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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.
AuthorsAkanksha Gupta, Avadhesh C Sharma
JournalShock (Augusta, Ga.) (Shock) Vol. 20 Issue 4 Pg. 375-81 (Oct 2003) ISSN: 1073-2322 [Print] United States
PMID14501953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Endothelin-1
  • Glycopeptides
  • Lipopolysaccharides
  • Protease Inhibitors
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos2 protein, rat
  • Nos3 protein, rat
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Metalloendopeptidases
  • phosphoramidon
Topics
  • Animals
  • Blood Pressure (drug effects)
  • Endothelin-1 (blood, metabolism)
  • Endotoxemia (enzymology, physiopathology)
  • Glycopeptides (pharmacology)
  • Heart (drug effects)
  • Lipopolysaccharides (toxicity)
  • Male
  • Metalloendopeptidases (antagonists & inhibitors)
  • Mitogen-Activated Protein Kinases (metabolism)
  • Models, Biological
  • Myocardium (enzymology)
  • Nitric Oxide Synthase (metabolism)
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Phosphorylation
  • Protease Inhibitors (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • p38 Mitogen-Activated Protein Kinases

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