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.


METHODS
Randomized, controlled, interventional trial.


METHODS
University animal laboratory.


METHODS
A total of 65 male New Zealand White rabbits, randomly assigned to one of eight groups.


METHODS
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.


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.


CONCLUSIONS
These data suggest that perindopril can prevent endothelial dysfunction in endotoxin-induced shock through an NO-dependent mechanism.
Wiel
Eric
E
Department of Anesthesiology, Lille University Hospital, Lille, France.
Pu
Qian
Q
Leclerc
Jérôme
J
Corseaux
Delphine
D
Bordet
Régis
R
Lund
Niels
N
Jude
Brigitte
B
Vallet
Benoît
B
D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001784:Blood Gas Analysis; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006487:Hemostasis / Q000187:drug effects*; D007150:Immunohistochemistry; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020913:Perindopril / Q000494:pharmacology*; D011817:Rabbits; D012044:Regression Analysis; D012772:Shock, Septic / Q000139:chemically induced / Q000503:physiopathology*; D018709:Statistics, Nonparametric
D000806:Angiotensin-Converting Enzyme Inhibitors; D019331:NG-Nitroarginine Methyl Ester; D020913:Perindopril