Ouyang Wei, Wang Gang, Hemmings Hugh C
Department of Anesthesiology, Box 50, LC-203, 525 E. 68th St., Weill Medical College of Cornell University, New York, NY 10021, USA.
Mol Pharmacol. 2003 Aug;64(2):373-81. doi: 10.1124/mol.64.2.373.
Mounting electrophysiological evidence indicates that certain general anesthetics, volatile anesthetics in particular, depress excitatory synaptic transmission by presynaptic mechanisms. We studied the effects of representative general anesthetics on voltage-gated Na+ currents (INa) in nerve terminals isolated from rat neurohypophysis using patch-clamp electrophysiological analysis. Both isoflurane and propofol inhibited INa in a dose-dependent and reversible manner. At holding potentials of -70 or -90 mV, isoflurane inhibited peak INa with IC50 values of 0.45 and 0.56 mM, and propofol inhibited peak INa with IC50 values of 4.1 and 6.0 microM, respectively. Isoflurane (0.8 mM) did not significantly alter the V1/2 of activation; propofol caused a small positive shift. Isoflurane (0.8 mM) or propofol (5 microM) produced a negative shift in the voltage dependence of inactivation. Recovery of INa from inactivation was slower from a holding potential of -70 mV than from -90 mV; isoflurane and propofol further delayed recovery from inactivation. In conclusion, the volatile anesthetic isoflurane and the intravenous anesthetic propofol inhibit voltage-gated Na+ currents in isolated neurohypophysial nerve terminals in a concentration- and voltage-dependent manner. Marked effects on the voltage dependence and kinetics of inactivation and minimal effects on activation support preferential anesthetic interactions with the fast inactivated state of the Na+ channel. These results are consistent with direct inhibition of oxytocin and vasopressin release from the neurohypophysis by isoflurane and propofol. Inhibition of voltage-gated Na+ channels may contribute to the presynaptic effects of general anesthetics on nerve terminal excitability and neurotransmitter release.
越来越多的电生理证据表明，某些全身麻醉药，尤其是挥发性麻醉药，通过突触前机制抑制兴奋性突触传递。我们使用膜片钳电生理分析方法，研究了具有代表性的全身麻醉药对从大鼠神经垂体分离出的神经末梢中电压门控性Na+电流（INa）的影响。异氟烷和丙泊酚均以剂量依赖性和可逆性方式抑制INa。在-70或-90 mV的钳制电位下，异氟烷抑制峰值INa的IC50值分别为0.45和0.56 mM，丙泊酚抑制峰值INa的IC50值分别为4.1和6.0 microM。异氟烷（0.8 mM）并未显著改变激活的V1/2；丙泊酚则引起了较小的正向偏移。异氟烷（0.8 mM）或丙泊酚（5 microM）使失活的电压依赖性产生负向偏移。从-70 mV的钳制电位恢复INa失活比从-90 mV恢复要慢；异氟烷和丙泊酚进一步延迟了失活后的恢复。总之，挥发性麻醉药异氟烷和静脉麻醉药丙泊酚以浓度和电压依赖性方式抑制分离的神经垂体神经末梢中的电压门控性Na+电流。对失活的电压依赖性和动力学有显著影响，而对激活的影响最小，这支持了麻醉药与Na+通道快速失活状态的优先相互作用。这些结果与异氟烷和丙泊酚直接抑制神经垂体释放催产素和血管升压素一致。抑制电压门控性Na+通道可能有助于全身麻醉药对神经末梢兴奋性和神经递质释放的突触前作用。
