Differential electrophysiologic effects of chronically administered amiodarone on canine Purkinje fibers versus ventricular muscle

J. Papp, Mikós Németh, Irén Krassói, Lajos Mester, O. Hála, A. Varró

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 μM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. Methods and Results: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) (from 227.8 ± 6.3 ms (n = 20) to 262.3 ± 5.2 ms (n = 21; P <.01), but shortened that of Purkinje fibers from 337.6 ± 9.2 (n = 21) to 308.3 ± 7.1 (n = 19; P <.05). Acute superfusion of 5 μM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 ± 13.6 ms to 281.9 ± 11.9 ms (n = 8; P <.05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 μM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 μM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 μM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 μM dofetilide + 20 μM BaCl2 + 2 mM CsCI) in 5 of 6 experiments and caused strong use-dependent Vmax block with relatively fast onset kinetics (rate constant = 1.23 ± 0.13 AP-1, n = 5) and offset (time constant = 364 ± 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 μM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. Conclusions: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings.

Original languageEnglish
Pages (from-to)287-296
Number of pages10
JournalJournal of Cardiovascular Pharmacology and Therapeutics
Volume1
Issue number4
DOIs
Publication statusPublished - 1996

Fingerprint

Purkinje Fibers
Amiodarone
Canidae
Muscles
Action Potentials
Sotalol
pamidronate
Anti-Arrhythmia Agents
Dogs
Pinacidil
Torsades de Pointes
Potassium Channels
Transcription Factor AP-1
Microelectrodes
Baths
Myocardium

Keywords

  • Amiodarone
  • Arrhythmia
  • Dispersion of repolarization
  • Early afterdepolarization
  • Reverse use dependency
  • Sotalol

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

@article{86428c88a4bd404a8393c75166dc6483,
title = "Differential electrophysiologic effects of chronically administered amiodarone on canine Purkinje fibers versus ventricular muscle",
abstract = "Background: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 μM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. Methods and Results: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) (from 227.8 ± 6.3 ms (n = 20) to 262.3 ± 5.2 ms (n = 21; P <.01), but shortened that of Purkinje fibers from 337.6 ± 9.2 (n = 21) to 308.3 ± 7.1 (n = 19; P <.05). Acute superfusion of 5 μM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 ± 13.6 ms to 281.9 ± 11.9 ms (n = 8; P <.05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 μM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 μM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 μM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 μM dofetilide + 20 μM BaCl2 + 2 mM CsCI) in 5 of 6 experiments and caused strong use-dependent Vmax block with relatively fast onset kinetics (rate constant = 1.23 ± 0.13 AP-1, n = 5) and offset (time constant = 364 ± 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 μM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. Conclusions: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings.",
keywords = "Amiodarone, Arrhythmia, Dispersion of repolarization, Early afterdepolarization, Reverse use dependency, Sotalol",
author = "J. Papp and Mik{\'o}s N{\'e}meth and Ir{\'e}n Krass{\'o}i and Lajos Mester and O. H{\'a}la and A. Varr{\'o}",
year = "1996",
doi = "10.1177/107424849600100404",
language = "English",
volume = "1",
pages = "287--296",
journal = "Journal of Cardiovascular Pharmacology and Therapeutics",
issn = "1074-2484",
publisher = "SAGE Publications Ltd",
number = "4",

}

TY - JOUR

T1 - Differential electrophysiologic effects of chronically administered amiodarone on canine Purkinje fibers versus ventricular muscle

AU - Papp, J.

AU - Németh, Mikós

AU - Krassói, Irén

AU - Mester, Lajos

AU - Hála, O.

AU - Varró, A.

PY - 1996

Y1 - 1996

N2 - Background: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 μM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. Methods and Results: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) (from 227.8 ± 6.3 ms (n = 20) to 262.3 ± 5.2 ms (n = 21; P <.01), but shortened that of Purkinje fibers from 337.6 ± 9.2 (n = 21) to 308.3 ± 7.1 (n = 19; P <.05). Acute superfusion of 5 μM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 ± 13.6 ms to 281.9 ± 11.9 ms (n = 8; P <.05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 μM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 μM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 μM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 μM dofetilide + 20 μM BaCl2 + 2 mM CsCI) in 5 of 6 experiments and caused strong use-dependent Vmax block with relatively fast onset kinetics (rate constant = 1.23 ± 0.13 AP-1, n = 5) and offset (time constant = 364 ± 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 μM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. Conclusions: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings.

AB - Background: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 μM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. Methods and Results: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) (from 227.8 ± 6.3 ms (n = 20) to 262.3 ± 5.2 ms (n = 21; P <.01), but shortened that of Purkinje fibers from 337.6 ± 9.2 (n = 21) to 308.3 ± 7.1 (n = 19; P <.05). Acute superfusion of 5 μM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 ± 13.6 ms to 281.9 ± 11.9 ms (n = 8; P <.05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 μM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 μM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 μM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 μM dofetilide + 20 μM BaCl2 + 2 mM CsCI) in 5 of 6 experiments and caused strong use-dependent Vmax block with relatively fast onset kinetics (rate constant = 1.23 ± 0.13 AP-1, n = 5) and offset (time constant = 364 ± 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 μM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. Conclusions: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings.

KW - Amiodarone

KW - Arrhythmia

KW - Dispersion of repolarization

KW - Early afterdepolarization

KW - Reverse use dependency

KW - Sotalol

UR - http://www.scopus.com/inward/record.url?scp=79956074548&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79956074548&partnerID=8YFLogxK

U2 - 10.1177/107424849600100404

DO - 10.1177/107424849600100404

M3 - Article

AN - SCOPUS:79956074548

VL - 1

SP - 287

EP - 296

JO - Journal of Cardiovascular Pharmacology and Therapeutics

JF - Journal of Cardiovascular Pharmacology and Therapeutics

SN - 1074-2484

IS - 4

ER -