HCN1 Channels Contribute to the Effects of Amnesia and Hypnosis but not Immobility of Volatile Anesthetics.
HCN1 Channels Contribute to the Effects of Amnesia and Hypnosis but not Immobility of Volatile Anesthetics.
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HCN 通道有助于遗忘和昏迷的效果，但不会影响挥发性麻醉剂的不动性
DOI：
10.1213/ane.0000000000000830
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发表时间：
2015-09
影响因子：
5.7
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Zhou C;Liang P;Liu J;Ke B;Wang X;Li F;Li T;Bayliss DA;Chen X
HCN 1通道已被确定为氯胺酮产生催眠的靶点。挥发性麻醉剂也抑制HCN 1通道。然而，HCN 1通道在体内对挥发性麻醉药的影响仍然是难以捉摸的。本研究使用整体和条件性HCN 1基因敲除小鼠来评估HCN 1通道如何影响挥发性麻醉药的作用。在野生型（WT）小鼠、全HCN 1通道敲除小鼠（HCN 1 −/−）、HCN 1通道基因敲除小鼠（HCN 1f/f）和前脑选择性HCN 1通道敲除小鼠（HCN 1f/f：cre）中测定诱导不动（不动MAC）和/或催眠（催眠MAC）的异氟烷和七氟烷最小肺泡浓度（MAC）。小鼠的不动性定义为对夹尾刺激没有目的性反应，催眠定义为翻正反射（LORR）丧失。在这四种品系的小鼠中通过恐惧增强惊吓来评价异氟烷和七氟烷的遗忘作用。所有MAC值均表示为平均值± SEM。对于异氟烷的不动MAC，野生型、HCN 1 −/−、HCN 1f/f和HCN 1f/f：cre小鼠之间未发现显著差异（均约为1.24-1.29%异氟烷）。对于HCN 1 −/−和HCN 1f/f：cre小鼠，异氟烷催眠的MAC（每种约1.05%异氟烷）显著高于其非敲除对照：HCN 1 −/− vs.野生型（0.86± 0.03%，P<0.001）和HCN 1f/f：cre vs. HCN 1f/f小鼠（0.84± 0.03%，P<0.001）;未发现HCN 1 −/−和HCN 1f/f：cre小鼠之间存在显著差异。对于七氟烷的不动MAC，野生型、HCN 1 −/−、HCN 1f/f和HCN 1f/f：cre小鼠之间未发现显著差异（均约为2.6-2.7%七氟烷）。对于HCN 1 −/−和HCN 1f/f：cre小鼠，七氟烷（各约1.90%七氟烷）的催眠MAC显著高于其非敲除对照：HCN 1 −/− vs.野生型（1.58± 0.05%，P<0.001）和HCN 1f/f：cre vs. HCN 1f/f小鼠（1.56± 0.05%，P<0.001）。在HCN 1 −/−和HCN 1f/f：cre小鼠之间没有发现显著差异。通过恐惧增强惊吓实验，异氟烷和七氟烷的遗忘作用在HCN 1 −/−和HCN 1f/f：cre小鼠中显著减弱（与野生型或HCN 1f/f小鼠相比，P均<0.002）。在HCN 1 −/−和HCN 1f/f：cre小鼠之间没有发现显著差异。前脑HCN 1通道参与挥发性麻醉药的催眠和遗忘作用，但HCN 1通道不参与挥发性麻醉药的制动作用。
HCN1 channels have been identified as targets of ketamine to produce hypnosis. Volatile anesthetics also inhibit HCN1 channels. However, the effects of HCN1 channels on volatile anesthetics in vivo is still elusive. This study uses global and conditional HCN1 knockout mice to evaluate how HCN1 channels affect the actions of volatile anesthetics. Minimum alveolar concentrations (MAC) of isoflurane and sevoflurane that induced immobility (MAC of immobility) and/or hypnosis (MAC of hypnosis) were determined in wild-type (WT) mice, global HCN1 channel knockout mice (HCN1−/−), floxed HCN1 channel gene (HCN1f/f) mice and forebrain-selective HCN1 channel knockout (HCN1f/f: cre) mice. Immobility of mice was defined as no purposeful reactions to tail-clamping stimulus and hypnosis was defined as loss of righting reflex (LORR). The amnestic effects of isoflurane and sevoflurane were evaluated by fear-potentiated startle in these four strains of mice. All MAC values were expressed as mean ± SEM. For MAC of immobility of isoflurane, no significant difference was found among wild-type, HCN1−/−, HCN1f/f and HCN1f/f: cre mice (all ~1.24-1.29% isoflurane). For both HCN1−/− and HCN1f/f: cre mice, the MAC of hypnosis for isoflurane (each ~1.05% isoflurane) were significantly increased over their nonknockout controls: HCN1−/− vs. wild-type (0.86±0.03%, P<0.001) and HCN1f/f: cre vs. HCN1f/f mice (0.84±0.03%, P<0.001); no significant difference was found between HCN1−/− and HCN1f/f: cre mice. For MAC of immobility of sevoflurane, no significant difference was found among wild-type, HCN1−/−, HCN1f/f and HCN1f/f: cre mice (all ~2.6-2.7% sevoflurane). For both HCN1−/− and HCN1f/f: cre mice, the MAC of hypnosis for sevoflurane (each ~1.90% sevoflurane) was significantly increased over their nonknockout controls: HCN1−/− vs. wild-type (1.58±0.05%, P<0.001) and HCN1f/f: cre vs. HCN1f/f mice (1.56±0.05%, P<0.001). No significant difference was found between HCN1−/− and HCN1f/f: cre mice. By fear-potentiated startle experiments, amnestic effects of isoflurane and sevoflurane were significantly attenuated in HCN1−/− and HCN1f/f: cre mice (both P<0.002 vs. wild-type or HCN1f/f mice). No significant difference was found between HCN1−/− and HCN1f/f: cre mice. Forebrain HCN1 channels contribute to hypnotic and amnestic effects of volatile anesthetics, but HCN1 channels are not involved in the immobilizing actions of volatile anesthetics.