Impact of beta-adrenoceptor antagonists on myofilament calcium sensitivity of rabbit and human myocardium.
Beta-adrenoceptor antagonists (beta-blockers) are commonly used in clinical pharmacotherapy of cardiovascular diseases. Carvedilol and nebivolol possess beneficial effects on myocardial function in situations of oxidative stress associated with intracellular calcium overload. This preservation of contractile function might be due to direct scavenging capacities or to compensation of the intracellular calcium overload through direct impact on myofilament calcium sensitivity. Accordingly, we measured the relation between calcium and force in the absence and in the presence of 10(-6) M carvedilol, nebivolol, or propranolol in skinned right ventricular trabeculae of rabbit hearts. In rabbit myocardium, nebivolol (10(-6) M) altered the pCa50% by a rightward shift (less sensitive) from 5.72 +/- 0.05 to 5.57 +/- 0.05 (p < 0.05). Maximal force development was reduced by nebivolol. In contrast, the same concentration of propranolol or carvedilol did not influence calcium sensitivity and force development. In additional experiments, we repeated this protocol in trabeculae from human failing hearts. As in rabbit trabeculae, nebivolol shifted the pCa50% by 0.16 +/- 0.04 pCa units to the right (p < 0.05). Experiments with intact rabbit trabeculae confirmed depressed contractility: when all beta-adrenoceptors were blocked by 10(-6) M propranolol, subsequent addition of 10(-6) M nebivolol reduced developed force of these muscles significantly from 3.1 +/- 0.9 to 1.7 +/- 0.4 mN/mm2. We conclude that nebivolol desensitizes cardiac myofilaments slightly, whereas neither propranolol nor carvedilol had an effect.
Zeitz
O
O
Department of Cardiology and Pneumology, University of Göttingen, Germany. zeitz@med.uni-goettingen.de
Rahman
A
A
Hasenfuss
G
G
Janssen
P M
PM
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000502:physiology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002122:Calcium Chloride / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium; D000068577:Nebivolol; D011412:Propanolamines / Q000494:pharmacology*; D011817:Rabbits
D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D002227:Carbazoles; D004983:Ethanolamines; D011412:Propanolamines; D000068577:Nebivolol; D000077261:Carvedilol; D002122:Calcium Chloride