Suppression of central nervous system sodium channels by propofol
Suppression of central nervous system sodium channels by propofol
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DOI：
10.1097/00000542-199908000-00026
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发表时间：
1999-08-01
期刊：
影响因子：
8.8
通讯作者：
Duch, DS
中科院分区：
文献类型：
--
作者：
Rehberg, B;Duch, DS
背景：先前的研究已经提供证据表明，临床水平的异丙酚改变电压依赖性钠通道的功能，从而抑制突触释放谷氨酸。然而;这些实验大多是在钠通道激活剂存在的情况下进行的，它改变了通道的失活。本研究电生理表征了异丙酚与未修饰钠通道的相互作用。方法：采用全细胞膜片钳法记录稳定转染的中国仓鼠卵巢细胞系中表达的大鼠脑钠离子通道的钠电流。在外用异丙酚存在或不存在的情况下，采用标准电生理方案记录钠电流。结果：异丙酚在临床上达到的浓度下，通过两种机制显著改变钠通道电流：电压无关的峰值电流阻滞和浓度依赖的稳态失活向超极化电位的转移，导致电流抑制的电压依赖。这两种作用结合在一起，产生了一种明显的浓度，在动作电位放电阈值电位附近（约-60毫伏）产生了10 μ M的半最大抑制效应，异丙酚的抑制作用也依赖于使用，在这种麻醉浓度下会进一步阻断钠电流。结论在药理学上未改变钠通道的实验中，异丙酚对电流的抑制发生在临床血浆浓度的8倍以上，因此在临床麻醉时达到脑浓度。因此，研究结果表明钠通道抑制可能在异丙酚麻醉中起作用。
Background: Previous studies have provided evidence that clinical levels of propofol alter the functions of voltage-dependent sodium channels, thereby inhibiting synaptic release of glutamate. However; most of these experiments were con ducted in the presence of sodium-channel activators, which alter channel inactivation. This study electrophysiological characterized the interactions of propofol with unmodified sodium channels.Methods: Sodium currents were measured using whole-cell patch-clamp recordings of rat brain Ha sodium channels expressed in a stably transfected Chinese hamster ovary cell line. Standard electrophysiologic protocols were used to record sodium currents in the presence or absence of externally applied propofol.Results: Propofol, at concentrations achieved clinically in the brain, significantly altered sodium channel currents by two mechanisms: a voltage-independent block of peak currents and a concentration-dependent shift in steady-state inactivation to hyperpolarized potentials, leading to a voltage dependence of current suppression. The two effects combined to give an apparent concentration yielding a half-maximal inhibitory effect of 10 mu M near the threshold potential of action potential firing (about -60 mV), Propofol inhibition was also use-dependent, causing a further block of sodium currents at these anesthetic concentrations.Conclusions In these experiments with pharmacologically unaltered sodium channels, propofol inhibition of currents occurred at concentrations about eight-fold above clinical plasma levels and thus at brain concentrations reached during clinical anesthesia. Therefore, the results indicate a possible role for sodium-channel suppression in propofol anesthesia.