Membrane effect of lidocaine is inhibited by interaction with peroxynitrite

Ueno, Takahiro; Mizogami, Maki; Takakura, Ko; Tsuchiya, Hironori

doi:10.1007/s00540-007-0583-1

Cited by 6 publications

(7 citation statements)

References 24 publications

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“…The present results suggest that infl ammatory peroxynitrite affects local anesthesia not only directly by interacting with lidocaine [9] but also indirectly by acting on nerve-cell membranes. Both the drug interaction and the membrane action would decrease the effi cacies of topical and infi ltration anesthesia, in which local anesthetics are applied into or close to infl amed tissues.…”

Section: Abstract Peroxynitrite · Lidocaine · Membrane Lipids · Fluimentioning

confidence: 89%

“…However, experimental verifi cations are challenging this mechanistic theory [7,8]. One alternative mechanism was proposed by focusing on peroxynitrite [9], which is produced by infl ammatory cells and is relevant to various diseases [10].…”

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confidence: 98%

“…Such a change is caused by the interaction of peroxynitrite with drugs or by the action of peroxynitrite on nerve-cell membranes, or both. The former was experimentally proven for lidocaine [9], whereas the latter has not yet been proven. Membrane fl uidizer anesthetics were previously hypothesized to interact with any compounds with the opposite membrane activAbstract Infl ammation frequently decreases local anesthetic effects, especially in dental anesthesia in patients with pulpitis and periodontitis.…”

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confidence: 99%

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Peroxynitrite affects lidocaine by acting on membrane-constituting lipids

et al. 2008

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Inflammation frequently decreases local anesthetic effects, especially in dental anesthesia in patients with pulpitis and periodontitis. The pharmacokinetics and the mode of action of local anesthetics are closely associated with the hydrophobic interactions between these drugs and lipid bilayers that change the membrane physicochemical property, fluidity. A lipid oxidant, peroxynitrite, is produced by inflammatory cells, and it may act on nerve cell membranes and affect anesthetic efficacy. With respect to this speculated action, we addressed whether peroxynitrite acted on membrane-constituting lipids to decrease the membrane interactivity of lidocaine. Membrane fluidity changes were determined by measuring the fluorescence polarization of liposomes prepared with different phospholipids. Peroxynitrite (0.1-50 microM) rigidified nerve-cell model membranes consisting of unsaturated phospholipids, as well as liposomal membranes consisting of 1,2-dioleoylphosphatidylcholine and 1-stearoyl-2-arachidonylphosphatidylcholine, but peroxynitrite did not rigidify 1, 2-dipalmitoylphosphatidylcholine liposomal membranes. The pretreatment of nerve-cell model membranes with peroxynitrite (0.1-50 microM) decreased the membrane-fluidizing effects of lidocaine (5.0 mg x ml(-1)) to 63%-86% of the control (not treated with peroxynitrite) depending on the peroxynitrite concentration. As one of the mechanisms of the local anesthetic failure associated with inflammation, inflammatory peroxynitrite may affect local anesthesia by acting on membrane-constituting unsaturated phospholipids.

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Section: Abstract Peroxynitrite · Lidocaine · Membrane Lipids · Fluimentioning

confidence: 89%

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confidence: 98%

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confidence: 99%

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Peroxynitrite affects lidocaine by acting on membrane-constituting lipids

et al. 2008

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“…The following DPH fluorescence polarization measurements showed that the membrane-fluidizing effects of local anesthetics were inhibited by the peroxynitrite treatment. Such inhibitions are causable by peroxynitrite directly acting on anesthetic molecules [45] and indirectly on membrane lipids [46]. …”

Section: Change Of Membrane Interactivitymentioning

confidence: 99%

Interaction of Local Anesthetics with Biomembranes Consisting of Phospholipids and Cholesterol: Mechanistic and Clinical Implications for Anesthetic and Cardiotoxic Effects

Tsuchiya

Mizogami

2013

Anesthesiology Research and Practice

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Despite a long history in medical and dental application, the molecular mechanism and precise site of action are still arguable for local anesthetics. Their effects are considered to be induced by acting on functional proteins, on membrane lipids, or on both. Local anesthetics primarily interact with sodium channels embedded in cell membranes to reduce the excitability of nerve cells and cardiomyocytes or produce a malfunction of the cardiovascular system. However, the membrane protein-interacting theory cannot explain all of the pharmacological and toxicological features of local anesthetics. The administered drug molecules must diffuse through the lipid barriers of nerve sheaths and penetrate into or across the lipid bilayers of cell membranes to reach the acting site on transmembrane proteins. Amphiphilic local anesthetics interact hydrophobically and electrostatically with lipid bilayers and modify their physicochemical property, with the direct inhibition of membrane functions, and with the resultant alteration of the membrane lipid environments surrounding transmembrane proteins and the subsequent protein conformational change, leading to the inhibition of channel functions. We review recent studies on the interaction of local anesthetics with biomembranes consisting of phospholipids and cholesterol. Understanding the membrane interactivity of local anesthetics would provide novel insights into their anesthetic and cardiotoxic effects.

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“…This depends on inflammation initiation and duration, and highly dependent on amount of recruited cells. Older studies have measured high hydrogen ion concentrations in inflamed tissue (down to pH 5.4), fracture related hematomas (down to pH 4.7), and in caridac ischemia (down to pH 5.7) . Indeed, our group has previously used AcDex for treating models of cardiac ischemia .…”

Section: Resultsmentioning

confidence: 99%

Disease‐Triggered Drug Release Effectively Prevents Acute Inflammatory Flare‐Ups, Achieving Reduced Dosing

Stubelius

Sheng

Lee

et al. 2018

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For conditions with inflammatory flare-ups, fast drug-release from a depot is crucial to reduce cell infiltration and prevent long-term tissue destruction. While this concept has been explored for chronic diseases, preventing acute inflammatory flares has not been explored. To address this issue, a preventative inflammation-sensitive system is developed and applied to acute gout, a condition where millions of inflammatory cells are recruited rapidly, causing excruciating and debilitating pain. Rapid drug release is first demonstrated from a pH-responsive acetalated dextran particle loaded with dexamethasone (AcDex-DXM), reducing proinflammatory cytokines in vitro as efficiently as free drug. Then, using the air pouch model of gout, mice are pretreated 24 h before inducing inflammation. AcDex-DXM reduces overall cell infiltration with decreased neutrophils, increases monocytes, and diminishes cytokines and chemokines. In a more extended prophylaxis model, murine joints are pretreated eight days before initiating inflammation. After quantifying cell infiltration, only AcDex-DXM reduces the overall joint inflammation, where neither free drug nor a conventional drug-depot achieves adequate anti-inflammatory effects. Here, the superior efficacy of disease-triggered drug-delivery to prevent acute inflammation is demonstrated over free drug and slow-release depots. This approach and results promise exciting treatment opportunities for multiple inflammatory conditions suffering from acute flares.

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Membrane effect of lidocaine is inhibited by interaction with peroxynitrite

Cited by 6 publications

References 24 publications

Peroxynitrite affects lidocaine by acting on membrane-constituting lipids

Peroxynitrite affects lidocaine by acting on membrane-constituting lipids

Interaction of Local Anesthetics with Biomembranes Consisting of Phospholipids and Cholesterol: Mechanistic and Clinical Implications for Anesthetic and Cardiotoxic Effects

Disease‐Triggered Drug Release Effectively Prevents Acute Inflammatory Flare‐Ups, Achieving Reduced Dosing

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