Nebivolol prevents desensitization of ß-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond ß1-adrenoceptor blockage.

ABSTRACT

The importance of chronic stimulation of ß-adrenoceptors in the development of cardiac dysfunction is the rationale for the use of ß-blockers in the treatment of heart failure. Nebivolol is a third-generation ß-blocker, which has further properties including stimulation of endothelial nitric oxide synthase and/or ß3-adrenoceptors. The aim of this study was to investigate whether nebivolol has additional effects on ß-adrenoceptor-mediated functional responses along with morphologic and molecular determinants of cardiac hypertrophy compared with those of metoprolol, a selective ß1-adrenoceptor blocker. Rats infused by isoprenaline (100 µg·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 Ca(2+) 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 ß-blockers improved the changes in mRNA expressions of ß1- and ß3-adrenoceptors. Our results suggest that nebivolol partially protects the responsiveness of ß-adrenoceptor signaling and the development of cardiac hypertrophy independent of its ß1-adrenoceptor blocking effect.