brugada 综合征和长 QT 综合征有关。心脏电压门控钠离子通道（Na1.5）与这两种综合征均有关，提示帕罗西汀可能对该通道有影响。因此，在本研究中，我们进行了膜片钳实验，以研究帕罗西汀对稳定表达于人胚肾 293（HEK-293）细胞的人 Na1.5 通道以及对分离的兔左心室心肌细胞动作电位的影响。此外，还进行了计算机模拟，以测试实验观察到的帕罗西汀诱导的 Na1.5 电流变化的功能影响。我们发现，帕罗西汀以浓度依赖性方式导致峰值 Na1.5 电流减小，IC50 为 6.8±1.1µM。此外，帕罗西汀导致 Na1.5 电流的稳态失活发生明显的超极化偏移，以及失活速率显著增加。帕罗西汀（3µM）影响左心室心肌细胞的动作电位，显著降低其最大上升速度和幅度，这两者主要受 Na1.5 电流调节。我们的计算机模拟表明，帕罗西汀可显著降低人左心室心肌细胞的快钠电流，从而减缓传导并降低细胞束的兴奋性，特别是如果 Na1.5 编码基因的功能丧失突变已经抑制了传导和兴奋性。总之，帕罗西汀作为 Na1.5 通道的抑制剂，可能增强 基因功能丧失突变的影响。
