Opposing Effects of β1- and β2-Adrenergic Receptors on Cardiac Myocyte Apoptosis: Role of a Pertussis Toxin–Sensitive G Protein

Abstract

Background—β-Adrenergic receptor (β-AR) stimulation increases apoptosis in adult rat cardiac (ventricular) myocytes (ARVMs) via activation of adenylyl cyclase. β 2-ARs may couple to a G i-mediated signaling pathway that can oppose the actions of adenylyl cyclase. Methods and Results—In ARVMs, β-AR stimulation for 24 hours increased the number of apoptotic cells as measured by flow cytometry. β-AR–stimulated apoptosis was abolished by the β 1-AR–selective antagonist CGP 20712A (P<0.05 versus β-AR stimulation alone) but was potentiated by the β 2-AR–selective antagonist ICI 118,551 (P<0.05 versus β-AR stimulation alone). The muscarinic agonist carbachol also prevented β-AR–stimulated apoptosis (P<0.05 versus β-AR stimulation alone), whereas pertussis toxin potentiated the apoptotic action of β-AR stimulation (P<0.05 versus β-AR stimulation alone) and prevented the antiapoptotic action of carbachol. Conclusions—In ARVMs, stimulation of β 1-ARs increases apoptosis via a cAMP-dependent mechanism, whereas stimulation of β 2-ARs inhibits apoptosis via a G i-coupled pathway. These findings have implications for the pathophysiology and treatment of myocardial failure.