Bupivacaine uncouples the mitochondrial oxidative phosphorylation, inhibits respiratory chain complexes I and III and enhances ROS production: Results of a study on cell cultures
Bupivacaine uncouples the mitochondrial oxidative phosphorylation, inhibits respiratory chain complexes I and III and enhances ROS production: Results of a study on cell cultures
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DOI：
10.1016/j.mito.2010.05.005
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发表时间：
2010-08-01
期刊：
影响因子：
4.4
通讯作者：
Capitanio, Nazzareno
中科院分区：
文献类型：
--
作者：
Cela, Olga;Piccoli, Claudia;Capitanio, Nazzareno
本研究旨在原位验证提出的布比卡因细胞毒性机制，指出线粒体氧化代谢受损。在一组细胞培养物上进行的高分辨率氧饱和度测定显示，布比卡因具有双剂量和时间依赖性作用，包括以环孢素a不敏感的方式解耦mt δ mu（H+）控制的呼吸速率，并进一步抑制呼吸速率。有趣的是，相对较小的mt δ Psi下降（约20 mV）足以解释布比卡因和fccp介导的氧化磷酸化偶联损伤，从而支持共同的质子保护作用机制。布比卡因诱导的细胞呼吸抑制与复合物I和III的特异性抑制有关，并伴有活性氧的产生。重要的是，抗氧化剂可以阻止呼吸链复合物的抑制作用，并在去除麻醉剂后逆转，从而表明氧化剂介导的反馈机制加强了麻醉剂的初级抑制作用。(C) 2010 Elsevier B.V.与线粒体研究学会。版权所有。
This study aimed to validate, in situ, proposed mechanisms of bupivacaine citotoxicity pointing to impairment of the mitochondrial oxidative metabolism. High resolution oxymetry, carried out on a panel of cell cultures, revealed a dual dose- and time-dependent effect of bupivacaine consisting of uncoupling of the mt Delta mu(H+)-controlled respiratory rates in a cyclosporine A-insensitive manner and further inhibition of the respiratory rates. Intriguingly, a relatively small decrease on the mt Delta Psi (about 20 mV) was sufficient to account for both the bupivacaine- and the FCCP-mediated impairment of the oxidative phosphorylation coupling thereby supporting a common protonophoric mechanism of action. The bupivacaine-induced depression of the cell respiration related to specific inhibition of complexes I and III and accompanied with production of reactive oxygen species. Importantly, inhibition of the respiratory chain complexes was prevented by antioxidant treatment and reversed following removal of the anaesthetic thereby suggesting an oxidant-mediated feed-back mechanism reinforcing the primary inhibitory action of the anaesthetic. (C) 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved.