Volatile anaesthetics depolarize neural mitochondria by inhibiton of the electron transport chain
Volatile anaesthetics depolarize neural mitochondria by inhibiton of the electron transport chain
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DOI：
10.1111/j.1399-6576.2006.00988.x
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发表时间：
2006-05-01
影响因子：
2.1
通讯作者：
Vinje, ML
中科院分区：
文献类型：
--
作者：
Bains, R;Moe, MC;Vinje, ML
背景：线粒体膜电位(Delta Psi(M))控制着三磷酸腺苷(ATP)和活性氧的生成，以及细胞内钙离子的隔离。七氟醚的临床浓度影响神经线粒体中的Delta Psi(M)，但其机制仍不清楚。本研究的目的是比较异氟醚和七氟烷对大鼠突触前终末(突触体)Delta Psi(M)的影响，并探讨这两种药物是否通过抑制呼吸链而影响Delta Psi(M)。方法：将荧光探针JC-1(Delta Psi(M))和Fura-2([Ca2+](I))负载突触体内，分别暴露于异氟烷或七氟烷。结果：异氟醚1和2的最低肺泡浓度(MAC)使JC-1比值从对照组的0.92+/-0.03分别降至0.86+/-0.02和0.81+/-0.01，反映线粒体膜的去极化(n=9)。异氟醚-2MAC增加[Ca~(2+)](I)。在钙耗竭的介质中，异氟醚仍可降低Delta Psi(M)，而[Ca~(2+)](I)无明显变化。异氟醚的作用比七氟醚更明显。阻断呼吸链复合体V可增强异氟醚和七氟烷诱导的线粒体去极化作用，而阻断复合体I和V可使DeltaPsi(M)在对照、异氟烷和七氟烷实验中有相同程度的降低。结论：异氟烷和七氟烷可能通过抑制电子传递链而使突触前线粒体去极化，从而发挥代谢抑制作用，尽管异氟烷对线粒体功能的抑制似乎比七氟烷更明显。这两种药物都能充分抑制呼吸链，导致ATP合成酶逆转。
Background: The mitochondrial membrane potential (Delta Psi(m)) controls the generation of adenosine triphosphate (ATP) and reactive oxygen species, and sequesteration of intracellular Ca2+[Ca2+](i). Clinical concentrations of sevoflurane affect the Delta Psi(m) in neural mitochondria, but the mechanisms remain elusive. The aim of the present study was to compare the effect of isoflurane and sevoflurane on Delta Psi(m) in rat pre-synaptic terminals (synaptosomes), and to investigate whether these agents affect Delta Psi(m) by inhibiting the respiratory chain.Methods: Synaptosomes were loaded with the fluorescent probes JC-1 (Delta Psi(m)) and Fura-2 ([Ca2+](i)) and exposed to isoflurane or sevoflurane. The effect of the anaesthetics on the electron transport chain was investigated by blocking complex I and complex V.Results: Isoflurane 1 and 2 minimum alveolar concentration (MAC) decreased the normalized JC-1 ratio from 0.92 +/- 0.03 in control to 0.86 +/- 0.02 and 0.81 +/- 0.01, respectively, reflecting a depolarization of the mitochondrial membrane (n = 9). Isoflurane 2 MAC increased [Ca2+](i). In Ca2+-depleted medium, isoflurane still decreased Delta Psi(m) while [Ca2+](i) remained unaltered. The effect of isoflurane was more pronounced than for sevoflurane. Blocking complex V of the respiratory chain enhanced the isoflurane- and sevoflurane-induced mitochondrial depolarization, whereas blocking complex I and V decreased Delta Psi(m) to the same extent in control, isoflurane and sevoflurane experiments.Conclusions: Isoflurane and sevoflurane may act as metabolic inhibitors by depolarizing pre-synaptic mitochondria through inhibition of the electron transport chain, although isoflurane seems to inhibit mitochondrial function more significantly than sevoflurane. Both agents inhibit the respiratory chain sufficiently to cause ATP synthase reversal.