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J Am Coll Cardiol ; 57(5): 601-11, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-21272752

ABSTRACT

OBJECTIVES: The aim of this study was to investigate whether nebivolol has added effects on left ventricular (LV) dysfunction and remodeling early after myocardial infarction (MI) beyond its ß1-receptor-blocking properties. BACKGROUND: Nebivolol is a third-generation selective ß1-adrenoreceptor antagonist that stimulates endothelial cell nitric oxide (NO) production and prevents vascular reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. Both endothelial NO synthase-derived NO production and NADPH oxidase activation are critical modulators of LV dysfunction early after MI. METHODS: Mice with extensive anterior MI (n = 90) were randomized to treatment with nebivolol (10 mg/kg/day), metoprolol-succinate (20 mg/kg/day), or placebo for 30 days starting on day 1 after surgery. RESULTS: Infarct size was similar among the groups. Both ß1-adrenergic receptor antagonists caused a similar decrease in heart rate. Nebivolol therapy improved endothelium-dependent vasorelaxation and increased early endothelial progenitor cells 4 weeks after MI compared with metoprolol and placebo. Nebivolol, but not metoprolol, inhibited cardiac NADPH oxidase activation after MI, as detected by electron spin resonance spectroscopy analysis. Importantly, nebivolol, but not metoprolol, improved LV dysfunction 4 weeks after MI (LV ejection fraction: nebivolol vs. metoprolol vs. placebo: 32 ± 4% vs. 17 ± 6% vs. 19 ± 4%; nebivolol vs. metoprolol: p < 0.05) and was associated with improved survival 4 weeks post-MI compared with placebo. Nebivolol had a significantly more pronounced inhibitory effect on cardiomyocyte hypertrophy after MI compared with metoprolol. CONCLUSIONS: Nebivolol improves LV dysfunction and survival early after MI likely beyond the effects provided by conventional ß1-receptor blockade. Nebivolol induced effects on NO-mediated endothelial function, early endothelial progenitor cells and inhibition of myocardial NADPH oxidase likely contribute to these beneficial effects of nebivolol early after MI.


Subject(s)
Adrenergic beta-1 Receptor Antagonists/therapeutic use , Benzopyrans/therapeutic use , Ethanolamines/therapeutic use , Hematopoietic Stem Cells/physiology , Myocardial Infarction/drug therapy , Neovascularization, Physiologic/physiology , Ventricular Dysfunction, Left/drug therapy , Animals , Cells, Cultured , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiology , Hematopoietic Stem Cells/drug effects , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardial Infarction/complications , Myocardial Infarction/physiopathology , Nebivolol , Neovascularization, Physiologic/drug effects , Random Allocation , Rats , Time Factors , Ventricular Dysfunction, Left/etiology , Ventricular Dysfunction, Left/physiopathology
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