Conventional electric stimuli of micro- and millisecond duration excite or activate cells at voltages 10–100 times below the electroporation threshold. This ratio is remarkably different for nanosecond electric pulses (nsEP), which caused excitation and activation only at or above the electroporation threshold in diverse cell lines, primary cardiomyocytes, neurons, and chromaffin cells. Depolarization to the excitation threshold often results from (or is assisted by) the loss of the resting membrane potential due to ion leaks across the membrane permeabilized by nsEP. Slow membrane resealing and the build-up of electroporation damages prevent repetitive excitation by nsEP. However, peripheral nerves and muscles are exempt from this rule and withstand multiple cycles of excitation by nsEP without the loss of function or signs of electroporation. We show that the damage-free excitation by nsEP may be enabled by the membrane charging time constant sufficiently large to (1) cap the peak transmembrane voltage during nsEP below the electroporation threshold, and (2) extend the post-nsEP depolarization long enough to activate voltage-gated ion channels. The low excitatory efficacy of nsEP compared to longer pulses makes them advantageous for medical applications where the neuromuscular excitation is an unwanted side effect, such as electroporation-based cancer and tissue ablation.

微秒和毫秒持续时间的常规电刺激以低于电穿孔阈值 10-100 倍的电压激发或激活细胞。这个比率对于纳秒电脉冲 (nsEP) 来说是显着不同的，它在不同的细胞系、原代心肌细胞、神经元和嗜铬细胞中仅在或高于电穿孔阈值时引起激发和激活。激发阈值的去极化通常是由于（或由）静息膜电位的损失引起的，这是由于离子泄漏穿过 nsEP 透化的膜。缓慢的膜重新密封和电穿孔损伤的积累防止了 nsEP 的重复激发。然而，周围神经和肌肉不受此规则的约束，并且可以承受 nsEP 的多次激发循环，而不会丧失功能或电穿孔的迹象。我们表明，nsEP 的无损伤激发可以通过足够大的膜充电时间常数来实现，以 (1) 将 nsEP 期间的跨膜峰值电压限制在电穿孔阈值以下，以及 (2) 延长 nsEP 后去极化足够长的时间激活电压门控离子通道。与更长的脉冲相比，nsEP 的低兴奋性使其有利于神经肌肉兴奋是有害副作用的医学应用，例如基于电穿孔的癌症和组织消融。