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Cardiovascular Research 2002 55(2):300-308; doi:10.1016/S0008-6363(02)00406-6
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Intracellular β-blockade: overexpression of G{alpha}i2 depresses the β-adrenergic response in intact myocardium

Paul M.L Janssena,b,*, Wolfgang Schillingera, J.Kevin Donahueb, Oliver Zeitza, Shahriyar Emamia, Stephan E Lehnarta, Joachim Weilc, Thomas Eschenhagenc, Gerd Hasenfussa and Juergen Prestlea

aDepartment Cardiology and Pneumology, University of Göttingen, Göttingen, Germany
bInstitute of Molecular Cardiobiology, Johns Hopkins University School of Medicine, 844 Ross Building, 720 Rutland Ave., Baltimore, MD 21205, USA
cInstitute of Pharmacology and Toxicology, University of Erlangen, Erlangen, Germany

* Corresponding author. Present address: Dept. of Physiology and Cell Biology, Ohio State University, 302 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA. Tel.: +1-614-247-7838; fax: +1-614-292-4888 janssen.10{at}osu.edu

Objective: Increased levels of inhibitory G proteins have been observed in heart failure, but their physiological relevance in mediating the reduced β-adrenergic response is largely unknown. Methods: To evaluate the functional consequences of G{alpha}i2 overexpression, we studied myocardial contraction in intact isometric contracting cardiac rabbit trabeculae and isolated myocytes after adenovirus-mediated gene transfer of G{alpha}i2. Results: Neither G{alpha}i2 nor lacZ (control) overexpression altered baseline contractile force. After 72 h of continuous contractions, developed force (Fdev) increased after addition of 1 µM isoproterenol by 28.5±9.7 mN/mm2 in the control group, which was unchanged from the initial response at t = 0 h (23.7±3.8 mN/mm2). In sharp contrast, in preparations transfected with AdG{alpha}i2, the response to isoproterenol was significantly attenuated (5.9±2.0 vs. 27.6±4.2 mN/mm2, t = 72 vs. 0 h, respectively, P<0.01). In a primary culture of transfected isolated myocytes from a nearly identical baseline, isoproterenol increased cell shortening by 3.1±0.6% in the lacZ transfected myocytes, but only by 1.3±0.5% in G{alpha}i2 transfected myocytes (t = 72 h, P<0.01). In G{alpha}i2 transfected myocytes, pertussis toxin restored β-adrenergic responsiveness, indicating specificity of attenuation by the transgene. Conclusions: Overexpression of G{alpha}i2 attenuates the positive inotropic effects of β-adrenergic stimulation in myocardium. In addition, the method we developed allows investigation of a causal link between altered protein expression and subsequent alterations in contractile function in a physiological relevant in vitro manner.

KEYWORDS Adrenergic (ant)agonists; Contractile function; e-c coupling; G-proteins; Gene expression; Inotropic agents


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