Norepinephrine Stimulates Apoptosis in Adult Rat Ventricular Myocytes by Activation of the β-Adrenergic Pathway

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Abstract
Background—Myocardial sympathetic activity is increased in heart failure. We tested the hypothesis that norepinephrine (NE) stimulates apoptosis in adult rat ventricular myocytes in vitro. Methods and Results—Myocytes were exposed to NE alone (10 μmol/L), NE+propranolol (2 μmol/L), NE+prazosin (0.1 μmol/L), or isoproterenol (ISO, 10 μmol/L) for 24 hours. NE and ISO decreased the number of viable myocytes by ≈35%. This effect was completely blocked by the β-adrenergic antagonist propranolol but was not affected by the α1-adrenergic antagonist prazosin. NE increased DNA laddering on agarose gel electrophoresis and increased the percentage of cells that were stained by terminal deoxynucleotidyl transferase–mediated nick end-labeling from 5.8±1.0% to 21.0±2.3% (PPConclusions—NE, acting via the β-adrenergic pathway, stimulates apoptosis in adult rat cardiac myocytes in vitro. This effect is mediated by protein kinase A and requires calcium entry via voltage-dependent calcium channels. NE-stimulated apoptosis of cardiac myocytes may contribute to the progression of myocardial failure.