β-Adrenergic Receptor Subtypes Differentially Affect Apoptosis in Adult Rat Ventricular Myocytes

BACKGROUND-Catecholamine-induced apoptosis is mediated by activation of the beta-adrenergic signaling pathway. We tested the hypothesis that beta(1)- and beta(2)-adrenergic receptor (AR) subtypes differentially affect apoptosis in adult rat ventricular myocytes in vitro. METHODS AND RESULTS-Myocytes were first exposed to norepinephrine (NE) alone (10 mcmol/L) or NE+atenolol (AT) (10 mcmol/L) for 12 hours. AT, a beta(1)-selective AR antagonist, abolished the NE-induced increase in nick end-labeling (TUNEL)-positive cells compared with control (NE, 33+/-3% versus control, 3+/-1%, Pbeta(1)). ISO and ALB induced significantly less apoptosis than NE (beta(1)>beta(2)) at equimolar concentrations as assessed by TUNEL staining 1 mcmol/L: NE (8+/-2%) approximately ISO (7+/-1%)>ALB (2+/-1%); 10 mcmol/L: NE (35+/-2%)>ISO (23+/-1%)>ALB (3+/-1%); 100 mcmol/L: NE (50+/-2%)>ISO (29+/-2%)>ALB (14+/-1%), P<0.0001 except for NE versus ISO at 1 mcmol/L with P=0.62. ALB-induced apoptosis at 100 mcmol/L was abolished by AT (10 mcmol/L), indicating a beta(1)AR-mediated effect. Importantly, ICI 118551 (0.1 mcmol/L), a highly selective beta(2)AR antagonist, did not decrease the percentage of NE-, ISO-, and ALB-induced apoptosis. Reverse transcription-polymerase chain reaction studies revealed that AT completely reversed the beta-adrenergic signaling-induced changes in the Bcl-2-to-Bax ratio. CONCLUSIONS-These observations provide evidence that beta AR-mediated apoptotic death signaling is largely dissociated from beta(2)ARs and selectively mediated by beta(1)ARs in adult rat ventricular myocytes.