Alpha(1) Adrenoceptor Activation By Norepinephrine Inhibits Lps-Induced Cardiomyocyte Tnf-Alpha Production Via Modulating Erk1/2 And Nf-Kappa B Pathway

Cardiomyocyte tumour necrosis factor (TNF-) production contributes to myocardial depression during sepsis. This study was designed to observe the effect of norepinephrine (NE) on lipopolysaccharide (LPS)-induced cardiomyocyte TNF- expression and to further investigate the underlying mechanisms in neonatal rat cardiomyocytes and endotoxaemic mice. In cultured neonatal rat cardiomyocytes, NE inhibited LPS-induced TNF- production in a dose-dependent manner. (1)- adrenoceptor (AR) antagonist (prazosin), but neither (1)- nor (2)-AR antagonist, abrogated the inhibitory effect of NE on LPS-stimulated TNF- production. Furthermore, phenylephrine (PE), an (1)-AR agonist, also suppressed LPS-induced TNF- production. NE inhibited p38 phosphorylation and NF-B activation, but enhanced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and c-Fos expression in LPS-treated cardiomyocytes, all of which were reversed by prazosin pre-treatment. To determine whether ERK1/2 regulates c-Fos expression, p38 phosphorylation, NF-B activation and TNF- production, cardiomyocytes were also treated with U0126, a selective ERK1/2 inhibitor. Treatment with U0126 reversed the effects of NE on c-Fos expression, p38 mitogen-activated protein kinase (MAPK) phosphorylation and TNF- production, but not NF-B activation in LPS-challenged cardiomyocytes. In addition, pre-treatment with SB202190, a p38 MAPK inhibitor, partly inhibited LPS-induced TNF- production in cardiomyocytes. In endotoxaemic mice, PE promoted myocardial ERK1/2 phosphorylation and c-Fos expression, inhibited p38 phosphorylation and IB degradation, reduced myocardial TNF- production and prevented LPS-provoked cardiac dysfunction. Altogether, these findings indicate that activation of (1)-AR by NE suppresses LPS-induced cardiomyocyte TNF- expression and improves cardiac dysfunction during endotoxaemia via promoting myocardial ERK phosphorylation and suppressing NF-B activation.