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

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 · kg1 · d1. Plasma and myocardial levels of amiodarone and N-desethylamiodarone increased dose-dependently, reaching therapeutic ranges observed in human. Plasma triiodothyronine levels decreased, whereas reverse triiodothy-ronine 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 Ito,f, IK,slow, and INa 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 i