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.