title: Carvedilol blocks beta2- more than beta1-adrenoceptors in human heart.
abstract: OBJECTIVE
  To understand the basis of the effectiveness of carvedilol in heart failure by determining its specific properties at human heart beta1- and beta2-adrenoceptors.
  
  
  METHODS
  The positive inotropic effects of noradrenaline (in the presence of the beta2-selective antagonist ICI118551) and adrenaline (in the presence of the beta1-selective antagonist CGP20712), mediated through beta1- and beta2-adrenoceptors, respectively, were investigated in atrial and ventricular trabeculae. The patch-clamp technique was used to investigate effects of noradrenaline and adrenaline on L-type Ca2+ current in human atrial myocytes.
  
  
  RESULTS
  Carvedilol was a 13-fold more potent competitive antagonist of the effects of adrenaline at beta2-adrenoceptors (-logKB=10.13+/-0.08) than of noradrenaline at beta1-adrenoceptors (-logKB=9.02+/-0.07) in human right atrium. Chronic carvedilol treatment of patients with non-terminal heart failure reduced the inotropic sensitivity of atrial trabeculae to noradrenaline and adrenaline 5.6-fold and 91.2-fold, respectively, compared to beta1-blocker-treated patients, consistent with persistent preferential blockade of beta2-adrenoceptors. In terminal heart failure carvedilol treatment reduced 1.8-fold and 25.1-fold the sensitivity of right ventricular trabeculae to noradrenaline and adrenaline, respectively, but metoprolol treatment did not reduce the sensitivity to the catecholamines. Increases of current (ICa,L) produced by noradrenaline and adrenaline were not different in atrial myocytes obtained from non-terminal heart failure patients treated with metoprolol or carvedilol, consistent with dissociation of both beta-blockers from the receptors.
  
  
  CONCLUSIONS
  Carvedilol blocks human cardiac beta2-adrenoceptors more than beta1-adrenoceptors, thereby conceivably contributing to the beneficial effects in heart failure. The persistent blockade of beta-adrenoceptors is attributed to accumulation of carvedilol in cardiac tissue.
authors.affiliation: Department of Medicine, The Prince Charles Hospital, University of Queensland, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Molenaar
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Alberto
authors.initials: A
authors.lastname: Kaumann
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D006325:Heart Atria; D006333:Heart Failure / Q000378:metabolism*; D006352:Heart Ventricles; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008790:Metoprolol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011412:Propanolamines / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D011941:Receptors, Adrenergic / Q000187:drug effects*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D020746:Calcium Channels, L-Type; D002227:Carbazoles; D007093:Imidazoles; D011412:Propanolamines; D011941:Receptors, Adrenergic; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000077261:Carvedilol; C026777:ICI 118551; D011433:Propranolol; C049763:CGP 20712A; D008790:Metoprolol; D009638:Norepinephrine; D004837:Epinephrine