Herold Karl F, Nau Carla, Ouyang Wei, Hemmings Hugh C
Department of Anesthesiology, Weill Cornell Medical College, New York, New York, USA.
Anesthesiology. 2009 Sep;111(3):591-9. doi: 10.1097/ALN.0b013e3181af64d4.
Voltage-gated sodium channels (Nav) mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant (TTX-r) compared to other isoforms. Nav1.8 is highly expressed in dorsal root ganglion neurons and is functionally linked to nociception, but the sensitivity of TTX-r isoforms to inhaled anesthetics is unclear.
The sensitivities of heterologously expressed rat TTX-r Nav1.8 and endogenous tetrodotoxin-sensitive (TTX-s) Nav to the prototypic inhaled anesthetic isoflurane were tested in mammalian ND7/23 cells using patch-clamp electrophysiology.
From a holding potential of -70 mV, isoflurane (0.53 +/- 0.06 mM, 1.8 minimum alveolar concentration at 24 degrees C) reduced normalized peak Na current (INa) of Nav1.8 to 0.55 +/- 0.03 and of endogenous TTX-s Nav to 0.56 +/- 0.06. Isoflurane minimally inhibited INa from a holding potential of -140 mV. Isoflurane did not affect voltage-dependence of activation, but it significantly shifted voltage-dependence of steady-state inactivation by -6 mV for Nav1.8 and by -7 mV for TTX-s Nav. IC50 values for inhibition of peak INa were 0.67 +/- 0.06 mM for Nav1.8 and 0.66 +/- 0.09 mM for TTX-s Nav; significant inhibition occurred at clinically relevant concentrations as low as 0.58 minimum alveolar concentration. Isoflurane produced use-dependent block of Nav1.8; at a stimulation frequency of 10 Hz, 0.56 +/- 0.08 mM isoflurane reduced INa to 0.64 +/- 0.01 versus 0.78 +/- 0.01 for control.
Isoflurane inhibited the tetrodotoxin-resistant isoform Nav1.8 with potency comparable to that for endogenous tetrodotoxin-sensitive Nav isoforms, indicating that sensitivity to inhaled anesthetics is conserved across diverse Nav family members. Block of Nav1.8 in dorsal root ganglion neurons could contribute to the effects of inhaled anesthetics on peripheral nociceptive mechanisms.
电压门控钠通道（Nav）介导神经元动作电位。河豚毒素可抑制所有Nav亚型，但与其他亚型相比，Nav1.8和Nav1.9对河豚毒素具有相对抗性（TTX-r）。Nav1.8在背根神经节神经元中高表达，且在功能上与伤害感受相关，但TTX-r亚型对吸入性麻醉药的敏感性尚不清楚。
使用膜片钳电生理学技术，在哺乳动物ND7/23细胞中检测异源表达的大鼠TTX-r Nav1.8和内源性河豚毒素敏感型（TTX-s）Nav对典型吸入性麻醉药异氟烷的敏感性。
从-70 mV的钳制电位开始，异氟烷（0.53±0.06 mM，24℃时为1.8倍最低肺泡浓度）使Nav1.8的标准化峰值钠电流（INa）降至0.55±0.03，使内源性TTX-s Nav的标准化峰值钠电流降至0.56±0.06。异氟烷从-140 mV的钳制电位开始对INa的抑制作用最小。异氟烷不影响激活的电压依赖性，但它使Nav1.8的稳态失活电压依赖性显著负移6 mV，使TTX-s Nav的稳态失活电压依赖性显著负移7 mV。抑制峰值INa的半数抑制浓度（IC50）值，Nav1.8为0.67±0.06 mM，TTX-s Nav为0.66±0.09 mM；在低至0.58倍最低肺泡浓度的临床相关浓度下即出现显著抑制。异氟烷对Nav1.8产生使用依赖性阻滞；在10 Hz的刺激频率下，0.56±0.08 mM异氟烷使INa降至0.64±0.01，而对照组为0.78±0.01。
异氟烷抑制河豚毒素抗性亚型Nav1.8的效力与内源性河豚毒素敏感型Nav亚型相当，表明不同Nav家族成员对吸入性麻醉药的敏感性具有保守性。背根神经节神经元中Nav1.8的阻滞可能有助于吸入性麻醉药对外周伤害感受机制的影响。
