Mitochondrial Injury and Caspase Activation by the Local Anesthetic Lidocaine

Johnson, Michael E.; Uhl, Cindy B.; Spittler, Karl Heinz; Wang, Hongxun; Gores, Gregory J.

doi:10.1097/00000542-200411000-00019

Cited by 162 publications

(121 citation statements)

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“…Both amides, lidocaine and bupivacaine, are uncouplers of oxidative phosphorylation 34 that collapse the pH gradient and electrical potential across the inner mitochondrial membrane. 35 Consequently, lidocaine induces cell apoptosis or necrosis by recruiting the intrinsic mitochondrial pathway in neuronal or nonneuronal systems, [35][36][37] but at concentrations higher than those used in this study (usually above 5 mM). However, this form of toxicity may be prominent for lower concentrations of the more lipophilic agent, bupivacaine.…”

Section: Discussionmentioning

confidence: 86%

Vacuolar ATPase-mediated sequestration of local anesthetics in swollen macroautophagosomes

Bawolak

Morissette

Marceau

2010

Can J Anesth/J Can Anesth

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Purpose Local anesthetics in their therapeutic concentration range cause a vacuolar cytopathology that has been observed in vivo and in various types of mammalian cells. We examined whether active concentration ranges of drugs and the kinetics of the vacuolar response are clinically relevant and whether this phenomenon is associated with cytotoxicity, autophagy, and cell stress signalling. Methods We compared procaine and lidocaine for morphological, functional, and signalling responses in a previously exploited non-neuronal system, primary smooth muscle cells. Several markers conjugated to fluorescent proteins allowed morphological and functional analysis of vacuolar cells. Signalling related to autophagy and cell stress was addressed (immunoblotting of cell lysates). Results Within 2-4 hr, lidocaine and procaine (C1 mM) induced massive cell vacuolization, a response abated by the V-ATPase inhibitor, bafilomycin A1, and activated macroautophagic signalling (LC3 II formation) but not other stress signalling (p38, ERK1/2, p53, no influence on serum-controlled Akt phosphorylation). Novel aspects of the morphological analysis include reduced LC3 labelling of the large vacuoles in cells treated with 3-methyl-adenine, inhibition of CD63 labelling of these vacuoles by co-expression of dominant negative Rab7, retention of secretory green fluorescent protein (GFP) possessing a signal sequence in vacuolar cells, and partial vacuole labelling with lysosomal-associated membrane protein 1 (LAMP1). Lidocaine (2.5-5 mM) was not overtly cytotoxic but arrested cell division over 48 hr. Conclusions V-ATPase-mediated sequestration of clinically relevant concentrations of local anesthetics sequentially involves vacuolization, macroautophagic signalling, and lysosome fusion to large vacuoles. Disruption of the secretory pathway and mitotic arrest were also observed over several hours without major cytotoxicity. RésuméObjectif A`concentration the´rapeutique, les anesthe´siques locaux causent une cytopathologie vacuolaire qui a e´teó bserve´e in vivo et dans divers types de cellules en culture. Nous avons examine´si les concentrations actives de me´dicaments et la cine´tique de cette re´ponse sont cliniquement pertinentes et si ce phe´nome`ne est associe´al a cytotoxicite´, l'autophagie et la signalisation de stress cellulaire.Méthode On a compare´les re´ponses morphologiques, fonctionnelles et signale´tiques a`la procaı¨ne et la lidocaı¨ne dans un syste`me non neuronal pre´alablement exploite´, le muscle lisse en culture primaire, afin d'e´clairer leurs effets toxicologiques a`des niveaux the´rapeutiques. Plusieurs marqueurs conjugue´s à des prote´ines fluorescentes ont permis des analyses morphologiques et fonctionnelles des cellules vacuolaires. La signalisation autophagique et celle relie´e au stress cellulaire ont e´te´e´value´es (immunobuvardage de lysats cellulaires). Résultats La lidocaı¨ne et la procaı¨ne (C1 mM) induisent en 2-4 hr une vacuolisation cellulaire massive, une

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Section: Discussionmentioning

confidence: 86%

Vacuolar ATPase-mediated sequestration of local anesthetics in swollen macroautophagosomes

Bawolak

Morissette

Marceau

2010

Can J Anesth/J Can Anesth

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“…We evaluated the sensitivity of hTREK1 to varying concentrations of the local anesthetic lidocaine (10 M-5 mM). The reported plasma concentration of lidocaine is estimated between 20 and 30 M when lidocaine is administered intravenously for arrhythmia or neuroprotection (Johnson et al, 2004), whereas local anesthetic-induced seizure and cardiovascular collapse ensue when the plasma concentrations of lidocaine exceeds 50 M (DeToledo, 2000). During spinal or epidural anesthesia, lidocaine concentration in the cerebrospinal fluid normally reaches as high as 10 mM for the first 15 min after injection (Johnson et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

