Isoform-selective effects of isoflurane on voltage-gated Na+ channels
Isoform-selective effects of isoflurane on voltage-gated Na+ channels
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DOI：
10.1097/01.anes.0000268390.28362.4a
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发表时间：
2007-07-01
期刊：
影响因子：
8.8
通讯作者：
Hemmings, Hugh C., Jr.
中科院分区：
文献类型：
--
作者：
Wei OuYang;Hemmings, Hugh C., Jr.
背景：电压门控Na+通道调节可兴奋组织的膜兴奋性。Na+通道的抑制与挥发性麻醉剂对神经和外周兴奋组织的影响有关。方法：采用全细胞电压钳记录法分析大鼠卵巢细胞Na（v）1.2、Na（v）1.4和Na（v）1.5 a亚基的异源表达。结果：心脏Na（v）1.5亚型在负电位（I-Na峰值为-30 mV）下激活的频率高于神经元Na（v）1.2亚型（0 mV）或骨骼肌Na（v）1.4亚型（-10 mV）。在临床浓度下，异氟烷可逆性以浓度和电压依赖性方式抑制所有三种亚型（Na（v）1.2、Na（v）1.4和Na（v）1.5的IC 50分别为0.70、0.61和0.45 mM，生理保持电位为-70 mV）。抑制作用在保持电位为-70 mV时大于-100 mV时，尤其是对于Na（v）1.4和Na（v）1.5。由于稳态快速失活的电压依赖性的超极化转变，异氟烷增强了所有三种亚型的失活。异氟烷对Na（v）1.4和Na（v）1.5的抑制作用主要归因于增强的失活，而对Na（v）1.2的抑制作用主要归因于强直性阻滞，Na（v）1.2具有更正的失活V-1/2。由于稳态快速失活的电压依赖性中的超极化移位而增强的失活（Na（v）1.5近似于Na（v）1.4 > Na（v）1（.）2)强直性阻滞（Na（v）1.2 > Na（v）1.4，接近Na（v）1.5）。在亚型之间观察到的这些新的机制差异表明了区分Na+通道亚型以增强麻醉特异性的潜在药理学基础。
Background: Voltage-gated Na+ channels modulate membrane excitability in excitable tissues. Inhibition of Na+ channels has been implicated in the effects of volatile anesthetics on both nervous and peripheral excitable tissues. The authors investigated isoform-selective effects of isoflurane on the major Na+ channel isoforms expressed in excitable tissues.Methods: Rat Na(v)1.2, Na(v)1.4, or Na(v)1.5 a subunits heterologously expressed in Chinese hamster ovary cells were analyzed by whole cell voltage clamp recording. The effects of isoflurane on Na+ current activation, inactivation, and recovery from inactivation were analyzed.Results: The cardiac isoform Na(v)1.5 activated at more negative potentials (peak I-Na at -30 mV) than the neuronal Na(v)1.2 (0 mV) or skeletal muscle Na(v)1.4 (-10 mV) isoforms. Isoflurane reversibiv inhibited all three isoforms in a concentration- and voltage-de pendent manner at clinical concentrations (IC50 0.70, 0.61, and 0.45 mM, respectively, for Na(v)1.2, Na(v)1.4, and Na(v)1.5 from a physiologic holding potential of -70 mV). Inhibition was greater from a holding potential of -70 mV than from -100 mV, especially for Na(v)1.4 and Na(v)1.5. Isoflurane enhanced inactivation of all three isoforms due to a hyperpolarizing shift in the voltage dependence of steady state fast inactivation. Inhibition of Na(v)1.4 and Na(v)1.5 by isoflurane was attributed primarily to enhanced inactivation, whereas inhibition of Na(v)1.2, which had a more positive V-1/2 of inactivation, was due primarily to tonic block.Conclusions: Two principal mechanisms contribute to Na+ channel inhibition by isoflurane: enhanced inactivation due to a hyperpolarizing shift in the voltage dependence of steady state fast inactivation (Na(v)1.5 approximate to Na(v)1.4 > Na(v)1(.)2) and tonic block (Na(v)1.2 > Na(v)1.4 approximate to Na(v)1.5). These novel mechanistic differences observed between isoforms suggest a potential pharmacologic basis for discrimination between Na+ channel isoforms to enhance anesthetic specificity.