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Cardiovascular Research 2006 69(1):128-139; doi:10.1016/j.cardiores.2005.08.024
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Copyright © 2005, European Society of Cardiology

Carvedilol blocks β2- more than β1-adrenoceptors in human heart

Peter Molenaara,1, Torsten Christb,1, Ursula Ravensb and Alberto Kaumannc,*

aDepartment of Medicine, The Prince Charles Hospital, University of Queensland, Australia
bDepartment of Pharmacology and Toxicology, University of Technology, Dresden, Germany
cDepartment of Physiology, University of Cambridge, Downing Street, Cambridge CB23EG, UK

* Corresponding author. Tel.: +44 122 3333810; fax: +44 122 3333840. Email address: ajk41{at}hermes.cam.ac.uk

Objective: To understand the basis of the effectiveness of carvedilol in heart failure by determining its specific properties at human heart β1- and β2-adrenoceptors.

Methods: The positive inotropic effects of noradrenaline (in the presence of the β2-selective antagonist ICI118551) and adrenaline (in the presence of the β1-selective antagonist CGP20712), mediated through β1- and β2-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 β2-adrenoceptors (–logKB=10.13 ± 0.08) than of noradrenaline at β1-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 β1-blocker-treated patients, consistent with persistent preferential blockade of β2-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 β-blockers from the receptors.

Conclusions: Carvedilol blocks human cardiac β2-adrenoceptors more than β1-adrenoceptors, thereby conceivably contributing to the beneficial effects in heart failure. The persistent blockade of β-adrenoceptors is attributed to accumulation of carvedilol in cardiac tissue.

KEYWORDS Human heart; β1- and β2-adrenoceptors; Heart failure; Noradrenaline; Adrenaline; Carvedilol

1 PM and TC contributed equally to this work.

Time for primary review 17 days


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