Activated protein C increases sensitivity to vasoconstriction in rabbit Escherichia coli endotoxin-induced shock

Introduction 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. Method 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 N-G-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 mu M in rings with endothelium (E+) versus 1.0 +/- 0.2 mu M in E-rings ( p < 0.05) in the LPS+ aPC group versus 2.4 +/- 0.3 mu M in E+ rings versus 2.2 +/- 0.2 mu M 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). Conclusion 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.