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(Circulation. 2001;104:2485.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Augmentation of Cardiac Contractility Mediated by the Human ß₃-Adrenergic Receptor Overexpressed in the Hearts of Transgenic Mice

Trudy A. Kohout, PhD; Hideyuki Takaoka, MD, PhD; Patricia H. McDonald, PhD; Stephen J. Perry, PhD; Lan Mao, MD; Robert J. Lefkowitz, MD; Howard A. Rockman, MD

From Howard Hughes Medical Institute, Departments of Medicine (T.A.K., H.T., P.H.M., S.J.P., L.M., R.J.L., H.A.R.), Cell Biology (H.T., L.M., H.A.R.), and Biochemistry (T.A.K., P.H.M., S.J.P., R.J.L.), Duke University Medical Center, Durham, NC.

Correspondence to Robert J. Lefkowitz, MD, Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Box 3821, Durham, NC 27710. E-mail lefko001{at}receptor-biol.duke.edu

Background— Stimulation of ß₁- and ß₂-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the ß₃AR 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 ß₃ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human ß₃AR (TGß₃ 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 ß₁- and ß₂ARs, isoproterenol resulted in an increase in contractility in the TGß₃ mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human ß₃AR agonist L-755,507 significantly increased contractility in the TGß₃ 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 TGß₃ mice was investigated in terms of ß₃AR–G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGß₃ mice with L-755,507 resulted in a pertussis toxin–insensitive 1.33-fold increase in [³⁵S]GTPS loading and a 1.6-fold increase in adenylyl cyclase activity.

Conclusions— Cardiac overexpression of human ß₃ARs results in positive inotropy only on stimulation with a ß₃AR agonist. Overexpressed ß₃ARs couple to G_s and activate adenylyl cyclase on agonist stimulation.

Key Words: signal transduction • pharmacology • gene therapy • inotropic agents

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