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

Julius G.Y. Papp, Mikós Németh, Irén Krassói, Lajos Mester, Ottó Hála, András Varró

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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 - Dec 1 1996

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Keywords

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

ASJC Scopus subject areas

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

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