Carvedilol blocks beta2- more than beta1-adrenoceptors in human heart.
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.
Molenaar
Peter
P
Department of Medicine, The Prince Charles Hospital, University of Queensland, Australia.
Christ
Torsten
T
Ravens
Ursula
U
Kaumann
Alberto
A
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
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