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

Background—Myocardial contractile response to 1and 2-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which Gi signaling and the ratio of 2/ 1 are often increased. Because 2-AR but not 1-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 -AR subtypes and, if so, whether inhibition of Gi or selective activation of 2-AR/Gs by ligands restores 2-AR contractile response in the failing heart. Methods and Results—Cardiomyocytes were isolated from 18to 24-month-old failing spontaneously hypertensive (SHR) or age-matched Wistar-Kyoto (WKY) rat hearts. In SHR cardiomyocytes, either -AR subtype–mediated inotropic effect was markedly diminished, whereas Gi proteins and the 2/ 1 ratio were increased. Disruption of Gi signaling by pertussis toxin (PTX) enabled 2but not 1-AR to induce a full positive inotropic response in SHR myocytes. Furthermore, screening of a panel of 2-AR ligands revealed that the contractile response mediated by most 2-AR agonists, including zinterol, salbutamol, and procaterol, was potentiated by PTX, indicating concurrent Gs and Gi activation. In contrast, fenoterol, another 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 2but not 1-AR in failing SHR hearts and that disruption of Gi signaling by PTX or selective activation of 2-AR/Gs signaling by fenoterol restores the blunted 2-AR contractile response in the failing heart. (Circulation. 2003;108:1633-1639.)