Augmentation of Cardiac Contractility Mediated by the Human &bgr;3-Adrenergic Receptor Overexpressed in the Hearts of Transgenic Mice

Background—Stimulation of &bgr;1- and &bgr;2-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the &bgr;3AR 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 &bgr;3ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human &bgr;3AR (TG&bgr;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 &bgr;1- and &bgr;2ARs, isoproterenol resulted in an increase in contractility in the TG&bgr;3 mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human &bgr;3AR agonist L-755,507 significantly increased contractility in the TG&bgr;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 TG&bgr;3 mice was investigated in terms of &bgr;3AR–G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TG&bgr;3 mice with L-755,507 resulted in a pertussis toxin–insensitive 1.33-fold increase in [35S]GTP&ggr;S loading and a 1.6-fold increase in adenylyl cyclase activity. Conclusions—Cardiac overexpression of human &bgr;3ARs results in positive inotropy only on stimulation with a &bgr;3AR agonist. Overexpressed &bgr;3ARs couple to Gs and activate adenylyl cyclase on agonist stimulation.