title: Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression.
abstract: OBJECTIVE
  Recent clinical data suggest beneficial effects of ivabradine, a specific heart rate (HR)-lowering drug, in heart failure patients. However, the mechanisms responsible for these effects have not been completely clarified. Thus, we investigated functional/molecular changes in I(f), the specific target of ivabradine, in the failing atrial and ventricular myocytes where this current is up-regulated as a consequence of maladaptive remodelling.
  
  
  METHODS
  We investigated the effects of ivabradine (IVA; 10 mg·kg(-1) ·day(-1) for 90 days) on electrophysiological remodelling in left atrial (LA), left ventricular (LV) and right ventricular (RV) myocytes from post-mycardial infarcted (MI) rats, with sham-operated (sham or sham + IVA) rats as controls. I(f) current was measured by patch-clamp; hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms and microRNA (miRNA-1 and miR-133) expression were evaluated by reverse transcription quantitative PCR.
  
  
  RESULTS
  Maximal specific conductance of I(f) was increased in MI, versus sham, in LV (P < 0.01) and LA myocytes (P < 0.05). Ivabradine reduced HR in both MI and sham rats (P < 0.05). In MI + IVA, I(f) overexpression was attenuated and HCN4 transcription reduced by 66% and 54% in LV and RV tissue, respectively, versus MI rats (all P < 0.05). miR-1 and miR-133, which modulate post-transcriptional expression of HCN2 and HCN4 genes, were significantly increased in myocytes from MI + IVA.
  
  
  CONCLUSIONS
  The beneficial effects of ivabradine may be due to the reversal of electrophysiological cardiac remodelling in post-MI rats by reduction of functional overexpression of HCN channels. This is attributable to transcriptional and post-transcriptional mechanisms.
authors.affiliation: Center of Molecular Medicine (C.I.M.M.B.A.), Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Suffredini
authors.forename: F
authors.initials: F
authors.lastname: Stillitano
authors.forename: L
authors.initials: L
authors.lastname: Comini
authors.forename: M
authors.initials: M
authors.lastname: Bouly
authors.forename: S
authors.initials: S
authors.lastname: Brogioni
authors.forename: C
authors.initials: C
authors.lastname: Ceconi
authors.forename: R
authors.initials: R
authors.lastname: Ferrari
authors.forename: A
authors.initials: A
authors.lastname: Mugelli
authors.forename: E
authors.initials: E
authors.lastname: Cerbai
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D000077550:Ivabradine; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics
chemical_list: D001552:Benzazepines; D054815:Cyclic Nucleotide-Gated Cation Channels; C513836:HCN4 protein, rat; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; C542191:MIRN1 microRNA, rat; C549446:MIRN133 microRNA, rat; D035683:MicroRNAs; D015221:Potassium Channels; D000077550:Ivabradine