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

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Abstract

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 NG-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 (Emax=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.

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Acknowledgements

The ACE activity measurements were performed in collaboration with Dr. Racadot and Mrs. Michiels, Department of Biochemistry and Perinatal Endocrinology (University Hospital of Lille). Perindopril was kindly provided by Institut de Recherches Internationales Servier, France.

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Author notes

  1. Benoît Vallet

    Present address: Département d’Anesthésie-Réanimation 2, Hôpital Claude Huriez, Centre Hospitalier Universitaire de Lille, 59037, Lille cedex, France

Authors and Affiliations

  1. Departments of Anesthesiology and Intensive Care, Lille University Hospital, Lille, France

    Eric Wiel, Jérôme Leclerc & Benoît Vallet

  2. Department of Pharmacology, Lille University Hospital, Lille, France

    Qian Pu & Régis Bordet

  3. Department of Hematology, Lille University Hospital, Lille, France

    Delphine Corseaux & Brigitte Jude

  4. Department of Anesthesiology, University of Rochester, Rochester, New York, USA

    Niels Lund

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  1. Eric Wiel
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Correspondence to Benoît Vallet.

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Wiel, E., Pu, Q., Leclerc, J. et al. Effects of the angiotensin-converting enzyme inhibitor perindopril on endothelial injury and hemostasis in rabbit endotoxic shock. Intensive Care Med 30, 1652–1659 (2004). https://doi.org/10.1007/s00134-004-2198-4

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  • DOI: https://doi.org/10.1007/s00134-004-2198-4

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