挥发性麻醉剂激活梯形核神经元中的渗漏钠电导，以维持小鼠麻醉期间的呼吸。
Volatile Anesthetics Activate a Leak Sodium Conductance in Retrotrapezoid Nucleus Neurons to Maintain Breathing during Anesthesia in Mice.
出版信息
Anesthesiology. 2020 Oct 1;133(4):824-838. doi: 10.1097/ALN.0000000000003493.
BACKGROUND
Volatile anesthetics moderately depress respiratory function at clinically relevant concentrations. Phox2b-expressing chemosensitive neurons in the retrotrapezoid nucleus, a respiratory control center, are activated by isoflurane, but the underlying mechanisms remain unclear. The hypothesis of this study was that the sodium leak channel contributes to the volatile anesthetics-induced modulation of retrotrapezoid nucleus neurons and to respiratory output.
METHODS
The contribution of sodium leak channels to isoflurane-, sevoflurane-, and propofol-evoked activity of Phox2b-expressing retrotrapezoid nucleus neurons and respiratory output were evaluated in wild-type and genetically modified mice lacking sodium leak channels (both sexes). Patch-clamp recordings were performed in acute brain slices. Whole-body plethysmography was used to measure the respiratory activity.
RESULTS
Isoflurane at 0.42 to 0.50 mM (~1.5 minimum alveolar concentration) increased the sodium leak channel-mediated holding currents and conductance from -75.0 ± 12.9 to -130.1 ± 34.9 pA (mean ± SD, P = 0.002, n = 6) and 1.8 ± 0.5 to 3.6 ± 1.0 nS (P = 0.001, n = 6), respectively. At these concentrations, isoflurane increased activity of Phox2b-expressing retrotrapezoid nucleus neurons from 1.1 ± 0.2 to 2.8 ± 0.2 Hz (P < 0.001, n = 5), which was eliminated by bath application of gadolinium or genetic silencing of sodium leak channel. Genetic silencing of sodium leak channel in the retrotrapezoid nucleus resulted in a diminished ventilatory response to carbon dioxide in mice under control conditions and during isoflurane anesthesia. Sevoflurane produced an effect comparable to that of isoflurane, whereas propofol did not activate sodium leak channel-mediated holding conductance.
CONCLUSIONS
Isoflurane and sevoflurane increase neuronal excitability of chemosensitive retrotrapezoid nucleus neurons partly by enhancing sodium leak channel conductance. Sodium leak channel expression in the retrotrapezoid nucleus is required for the ventilatory response to carbon dioxide during anesthesia by isoflurane and sevoflurane, thus identifying sodium leak channel as a requisite determinant of respiratory output during anesthesia of volatile anesthetics.
背景
挥发性麻醉剂在临床相关浓度下会适度抑制呼吸功能。在呼吸控制中心的梯形核内，Phox2b 表达的化学敏感神经元被异氟醚激活，但潜在机制尚不清楚。本研究的假设是，钠泄漏通道有助于挥发性麻醉剂对梯形核神经元的调制和呼吸输出。
方法
在野生型和缺乏钠泄漏通道的基因修饰（雌雄同体）小鼠中，评估钠泄漏通道对异氟醚、七氟醚和异丙酚诱导的 Phox2b 表达的梯形核神经元活动和呼吸输出的贡献。在急性脑切片中进行膜片钳记录。全身呼吸描记术用于测量呼吸活动。
结果
在 0.42 至 0.50 mM 异氟醚（~1.5 最低肺泡浓度）下，钠泄漏通道介导的保持电流和电导从-75.0 ± 12.9 增加到-130.1 ± 34.9 pA（平均值 ± SD，P = 0.002，n = 6）和 1.8 ± 0.5 增加到 3.6 ± 1.0 nS（P = 0.001，n = 6）。在这些浓度下，异氟醚将 Phox2b 表达的梯形核神经元的活性从 1.1 ± 0.2 增加到 2.8 ± 0.2 Hz（P < 0.001，n = 5），这一效应可被浴液应用钆或钠泄漏通道的基因沉默消除。在控制条件下和异氟醚麻醉期间，梯形核内钠泄漏通道的基因沉默导致小鼠对二氧化碳的通气反应减弱。七氟醚产生的作用与异氟醚相似，而异丙酚则不能激活钠泄漏通道介导的保持电导。
结论
异氟醚和七氟醚通过增强钠泄漏通道电导来增加化学敏感的梯形核神经元的兴奋性。在异氟醚和七氟醚麻醉期间，对二氧化碳的通气反应需要梯形核内钠泄漏通道的表达，因此，钠泄漏通道是挥发性麻醉剂麻醉期间呼吸输出的必要决定因素。
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