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

Abstract

Background— Myocardial contractile response to β 1 - and β 2 -adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which G i signaling and the ratio of β 2 /β 1 are often increased. Because β 2 -AR but not β 1 -AR couples to G s and G i with the G i coupling negating the G s -mediated contractile response, we determined whether the heart failure–associated augmentation of G i signaling contributes differentially to the defects of these β-AR subtypes and, if so, whether inhibition of G i or selective activation of β 2 -AR/G s by ligands restores β 2 -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 G i proteins and the β 2 /β 1 ratio were increased. Disruption of G i signaling by pertussis toxin (PTX) enabled β 2 - but not β 1 -AR to induce a full positive inotropic response in SHR myocytes. Furthermore, screening of a panel of β 2 -AR ligands revealed that the contractile response mediated by most β 2 -AR agonists, including zinterol, salbutamol, and procaterol, was potentiated by PTX, indicating concurrent G s and G i activation. In contrast, fenoterol, another β 2 -AR agonist, induced a full positive inotropic effect in SHR myocytes even in the absence of PTX. Conclusions— We conclude that enhanced G i signaling is selectively involved in the dysfunction of β 2 - but not β 1 -AR in failing SHR hearts and that disruption of G i signaling by PTX or selective activation of β 2 -AR/G s signaling by fenoterol restores the blunted β 2 -AR contractile response in the failing heart.