title: Nebivolol prevents desensitization of β-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond β1-adrenoceptor blockage.
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.
authors: Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara, Turkey. ozakca@ankara.edu.tr
authors: Isil
authors: I
authors: Ozakca
authors: Ebru
authors: E
authors: Arioglu-Inan
authors: Hrag
authors: H
authors: Esfahani
authors: V Melih
authors: VM
authors: Altan
authors: Jean-Luc
authors: JL
authors: Balligand
authors: Gizem
authors: G
authors: Kayki-Mutlu
authors: A Tanju
authors: AT
authors: Ozcelikay
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000517:prevention & control*; D003326:Coronary Circulation / Q000187:drug effects; D004983:Ethanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use; D000068577:Nebivolol; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000099211:Phospholamban
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D009320:Atrial Natriuretic Factor; D001578:Benzopyrans; D002135:Calcium-Binding Proteins; D004983:Ethanolamines; D007545:Isoproterenol; D008790:Metoprolol; D000068577:Nebivolol; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
keywords: adrenergic stimulation; inotropy; nebivolol; β-adrenoceptors