Activated protein C increases sensitivity to vasoconstriction in rabbit Escherichia coli endotoxin-induced shock.
BACKGROUND
The aim of this study was to investigate the effects of activated protein C (aPC) on vascular function, endothelial injury, and haemostasis in a rabbit endotoxin-induced shock model.


METHODS
This study included 22 male New Zealand rabbits weighing 2.5 to 3 kg each. In vitro vascular reactivity, endothelium CD31-PECAM1 immunohistochemistry, plasma coagulation factors and monocyte tissue factor (TF) expression were performed 5 days (D5) after onset of endotoxic shock (initiated by 0.5 mg/kg intravenous bolus of Escherichia coli lipopolysaccharide (LPS)) with or without treatment with aPC injected as an intravenous 2 mg/kg bolus 1 hour after LPS (LPS+aPC group and LPS group, respectively).


RESULTS
LPS decreased the sensitivity to phenylephrine (PE) in aortic rings without endothelium (E-) when compared to E- rings from the control group (p < 0.05). This was abolished by NG-nitro-L-arginine methyl ester and not observed in E- rings from aPC-treated rabbits. Although aPC failed to decrease monocyte TF expression in endotoxinic animals at D5, aPC treatment restored the endothelium-dependent sensitivity in response to PE (2.0 +/- 0.2 muM in rings with endothelium (E+) versus 1.0 +/- 0.2 microM in E- rings (p < 0.05) in the LPS+aPC group versus 2.4 +/- 0.3 microM in E+ rings versus 2.2 +/- 0.2 microM in E- rings (p value not significant), in the LPS group). Endotoxin-induced de-endothelialisation was reduced by aPC at D5 (28.5 +/- 2.3% in the LPS+aPC group versus 40.4 +/- 2.4% in the LPS group, p < 0.05).


CONCLUSIONS
These data indicate that aPC increased the sensitivity to a vasoconstrictor agent (PE) associated with restoration of endothelial modulation, and protected against endothelial histological injury in endotoxin-induced shock. It failed to inhibit TF expression at D5 after LPS injection.
Wiel
Eric
E
EA 1046, Laboratory of Pharmacology, University Hospital of Lille, France. e-wiel@chru-lille.fr
Costecalde
Marion Elizabeth
ME
Lebuffe
Gilles
G
Corseaux
Delphine
D
Jude
Brigitte
B
Bordet
Régis
R
Tavernier
Benoît
B
Vallet
Benoît
B
D000818:Animals; D004731:Endotoxins / Q000633:toxicity*; D006801:Humans; D008297:Male; D011486:Protein C / Q000633:toxicity*; D011817:Rabbits; D012772:Shock, Septic / Q000097:blood* / Q000503:physiopathology*; D014661:Vasoconstriction / Q000502:physiology*
D004731:Endotoxins; D011486:Protein C; C044101:endotoxin, Escherichia coli