Document Detail


Enhanced contractility and decreased beta-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine.
MedLine Citation:
PMID:  10338466     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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. 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. 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.
Authors:
M C Cho; M Rao; W J Koch; S A Thomas; R D Palmiter; H A Rockman
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation     Volume:  99     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  1999 May 
Date Detail:
Created Date:  1999-06-15     Completed Date:  1999-06-15     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2702-7     Citation Subset:  AIM; IM    
Affiliation:
Department of Medicine, University of North Carolina at Chapel Hill, 27599-7075, USA.
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-Agonists / pharmacology
Animals
Cyclic AMP-Dependent Protein Kinases / metabolism*
Dobutamine / pharmacology
Dopamine beta-Hydroxylase / genetics
Epinephrine / deficiency*
Female
GTP-Binding Proteins / metabolism
Gene Targeting
Hemodynamics / drug effects,  physiology
Male
Mice
Mice, Mutant Strains
Myocardial Contraction / drug effects,  physiology*
Norepinephrine / deficiency*
Receptors, Adrenergic, beta / metabolism
Sarcolemma / metabolism
beta-Adrenergic Receptor Kinases
Grant Support
ID/Acronym/Agency:
HD-09172/HD/NICHD NIH HHS; HL-56687/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/Receptors, Adrenergic, beta; 34368-04-2/Dobutamine; 51-41-2/Norepinephrine; 51-43-4/Epinephrine; EC 1.14.17.1/Dopamine beta-Hydroxylase; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 2.7.11.15/beta-Adrenergic Receptor Kinases; EC 3.6.1.-/GTP-Binding Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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