Lidocaine depolarizes the mitochondrial membrane potential by intracellular alkalization in rat dorsal root ganglion neurons

Purpose The mitochondrial membrane potential (ΔΨm) is an important factor for apoptosis, and it is produced by the proton electrochemical gradient (ΔµH + ). Therefore, the intracellular proton concentration (pH in ) is an important factor for modifying the ΔΨm. However, the effects of lidocaine on p...

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Published in:	Journal of anesthesia Vol. 25; no. 2; pp. 229 - 239
Main Authors:	Onizuka, Shin, Yonaha, Tetsu, Tamura, Ryuji, Kasiwada, Masatoshi, Shirasaka, Toshiro, Tsuneyoshi, Isao
Format:	Journal Article
Language:	English
Published:	Japan Springer Japan 01-04-2011 Springer
Subjects:	Anesthesiology Anesthetics, Local - pharmacology Animals Apoptosis Apoptosis - drug effects Critical Care Medicine Emergency Medicine Female Flavin-Adenine Dinucleotide - analysis Fluorescence Ganglia, Spinal - drug effects Ganglia, Spinal - metabolism Ganglion Hydrogen-Ion Concentration Intensive Lidocaine Lidocaine - pharmacology Male Medicine Medicine & Public Health Membrane Potential, Mitochondrial - drug effects Mitochondrial DNA NAD - analysis Neurons Niacinamide Original Article Pain Medicine Purines Rats Rats, Wistar Superoxide Superoxides - metabolism Japan Lidocaine Intracellular alkalization Mitochondrial membrane potential
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Summary:	Purpose The mitochondrial membrane potential (ΔΨm) is an important factor for apoptosis, and it is produced by the proton electrochemical gradient (ΔµH + ). Therefore, the intracellular proton concentration (pH in ) is an important factor for modifying the ΔΨm. However, the effects of lidocaine on pH in are unclear. To investigate mitochondrial responses to lidocaine, therefore, we simultaneously measured pH in with ΔΨm, flavin adenine dinucleotide (FAD), and reduced form of nicotinamide adenine dinucleotide (NADH) fluorescence, and calculated the FAD/NADH ratio (redox ratio), the superoxide production in mitochondria. Methods Morphological change and early apoptosis were observed by annexin-V FITC staining under fluorescent microscope. The ratiometric fluorescent probe JC-1 and HPTS were used for the simultaneous measurements of ΔΨm with pH in in rat dorsal root ganglion (DRG) neurons. FAD and NADH autofluorescence were simultaneously measured, and the FAD/NADH fluorescence ratio (redox ratio) was calculated. The superoxide was measured by mitosox-red fluorescent probe for mitochondrial superoxide. Lidocaine was evaluated at 1, 5, and 10 mM. Results Morphological change and early apoptosis were observed after 10 mM lidocaine administration. Lidocaine depolarized ΔΨm with increased pH in in a dose-dependent manner. In low-pH saline (pH 6), in the presence of both the weak acids (acetate and propionate), lidocaine failed to depolarize ΔΨm and increase pH in . On the other hand, lidocaine decreased the redox ratio in the cell and increased the levels of superoxide in a dose-dependent manner. Conclusion These results demonstrated that lidocaine depolarizes ΔΨm by intracellular alkalization. These results may indicate one of the mechanisms responsible for lidocaine-induced neurotoxicity.
ISSN:	0913-8668 1438-8359
DOI:	10.1007/s00540-010-1079-y