Background—Catecholamine-induced apoptosis is mediated by activation of the β-adrenergic signaling pathway. We tested the hypothesis that β₁- and β₂-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 μmol/L) or NE+atenolol (AT) (10 μmol/L) for 12 hours. AT, a β₁-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%, P<0.0001; NE+AT, 4±2% versus control, 3±1%, P=0.98). Annexin V staining, DNA laddering, and caspase activity determinations corroborated these results. Subsequent experiments under prazosin treatment established the apoptosis dose-response curves for the increasingly β₂-selective AR agonists isoproterenol (ISO) (β₁≈β₂) and albuterol (ALB) (β₂>β₁). ISO and ALB induced significantly less apoptosis than NE (β₁>β₂) at equimolar concentrations as assessed by TUNEL staining [1 μmol/L: NE (8±2%)≈ISO (7±1%)>ALB (2±1%); 10 μmol/L: NE (35±2%)>ISO (23±1%)>ALB (3±1%); 100 μmol/L: NE (50±2%)>ISO (29±2%)>ALB (14±1%), P<0.0001 except for NE versus ISO at 1 μmol/L with P=0.62]. ALB-induced apoptosis at 100 μmol/L was abolished by AT (10 μmol/L), indicating a β₁AR-mediated effect. Importantly, ICI 118551 (0.1 μmol/L), a highly selective β₂AR 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 β-adrenergic signaling–induced changes in the Bcl-2–to-Bax ratio.

Conclusions—These observations provide evidence that βAR-mediated apoptotic death signaling is largely dissociated from β₂ARs and selectively mediated by β₁ARs in adult rat ventricular myocytes.