Bigendothelin-1 (1-21) fragment during early sepsis modulates tau, p38-MAPK phosphorylation and nitric oxide synthase activation.
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.
Brahmbhatt
Sachin
S
Cardionome Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, 208, Sudro Hall, Fargo, ND, USA.
Gupta
Akanksha
A
Sharma
Avadhesh C
AC
D000818:Animals; D019332:Endothelin-1 / Q000097:blood / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism*
D019332:Endothelin-1; D010446:Peptide Fragments; D016875:tau Proteins; D009569:Nitric Oxide; 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