Nebivolol prevents desensitization of [Beta]-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond [Beta]^sub 1^-adrenoceptor blockage

• Published in: American journal of physiology. Heart and circulatory physiology 2013-05, Vol.304 (9), p.H1267
• Main Authors: Ozakca, Isil, Arioglu-Inan, Ebru, Esfahani, Hrag, Altan, V Melih, Balligand, Jean-Luc, Kayki-Mutlu, Gizem, Ozcelikay, A Tanju
• Format: Article
• Language: English
• Subjects: Cardiac arrhythmia; Heart failure; Nitric oxide; Physiology; Ribonucleic acid; RNA; Signal transduction
• ISSN: 0363-6135; 1522-1539

The importance of chronic stimulation of β-adrenoceptors in the development of cardiac dysfunction is the rationale for the use of β-blockers in the treatment of heart failure. Nebivolol is a third-generation β-blocker, which has further properties including stimulation of endothelial nitric oxide synthase and/or β3-adrenoceptors. The aim of this study was to investigate whether nebivolol has additional effects on β-adrenoceptor-mediated functional responses along with morphologic and molecular determinants of cardiac hypertrophy compared with those of metoprolol, a selective β1-adrenoceptor blocker. Rats infused by isoprenaline (100 μg-kg...-day..., 14 days) were randomized into three groups according to the treatment with metoprolol (30 mg-kg...-day...), nebivolol (10 mg-kg...-day...), or placebo for 13 days starting on day 1 after implantation of minipump. Both metoprolol and nebivolol caused a similar reduction on heart rate. Nebivolol mediated a significant improvement on cardiac mass, coronary flow, mRNA expression levels of sarcoplasmic reticulum Ca... ATPase (SERCA2a) and atrial natriuretic peptide and phospholamban (PLN)/SERCA2a and phospho-PLN/PLN ratio compared with metoprolol and placebo. Nebivolol prevented the detrimental effects of isoprenaline infusion on isoprenaline (68% of control at 30 μM), BRL37344 (63% of control at 0.1 μM), and forskolin (64% of control at 1 μM) responses compared with metoprolol (isoprenaline, 34% of control; BRL37344, no response; forskolin, 26% of control) and placebo (isoprenaline, 33% of control; BRL37344, 28% of control; forskolin, 12% of control). Both β-blockers improved the changes in mRNA expressions of β1- and β3-adrenoceptors. Our results suggest that nebivolol partially protects the responsiveness of β-adrenoceptor signaling and the development of cardiac hypertrophy independent of its β1-adrenoceptor blocking effect. (ProQuest: ... denotes formulae/symbols omitted.)