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 β 2-AR but not β1-AR couples to Gs and Gi with the Gi coupling negating the G s-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 β 2-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 β 2-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.
|Number of pages||7|
|State||Published - Sep 30 2003|
- Heart failure
- Receptors, adrenergic, beta