© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Differential effects of carvedilol and metoprolol on isoprenaline-induced changes in β-adrenoceptor density and systolic function in rat cardiac myocytes
aKlinik III für Innere Medizin der Universität zu Köln, Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany
bUniversitaetskliniken des Saarlandes, Innere Medizin III, 66421 Homburg, Germany
cPhysiologisches Institut der Justus-Liebig-Universität, Aulweg 129, 35392 Giessen, Germany
dInstitut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054 Erlangen, Germany
* Corresponding author. Tel.: +49-221-478-4503; fax: +49-221-478-6550 markus.flesch{at}medizin.uni-koeln.de
Objective: β-Blockers improve cardiac function and survival in heart failure patients. The underlying mechanisms are not completely elucidated. Differences between agents might be important for the development of more specific therapeutical approaches. This study investigated whether metoprolol or carvedilol alter β-adrenergic signaling differently. Methods: β-Adrenoceptor density and systolic function were determined in rat adult ventricular cardiac myocytes. Results: 12 h isoprenaline-treatment (Iso, 1 µmol/l) reduced β-adrenoceptor density by 33% (P<0.01). The effect was abolished by incubation with isoprenaline plus metoprolol (3 µmol/l), but was more pronounced after coincubation with carvedilol (0.003 µmol/l, P<0.05 Carv vs. Iso). Metoprolol alone had no effect on β-adrenoceptor density, but carvedilol induced a decrease in receptor density even in absence of isoprenaline (P<0.05 Carv vs. ctr.). The isoprenaline (0.0003–10 µmol/l) induced concentration-dependent increase in myocyte shortening was blunted after 12 h preincubation with Iso (1 µmol/l, P<0.001). This reduction was abolished or partly prevented by coincubation with metoprolol or carvedilol, respectively. Carvedilol decreased the number of receptors which had to be occupied by isoprenaline in order to obtain 50% and 90% increase in myocyte cell shortening. Comparison of guanine nucleotide-dependent binding characteristics of isoprenaline, carvedilol and metoprolol revealed β-receptor agonist like binding characteristics for carvedilol, but antagonist like binding characteristics for metoprolol. Conclusion: Metoprolol but not carvedilol prevents isoprenaline-induced downregulation of myocyte β-adrenoceptors. The difference might be due to specific binding properties of the β-blockers. Restoration of isoprenaline responsiveness by carvedilol might be due to improved coupling of β-receptors to postreceptor effects.
KEYWORDS Adrenergic (ant)agonists; Heart failure; Myocytes; Receptors
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