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Enhanced contractility and decreased beta-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine.
- Source :
-
Circulation [Circulation] 1999 May 25; Vol. 99 (20), pp. 2702-7. - Publication Year :
- 1999
-
Abstract
- Background: Elevated circulating norepinephrine (NE) has been implicated in causing the profound beta-adrenergic receptor (betaAR) downregulation and receptor uncoupling that are characteristic of end-stage human dilated cardiomyopathy, a process mediated in part by increased levels of beta-adrenergic receptor kinase (betaARK1). To explore whether chronic sustained NE stimulation is a primary stimulus that promotes deterioration in cardiac signaling, we characterized a gene-targeted mouse in which activation of the sympathetic nervous system cannot lead to an elevation in plasma NE and epinephrine.<br />Methods and Results: Gene-targeted mice that lack dopamine beta-hydroxylase (dbh-/-), the enzyme needed to convert dopamine to NE, were created by homologous recombination. In vivo contractile response to the beta1AR agonist dobutamine, measured by a high-fidelity left ventricular micromanometer, was enhanced in mice lacking the dbh gene. In unloaded adult myocytes isolated from dbh-/- mice, basal contractility was significantly increased compared with control cells. Furthermore, the increase in betaAR responsiveness and enhanced cellular contractility were associated with a significant reduction in activity and protein level of betaARK1 and increased high-affinity agonist binding without changes in betaAR density or G-protein levels.<br />Conclusions: Mice that lack the ability to generate NE or epinephrine show increased contractility associated primarily with a decrease in the level of betaARK1 protein and kinase activity. This animal model will be valuable in testing whether NE is required for the pathogenesis of heart failure through mating strategies that cross the dbh-/- mouse into genetically engineered models of heart failure.
- Subjects :
- Adrenergic beta-Agonists pharmacology
Animals
Dobutamine pharmacology
Dopamine beta-Hydroxylase genetics
Female
GTP-Binding Proteins metabolism
Gene Targeting
Hemodynamics drug effects
Hemodynamics physiology
Male
Mice
Mice, Mutant Strains
Myocardial Contraction drug effects
Receptors, Adrenergic, beta metabolism
Sarcolemma metabolism
beta-Adrenergic Receptor Kinases
Cyclic AMP-Dependent Protein Kinases metabolism
Epinephrine deficiency
Myocardial Contraction physiology
Norepinephrine deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 99
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 10338466
- Full Text :
- https://doi.org/10.1161/01.cir.99.20.2702