Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065, United States.
Neuropharmacology. 2011 Sep;61(4):699-706. doi: 10.1016/j.neuropharm.2011.05.013. Epub 2011 May 30.
Stimulus evoked neurotransmitter release requires that Na(+) channel-dependent nerve terminal depolarization be transduced into synaptic vesicle exocytosis. Inhaled anesthetics block presynaptic Na(+) channels and selectively inhibit glutamate over GABA release from isolated nerve terminals, indicating mechanistic differences between excitatory and inhibitory transmitter release. We compared the effects of isoflurane on depolarization-evoked [(3)H]glutamate and [(14)C]GABA release from isolated nerve terminals prepared from four regions of rat CNS evoked by 4-aminopyridine (4AP), veratridine (VTD), or elevated K(+). These mechanistically distinct secretegogues distinguished between Na(+) channel- and/or Ca(2+) channel-mediated presynaptic effects. Isoflurane completely inhibited total 4AP-evoked glutamate release (IC(50) = 0.42 ± 0.03 mM) more potently than GABA release (IC(50) = 0.56 ± 0.02 mM) from cerebral cortex (1.3-fold greater potency), hippocampus and striatum, but inhibited glutamate and GABA release from spinal cord terminals equipotently. Na(+) channel-specific VTD-evoked glutamate release from cortex was also significantly more sensitive to inhibition by isoflurane than was GABA release. Na(+) channel-independent K(+)-evoked release was insensitive to isoflurane at clinical concentrations in all four regions, consistent with a target upstream of Ca(2+) entry. Isoflurane inhibited Na(+) channel-mediated (tetrodotoxin-sensitive) 4AP-evoked glutamate release (IC(50) = 0.30 ± 0.03 mM) more potently than GABA release (IC(50) = 0.67 ± 0.04 mM) from cortex (2.2-fold greater potency). The magnitude of inhibition of Na(+) channel-mediated 4AP-evoked release by a single clinical concentration of isoflurane (0.35 mM) varied by region and transmitter: Inhibition of glutamate release from spinal cord was greater than from the three brain regions and greater than GABA release for each CNS region. These findings indicate that isoflurane selectively inhibits glutamate release compared to GABA release via Na(+) channel-mediated transduction in the four CNS regions tested, and that differences in presynaptic Na(+) channel involvement determine differences in anesthetic pharmacology.
刺激诱发的神经递质释放需要 Na(+) 通道依赖性神经末梢去极化转化为突触小泡胞吐。吸入麻醉剂阻断突触前 Na(+) 通道，并选择性抑制谷氨酸而不是 GABA 从分离的神经末梢释放，表明兴奋性和抑制性递质释放之间存在机制差异。我们比较了异氟醚对由 4-氨基吡啶（4AP）、藜芦碱（VTD）或升高的 K(+) 诱发的大鼠中枢神经系统四个区域分离的神经末梢中去极化诱发的 [(3)H]谷氨酸和 [(14)C]GABA 释放的影响。这些机制上不同的分泌剂区分了 Na(+) 通道和/或 Ca(2+) 通道介导的突触前效应。异氟醚完全抑制了总 4AP 诱发的谷氨酸释放（IC(50) = 0.42 ± 0.03 mM），比 GABA 释放（IC(50) = 0.56 ± 0.02 mM）更有效，来自大脑皮层（效力高 1.3 倍）、海马和纹状体，但对脊髓末梢的谷氨酸和 GABA 释放具有相同的抑制作用。VTD 诱发的 Na(+) 通道特异性谷氨酸释放也比 GABA 释放对异氟醚的抑制更为敏感。在所有四个区域，临床浓度的异氟醚对 Na(+) 通道非依赖性 K(+) 诱发的释放没有作用，这与 Ca(2+) 进入上游的靶点一致。异氟醚抑制了 Na(+) 通道介导的（河豚毒素敏感的）4AP 诱发的谷氨酸释放（IC(50) = 0.30 ± 0.03 mM），比 GABA 释放（IC(50) = 0.67 ± 0.04 mM）更有效，来自大脑皮层（效力高 2.2 倍）。临床浓度的异氟醚对单个 Na(+) 通道介导的 4AP 诱发释放的抑制程度因区域和递质而异：异氟醚对脊髓释放的抑制作用大于对三个脑区的释放，对每个中枢神经系统区域的 GABA 释放的抑制作用也大于 GABA 释放。这些发现表明，异氟醚通过在测试的四个中枢神经系统区域中通过 Na(+) 通道介导的转导选择性抑制谷氨酸释放而不是 GABA 释放，并且突触前 Na(+) 通道的参与程度决定了麻醉药理学的差异。
