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Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.

dc.contributor.author Kohout, TA
dc.contributor.author Takaoka, H
dc.contributor.author McDonald, PH
dc.contributor.author Perry, SJ
dc.contributor.author Mao, L
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Rockman, HA
dc.coverage.spatial United States
dc.date.accessioned 2012-10-22T20:30:25Z
dc.date.issued 2001-11-13
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/11705829
dc.identifier.uri https://hdl.handle.net/10161/5906
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.language eng
dc.publisher Ovid Technologies (Wolters Kluwer Health)
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.contributor.id Mao, L|0228206
duke.contributor.id Lefkowitz, RJ|0096962
duke.contributor.id Rockman, HA|0223027
duke.description.issue 20
duke.description.volume 104
dc.relation.journal Circulation
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/11705829
pubs.begin-page 2485
pubs.end-page 2491
pubs.issue 20
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biochemistry
pubs.organisational-group Cell Biology
pubs.organisational-group Chemistry
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Cardiology
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Pathology
pubs.organisational-group School of Medicine
pubs.organisational-group Trinity College of Arts & Sciences
pubs.publication-status Published
pubs.volume 104
dc.identifier.eissn 1524-4539


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