Low catecholamine concentrations protect adult rat ventricular myocytes against apoptosis through cAMP-dependent extracellular signal-regulated kinase activation

Catecholamines have complex effects on cardiac myocyte growth and survival, including the triggering of apoptosis at high concentration. Here, we exam ined whether at a lower concentration, catecholamine protected adult rat ve ntricular myocytes from apoptosis in vitro. Myocytes were exposed to stauro sporine (ST, 10 muM) for 18 h, with or without epinephrine (0.1 or 10 muM) or fetal calf serum (10%). Apoptosis was assessed after 48 h of culture in terms of DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method, DNA gel electrophoresis). Epinephrine (0.1 m uM) and serum reduced ST-induced myocyte apoptosis by similar to 50% (n = 1 2 cultures, P < .001), whereas epinephrine and serum alone did not influenc e the low apoptotic rate in control cultures. In contrast, 10 <mu>M epineph rine induced marked apoptosis in ST-free conditions. The protective effects of 0.1 muM epinephrine and serum were blunted by the tyrosine kinase inhib itor genistein (n = 12 cultures, P < .001). Extracellular signal-regulated kinase (ERK) activity was stimulated by 0.1 <mu>M epinephrine but not by 10 muM epinephrine. Furthermore, the protective effect of epinephrine was mim icked by isoproterenol (1 muM) and forskolin (1 muM) but not by phenylephri ne (10 muM) and was blunted by propranolol (10 mM) but not by prazozin (10 muM). Finally, isoproterenol and forskolin activated ERK, an effect that wa s blunted by propranolol. In conclusion, low epinephrine concentrations att enuate ST-induced apoptosis of adult cardiac myocytes in vitro, an effect m ediated by coupling between the cAMP pathway and ERK activation. This sugge sts that a minimal adrenergic tone is essential for myocyte survival in con ditions of unusual stress.