Upregulation of β 3 -Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium
- 27 March 2001
- journal article
- other
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 103 (12), 1649-1655
- https://doi.org/10.1161/01.cir.103.12.1649
Abstract
Background —Contrary to β 1 - and β 2 -adrenoceptors, β 3 -adrenoceptors mediate a negative inotropic effect in human ventricular muscle. To assess their functional role in heart failure, our purpose was to compare the expression and contractile effect of β 3 -adrenoceptors in nonfailing and failing human hearts. Methods and Results —We analyzed left ventricular samples from 29 failing (16 ischemic and 13 dilated cardiomyopathic) hearts (ejection fraction 18.6±2%) and 25 nonfailing (including 12 innervated) explanted hearts (ejection fraction 64.2±3%). β 3 -Adrenoceptor proteins were identified by immunohistochemistry in ventricular cardiomyocytes from nonfailing and failing hearts. Contrary to β 1 -adrenoceptor mRNA, Western blot analysis of β 3 -adrenoceptor proteins showed a 2- to 3-fold increase in failing compared with nonfailing hearts. A similar increase was observed for Gα i-2 proteins that couple β 3 -adrenoceptors to their negative inotropic effect. Contractile tension was measured in electrically stimulated myocardial samples ex vivo. In failing hearts, the positive inotropic effect of the nonspecific amine isoprenaline was reduced by 75% compared with that observed in nonfailing hearts. By contrast, the negative inotropic effect of β 3 -preferential agonists was only mildly reduced. Conclusions —Opposite changes occur in β 1 - and β 3 -adrenoceptor abundance in the failing left ventricle, with an imbalance between their inotropic influences that may underlie the functional degradation of the human failing heart.Keywords
This publication has 20 references indexed in Scilit:
- β3-adrenoceptor deficiency blocks nitric oxide–dependent inhibition of myocardial contractilityJCI Insight, 2000
- The tissue distribution of the human β3-adrenoceptor studied using a monoclonal antibody: Direct evidence of the β3-adrenoceptor in human adipose tissue, atrium and skeletal muscleInternational Journal of Obesity, 1999
- The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle.JCI Insight, 1998
- Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.JCI Insight, 1997
- Functional beta3-adrenoceptor in the human heart.JCI Insight, 1996
- Endomyocardial Biopsies: A New Approach for Studying the Electrical and Mechanical Properties of Human Ventricular MyocardiumJournal of Molecular and Cellular Cardiology, 1994
- Enhanced Myocardial Function in Transgenic Mice Overexpressing the β 2 -Adrenergic ReceptorScience, 1994
- Reduced beta 1 receptor messenger RNA abundance in the failing human heart.JCI Insight, 1993
- Tissue distribution of beta 3-adrenergic receptor mRNA in man.JCI Insight, 1993
- Altered expression of α-subunits of G proteins in failing human heartsJournal of Molecular and Cellular Cardiology, 1989