AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, vol.304, no.9, 2013 (SCI-Expanded)
The importance of chronic stimulation of beta-adrenoceptors in the development of cardiac dysfunction is the rationale for the use of beta-blockers in the treatment of heart failure. Nebivolol is a third-generation beta-blocker, which has further properties including stimulation of endothelial nitric oxide synthase and/or beta(3)-adrenoceptors. The aim of this study was to investigate whether nebivolol has additional effects on beta-adrenoceptor-mediated functional responses along with morphologic and molecular determinants of cardiac hypertrophy compared with those of metoprolol, a selective beta(1)-adrenoceptor blocker. Rats infused by isoprenaline (100 mu g.kg(-1).day(-1), 14 days) were randomized into three groups according to the treatment with metoprolol (30 mg.kg(-1).day(-1)), nebivolol (10 mg.kg(-1).day(-1)), 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 Ca2+ 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 mu M), BRL37344 (63% of control at 0.1 mu M), and forskolin (64% of control at 1 mu M) 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 beta-blockers improved the changes in mRNA expressions of beta(1)- and beta(3)-adrenoceptors. Our results suggest that nebivolol partially protects the responsiveness of beta-adrenoceptor signaling and the development of cardiac hypertrophy independent of its beta(1)-adrenoceptor blocking effect.