title: Metalloendopeptidase inhibition regulates phosphorylation of p38-mitogen-activated protein kinase and nitric oxide synthase in heart after endotoxemia.
abstract: 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.
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism; D019446:Endotoxemia / Q000201:enzymology* / Q000503:physiopathology; D006020:Glycopeptides / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D019332:Endothelin-1; D006020:Glycopeptides; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008666:Metalloendopeptidases; C008890:phosphoramidon