The effects of mexiletine on action potential duration and its restitution in guinea pig ventricular muscles.

Matsuo, Shogo; Kuroda, Hiroshi; Munakata, Kazuo; Atarashi, Hirotsugu

doi:10.1536/ihj.26.271

Cited by 2 publications

(2 citation statements)

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“…In addition, mexiletine can inhibit I Na , I Ca-L , I NCX , I Ks and I to, and activate I KATP (Supplementary Table 1) (Wang et al, 1996;Yonemizu et al, 2019;Rahm et al, 2020;Mitcheson and Hancox, 1997). The I Ca-L -inhibiting and I KATP -activation can explain the APDshortening effect of mexiletine in wild-type cardiomyocytes (Table 1) (Matsuo et al, 1985;Sato et al, 1995). The I Kr -, I Ksand I to -inhibiting effects can be the reason for APD-prolonging effect observed in SQT-cells (Frommeyer et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Huang

Liao

et al. 2021

Front. Pharmacol.

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Aims: The short QT syndrome type 1 (SQT1) is linked to hERG channel mutations (e.g., N588K). Drug effects on hERG channel gating kinetics in SQT1-cells have not been investigated.Methods: This study used hiPSC-CMs of a healthy donor and a SQT1-patient carrying the N588K mutation and patch clamp to examine the drug effects on hERG channel gating kinetics.Results: Ajmaline, amiodarone, ivabradine, flecainide, quinidine, mexiletine and ranolazine inhibited the hERG channel current (IKr) less strongly in hiPSC-CMs from the SQTS1-patient (SQT1-hiPSC-CMs) comparing with cells from the healthy donor (donor-hiPSC-CMs). Quinidine and mexiletine reduced, but ajmaline, amiodarone, ivabradine and ranolazine increased the time to peak of IKr similarly in SQT1-hiPSC-CMs and donor-hiPSC-CMs. Although regarding the shift of activation and inactivation curves, tested drugs showed differential effects in donor- and SQT1-hiPSC-CMs, quinidine, ajmaline, ivabradine and mexiletine but not amiodarone, flecainide and ranolazine reduced the window current in SQT1-hiPSC-CMs. Quinidine, ajmaline, ivabradine and mexiletine differentially changed the time constant of recovery from inactivation, but all of them increased the time constant of deactivation in SQT1-hiPSC-CMs.Conclusion: The window current-reducing and deactivation-slowing effects may be important for the antiarrhythmic effect of ajmaline, ivabradine, quinidine and mexiletine in SQT1-cells. This information may be helpful for selecting drugs for treating SQT1-patients with hERG channel mutation.

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Section: Discussionmentioning

confidence: 99%

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Huang

Liao

et al. 2021

Front. Pharmacol.

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“…Conversely, mexiletine has been shown to cause a significant reduction in action potential duration (APD) mainly through its inhibition of the sodium current (Matsuo et al. ; Roden et al. ); this mechanism has been considered as an advantage for the treatment of patients with LQT3 (Wang et al.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m‐hydroxymexiletine

Gualdani

Tadini‐Buoninsegni

Roselli

et al. 2015

Pharmacology Res & Perspec

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Mexiletine is a sodium channel blocker, primarily used in the treatment of ventricular arrhythmias. Moreover, recent studies have demonstrated its therapeutic value to treat myotonic syndromes and to relieve neuropathic pain. The present study aims at investigating the direct blockade of hERG potassium channel by mexiletine and its metabolite m-hydroxymexiletine (MHM). Our data show that mexiletine inhibits hERG in a time- and voltage-dependent manner, with an IC50 of 3.7 ± 0.7 μmol/L. Analysis of the initial onset of current inhibition during a depolarizing test pulse indicates mexiletine binds preferentially to the open state of the hERG channel. Looking for a possible mexiletine alternative, we show that m-hydroxymexiletine (MHM), a minor mexiletine metabolite recently reported to be as active as the parent compound in an arrhythmia animal model, is a weaker hERG channel blocker, compared to mexiletine (IC50 = 22.4 ± 1.2 μmol/L). The hERG aromatic residues located in the S6 helix (Tyr652 and Phe656) are crucial in the binding of mexiletine and the different affinities of mexiletine and MHM with hERG channel are interpreted by modeling their corresponding binding interactions through ab initio calculations. The simulations demonstrate that the introduction of a hydroxyl group on the meta-position of the aromatic portion of mexiletine weakens the interaction of the drug xylyloxy moiety with Tyr652. These results provide further insights into the molecular basis of drug/hERG interactions and, in agreement with previously reported results on clofilium and ibutilide analogs, support the possibility of reducing hERG potency and related toxicity by modifying the aromatic pattern of substitution of clinically relevant compounds.

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The effects of mexiletine on action potential duration and its restitution in guinea pig ventricular muscles.

Cited by 2 publications

References 38 publications

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m‐hydroxymexiletine

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