Effects of the angiotensin-converting enzyme inhibitor perindopril on endothelial injury and hemostasis in rabbit endotoxic shock

Objective. To assess the effects of the angiotensin-converting enzyme (ACE) inhibitor (ACEI) perindopril on prolonged endothelial cell dysfunction in a rabbit endotoxic model. Design. Randomized, controlled, interventional trial. Setting. University animal laboratory. Subjects. A total of 65 male New Zealand White rabbits, randomly assigned to one of eight groups. Interventions. Endotoxic shock was induced by a single lipopolysaccharide (LPS, serotype O55:B5) bolus (0.5 mg.kg(-1), i.v., Escherichia coli endotoxin). Coagulation factors and expression of monocyte tissue factor (TF) were determined by functional assay. Endothelium-dependent vascular relaxation was assessed by in vitro vascular reactivity. Immunohistochemical staining (CD31) was performed to assess endothelial injury of the abdominal aorta. These parameters were studied 5 days (D5) after the onset of endotoxic shock. Rabbits were randomized to receive perindopril (1 mg kg(-1) day(-1) orally) alone, or with N-G-nitro-L-arginine methyl ester (L-NAME; 15 mg kg(-1) day(-1) orally), or L-NAME alone initiated 7 days before the onset of endotoxic shock and maintained for 5 days afterward. Measurements and results. Perindopril prevented altered endothelium-dependent relaxation to acetylcholine induced by LPS injection (E-max=75.6+/-3.7 vs 42.3+/-9.4% in LPS group, p<0.05). This effect was inhibited by co-treatment with L-NAME. Perindopril had no effect on either LPS-induced endothelial histological injury or monocyte TF expression. Conclusion. These data suggest that perindopril can prevent endothelial dysfunction in endotoxin-induced shock through an NO-dependent mechanism.