Chronic heart rate reduction remodels ion channel transcripts in the mouse sinoatrial node but not in the ventricle.
We investigated the effects of chronic and moderate heart rate (HR) reduction on ion channel expression in the mouse sinoatrial node (SAN) and ventricle. Ten-week-old male C57BL/6 mice were treated twice daily with either vehicle or ivabradine at 5 mg/kg given orally during 3 wk. The effects of HR reduction on cardiac electrical activity were investigated in anesthetized mice with serial ECGs and in freely moving mice with telemetric recordings. With the use of high-throughput real-time RT-PCR, the expression of 68 ion channel subunits was evaluated in the SAN and ventricle at the end of the treatment period. In conscious mice, ivabradine induced a mean 16% HR reduction over a 24-h period that was sustained over the 3-wk administration. Other ECG parameters were not modified. Two-way hierarchical clustering analysis of gene expression revealed a separation of ventricles from SANs but no discrimination between treated and untreated ventricles, indicating that HR reduction per se induced limited remodeling in this tissue. In contrast, SAN samples clustered in two groups depending on the treatment. In the SAN from ivabradine-treated mice, the expression of nine ion channel subunits, including Navbeta1 (-25%), Cav3.1 (-29%), Kir6.1 (-28%), Kvbeta2 (-41%), and Kvbeta3 (-30%), was significantly decreased. Eight genes were significantly upregulated, including K+ channel alpha-subunits (Kv1.1, +30%; Kir2.1, +29%; Kir3.1, +41%), hyperpolarization-activated cation channels (HCN2, +24%; HCN4, +52%), and connexin 43 (+26%). We conclude that reducing HR induces a complex remodeling of ion channel expression in the SAN but has little impact on ion channel transcripts in the ventricle.
Leoni
Anne-Laure
AL
Institut National de la Santé et de la Recherche Médicale (INSERM), U533, l'Institut du Thorax, Nantes, France.
Marionneau
Céline
C
Demolombe
Sophie
S
Le Bouter
Sabrina
S
Mangoni
Matteo E
ME
Escande
Denis
D
Charpentier
Flavien
F
D000818:Animals; D001552:Benzazepines / Q000097:blood / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D007473:Ion Channels / Q000235:genetics*; D000077550:Ivabradine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012849:Sinoatrial Node / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*; D016276:Ventricular Function
D001552:Benzazepines; D007473:Ion Channels; C413689:S 18982; D000077550:Ivabradine