Enhanced Gi Signaling Selectively Negates β2-Adrenergic Receptor (AR)– but Not β1-AR–Mediated Positive Inotropic Effect in Myocytes From Failing Rat Hearts
RP Xiao, SJ Zhang, K Chakir, P Avdonin, W Zhu… - Circulation, 2003 - Am Heart Assoc
Circulation, 2003•Am Heart Assoc
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 …
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 …
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.
Am Heart Assoc