title: Differential effects of carvedilol and metoprolol on isoprenaline-induced changes in beta-adrenoceptor density and systolic function in rat cardiac myocytes.
abstract: OBJECTIVE
  beta-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 beta-adrenergic signaling differently.
  
  
  METHODS
  beta-Adrenoceptor density and systolic function were determined in rat adult ventricular cardiac myocytes.
  
  
  RESULTS
  12 h isoprenaline-treatment (Iso, 1 micromol/l) reduced beta-adrenoceptor density by 33% (P<0.01). The effect was abolished by incubation with isoprenaline plus metoprolol (3 micromol/l), but was more pronounced after coincubation with carvedilol (0.003 micromol/l, P<0.05 Carv vs. Iso). Metoprolol alone had no effect on beta-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 micromol/l) induced concentration-dependent increase in myocyte shortening was blunted after 12 h preincubation with Iso (1 micromol/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 beta-receptor agonist like binding characteristics for carvedilol, but antagonist like binding characteristics for metoprolol.
  
  
  CONCLUSIONS
  Metoprolol but not carvedilol prevents isoprenaline-induced downregulation of myocyte beta-adrenoceptors. The difference might be due to specific binding properties of the beta-blockers. Restoration of isoprenaline responsiveness by carvedilol might be due to improved coupling of beta-receptors to postreceptor effects.
authors.affiliation: Klinik III für Innere Medizin der Universität zu Köln, Joseph-Stelzmann-Strasse 9, 50924, Cologne, Germany. markus.flesch@medizin.uni-koeln.de
authors.forename: M
authors.initials: M
authors.lastname: Flesch
authors.forename: S
authors.initials: S
authors.lastname: Ettelbrück
authors.forename: S
authors.initials: S
authors.lastname: Rosenkranz
authors.forename: C
authors.initials: C
authors.lastname: Maack
authors.forename: B
authors.initials: B
authors.lastname: Cremers
authors.forename: K D
authors.initials: KD
authors.lastname: Schlüter
authors.forename: O
authors.initials: O
authors.lastname: Zolk
authors.forename: M
authors.initials: M
authors.lastname: Böhm
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004558:Electric Stimulation; D006165:Guanylyl Imidodiphosphate; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D008858:Microscopy, Phase-Contrast; D009206:Myocardium / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012044:Regression Analysis
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D006165:Guanylyl Imidodiphosphate; D008790:Metoprolol; D007545:Isoproterenol