Widespread inhibition of sodium channel-dependent glutamate release from isolated nerve terminals by isoflurane and propofol
Widespread inhibition of sodium channel-dependent glutamate release from isolated nerve terminals by isoflurane and propofol
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DOI：
10.1097/00000542-200112000-00027
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发表时间：
2001-12-01
期刊：
影响因子：
8.8
通讯作者：
Hemmings, HC
中科院分区：
文献类型：
--
作者：
Lingamaneni, R;Birch, ML;Hemmings, HC
背景：关于全麻抑制神经末梢谷氨酸释放的机制和作用仍有争议。为了确定这种效应的普遍性，并控制以往研究的方法学差异，作者分析了异氟醚和异丙酚对从几个物种和大脑区域分离的神经末梢释放谷氨酸的突触前效应。方法：分别从大鼠、小鼠、豚鼠大脑皮层和大鼠纹状体、海马中制备突触体。使用在线酶联荧光测定法监测了内源性谷氨酸的释放，这些释放是由20 μ m缬曲啶（通过防止失活打开电压依赖性Na+通道）或30 μ m KCl（通过膜去极化激活电压门控Ca2+通道）去极化引起的。结果：在大鼠、小鼠或豚鼠大脑皮层、大鼠海马或大鼠纹状体制备的突触体中，异氟醚（0.7 mM）（与最小肺泡浓度相似，半最大抑制浓度为1.5 mM）或异丙酚（40 mM）均不显著抑制细胞外KCl升高引起的去极化引起的谷氨酸释放。较低浓度的异氟醚或异丙酚显著抑制了三种物种（异氟醚IC50 = 0.41-0-50 mM；异丙酚IC50 = 11-18 muM）和大鼠脑区由自旋碱引起的谷氨酸释放。在大鼠皮质突触体中，缬草碱诱发的释放抑制对γ -氨基丁酸受体A型拮抗剂双库兰（100 muM）不敏感。结论：异氟醚和异丙酚对缬曲啶诱导的Na+通道谷氨酸释放的抑制作用大于KCl增加对三种哺乳动物和三种大鼠脑区的突触体的释放作用。这些发现与突触前Na+通道比与谷氨酸释放耦合的Ca2+通道对麻醉剂更敏感一致。全身麻醉剂的这种广泛的突触前作用不是由γ -氨基丁酸A型受体的增强介导的，尽管可能涉及其他机制。
Background: Controversy persists concerning the mechanisms and role of general anesthetic inhibition of glutamate release from nerve endings. To determine the generality of this effect and to control for methodologic differences between previous studies, the authors analyzed the presynaptic effects of isoflurane and propofol on glutamate release from nerve terminals isolated from several species and brain regions.Methods: Synaptosomes were prepared from rat, mouse, or guinea pig cerebral cortex and also from rat striatum and hippocampus. Release of endogenous glutamate evoked by depolarization with 20 mum veratridine (which opens voltage-dependent Na+ channels by preventing inactivation) or by 30 mM KCl (which activates voltage-gated Ca2+ channels by membrane depolarization) was monitored using an on-line enzyme-linked fluorometric assay.Results: Glutamate release evoked by depolarization with increased extracellular KCl was not significantly inhibited by isoflurane up to 0.7 mM (similar to2 minimum alveolar concentration; drug concentration for half-maximal inhibition > 1.5 mM) or propofol up to 40 muM in synaptosomes prepared from rat, mouse, or guinea pig cerebral cortex, rat hippocampus, or rat striatum. Lower concentrations of isoflurane or propofol significantly inhibited veratridine-evoked glutamate release in all three species (isoflurane IC50 = 0.41-0-50 mM; propofol IC50 = 11-18 muM) and rat brain regions. Inhibition of veratridine-evoked release was insensitive to the gamma -aminobutyric acid receptor type A antagonist bicuculline (100 muM) in rat cortical synaptosomes.Conclusions: Isoflurane and propofol inhibited Na+ channel-mediated glutamate release evoked by veratridine with greater potency than release evoked by increased KCl in synaptosomes prepared from three mammalian species and three rat brain regions. These findings are consistent with a greater sensitivity to anesthetics of presynaptic Na+ channels than of Ca2+ channels coupled to glutamate release. This widespread presynaptic action of general anesthetics is not mediated by potentiation of gamma -aminobutyric acid type A receptors, though additional mechanisms may be involved.