Selective depression by general anesthetics of glutamate versus GABA release from isolated cortical nerve terminals
Selective depression by general anesthetics of glutamate versus GABA release from isolated cortical nerve terminals
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DOI：
10.1124/jpet.102.044685
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发表时间：
2003-03-01
影响因子：
3.5
通讯作者：
Hemmings, HC
中科院分区：
文献类型：
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作者：
Westphalen, RI;Hemmings, HC
突触前机制在全麻抑制兴奋性谷氨酸能神经传递和促进gaba介导的抑制性神经传递中的作用尚不清楚。双同位素方法允许同时比较具有代表性的挥发性（异氟醚）和静脉注射（异丙酚）麻醉剂对离体大鼠脑皮质神经末梢（突触体）释放谷氨酸和GABA的影响。用L-[H-3]谷氨酸和[C-14] GABA预标记突触体，在没有或存在1.9 mM游离Ca2+的情况下，用30 mM K+或1 mM 4-氨基吡啶（4AP）脉冲灌注来测定释放。异氟醚最大限度地抑制Ca2+依赖性4ap诱发的L-[H-3]谷氨酸释放（抑制99 +/- 8%），其抑制程度大于[C-14] GABA释放（抑制74 +/- 6%；P = 0.023）。与[C-14] GABA释放相比，L-[H-3]谷氨酸对Na+通道拮抗剂河鲀毒素（99 +/- 4%对63 +/- 5%的抑制作用，P < 0.001）和利鲁唑（84 +/- 5%对52 +/- 12%的抑制作用，P = 0.041）的抑制作用更大。异丙酚对Ca2+依赖性4ap诱发的L-[H-3]谷氨酸释放的最大抑制作用（76 +/- 12%）与[C-14] GABA （84 +/- 31%, P = 0.99）的最大抑制作用没有差异。异氟醚（1mm）和异丙酚（15mu M）均不影响K+诱发释放，这与突触囊泡胞外机制或电压门控Ca2+通道与递质释放耦合的上游分子靶点一致。这些发现支持临床异氟醚浓度对兴奋性与抑制性神经传递的选择性突触前抑制，可能是Na+通道阻断的结果。
The role of presynaptic mechanisms in general anesthetic depression of excitatory glutamatergic neurotransmission and facilitation of GABA-mediated inhibitory neurotransmission is unclear. A dual isotope method allowed simultaneous comparisons of the effects of a representative volatile (isoflurane) and intravenous (propofol) anesthetic on the release of glutamate and GABA from isolated rat cerebrocortical nerve terminals (synaptosomes). Synaptosomes were prelabeled with L-[H-3] glutamate and [C-14] GABA, and release was determined by superfusion with pulses of 30 mM K+ or 1 mM 4-aminopyridine (4AP) in the absence or presence of 1.9 mM free Ca2+. Isoflurane maximally inhibited Ca2+-dependent 4AP-evoked L-[H-3] glutamate release (99 +/- 8% inhibition) to a greater extent than [C-14] GABA release (74 +/- 6% inhibition; P = 0.023). Greater inhibition of L-[H-3] glutamate versus [C-14] GABA release was also observed for the Na+ channel antagonists tetrodotoxin (99 +/- 4 versus 63 +/- 5% inhibition; P < 0.001) and riluzole (84 +/- 5 versus 52 +/- 12% inhibition; P = 0.041). Propofol did not differ in its maximum inhibition of Ca2+-dependent 4AP-evoked L-[H-3] glutamate release (76 +/- 12% inhibition) compared with [C-14] GABA (84 +/- 31% inhibition; P = 0.99) release. Neither isoflurane (1 mM) nor propofol (15 mu M) affected K+- evoked release, consistent with a molecular target upstream of the synaptic vesicle exocytotic machinery or voltage-gated Ca2+ channels coupled to transmitter release. These findings support selective presynaptic depression of excitatory versus inhibitory neurotransmission by clinical concentrations of isoflurane, probably as a result of Na+ channel blockade.