Published Online
on September 15, 2003

A more recent version of this article appeared on September 30, 2003

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Submitted on January 15, 2003
Revised on May 20, 2003
Accepted on May 21, 2003

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

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

From the Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Md (R.X., S.Z., K.C., P.A., W.Z., E.G.L., H.C.); the Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, Tex (R.A.B.); and the Departments of Physiology and Medicine, University of Maryland at Baltimore, and Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Md (C.W.B.).

^* To whom correspondence should be addressed. E-mail: xiaor{at}grc.nia.nih.gov.

Background--Myocardial contractile response to ₁- and ₂-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which G_i signaling and the ratio of ₂/₁ are often increased. Because ₂-AR but not 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 -AR subtypes and, if so, whether inhibition of G_i or selective activation of ₂-AR/G_s by ligands restores 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 -AR subtype-mediated inotropic effect was markedly diminished, whereas G_i proteins and the ₂/₁ ratio were increased. Disruption of G_i signaling by pertussis toxin (PTX) enabled ₂- but 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 G_s and G_i 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 G_i signaling is selectively involved in the dysfunction of ₂- but not ₁-AR in failing SHR hearts and that disruption of G_i signaling by PTX or selective activation of ₂-AR/G_s signaling by fenoterol restores the blunted ₂-AR contractile response in the failing heart.

Key words: receptors, adrenergic, beta • heart failure • proteins • contractility

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