Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression

S. Suffredini, F. Stillitano, L. Comini, M. Bouly, S. Brogioni, C. Ceconi, R. Ferrari, A. Mugelli, E. Cerbai

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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. CONCLUSION AND IMPLICATION 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.

Original languageEnglish
Pages (from-to)1457-1466
Number of pages10
JournalBritish Journal of Pharmacology
Volume165
Issue number5
DOIs
Publication statusPublished - Mar 2012

Keywords

  • electrophysiological remodelling
  • f-current
  • heart rate
  • hyperpolarization-activated cyclic nucleotide-gated channels
  • ivabradine
  • post-MI rat

ASJC Scopus subject areas

  • Pharmacology

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