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

Background-Stimulation of beta (1)- and beta (2)-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been report ed that the beta (3)AR is also expressed in the human heart and that its st imulation 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 overexpressio n of 330 fmol/mg protein of the human beta (3)AR (TG beta (3) mice). Hemody namic characterization was performed by cardiac catheterization in closed-c hest anesthetized mice, by pressure-volume-loop analysis, and by echocardio graphy in conscious mice. After propranolol blockade of endogenous beta (1) - and beta (2)ARs, isoproterenol resulted in an increase in contractility i n the TG beta (3) mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human beta (3)AR agonist L-755,507 significa ntly increased contractility in the TG beta (3) mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and by end-sy stolic pressure-volume relations. The underlying mechanism of the positive inotropy incurred with L-755,507 in the TG beta (3) mice was investigated i n terms Of beta (3)AR-G-protein coupling and adenylyl cyclase activation. S timulation of cardiac membranes from TG beta (3) mice with L-755,507 result ed in a pertussis toxin-insensitive 1.33-fold increase in [S-35]GTP-gammaS 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 .