Article

Long-term amiodarone administration remodels expression of ion channel transcripts in the mouse heart.

Institut du thorax, INSERM U533, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes Cedex, France.
Circulation (Impact Factor: 15.2). 12/2004; 110(19):3028-35. DOI: 10.1161/01.CIR.0000147187.78162.AC
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
92 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Voltage-gated potassium channels (VGPCs) are among the most complex families of ion channels. VGPCs are distributed widely among species but their biological roles remain unclear. In this study, the evolution of VGPCs and the functions of ancestral families are determined according to phylogenetic studies. We downloaded 127 genomic data of alpha subunits and 38 genomic data of beta subunits including those from human, rat, mice, Drosophila and Puccinellia tenuiflora. The genetic neighborhood of subfamily genes was determined by neighbor-joining, minimum evolution, maximum parsimony, and Bayes methods. Data was presented as phylogenetic trees. We also detected positive selection sites by site model. New insights into the evolutionary history of the VGPC family are provided. Our assumptions are as follows: (a) KCNH subfamily is likely the most original subfamily in alpha subunit; (b) VGPCs are related to neural and cardiac systems at the earliest time; (c) KCNA4 and KCNF1 may be as ancestors; (d) abnormality in one gene may cause both cardiac and neural diseases; and (e) abnormalities in KCNH6 and KCNQ7 are more likely to cause cardiac diseases.
    Journal of Molecular Neuroscience 12/2013; · 2.89 Impact Factor
  • Journal of Molecular and Cellular Cardiology 07/2005; 38(6):965-8. · 5.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Amiodarone-induced pulmonary toxicity is a serious side-effect, but the underlying molecular mechanisms remain unclear. We examined phospholipidosis and apoptosis in rat alveolar epithelial cells after medium-term oral amiodarone treatment. Amiodarone (30 mg/kg daily, a dosage corresponding to that used clinically) or vehicle was administered by gavage in 33 Wistar rats for two weeks. Apoptosis was assessed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labelling (TUNEL) and the expression of apoptosis- and phospholipidosis-related proteins was measured by immunohistochemistry. Amiodarone decreased phospholipase-C-γ1 and increased phosphatidylinositol-(4,5)-bisphosphate, resulting in phospholipidosis, evidenced by the appearance of intracellular inclusion bodies with a multi-lamellated interior. Amiodarone exerted two opposite effects on apoptosis; compared to controls, the expression of activated-caspase-8 was higher in treated rats, while the expression of apoptosis inhibitors survivin, Bcl-2 and c-Flip was lower. On the other hand, the expression of activated-caspase-3 was lower after treatment. Overall, amiodarone attenuated apoptosis, evidenced by fewer TUNEL-positive cells. Medium-term oral amiodarone administration induced phospholipidosis in rat alveolar epithelial cells. Although such treatment decreased anti-apoptotic proteins, apoptosis was attenuated via a decrease in the caspase-3 pathway. These findings improve current understanding on the mechanisms underlying amiodarone-induced pulmonary toxicity.
    Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 12/2010; 61(6):671-7. · 2.48 Impact Factor

Full-text

View
1 Download
Available from