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
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
SN - 0007-1188
VL - 165
SP - 1457
EP - 1466
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 5
ER -