Carvedilol causes greater persistent blockade of β2- than β1-adrenoceptors in human failing myocardium

1Alberto Kaumann, 2Torsten Christ, 2Ursula Ravens & 3Peter Molenaar. 1Department of Physiology, University of Cambridge, CB2 3EG, UK, 2Department of Pharmacology & Toxicology, University of Technology, Dresden, Germany, and 3Department of Medicine, The Prince Charles Hospital, University of Queensland, 4032 Brisbane, Australia.

β-Adrenoceptor blockade persists in human failing hearts after carvedilol-withdrawal (Metra et al. 2003). We have reported that carvedilol blocks β2-adrenoceptors more than β1-adrenoceptors in human atrium (Kaumann & Molenaar 2005) and would expect greater hyporesponsiveness through β2- than β1adrenoceptors in isolated myocardium obtained from patients treated with carvedilol. We investigated the positive inotropic effects of noradrenaline and adrenaline, mediated through β1 and β2-adrenoceptors respectively as in Kaumann & Molenaar (2005), in atrial and ventricular trabeculae, obtained from patients with heart failure treated with carvedilol or β1selective metoprolol or atenolol with matching ejection fractions (EF). –LogEC50M values are shown in table 1 (mean ± s.e.m., patient numbers between parentheses).

Table 1

*P>0.05 carvedilol-treated vs β1-blocker-treated.

Chronic carvedilol treatment reduced the inotropic sensitivity of atrial trabeculae to noradrenaline and adrenaline, 6-fold and 91-fold respectively, compared to β1blocker treated patients. Carvedilol treatment reduced 4-fold and 36-fold the ventricular sensitivity to noradrenaline and adrenaline respectively. In contrast to the selective β2-hyporesponsiveness, carvedilol treatment enhanced atrial inotropic responses to 5-HT (-logEC50M = 7.08 ± 0.12 (9) and 6.98 ± 0.15 (7) in carvedilol-treated and β1selective blocker-treated patients), as previously observed with β1selective blockers (Sanders et al.1995). Carvedilol treatment also failed to affect the ventricular inotropic potencies (-logEC50M) of histamine (carvedilol-treated, 5.43 ± 0.05 (7); non- β-blocker-treated, 5.25 ± 0.06 (5)) and dibutyryl cyclic AMP (carvedilol treated, 3.32 ± 0.06 (5); non- β-blocker-treated, 3.26 ± 0.07 (5)).

Since carvedilol accumulates in human heart (Behn et al. 2001), it may leak out chronically from tissues and maintain higher β2- than β1adrenoceptor occupancy.

Behn, F. et al. (2001) J.Chromatographic Sci. 39, 121-124.
Kaumann, A.J. & Molenaar, P. (2005) (this meeting).
Metra, M., et al. (2003) J. Am. Coll. Cardiol. 40, 1248-1258.
Sanders, L., et al. (1995) Circulation 92, 2526-2639.