Different electrophysiological effects of the levo- and dextro-rotatory isomers of mexiletine in isolated rabbit cardiac muscle

Zsolt Gurabi, Bence Patocskai, Balázs Györe, L. Virág, P. Mátyus, J. Papp, A. Varró, István Koncz

Research output: Article

Abstract

Racemic mexiletine is a widely used antiarrhythmic agent that blocks sodium channels. The effects of R-(-) and S-(+) mexiletine stereoisomers on maximum rate of depolarization ( max), conduction time, and repolarization have not yet been investigated in isolated cardiac preparations. We studied the effect of the R-(-) and S-(+) mexiletine on rabbit cardiac action potential parameters by using the conventional microelectrode technique. Both enantiomers at 20 µmol/L of therapeutically and experimentally relevant concentration, significantly depressed the max at fast heart rates (BCLs 300-700 ms). R-(-) mexiletine has more potent inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine significantly inhibited the max of early extrasystoles measured at 70 ms diastolic interval induced by S1-S2 stimuli. R-(-) mexiletine has more pronounced inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine increased significantly the ERP/APD90 ratio. The time constant (τ) of recovery of max was found to be τ = 376.0 ± 77.8 ms for R-(-) mexiletine and τ = 227.1 ± 23.4 ms for S-(+) mexiletine, which indicates a slower offset kinetics for R-(-) mexiletine from sodium channels than that of the S-(+) enantiomer. These data suggest that R-(-) mexiletine might be a more potent antiarrhythmic agent than S-(+) mexiletine.

Original languageEnglish
Pages (from-to)830-836
Number of pages7
JournalCanadian Journal of Physiology and Pharmacology
Volume95
Issue number7
DOIs
Publication statusPublished - jan. 1 2017

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Mexiletine
Myocardium
Rabbits
Sodium Channels
Premature Cardiac Complexes
Stereoisomerism
Microelectrodes

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

Cite this

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title = "Different electrophysiological effects of the levo- and dextro-rotatory isomers of mexiletine in isolated rabbit cardiac muscle",
abstract = "Racemic mexiletine is a widely used antiarrhythmic agent that blocks sodium channels. The effects of R-(-) and S-(+) mexiletine stereoisomers on maximum rate of depolarization ( max), conduction time, and repolarization have not yet been investigated in isolated cardiac preparations. We studied the effect of the R-(-) and S-(+) mexiletine on rabbit cardiac action potential parameters by using the conventional microelectrode technique. Both enantiomers at 20 µmol/L of therapeutically and experimentally relevant concentration, significantly depressed the max at fast heart rates (BCLs 300-700 ms). R-(-) mexiletine has more potent inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine significantly inhibited the max of early extrasystoles measured at 70 ms diastolic interval induced by S1-S2 stimuli. R-(-) mexiletine has more pronounced inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine increased significantly the ERP/APD90 ratio. The time constant (τ) of recovery of max was found to be τ = 376.0 ± 77.8 ms for R-(-) mexiletine and τ = 227.1 ± 23.4 ms for S-(+) mexiletine, which indicates a slower offset kinetics for R-(-) mexiletine from sodium channels than that of the S-(+) enantiomer. These data suggest that R-(-) mexiletine might be a more potent antiarrhythmic agent than S-(+) mexiletine.",
keywords = "Conduction time, Early extrasystoles, Papillary muscles, R-(-) mexiletine, S-(+) mexiletine, ",
author = "Zsolt Gurabi and Bence Patocskai and Bal{\'a}zs Gy{\"o}re and L. Vir{\'a}g and P. M{\'a}tyus and J. Papp and A. Varr{\'o} and Istv{\'a}n Koncz",
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TY - JOUR

T1 - Different electrophysiological effects of the levo- and dextro-rotatory isomers of mexiletine in isolated rabbit cardiac muscle

AU - Gurabi, Zsolt

AU - Patocskai, Bence

AU - Györe, Balázs

AU - Virág, L.

AU - Mátyus, P.

AU - Papp, J.

AU - Varró, A.

AU - Koncz, István

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Racemic mexiletine is a widely used antiarrhythmic agent that blocks sodium channels. The effects of R-(-) and S-(+) mexiletine stereoisomers on maximum rate of depolarization ( max), conduction time, and repolarization have not yet been investigated in isolated cardiac preparations. We studied the effect of the R-(-) and S-(+) mexiletine on rabbit cardiac action potential parameters by using the conventional microelectrode technique. Both enantiomers at 20 µmol/L of therapeutically and experimentally relevant concentration, significantly depressed the max at fast heart rates (BCLs 300-700 ms). R-(-) mexiletine has more potent inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine significantly inhibited the max of early extrasystoles measured at 70 ms diastolic interval induced by S1-S2 stimuli. R-(-) mexiletine has more pronounced inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine increased significantly the ERP/APD90 ratio. The time constant (τ) of recovery of max was found to be τ = 376.0 ± 77.8 ms for R-(-) mexiletine and τ = 227.1 ± 23.4 ms for S-(+) mexiletine, which indicates a slower offset kinetics for R-(-) mexiletine from sodium channels than that of the S-(+) enantiomer. These data suggest that R-(-) mexiletine might be a more potent antiarrhythmic agent than S-(+) mexiletine.

AB - Racemic mexiletine is a widely used antiarrhythmic agent that blocks sodium channels. The effects of R-(-) and S-(+) mexiletine stereoisomers on maximum rate of depolarization ( max), conduction time, and repolarization have not yet been investigated in isolated cardiac preparations. We studied the effect of the R-(-) and S-(+) mexiletine on rabbit cardiac action potential parameters by using the conventional microelectrode technique. Both enantiomers at 20 µmol/L of therapeutically and experimentally relevant concentration, significantly depressed the max at fast heart rates (BCLs 300-700 ms). R-(-) mexiletine has more potent inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine significantly inhibited the max of early extrasystoles measured at 70 ms diastolic interval induced by S1-S2 stimuli. R-(-) mexiletine has more pronounced inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine increased significantly the ERP/APD90 ratio. The time constant (τ) of recovery of max was found to be τ = 376.0 ± 77.8 ms for R-(-) mexiletine and τ = 227.1 ± 23.4 ms for S-(+) mexiletine, which indicates a slower offset kinetics for R-(-) mexiletine from sodium channels than that of the S-(+) enantiomer. These data suggest that R-(-) mexiletine might be a more potent antiarrhythmic agent than S-(+) mexiletine.

KW - Conduction time

KW - Early extrasystoles

KW - Papillary muscles

KW - R-(-) mexiletine

KW - S-(+) mexiletine

KW - 

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