Enhanced Gi Signaling Selectively Negates β2-Adrenergic Receptor (AR)– but Not β1-AR–Mediated Positive Inotropic Effect in Myocytes From Failing Rat Hearts

Background— Myocardial contractile response to β1- and β2-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which Gi signaling and the ratio of β2/β1 are often increased. Because β2-AR but not β1-AR couples to Gs and Gi with the Gi coupling negating the Gs-mediated contractile response, we determined whether the heart failure–associated augmentation of Gi signaling contributes differentially to the defects of these β-AR subtypes and, if so, whether inhibition of Gi or selective activation of β2-AR/Gs by ligands restores β2-AR contractile response in the failing heart. Methods and Results— Cardiomyocytes were isolated from 18- to 24-month-old failing spontaneously hypertensive (SHR) or age-matched Wistar-Kyoto (WKY) rat hearts. In SHR cardiomyocytes, either β-AR subtype–mediated inotropic effect was markedly diminished, whereas Gi proteins and the β2/β1 ratio were increased. Disruption of Gi signaling by pertussis toxin (PTX) enabled β2- but not β1-AR to induce a full p...