Clinical Concentrations of Local Anesthetics Bupivacaine and Lidocaine Differentially Inhibit Human Kir2.x Inward Rectifier K+ Channels

Nakahira, Kei; Oshita, Kensuke; Itoh, Masayuki; Takano, Makoto; Saito, Yoshiro; Ishihara, Keiko

doi:10.1213/ane.0000000000001137

Cited by 6 publications

(3 citation statements)

References 47 publications

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“…Despite the clinical relevance of local anesthesia, the question whether anesthesia is an outcome of anesthetic–lipid interactions or anesthetic–protein interactions (or a combination of both) is far from clear. Local anesthetics affect the function of a diverse variety of membrane proteins, ranging from ion channels (e.g., gramicidin) to membrane receptors, such as the serotonin 1A and nicotinic acetylcholine receptors. ,− The properties of local anesthetics therefore cannot be attributed to a specific protein. It is in this backdrop that the role of membrane lipids assumes relevance in modulating anesthetic–protein interaction, enabling the anesthetic effect .…”

Section: Resultsmentioning

confidence: 99%

Effect of Local Anesthetics on the Organization and Dynamics of Hippocampal Membranes: A Fluorescence Approach

et al. 2018

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Understanding the mechanism of action of local anesthetics has been challenging. We previously showed that the local anesthetic phenylethanol (PEtOH) inhibits the function of serotonin1A receptor, which is a member of the G protein-coupled receptor family and a neurotransmitter receptor. With the objective of gaining insight into the molecular mechanism underlying the anesthetic (PEtOH) action, we monitored the organization and dynamics of hippocampal membranes using multiple fluorescent reporters, which include a molecular rotor (BODIPY-C12) and a voltage-sensitive probe (4-(2-(6-(dioctylamino)-2-naphthalenyl)ethenyl)-1-(3-sulfopropyl)-pyridinium inner salt) (di-8-ANEPPS), besides pyrene. These interfacial membrane probes were chosen because membrane partitioning of PEtOH would be reflected in the membrane interfacial environment. Taken together, we report a reduction in dipole potential and microviscosity of hippocampal membranes, with a concomitant increase in lateral diffusion in the presence of PEtOH. The reduction in membrane dipole potential induced by PEtOH constitutes one of the first experimental demonstrations on the modulation of membrane dipole potential by local anesthetics. Our results assume significance in view of previous reports that correlate membrane-perturbing effects of local anesthetics to their anesthetic action. We envision that insights into the interaction of local anesthetics with membranes could serve as a crucial link in developing a comprehensive understanding of the molecular mechanisms involved in anesthesia.

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Section: Resultsmentioning

confidence: 99%

Effect of Local Anesthetics on the Organization and Dynamics of Hippocampal Membranes: A Fluorescence Approach

et al. 2018

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“…76 Recently, lidocaine's effect on inward rectifier K þ channels (K ir ) has been investigated. Lidocaine induced fast and reversible inhibition of three channels of the K ir 2.x subfamily (K ir 2.1, K ir 2.2, and K ir 2.3), albeit clearly above clinically relevant concentrations (IC 50 of 1.5e2.7 mM) 77,78 (Fig. 2).…”

Section: Potassium Channelsmentioning

confidence: 92%

Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: a narrative review

Hermanns

Hollmann

Stevens

et al. 2019

British Journal of Anaesthesia

192

165

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Systemic administration of the local anaesthetic lidocaine is antinociceptive in both acute and chronic pain states, especially in acute postoperative and chronic neuropathic pain. These effects cannot be explained by its voltage-gated sodium channel blocking properties alone, but the responsible mechanisms are still elusive. This narrative review focuses on available experimental evidence of the molecular mechanisms by which systemic lidocaine exerts its clinically documented analgesic effects. These include effects on the peripheral nervous system and CNS, where lidocaine acts via silencing ectopic discharges, suppression of inflammatory processes, and modulation of inhibitory and excitatory neurotransmission. We highlight promising objectives for future research to further unravel these antinociceptive mechanisms, which subsequently may facilitate the development of new analgesic strategies and therapies for acute and chronic pain.

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“…Проблему локальной токсичности местных анестетиков изучают многие годы. Поскольку местные анестетики не являются высокоселективными блокаторами потенциалзависимых натриевых каналов, они также могут блокировать кальциевые [1] и калиевые каналы [2]. Кроме того, местные анестетики влияют на различные сигнальные пути внутри клетки, активируя митохондриальный и ядерный пути апоптоза клетки [3,4].…”

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Double-Blind, Placebo-Controlled Study of Myotoxicity and Neurotoxicity of Bupivacaine in Rats

Lakhin

Гемуа

Шустров

2019

Neotložnaâ med. pomoŝʹ

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When penetrating into the cell, local anesthetics affect some structures and processes, in addition to blocking sodium channels, leading to the development of cell damage. The aim of the article was to study the damaging effect of bupivacaine on the sciatic nerve and biceps femoris in rats. The study is double-blind and placebo-controlled. We used 0.9% sodium chloride as the placebo. The studied concentrations of bupivacaine were 0.2%, 0.5%, 0.75%, and 1%. We performed perineural introduction of 0.2 ml into the sciatic nerve and administered 0.2 ml into the biceps femoris muscle under the ultrasound guidance. The samples were taken twice: 1 hour after administration, and over 14 days. Cell necrosis or apoptosis were not found in the muscle and nerve after the 0.9% sodium chloride administration; occasional inflammatory cells were detected. Introduction of all concentrations of bupivacaine induced damage and inflammatory infiltration of muscle tissue and neural structures compared with 0.9% sodium chloride solution. Dystrophic changes and neutrophilic infiltration were detected in nerve fibers. Perimuscular edema, apoptosis, polychromasia, necrosis, disappearance of cross-striation of muscles, clusters of inflammatory cells were found in the biceps femoris. Signs of damage and inflammatory infiltration decreased, but continued to persist over 14 days. The study showed the presence of neurotoxicity and myotoxicity of all concentrations of bupivacaine compared to a 0.9% sodium chloride solution. It was revealed that signs of damage and inflammatory infiltration persisted 14 days after the administration of bupivacaine.

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Clinical Concentrations of Local Anesthetics Bupivacaine and Lidocaine Differentially Inhibit Human Kir2.x Inward Rectifier K+ Channels

Abstract: The results indicate that both LAs at clinical concentrations equilibrated rapidly with the intracellular milieu, differentially inhibiting Kir2.x channel function from the cytoplasmic side.

Cited by 6 publications

References 47 publications

Effect of Local Anesthetics on the Organization and Dynamics of Hippocampal Membranes: A Fluorescence Approach

Effect of Local Anesthetics on the Organization and Dynamics of Hippocampal Membranes: A Fluorescence Approach

Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: a narrative review

Double-Blind, Placebo-Controlled Study of Myotoxicity and Neurotoxicity of Bupivacaine in Rats

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