Le Bouter, S. et al. Long-term amiodarone administration remodels expression of ion channel transcripts in the mouse heart. Circulation 110, 3028-3035

Department of Medical Physiology, University Medical Center Utrecht, Utrecht, Utrecht, Netherlands
Circulation (Impact Factor: 14.43). 12/2004; 110(19):3028-35. DOI: 10.1161/01.CIR.0000147187.78162.AC
Source: PubMed


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.
Adult male mice were treated for 6 weeks with vehicle or oral amiodarone at 30, 90, or 180 mg x kg(-1) x 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 alpha- and beta-subunits, such as KCNA4, KCNK1, KCNAB1, and KCNE3, were upregulated.
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.

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    • "Since acute and chronic amiodarone administration results in plasma levels of approximately 0.16 to 10 µM [36], inhibitory effects of amiodarone on SK2 channels can be seen with doses used in the clinical setting. Le Bouter et al. [37] demonstrated that mice fed with clinically used doses of amiodarone for 6 weeks showed significant increase of SK2 mRNA levels in their total heart tissue. Although IKAS were not determined in that study, it is reasonable to hypothesize that the transcripts could have increased as a compensatory mechanism to the inhibition of SK2 channels with chronic amiodarone therapy. "
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    ABSTRACT: Apamin sensitive potassium current (I KAS), carried by the type 2 small conductance Ca(2+)-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles. To test the hypothesis that amiodarone inhibits I KAS in human embryonic kidney 293 (HEK-293) cells. We used the patch-clamp technique to study I KAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration. Amiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67±0.25 µM with 1 µM intrapipette Ca(2+)). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6±3.1% of IKAS induced with 1 µM intrapipette Ca(2+) (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca(2+)-dependent: 30 µM amiodarone inhibited 81.5±1.9% of I KAS induced with 1 µM Ca(2+) (n = 4), and 16.4±4.9% with 250 nM Ca(2+) (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca(2+) dependent inhibition of I KAS. Both amiodarone and desethylamiodarone inhibit I KAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca(2+) concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles.
    Full-text · Article · Jul 2013 · PLoS ONE
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    • "As a final remark, however, it should be mentioned that not all pharmacological actions of amiodarone can be explained from the induction of a local hypothyroid-like condition in the heart. Evaluating the complete ion channel repertoire by real time PCR in hearts of mice treated with amiodarone, it became obvious that changes in transcript levels sometimes were similar to those seen in hypothyroid mice, but very frequently were completely different from the hypothyroid phenotype [26, 27]. Nevertheless, downregulation of the effect of thyroid hormone in the heart results in what has been called “cardiac metamorphosis” [28], which by decreasing energy demands and increasing energy availability might be advantageous with potential therapeutic implications. "
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    ABSTRACT: This review evaluates the hypothesis that the cardiac effects of amiodarone can be explained-at least partly-by the induction of a local 'hypothyroid-like condition' in the heart. Evidence supporting the hypothesis comprises the observation that amiodarone exerts an inhibitory effect on the binding of T3 to thyroid hormone receptors (TR) alpha-1 and beta-1 in vitro, and on the expression of particular T3-dependent genes in vivo. In the heart, amiodarone decreases heart rate and alpha myosin heavy chain expression (mediated via TR alpha-1), and increases sarcoplasmic reticulum calcium-activated ATPase and beta myosin heavy chain expression (mediated via TR beta-1). Recent data show a significant similarity in expression profiles of 8,435 genes in the heart of hypothyroid and amiodarone-treated animals, although similarities do not always exist in transcripts of ion channel genes. Induction of a hypothyroid cardiac phenotype by amiodarone may be advantageous by decreasing energy demands and increasing energy availability.
    Preview · Article · Jan 2009 · Heart Failure Reviews
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    • "When choosing amiodarone for this initial work, our reasoning was that if the drug were found not to affect ion channel expression in the heart, then there would be little chance that another drug does. Adult mice from the same inbred strain (C57BL/6) as used for the thyroid hormone study, were treated for 6 weeks with oral amiodarone [15]. Because mice poorly absorb amiodarone , very high daily doses were required to obtain plasma concentrations of the parent compound and of its main metabolite N-desethylamiodarone (DEA) compatible with therapeutic levels obtained in patients. "
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    ABSTRACT: Ion channels are an ensemble of specialized membrane proteins that act in concert to create and modulate the electrical activity of many excitable cells, including cardiac myocytes. Following completion of the sequencing of various genomes, including that of the human, the complete repertoire of ion channel genes has been elucidated for different species. How transcripts issued from this gene collection are expressed and modulated in relation to variable physiological and pathological situations is the subject of functional or physiological genomics. Specialized microarrays (IonChips) comprising probes for the ensemble of ion channel and regulatory genes were developed as an alternative to whole-genome DNA chips. Physiological genomics of cardiac ion channel genes is a growing field that, in combination with genetics, should markedly increase our comprehension of the molecular mechanisms leading to arrhythmias.
    Full-text · Article · Sep 2005 · Cardiovascular Research
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