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.


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.
Le Bouter
Sabrina
S
Institut du thorax, INSERM U533, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes Cedex, France.
El Harchi
Aziza
A
Marionneau
Céline
C
Bellocq
Chloé
C
Chambellan
Arnaud
A
van Veen
Toon
T
Boixel
Christophe
C
Gavillet
Bruno
B
Abriel
Hugues
H
Le Quang
Khai
K
Chevalier
Jean-Christophe
JC
Lande
Gilles
G
Léger
Jean J
JJ
Charpentier
Flavien
F
Escande
Denis
D
Demolombe
Sophie
S
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
D000889:Anti-Arrhythmia Agents; D007473:Ion Channels; D012333:RNA, Messenger; D014284:Triiodothyronine; D014285:Triiodothyronine, Reverse; C036116:desethylamiodarone; D000638:Amiodarone