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(Circulation. 2004;110:3028-3035.)
© 2004 American Heart Association, Inc.

Arrhythmia/Electrophysiology

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; 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.

Correspondence to Sophie Demolombe, INSERM U533, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes Cedex, France. E-mail sophie.demolombe{at}nantes.inserm.fr

Received June 15, 2004; revision received August 4, 2004; accepted August 19, 2004.

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 ß-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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