Lin Cai-Xia, Yang Su-Yu, Gu Jing-Li, Meng Jie, Xu Hai-Yan, Cao Ji-Min
a Department of Physiology , Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College , Beijing , China.
b Department of Biomedical Engineering , Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College , Beijing , China.
Nanotoxicology. 2017 Aug;11(6):827-837. doi: 10.1080/17435390.2017.1367047. Epub 2017 Aug 23.
This study focused on the potential toxicity of silver nanoparticles (AgNPs) on cardiac electrophysiology which is rarely investigated. We found that AgNPs (10-10g/ml) concentration-dependently depolarized the resting potential, diminished the action potential, and finally led to loss of excitability in mice cardiac papillary muscle cells in vitro. In cultured neonatal mice cardiomyocytes, AgNPs (10-10g/ml) concentration-dependently decreased the Na currents (I), accelerated the activation, and delayed the inactivation and recovery of Na channels from inactivation within 5 min. AgNPs at 10g/ml also rapidly decreased the inwardly rectifying K currents (I) and delayed the activation of I channels. Intravenous injection of AgNPs at 3 mg/kg only decreased the heart rate, while at ≥4 mg/kg sequentially induced sinus bradycardia, complete atrio-ventricular conduction block, and cardiac asystole. AgNPs at 10-10g/ml did not increase reactive oxygen species (ROS) generation and only at 10g/ml mildly induced lactate dehydrogenase (LDH) release in the cardiomyocytes within 5 min. Endocytosis of AgNPs by cardiomyocytes was not observed within 5 min, but was observed 1 h after exposing to AgNPs. Comparative Ag (≤0.02% of the AgNPs) could not induce above toxicities. We conclude that AgNPs exert rapid toxic effects on myocardial electrophysiology and induce lethal bradyarrhythmias. These acute toxicities are likely due to direct effects of AgNPs on ion channels at the nano-scale level, but not caused by Ag, ROS, and membrane injury. These findings provide warning to the nanomedical practice using AgNPs.
本研究聚焦于银纳米颗粒（AgNPs）对心脏电生理学的潜在毒性，而这方面的研究很少。我们发现，在体外实验中，AgNPs（10⁻¹⁰ g/ml）能使小鼠心脏乳头肌细胞的静息电位呈浓度依赖性去极化，降低动作电位，最终导致兴奋性丧失。在培养的新生小鼠心肌细胞中，AgNPs（10⁻¹⁰ g/ml）能使钠电流（Iₙₐ）呈浓度依赖性降低，加速钠通道的激活，并在5分钟内延迟钠通道失活及从失活状态恢复。10 g/ml的AgNPs还能迅速降低内向整流钾电流（Iₖ₁）并延迟Iₖ₁通道的激活。静脉注射3 mg/kg的AgNPs仅降低心率，而≥4 mg/kg时则依次诱发窦性心动过缓、完全性房室传导阻滞和心脏停搏。10⁻¹⁰ g/ml的AgNPs不会增加活性氧（ROS）的生成，仅10 g/ml能在5分钟内轻度诱导心肌细胞释放乳酸脱氢酶（LDH）。在5分钟内未观察到心肌细胞对AgNPs的内吞作用，但在暴露于AgNPs 1小时后可观察到。相比之下，银（≤AgNPs的0.02%）不会诱发上述毒性。我们得出结论，AgNPs对心肌电生理学具有快速毒性作用并诱发致命性缓慢性心律失常。这些急性毒性可能是由于AgNPs在纳米尺度水平上对离子通道的直接作用，而非由银、ROS和膜损伤引起。这些发现为使用AgNPs的纳米医学实践提供了警示。
