Bigendothelin-1 (1-21) fragment during early sepsis modulates tau, p38-MAPK phosphorylation and nitric oxide synthase activation.

Abstract

Earlier we have demonstrated that inhibition of endothelin biosynthesis ameliorates endotoxemia-induced inducible nitric oxide synthase (iNOS) activation and phosphorylation of p38-mitogen activated protein kinase (pp38-MAPK). Therefore, in the present study, we tested the hypothesis that activation of endothelin (ET)-1 biosynthesis using bigET-1 during early sepsis would upregulate iNOS and affect myocardial function in the rat. Male Sprague-Dawley rats (350-400 g) were anesthetised using Nembutal (50 mg/kg, i.p.) and jugular vein, tail artery (Mean arterial pressure, MAP) and right carotid arteries (advanced to left ventricle, LV) were cannulated. The rats were randomly divided into saline-, bigET-1- and C-terminal fragment of bigET-1 (bigET-1(22-38))-treated groups. Sepsis was induced using i.p. injection of cecal inoculum obtained from a donor rat (200 mg/kg in 5 ml 5% sterile dextrose water, D5W). Sham animals received an i.p. injection of D5W (5 ml/kg). MAP and LVP were recorded and cardiodynamic parameters were calculated at 0, 2, 6, 12 and 24 h post sham or sepsis-induction. A significant elevation in LV isovolumic relaxation rate constant (tau), LV end diastolic pressure (LVEDP) and rate pressure product (RPP) was observed in vehicle-treated septic group at 24 h. BigET-1 significantly increased concentration of LV ET-1 both in sham and septic groups. BigET-1 elevated tau and LVEDP both in sham and septic animals as early as 12 h which persisted through 24 h. However, bigET-1(22-38) elevated LVEDP in septic group at 24 h but not in sham group. BigET-1 accentuated the levels of plasma nitric oxide byproduct (NOx) levels in both sham and septic animals at 6, 12 and 24 h. Sepsis increased myocardial iNOS at 24 h. BigET-1 significantly upregulated expression of myocardial iNOS and pp38-MAPK. The data suggest that increased substrate availability for ET-1 at the time of sepsis-induction contributes in diastolic dysfunction, iNOS activation and p38-MAPK phosphorylation.

• Authors: Sachin Brahmbhatt, Akanksha Gupta, Avadhesh C Sharma
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 271 Issue 1-2 Pg. 225-37 (Mar 2005) ISSN: 0300-8177 [Print] Netherlands
• PMID: 15881674 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Endothelin-1
• Peptide Fragments
• tau Proteins
• Nitric Oxide
• 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

Topics

• Animals
• Endothelin-1 (blood, drug effects, metabolism)
• Enzyme Activation
• Hemodynamics (drug effects)
• Male
• Mitogen-Activated Protein Kinases (drug effects, metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase (drug effects, metabolism)
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Peptide Fragments (pharmacology)
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• Sepsis (metabolism)
• Ventricular Dysfunction, Left (metabolism)
• p38 Mitogen-Activated Protein Kinases (drug effects, metabolism)
• tau Proteins (drug effects, metabolism)