RT Journal Article SR Electronic T1 Differential Effects of Bucindolol and Carvedilol on Noradenaline-Induced Hypertrophic Response in Ventricular Cardiomyocytes of Adult Rats JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 71 OP 76 DO 10.1124/jpet.301.1.71 VO 301 IS 1 A1 Klaus Pönicke A1 Ingrid Heinroth-Hoffmann A1 Otto-Erich Brodde YR 2002 UL http://jpet.aspetjournals.org/content/301/1/71.abstract AB In adult rat ventricular cardiomyocytes, noradrenaline exerts dual effects on protein synthesis: increases via α1-adrenoceptors and decreases via β1-adrenoceptors. Carvedilol and bucindolol are β-blockers with additional α1-adrenoceptor blocking activities. We studied the effects of carvedilol and bucindolol on noradrenaline-induced protein synthesis (assessed by [3H]phenylalanine incorporation) in adult rat ventricular cardiomyocytes. Radioligand binding studies with [125I]iodocyanopindolol and [3H]prazosin revealed that carvedilol had a much higher affinity to α1-adrenoceptors than bucindolol (β1-/α1-adrenoceptor ratio for carvedilol, 1:2.7; for bucindolol, 1:43). Noradrenaline-evoked increases in protein synthesis were enhanced by propranolol (1 μM) and β1-adrenoceptor-selective antagonists bisoprolol (1 μM) and CGP 20712A [1-[2-((3-carbamoyl-4-hydroxy)phenoxy)-ethyl-amino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propranol methanesulfonate] (300 nM). Carvedilol (100 pM–10 μM) inhibited 1 μM noradrenaline-induced increase in protein synthesis with monophasic concentration-inhibition curves independent of whether CGP 20712A was present or not; Ki values for carvedilol were 5 to 6 nM. In contrast, bucindolol (100 pM–10 μM) inhibited l μM noradrenaline-induced increase in protein synthesis with a bell-shaped concentration-inhibition curve; it increased noradrenaline-induced protein synthesis at 10 nM, although at concentrations >100 nM it was inhibited. In the presence of 300 nM CGP 20712A or 1 μM propranolol, however, bucindolol inhibited 1 μM noradrenaline-induced increase in protein synthesis with monophasic concentration-inhibition curves; Ki values were 40 to 75 nM. On the other hand, both carvedilol and bucindolol inhibited 1 μM phenylephrine-induced protein synthesis with monophasic concentration-inhibition curves;Ki values were 4 (carvedilol) and 45 nM (bucindolol). These results indicate that, at low (β-adrenoceptor blocking) concentrations, bucindolol can enhance noradrenaline-induced protein synthesis whereas it is inhibited by carvedilol. The American Society for Pharmacology and Experimental Therapeutics