“…The reported plasma concentration of lidocaine is estimated between 20 and 30 M when lidocaine is administered intravenously for arrhythmia or neuroprotection (Johnson et al, 2004), whereas local anesthetic-induced seizure and cardiovascular collapse ensue when the plasma concentrations of lidocaine exceeds 50 M (DeToledo, 2000). During spinal or epidural anesthesia, lidocaine concentration in the cerebrospinal fluid normally reaches as high as 10 mM for the first 15 min after injection (Johnson et al, 2004). Thus, the steady-state concentration of lidocaine in the central nervous system and peripheral nervous system in various clinical conditions commensurate with the range we have used in the current study.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Human Two-Pore Domain K⁺ Channel TREK1 by Local Anesthetic Lidocaine: Negative Cooperativity and Half-of-Sites Saturation Kinetics

Nayak

Harinath²,

Nama³

et al. 2009

Mol Pharmacol

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TWIK-related Kϩ channel TREK1, a background leak K ϩ channel, has been strongly implicated as the target of several general and local anesthetics. Here, using the whole-cell and single-channel patch-clamp technique, we investigated the effect of lidocaine, a local anesthetic, on the human (h)TREK1 channel heterologously expressed in human embryonic kidney 293 cells by an adenoviral-mediated expression system. Lidocaine, at clinical concentrations, produced reversible, concentration-dependent inhibition of hTREK1 current, with IC 50 value of 180 M, by reducing the single-channel open probability and stabilizing the closed state. We have identified a strategically placed unique aromatic couplet (Tyr352 and Phe355) in the vicinity of the protein kinase A phosphorylation site, Ser348, in the C-terminal domain (CTD) of hTREK1, that is critical for the action of lidocaine. Furthermore, the phosphorylation state of Ser348 was found to have a regulatory role in lidocaine-mediated inhibition of hTREK1. It is interesting that we observed strong intersubunit negative cooperativity (Hill coefficient ϭ 0.49) and half-of-sites saturation binding stoichiometry (halfreaction order) for the binding of lidocaine to hTREK1. Studies with the heterodimer of wild-type (wt)-hTREK1 and ⌬119 Cterminal deletion mutant (hTREK1 wt -⌬119) revealed that single CTD of hTREK1 was capable of mediating partial inhibition by lidocaine, but complete inhibition necessitates the cooperative interaction between both the CTDs upon binding of lidocaine. Based on our observations, we propose a model that explains the unique kinetics and provides a plausible paradigm for the inhibitory action of lidocaine on hTREK1.

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“…Triggering of apoptosis (programmed cell death) is closely linked to calcium alterations, and has been noted as a delayed finding after local anesthetic injection. 19, 20 , 21 Mitochondrial damage as a contributing factor is suggested by loss of mitochondrial potential22 and leakage of cytochrome C, 20,22 but this is not a consistent finding. 21,23 Other studies focus on direct neuronal membrane damage by local anesthetics, 19,24,25 and inhibition of axonal transport has likewise been implicated, 26,27 probably through loss of axonal microtubules.…”

Section: Toxicity Of Injected Solutionmentioning

confidence: 99%

Pathophysiology of Peripheral Nerve Injury During Regional Anesthesia

Hogan¹

2008

Regional Anesthesia and Pain Medicine

129

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Mitochondrial Injury and Caspase Activation by the Local Anesthetic Lidocaine

Abstract: Collectively, these data indicate that lidocaine neurotoxicity involves mitochondrial dysfunction with activation of apoptotic pathways.

Cited by 162 publications

References 46 publications

Vacuolar ATPase-mediated sequestration of local anesthetics in swollen macroautophagosomes

Vacuolar ATPase-mediated sequestration of local anesthetics in swollen macroautophagosomes

Inhibition of Human Two-Pore Domain K⁺ Channel TREK1 by Local Anesthetic Lidocaine: Negative Cooperativity and Half-of-Sites Saturation Kinetics

Pathophysiology of Peripheral Nerve Injury During Regional Anesthesia

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Mitochondrial Injury and Caspase Activation by the Local Anesthetic Lidocaine

Abstract: Collectively, these data indicate that lidocaine neurotoxicity involves mitochondrial dysfunction with activation of apoptotic pathways.

Cited by 162 publications

References 46 publications

Vacuolar ATPase-mediated sequestration of local anesthetics in swollen macroautophagosomes

Vacuolar ATPase-mediated sequestration of local anesthetics in swollen macroautophagosomes

Inhibition of Human Two-Pore Domain K+ Channel TREK1 by Local Anesthetic Lidocaine: Negative Cooperativity and Half-of-Sites Saturation Kinetics

Pathophysiology of Peripheral Nerve Injury During Regional Anesthesia

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Inhibition of Human Two-Pore Domain K⁺ Channel TREK1 by Local Anesthetic Lidocaine: Negative Cooperativity and Half-of-Sites Saturation Kinetics