Vol. 301, Issue 1, 71-76, April 2002

Differential Effects of Bucindolol and Carvedilol on Noradenaline-Induced Hypertrophic Response in Ventricular Cardiomyocytes of Adult Rats

Klaus Pönicke, Ingrid Heinroth-Hoffmann and Otto-Erich Brodde

Institute of Pharmacology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany

In adult rat ventricular cardiomyocytes, noradrenaline exerts dual effects on protein synthesis: increases via ₁-adrenoceptors and decreases via ₁-adrenoceptors. Carvedilol and bucindolol are -blockers with additional ₁-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 ₁-adrenoceptors than bucindolol (₁-/₁-adrenoceptor ratio for carvedilol, 1:2.7; for bucindolol, 1:43). Noradrenaline-evoked increases in protein synthesis were enhanced by propranolol (1 µM) and ₁-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; K_i 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; K_i 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; K_i values were 4 (carvedilol) and 45 nM (bucindolol). These results indicate that, at low (-adrenoceptor blocking) concentrations, bucindolol can enhance noradrenaline-induced protein synthesis whereas it is inhibited by carvedilol.