Enhanced Gi signaling selectively negates β 2-adrenergic receptor (AR)- but not β1-AR-mediated positive inotropic effect in myocytes from failing rat hearts

Rui Ping Xiao, Sheng Jun Zhang, Khalid Chakir, Pavel Avdonin, Weizhong Zhu, Richard A. Bond, C. William Balke, Edward G. Lakatta, Heping Cheng

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

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 β21 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 β21 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.

Original languageEnglish (US)
Pages (from-to)1633-1639
Number of pages7
JournalCirculation
Volume108
Issue number13
DOIs
StatePublished - Sep 30 2003
Externally publishedYes

Keywords

  • Contractility
  • Heart failure
  • Proteins
  • Receptors, adrenergic, beta

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint

Dive into the research topics of 'Enhanced Gi signaling selectively negates β 2-adrenergic receptor (AR)- but not β1-AR-mediated positive inotropic effect in myocytes from failing rat hearts'. Together they form a unique fingerprint.

Cite this