Enhanced G i Signaling Selectively Negates β 2 -Adrenergic Receptor (AR)– but Not β 1 -AR–Mediated Positive Inotropic Effect in Myocytes From Failing Rat Hearts

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Abstract
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 positive inotropic response in SHR myocytes. Furthermore, screening of a panel of β2-AR ligands revealed that the contractile response mediated by most β2-AR agonists, including zinterol, salbutamol, and procaterol, was potentiated by PTX, indicating concurrent Gs and Gi activation. In contrast, fenoterol, another β2-AR agonist, induced a full positive inotropic effect in SHR myocytes even in the absence of PTX. Conclusions— We conclude that enhanced Gi signaling is selectively involved in the dysfunction of β2- but not β1-AR in failing SHR hearts and that disruption of Gi signaling by PTX or selective activation of β2-AR/Gs signaling by fenoterol restores the blunted β2-AR contractile response in the failing heart.