title: Long-term amiodarone administration remodels expression of ion channel transcripts in the mouse heart.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Institut du thorax, INSERM U533, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes Cedex, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Le Bouter
authors.forename: Aziza
authors.initials: A
authors.lastname: El Harchi
authors.forename: Céline
authors.initials: C
authors.lastname: Marionneau
authors.forename: Chloé
authors.initials: C
authors.lastname: Bellocq
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chambellan
authors.forename: Toon
authors.initials: T
authors.lastname: van Veen
authors.forename: Christophe
authors.initials: C
authors.lastname: Boixel
authors.forename: Bruno
authors.initials: B
authors.lastname: Gavillet
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.forename: Khai
authors.initials: K
authors.lastname: Le Quang
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Chevalier
authors.forename: Gilles
authors.initials: G
authors.lastname: Lande
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Léger
authors.forename: Flavien
authors.initials: F
authors.lastname: Charpentier
authors.forename: Denis
authors.initials: D
authors.lastname: Escande
authors.forename: Sophie
authors.initials: S
authors.lastname: Demolombe
mesh_terms: D000638:Amiodarone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000097:blood; D014285:Triiodothyronine, Reverse / Q000097:blood
chemical_list: D000889:Anti-Arrhythmia Agents; D007473:Ion Channels; D012333:RNA, Messenger; D014284:Triiodothyronine; D014285:Triiodothyronine, Reverse; C036116:desethylamiodarone; D000638:Amiodarone