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

dc.contributor.author

Kohout, TA

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Takaoka, H

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McDonald, PH

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Perry, SJ

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Mao, L

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Lefkowitz, RJ

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Rockman, HA

dc.coverage.spatial

United States

dc.date.accessioned

2012-10-22T20:30:25Z

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2001-11-13

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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.identifier

https://www.ncbi.nlm.nih.gov/pubmed/11705829

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1524-4539

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https://hdl.handle.net/10161/5906

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eng

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Ovid Technologies (Wolters Kluwer Health)

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Circulation

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Circulation

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Adenylyl Cyclases

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Adrenergic beta-Agonists

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Animals

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Echocardiography

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Guanosine 5'-O-(3-Thiotriphosphate)

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Hemodynamics

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Humans

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Isoproterenol

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Mice

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Mice, Transgenic

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Myocardial Contraction

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Myocardium

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Receptors, Adrenergic, beta-3

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Signal Transduction

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Stimulation, Chemical

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Sulfonamides

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Transcription, Genetic

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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.orcid

Lefkowitz, RJ|0000-0003-1472-7545

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Rockman, HA|0000-0003-2921-1584

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20

duke.description.volume

104

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

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Biochemistry

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Cell Biology

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Chemistry

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Clinical Science Departments

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Duke

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Duke Cancer Institute

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Institutes and Centers

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Medicine

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Medicine, Cardiology

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Molecular Genetics and Microbiology

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Pathology

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School of Medicine

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Trinity College of Arts & Sciences

pubs.publication-status

Published

pubs.volume

104

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