We tested the hypothesis that
metalloendopeptidase inhibition using
phosphoramidon during induction of
endotoxemia 24 h later would down-regulate the
protein expression of myocardial
inducible nitric oxide synthase (iNOS) and phosphorylation of p38-mitogen-activated
protein kinase (p38-MAPK). Male Sprague-Dawley rats (350-400 g) were randomly divided into
sham-treated and LPS-treated groups (Escherichia. coli
lipopolysaccharide [LPS] 2 mg/kg bolus + 2 mg/kg infusion for 30 min). The animals in each group were further subdivided into vehicle- and
phosphoramidon (1 mg/kg bolus)-treated subgroups. Blood and heart samples were collected at 2- and 24-h postendotoxemia/
phosphoramidon treatment. LPS at 2 h after its administration produced a significant decrease in mean arterial pressure that was blocked by
phosphoramidon treatment. LPS at 2 and 24 h produced a significant elevation in the concentration of left ventricular
endothelin-1 (ET-1) both in heart and plasma as compared with control group. This LPS-induced left ventricular ET-1 elevation at 24 h was significantly reduced by
phosphoramidon. No significant alterations were observed in the myocardial
protein expression of preproET-1, iNOS, and eNOS at 2 h post LPS. In 24-h post treatment groups
phosphoramidon upregulated the expression of myocardial preproET-1
protein both in control and endotoxemic rat groups. Also, LPS-induced upregulated
protein expression of myocardial-
inducible nitric oxide synthase and increased levels of
nitric oxide byproducts at 24 h were blocked by
phosphoramidon.
Phosphoramidon inhibited LPS-induced down-regulated expression of myocardial
endothelial nitric oxide synthase and upregulated p38-MAPK phosphorylation. These results indicated that inhibition of
metalloendopeptidase during induction of
endotoxemia could regulate the phosphorylation of myocardial p38-MAPK and iNOS
protein expression at 24-h post
endotoxemia. We concluded that inhibition of
metalloendopeptidases during early
endotoxemia not only decreased the biosynthesis of ET-1 in heart locally but also simultaneously down-regulated myocardial
protein expression of iNOS and p38-MAPK phosphorylation in the later stage of
endotoxemia.