ALPHA-1 ADRENERGIC RECEPTOR AGONIST PHENYLEPHRINE INHIBITS SEPSIS-INDUCED CARDIOMYOCYTE APOPTOSIS AND CARDIAC DYSFUNCTION VIA ACTIVATING ERK1/2 SIGNAL PATHWAY

It was demonstrated that alpha(1) adrenergic receptor (alpha(1)-AR) activation by phenylephrine (PE) attenuated cardiac dysfunction in lipopolysaccharide (LPS)-challenged mice. However, it is unclear whether PE suppresses sepsis-induced cardiomyocyte apoptosis. Here, we investigated the effects of PE on cardiomyocyte apoptosis in LPS-treated adult rat ventricular myocytes (ARVMs) and septic rats induced by cecal ligation and puncture. Cardiomyocyte apoptosis and caspase activity were detected by TUNEL and spectrophotometrical assay, respectively. Bax, Bcl-2 and cytochrome c (Cyt c) levels as well as I kappa B alpha, ERK1/2, p38 MAPK, JNK and cardiac troponin I (cTnI) phosphorylation were analyzed by Western blotting, and TNF-alpha concentration was analyzed by ELISA. PE inhibited LPS-induced caspase-3 activation in ARVMs, which was reversed by prazosin (a membrane permeable alpha(1)-AR antagonist), but not by CGP12177A (a membrane impermeable alpha(1)-AR antagonist). PE upregulated phosphorylated ERK1/2 and Bcl-2 contents, decreased TNF-alpha and Bax levels, Cyt c release, caspase-8/-9 activities as well as I kappa B alpha, p38MAPK and JNK phosphorylation in LPS-treated ARVMs, all of which were abolished by prazosin. Treatment with U0126 (a specific ERK1/2 inhibitor) reversed the effects of PE on I kappa B alpha, p38MAPK and JNK phosphorylation as well as caspase-3/-8/-9 activation in LPS-treated ARVMs. In septic rats, PE not only inhibited myocardial apoptosis as well as I kappa B alpha, p38MAPK, and JNK phosphorylation, but also upregulated myocardial phosphorylated ERK1/2. Furthermore, PE inhibited myocardial cTnI(Ser23/24) phosphorylation and improved cardiac function in septic rats. Taken together, our data suggest that alpha(1)-AR activation by PE inhibits sepsis-induced cardiomyocyte apoptosis and cardiac dysfunction via activating ERK1/2 signal pathway.