Enhanced G(i) signaling selectively negates beta(2)-adrenergic receptor (AR)- but not beta(1)-AR-mediated positive inotropic effect in myocytes from failing rat hearts

Article

关键词: PERTUSSIS-TOXIN;    G-PROTEIN;    BETA(1)-ADRENERGIC RECEPTOR;    CARDIAC MYOCYTES;    CA2+ CURRENT;    CELL-DEATH;    HYPERTROPHY;    CONTRACTION;    CAMP;    EXPRESSION;   

DOI  :  10.1161/01.CIR.0000087595.17277.73

来源: SCIE

【 摘 要 】

Background - Myocardial contractile response to beta(1)- and beta(2)-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which G(i) signaling and the ratio of beta(2)/beta(1) are often increased. Because beta(2)-AR but not beta(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 beta-AR subtypes and, if so, whether inhibition of G(i) or selective activation of beta(2)-AR/G(s) by ligands restores beta(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 beta-AR subtype - mediated inotropic effect was markedly diminished, whereas G(i) proteins and the beta(2)/beta(1) ratio were increased. Disruption of G(i) signaling by pertussis toxin (PTX) enabled beta(2)- but not beta(1)-AR to induce a full positive inotropic response in SHR myocytes. Furthermore, screening of a panel of beta(2)-AR ligands revealed that the contractile response mediated by most beta(2)-AR agonists, including zinterol, salbutamol, and procaterol, was potentiated by PTX, indicating concurrent G(s) and G(i) activation. In contrast, fenoterol, another beta(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 beta(2)- but not beta(1)-AR in failing SHR hearts and that disruption of G(i) signaling by PTX or selective activation of beta(2)-AR/G(s) signaling by fenoterol restores the blunted beta(2)-AR contractile response in the failing heart.

【 授权许可】

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