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(Circulation. 2003;108:1633.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Enhanced G_i Signaling Selectively Negates ß₂-Adrenergic Receptor (AR)– but Not ß₁-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; 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.).

Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail xiaor{at}grc.nia.nih.gov

Received January 15, 2003; revision received May 20, 2003; accepted May 21, 2003.

Background— Myocardial contractile response to ß₁- and ß₂-adrenergic receptor (AR) stimulation is severely impaired in chronic heart failure, in which G_i signaling and the ratio of ß₂/ß₁ are often increased. Because ß₂-AR but not ß₁-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 ß-AR subtypes and, if so, whether inhibition of G_i or selective activation of ß₂-AR/G_s by ligands restores ß₂-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 ß-AR subtype–mediated inotropic effect was markedly diminished, whereas G_i proteins and the ß₂/ß₁ ratio were increased. Disruption of G_i signaling by pertussis toxin (PTX) enabled ß₂- but not ß₁-AR to induce a full positive inotropic response in SHR myocytes. Furthermore, screening of a panel of ß₂-AR ligands revealed that the contractile response mediated by most ß₂-AR agonists, including zinterol, salbutamol, and procaterol, was potentiated by PTX, indicating concurrent G_s and G_i activation. In contrast, fenoterol, another ß₂-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 ß₂- but not ß₁-AR in failing SHR hearts and that disruption of G_i signaling by PTX or selective activation of ß₂-AR/G_s signaling by fenoterol restores the blunted ß₂-AR contractile response in the failing heart.

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

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