Nebivolol prevents desensitization of beta-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond beta(1)-adrenoceptor blockage

Ozakca I., Arioglu-Inan E., ESFAHANI H., Altan V. M., BALLIGAND J., Kayki-Mutlu G., ...More

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, vol.304, no.9, 2013 (SCI-Expanded) identifier identifier identifier


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, 14 days) were randomized into three groups according to the treatment with metoprolol (30, nebivolol (10, 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.