Effects of thrombin inhibition with melagatran on renal hemodynamics and function and liver integrity during early endotoxemia.
Sepsis is associated with an activation of the coagulation system and multiorgan failure. The aim of the study was to examine the effects of selective thrombin inhibition with melagatran on renal hemodynamics and function, and liver integrity, during early endotoxemia. Endotoxemia was induced in thiobutabarbital-anesthetized rats by an intravenous bolus dose of lipopolysaccharide (LPS; 6 mg/kg). Sham-Saline, LPS-Saline, and LPS-Melagatran study groups received isotonic saline or melagatran immediately before (0.75 micromol/kg iv) and continuously during (0.75 micromol.kg(-1).h(-1) iv) 4.5 h of endotoxemia. Kidney function, renal blood flow (RBF), and intrarenal cortical and outer medullary perfusion (OMLDF) measured by laser-Doppler flowmetry were analyzed throughout. Markers of liver injury and tumor necrosis factor (TNF)-alpha were measured in plasma after 4.5 h of endotoxemia. In addition, liver histology and gene expression were examined. Melagatran treatment prevented the decline in OMLDF observed in the LPS-Saline group (P < 0.05, LPS-Melagatran vs. LPS-Saline). However, melagatran did not ameliorate reductions in mean arterial pressure, RBF, renal cortical perfusion, and glomerular filtration rate or attenuate tubular dysfunctions during endotoxemia. Melagatran reduced the elevated plasma concentrations of aspartate aminotransferase (-34 +/- 11%, P < 0.05), alanine aminotransferase (-21 +/- 7%, P < 0.05), bilirubin (-44 +/- 9%, P < 0.05), and TNF-alpha (-32 +/- 14%, P < 0.05) in endotoxemia. Melagatran did not diminish histological abnormalities in the liver or the elevated hepatic gene expression of TNF-alpha, intercellular adhesion molecule-1, and inducible nitric oxide synthase in endotoxemic rats. In summary, thrombin inhibition with melagatran preserved renal OMLDF, attenuated liver dysfunction, and reduced plasma TNF-alpha levels during early endotoxemia.
Nitescu
Nicoletta
N
Department of Anesthesiology and Intensive Care, Institute of Clinical Sciences, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. nicoletta.nitescu@vgregion.se
Grimberg
Elisabeth
E
Ricksten
Sven-Erik
SE
Marcussen
Niels
N
Nordlinder
Hans
H
Guron
Gregor
G
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D019446:Endotoxemia / Q000139:chemically induced / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D008070:Lipopolysaccharides; C109573:melagatran; D013917:Thrombin