Background Stimulation of β₁- and β₂-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the β₃AR 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 β₃ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human β₃AR (TGβ₃ 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 β₁- and β₂ARs, isoproterenol resulted in an increase in contractility in the TGβ₃ mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human β₃AR agonist L-755,507 significantly increased contractility in the TGβ₃ 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 TGβ₃ mice was investigated in terms of β₃AR–G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGβ₃ mice with L-755,507 resulted in a pertussis toxin–insensitive 1.33-fold increase in [³⁵S]GTPγS loading and a 1.6-fold increase in adenylyl cyclase activity.

Conclusions Cardiac overexpression of human β₃ARs results in positive inotropy only on stimulation with a β₃AR agonist. Overexpressed β₃ARs couple to G_s and activate adenylyl cyclase on agonist stimulation.