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 journalArticle

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

Fingerprint

ivabradine
Muscle Cells
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
MicroRNAs
Heart Rate
Therapeutics
Reverse Transcription
Protein Isoforms
Heart Failure
Polymerase Chain Reaction

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression. / Suffredini, S.; Stillitano, F.; Comini, L.; Bouly, M.; Brogioni, S.; Ceconi, C.; Ferrari, R.; Mugelli, A.; Cerbai, E.

In: British Journal of Pharmacology, Vol. 165, No. 5, 03.2012, p. 1457-1466.

Research output: Contribution to journalArticle

Suffredini, S, Stillitano, F, Comini, L, Bouly, M, Brogioni, S, Ceconi, C, Ferrari, R, Mugelli, A & Cerbai, E 2012, 'Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression', British Journal of Pharmacology, vol. 165, no. 5, pp. 1457-1466. https://doi.org/10.1111/j.1476-5381.2011.01627.x
Suffredini, S. ; Stillitano, F. ; Comini, L. ; Bouly, M. ; Brogioni, S. ; Ceconi, C. ; Ferrari, R. ; Mugelli, A. ; Cerbai, E. / Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression. In: British Journal of Pharmacology. 2012 ; Vol. 165, No. 5. pp. 1457-1466.
@article{fdba968b7ebe4e03adbf2c5319e02824,
title = "Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression",
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.",
keywords = "electrophysiological remodelling, f-current, heart rate, hyperpolarization-activated cyclic nucleotide-gated channels, ivabradine, post-MI rat",
author = "S. Suffredini and F. Stillitano and L. Comini and M. Bouly and S. Brogioni and C. Ceconi and R. Ferrari and A. Mugelli and E. Cerbai",
year = "2012",
month = "3",
doi = "10.1111/j.1476-5381.2011.01627.x",
language = "English",
volume = "165",
pages = "1457--1466",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression

AU - Suffredini, S.

AU - Stillitano, F.

AU - Comini, L.

AU - Bouly, M.

AU - Brogioni, S.

AU - Ceconi, C.

AU - Ferrari, R.

AU - Mugelli, A.

AU - Cerbai, E.

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

KW - electrophysiological remodelling

KW - f-current

KW - heart rate

KW - hyperpolarization-activated cyclic nucleotide-gated channels

KW - ivabradine

KW - post-MI rat

UR - http://www.scopus.com/inward/record.url?scp=84857072536&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857072536&partnerID=8YFLogxK

U2 - 10.1111/j.1476-5381.2011.01627.x

DO - 10.1111/j.1476-5381.2011.01627.x

M3 - Article

C2 - 21838751

AN - SCOPUS:84857072536

VL - 165

SP - 1457

EP - 1466

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 5

ER -