Published Online
on November 1, 2004

A more recent version of this article appeared on November 9, 2004

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Submitted on June 15, 2004
Revised on August 4, 2004
Accepted on August 19, 2004

Long-Term Amiodarone Administration Remodels Expression of Ion Channel Transcripts in the Mouse Heart

Sabrina Le Bouter MSc, Aziza El Harchi MSc, Céline Marionneau MSc, Chloé Bellocq MSc, Arnaud Chambellan MD, Toon van Veen PhD, Christophe Boixel PhD, Bruno Gavillet MSc, Hugues Abriel MD, PhD, Khai Le Quang MD, Jean-Christophe Chevalier MD, Gilles Lande MD, Jean J. Léger PhD, Flavien Charpentier PhD, Denis Escande MD, PhD, and Sophie Demolombe PhD^*

From l’Institut du thorax--INSERM U533 (S.L.B., A.E.H., C.M., C.B., A.C., K.L.Q., J.C.C., G.L., J.J.L., F.C., D.E., S.D.), Faculté de Médecine, Nantes, France; the Department of Medical Physiology (T.V.V.), University Medical Center, Utrecht, The Netherlands; and Institut de Pharmacologie (C.B., B.G, H.A.), Lausanne, Switzerland.

^* To whom correspondence should be addressed. E-mail: sophie.demolombe{at}nantes.inserm.fr.

Background--The basis for the unique effectiveness of long-term amiodarone treatment on cardiac arrhythmias is incompletely understood. The present study investigated the pharmacogenomic profile of amiodarone on genes encoding ion-channel subunits.

Methods and Results--Adult male mice were treated for 6 weeks with vehicle or oral amiodarone at 30, 90, or 180 mg · kg^-1 · d^-1. Plasma and myocardial levels of amiodarone and N-desethylamiodarone increased dose-dependently, reaching therapeutic ranges observed in human. Plasma triiodothyronine levels decreased, whereas reverse triiodothyronine levels increased in amiodarone-treated animals. In ECG recordings, amiodarone dose-dependently prolonged the RR, PR, QRS, and corrected QT intervals. Specific microarrays containing probes for the complete ion-channel repertoire (IonChips) and real-time reverse transcription-polymerase chain reaction experiments demonstrated that amiodarone induced a dose-dependent remodeling in multiple ion-channel subunits. Genes encoding Na⁺ (SCN4A, SCN5A, SCN1B), connexin (GJA1), Ca²⁺ (CaCNA1C), and K⁺ channels (KCNA5, KCNB1, KCND2) were downregulated. In patch-clamp experiments, lower expression of K⁺ and Na⁺ channel genes was associated with decreased I_to,f, I_K,slow, and I_Na currents. Inversely, other K⁺ channel - and -subunits, such as KCNA4, KCNK1, KCNAB1, and KCNE3, were upregulated.

Conclusions--Long-term amiodarone treatment induces a dose-dependent remodeling of ion-channel expression that is correlated with the cardiac electrophysiologic effects of the drug. This profile cannot be attributed solely to the amiodarone-induced cardiac hypothyroidism syndrome. Thus, in addition to the direct effect of the drug on membrane proteins, part of the therapeutic action of long-term amiodarone treatment is likely related to its effect on ion-channel transcripts.

Key words: antiarrhythmic agents • ion channels • molecular biology • electrophysiology

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