α- and β-Adrenergic Pathways Differentially Regulate Cell Type–Specific Apoptosis in Rat Cardiac Myocytes

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Abstract
Background—The apoptosis of cardiac myocytes may play a role in the development of heart failure. Norepinephrine is one of the factors activated in heart failure and can induce myocardial cell apoptosis in culture. However, it is unknown if α- and β-adrenergic pathways coordinately or differentially regulate apoptosis and if this apoptotic pathway uses common or cell type–specific apoptotic signals. Methods and Results—We stimulated cultured neonatal rat cardiac myocytes with an α1-adrenergic agonist (PE, phenylephrine), a β-adrenergic agonist (isoproterenol [Iso]) or a membrane-permeable cAMP analogue (8-Br-cAMP) in serum-free conditions for 48 hours. Iso and 8-Br-cAMP markedly increased the number of TUNEL-positive cells (%TUNEL-positive nuclei >40%) compared with saline stimulation (<10%). DNA fragmentation was also confirmed by ladder formation in agarose gels. Apoptotic myocytes were characterized by cell shrinkage and nuclear condensation, consistent with morphological features of apoptosis. The Iso...