Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β1-adrenoceptor blockage

Am J Physiol Heart Circ Physiol. 2013 May;304(9):H1267-76. doi: 10.1152/ajpheart.00352.2012. Epub 2013 Mar 1.

Abstract

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(-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 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.

Keywords: adrenergic stimulation; inotropy; nebivolol; β-adrenoceptors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Antagonists / pharmacology*
  • Adrenergic beta-1 Receptor Antagonists / therapeutic use
  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Atrial Natriuretic Factor / genetics
  • Atrial Natriuretic Factor / metabolism
  • Benzopyrans / pharmacology*
  • Benzopyrans / therapeutic use
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cardiomegaly / metabolism
  • Cardiomegaly / prevention & control*
  • Coronary Circulation / drug effects
  • Ethanolamines / pharmacology*
  • Ethanolamines / therapeutic use
  • Heart Rate / drug effects
  • In Vitro Techniques
  • Isoproterenol / pharmacology
  • Male
  • Metoprolol / pharmacology
  • Metoprolol / therapeutic use
  • Nebivolol
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta / genetics
  • Receptors, Adrenergic, beta / metabolism*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Transcription, Genetic / drug effects

Substances

  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-Agonists
  • Benzopyrans
  • Calcium-Binding Proteins
  • Ethanolamines
  • RNA, Messenger
  • Receptors, Adrenergic, beta
  • phospholamban
  • Nebivolol
  • Atrial Natriuretic Factor
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Metoprolol
  • Isoproterenol