Show simple item record Kohout, TA Takaoka, H McDonald, PH Perry, SJ Mao, L Lefkowitz, RJ Rockman, HA
dc.coverage.spatial United States 2012-10-22T20:30:25Z 2001-11-13
dc.identifier.citation Circulation, 2001, 104 (20), pp. 2485 - 2491
dc.description.abstract BACKGROUND: Stimulation of beta(1)- and beta(2)-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the beta(3)AR is also expressed in the human heart and that its stimulation leads to negative inotropic effects. METHODS AND RESULTS: To better understand the role of beta(3)ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human beta(3)AR (TGbeta(3) mice). Hemodynamic characterization was performed by cardiac catheterization in closed-chest anesthetized mice, by pressure-volume-loop analysis, and by echocardiography in conscious mice. After propranolol blockade of endogenous beta(1)- and beta(2)ARs, isoproterenol resulted in an increase in contractility in the TGbeta(3) mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human beta(3)AR agonist L-755,507 significantly increased contractility in the TGbeta(3) mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and by end-systolic pressure-volume relations. The underlying mechanism of the positive inotropy incurred with L-755,507 in the TGbeta(3) mice was investigated in terms of beta(3)AR-G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGbeta(3) mice with L-755,507 resulted in a pertussis toxin-insensitive 1.33-fold increase in [(35)S]GTPgammaS loading and a 1.6-fold increase in adenylyl cyclase activity. CONCLUSIONS: Cardiac overexpression of human beta(3)ARs results in positive inotropy only on stimulation with a beta(3)AR agonist. Overexpressed beta(3)ARs couple to G(s) and activate adenylyl cyclase on agonist stimulation.
dc.format.extent 2485 - 2491
dc.language eng
dc.relation.ispartof Circulation
dc.subject Adenylyl Cyclases
dc.subject Adrenergic beta-Agonists
dc.subject Animals
dc.subject Echocardiography
dc.subject Guanosine 5'-O-(3-Thiotriphosphate)
dc.subject Hemodynamics
dc.subject Humans
dc.subject Isoproterenol
dc.subject Mice
dc.subject Mice, Transgenic
dc.subject Myocardial Contraction
dc.subject Myocardium
dc.subject Receptors, Adrenergic, beta-3
dc.subject Signal Transduction
dc.subject Stimulation, Chemical
dc.subject Sulfonamides
dc.subject Transcription, Genetic
dc.subject Ventricular Function, Left
dc.title Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.
dc.type Journal Article
duke.description.endpage 2491 en_US
duke.description.issue 20 en_US
duke.description.startpage 2485 en_US
duke.description.volume 104 en_US
dc.relation.journal Circulation en_US
pubs.issue 20
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biochemistry
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Cell Biology
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Cardiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/Trinity College of Arts & Sciences
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Chemistry
pubs.publication-status Published
pubs.volume 104
dc.identifier.eissn 1524-4539

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