Differential effects of bucindolol and carvedilol on noradenaline-induced hypertrophic response in ventricular cardiomyocytes of adult rats.
In adult rat ventricular cardiomyocytes, noradrenaline exerts dual effects on protein synthesis: increases via alpha(1)-adrenoceptors and decreases via beta(1)-adrenoceptors. Carvedilol and bucindolol are beta-blockers with additional alpha(1)-adrenoceptor blocking activities. We studied the effects of carvedilol and bucindolol on noradrenaline-induced protein synthesis (assessed by [(3)H]phenylalanine incorporation) in adult rat ventricular cardiomyocytes. Radioligand binding studies with [(125)I]iodocyanopindolol and [(3)H]prazosin revealed that carvedilol had a much higher affinity to alpha(1)-adrenoceptors than bucindolol (beta(1)-/alpha(1)-adrenoceptor ratio for carvedilol, 1:2.7; for bucindolol, 1:43). Noradrenaline-evoked increases in protein synthesis were enhanced by propranolol (1 microM) and beta(1)-adrenoceptor-selective antagonists bisoprolol (1 microM) 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 microM) inhibited 1 microM 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 microM) inhibited l microM 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 microM propranolol, however, bucindolol inhibited 1 microM 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 microM 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 (beta-adrenoceptor blocking) concentrations, bucindolol can enhance noradrenaline-induced protein synthesis whereas it is inhibited by carvedilol.
Pönicke
Klaus
K
Institute of Pharmacology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany.
Heinroth-Hoffmann
Ingrid
I
Brodde
Otto-Erich
OE
D000316:Adrenergic alpha-Agonists / Q000633:toxicity*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D007700:Kinetics; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010649:Phenylalanine / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar
D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D009124:Muscle Proteins; D011412:Propanolamines; D000077261:Carvedilol; D010649:Phenylalanine; C024307:bucindolol; D009638:Norepinephrine