Document Detail


Ivabradine reduces heart rate while preserving metabolic fluxes and energy status of healthy normoxic working hearts.
MedLine Citation:
PMID:  21257916     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Heart rate reduction (HRR) is an important target in the management of patients with chronic stable angina. Most available drugs for HRR, such as β-blockers, have adverse effects, including on cardiac energy substrate metabolism, a well-recognized determinant of cardiac homeostasis. This study aimed at 1) testing whether HRR by ivabradine (IVA) alters substrate metabolism in the healthy normoxic working heart and 2) comparing the effect of IVA with that of the β-blocker metoprolol (METO). This was assessed using our well-established model of ex vivo mouse heart perfusion in the working mode, which enables concomitant evaluation of myocardial contractility and metabolic fluxes using (13)C-labeled substrates. Hearts were perfused in the absence (controls; n = 10) or presence of IVA (n = 10, 3 μM) with or without atrial pacing to abolish HRR in the IVA group. IVA significantly reduced HR (35 ± 5%) and increased stroke volume (39 ± 9%) while maintaining similar cardiac output, contractility, power, and efficiency. Effects of IVA on HR and stroke volume were reversed by atrial pacing. At the metabolic level, IVA did not impact on substrate selection to citrate formation, rates of glycolysis, or tissue levels of high-energy phosphates. In contrast, METO, at concentrations up to 40 μM, decreased markedly cardiac function (flow: 25 ± 6%; stroke volume: 30 ± 10%; contractility: 31 ± 9%) as well as glycolysis (2.9-fold) but marginally affected HR. Collectively, these results demonstrate that IVA selectively reduces HR while preserving energy substrate metabolism of normoxic healthy working mouse hearts perfused ex vivo, a model that mimics to some extent the denervated transplanted heart. Our results provide the impetus for testing selective HRR by IVA on cardiac substrate metabolism in pathological models.
Authors:
Benjamin Lauzier; Fanny Vaillant; Roselle Gélinas; Bertrand Bouchard; Roger Brownsey; Eric Thorin; Jean-Claude Tardif; Christine Des Rosiers
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-01-21
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  300     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-03-03     Completed Date:  2011-05-26     Revised Date:  2014-03-03    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H845-52     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-Antagonists / pharmacology
Animals
Benzazepines / pharmacology*
Cardiac Output / drug effects
Energy Metabolism / drug effects
Heart / drug effects*
Heart Rate / drug effects*
Male
Metoprolol / pharmacology
Mice
Mice, Inbred C57BL
Myocardium / metabolism*
Oxygen Consumption / drug effects
Grant Support
ID/Acronym/Agency:
87388-1//Canadian Institutes of Health Research; 89733-1//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Adrenergic beta-Antagonists; 0/Benzazepines; 155974-00-8/ivabradine; GEB06NHM23/Metoprolol
Comments/Corrections

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