Inhibition of cardiac Kv4.3 (Ito) channel isoforms by class I antiarrhythmic drugs lidocaine and mexiletine

Rahm, Ann‐Kathrin; Müller, Mara Elena; Gramlich, Dominik; Lugenbiel, Patrick; Uludag, Ecem; Rivinius, Rasmus; Ullrich, Nina D.; Schmack, Bastian; Ruhparwar, Arjang; Heimberger, Tanja; Weis, Tanja; Kretzler, Matthias; Katus, Hugo A.; Thomas, Dierk

doi:10.1016/j.ejphar.2020.173159

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…Further, mexiletine reduced the time constant of recovery from inactivation and the window current as well, which have not been shown before. 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).…”

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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“…In humans, two isoforms of K v 4.3, K v 4.3-S and K v 4.3-L have been described, and isoform-specific remodeling was detected in failing hearts due to DCM, with increased K v 4.3-L and reduced K v 4.3-S mRNA transcript levels [33]. As this finding was also confirmed for ICM, it may be a common feature of remodeling in cardiomyopathies [34]. Ventricular cardiomyocytes exhibit an inward rectifying potassium current (I K1 ) that contributes to phase 3 repolarization of ventricular action potentials and to the maintenance of the negative resting membrane potential.…”

Section: Apd Changesmentioning

confidence: 59%

Electrical Ventricular Remodeling in Dilated Cardiomyopathy

Mages

Gampp

Syren

et al. 2021

Cells

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Ventricular arrhythmias contribute significantly to morbidity and mortality in patients with heart failure (HF). Pathomechanisms underlying arrhythmogenicity in patients with structural heart disease and impaired cardiac function include myocardial fibrosis and the remodeling of ion channels, affecting electrophysiologic properties of ventricular cardiomyocytes. The dysregulation of ion channel expression has been associated with cardiomyopathy and with the development of arrhythmias. However, the underlying molecular signaling pathways are increasingly recognized. This review summarizes clinical and cellular electrophysiologic characteristics observed in dilated cardiomyopathy (DCM) with ionic and structural alterations at the ventricular level. Furthermore, potential translational strategies and therapeutic options are highlighted.

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“…In addition, other mechanisms beyond direct channel binding were not assessed and need to be investigated in future studies, and cardiac cell lines must be modified to assess isoform specific K v 4.3 characteristics [ 31 , 32 ]. In contrast to human ventricular cardiomyocytes in heart failure [ 4 , 33 ], differential K v 4.3 isoform expression and remodeling has not been assessed in cardiac cell lines so far. Finally, clinical consequences and the potential differential effect on arrhythmias would have to be investigated in clinical trials with head-to head comparisons.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of the Betablockers Carvedilol, Metoprolol and Bisoprolol on Cardiac Kv4.3 (Ito) Channel Isoforms

Rahm,

Hackbarth,

Müller

et al. 2023

IJMS

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Cardiac Kv4.3 channels contribute to the transient outward K+ current, Ito, during early repolarization of the cardiac action potential. Two different isoforms of Kv4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both Kv4.3 isoforms to explore their potential for isoform-specific therapy. Kv4.3 isoforms were expressed in Xenopus laevis oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two Kv4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked Kv4.3 L by 77 ± 2% and Kv4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (Kv4.3 L) and 35 ± 4% (Kv4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in Kv4.3 protein expression. Carvedilol inhibited Kv4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on Kv4.3. Blockade of repolarizing Kv4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.

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Inhibition of cardiac Kv4.3 (Ito) channel isoforms by class I antiarrhythmic drugs lidocaine and mexiletine

Cited by 5 publications

References 39 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

Electrical Ventricular Remodeling in Dilated Cardiomyopathy

Differential Effects of the Betablockers Carvedilol, Metoprolol and Bisoprolol on Cardiac Kv4.3 (Ito) Channel Isoforms

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