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Cardiovascular Research 1998 40(1):146-155; doi:10.1016/S0008-6363(98)00099-6
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

β-Adrenergic signal transduction following carvedilol treatment in hypertensive cardiac hypertrophy

Michael Böhma,*, Sylvia Ettelbrücka, Markus Flescha, Wiek H van Gilstb, Andreas Knorrc, Christoph Maacka, Yigal M Pintob, Martin Pauld, Ard C.H Teismanb and Oliver Zolka

aKlinik III für Innere Medizin der Universität zu Köln, Joseph-Stelzmann-Strasse 9, 50924 Köln, Germany
bDepartment of Clinical Pharmacology, University of Groningen, Groningen, Netherlands
cBayer AG, Wuppertal, Germany
dInstitut für Klinische Pharmakologie, Freie Universität Berlin, Germany

* Corresponding author. Tel.: 0049-221-478-6205 or 6207; Fax.: 0049-221-478-6550; E-mail: Michael.Boehm@Medizin.Uni-Koeln.De

Objective: Treatment with the β-blocker carvedilol leads to an improvement of outcome and ejection fraction in heart failure. These effects occur without affecting the number of β-adrenergic receptors, as determined in right ventricular biopsies from patients with heart failure. This study was aimed at investigating the effects of carvedilol on β-adrenergic signal transduction alterations in a model of left ventricular pressure overload, which is characterized by sympathetic activation and a desensitized β-adrenergic signal transduction. Methods: Transgenic rats with overexpression of renin [TG(mREN2)27] were treated with carvedilol (30 µg/kg) or held under control conditions and were compared with Sprague-Dawley rats. Myocardial β-adrenoceptors (125I-labeled iodocyanopindolol binding), Gi{alpha} (pertussis toxin labeling), Gs{alpha}-activity (reconstitution into cyc–S49 membranes) and adenylyl cyclase activity were measured. Blood pressure and heart rate, increase in heart rate during sacrifice and pressure rate products were determined. Results: β-Adrenoceptors were downregulated and Gi{alpha}-protein levels were significantly increased, producing a desensitization of basal, isoprenaline- and guanine nucleotide-stimulated adenylyl cyclase activity compared to controls. Carvedilol reduced heart rate, blood pressure and pressure rate product in TG(mREN2)27. Carvedilol did not restore biochemical alterations, but even further reduced β-adrenoceptor numbers and adenylyl cyclase. It exhibited a two affinity state, guanine nucleotide-sensitive binding to cardiac β-adrenergic receptors similar to isoprenaline but different from metoprolol. Conclusions: Carvedilol did not restore β-adrenergic signal transduction at concentrations producing antiadrenergic effects in vivo. This effect might be due to an atypical guanine nucleotide-dependent interaction with β-adrenergic receptors. Thus, ancillary properties could explain the recently reported beneficial effects in patients with heart failure independent from an upregulation of β-adrenergic receptors.

KEYWORDS β-Adrenoceptors; G-proteins; Carvedilol; Heart failure; Cardiac hypertrophy; Hypertensive heart disease


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