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Carvedilol blocks β2-adrenoceptors more than β1-adrenoceptors in human atrium Carvedilol is efficacious in heart failure but there is uncertainty about the affinity for β1- and β2-adrenoceptors. We have compared the blocking potency of carvedilol (0.1-100 nM) vs the effects of (-)-noradrenaline and adrenaline, mediated through β1- and β2-adrenoceptors respectively on human atrial trabeculae, paced at 1 Hz, obtained from patients treated with metoprolol or atenolol, undergoing coronary artery bypass surgery. The effects of noradrenaline and adrenaline were studied in the presence of 50 nM ICI 118551 (to block β2-adrenoceptors), and in the presence of 300 nM CGP20712 (to block β1-adrenoceptors) respectively (Kaumann & Sanders, 1993). To block both tissue capture of catecholamines and α-adrenoceptors, trabeculae were incubated for 90 min with phenoxybenzamine, followed by washout. A single concentration-effect curve for (-)-noradrenaline and (-)-adrenaline was determined in the absence or presence of carvedilol, pre-incubated 90 min and 240 min, respectively, times found to be sufficient for equilibrium blockade. Carvedilol caused surmountable antagonism of the positive inotropic effects of both catecholamines. pK B values and slopes of Schild-plots estimated were 9.03±0.07 and 0.97±0.10 vs (-)-noradrenaline (n=20 patients), and 10.13±0.08 and 1.00±0.09 vs (-)-adrenaline (n=14 patients). The antagonism by 10 nM carvedilol of the effects of both catecholamines was irreversible, 90 min after washout of carvedilol, consistent with persistent β-adrenoceptor blockade observed clinically after carvedilol withdrawal. The β2-adrenoceptor selectivity may contribute to the beneficial effects of carvedilol in heart failure, including the prevention of arrhythmias elicited by (-)-adrenaline through these receptors (Kaumann & Sanders 1993). Kaumann, A.J. & Sanders, L. (1993) Naunyn-Schmiedeberg’s Arch. Pharmacol. 311, 219-236. |
