Effects of candesartan and enalaprilat on the organ-specific microvascular permeability during haemorrhagic shock in rats

To counteract the contribution of angiotensin II to shock-induced ischaemic organ damage pharmacologic blockade of the renin–angiotensin-system (RAS) is currently under investigation. To evaluate potential side-effects of RAS blockade regarding capillary leak, we studied alterations in microvascular...

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Bibliographic Details
Published in:British journal of anaesthesia : BJA 2006-04, Vol.96 (4), p.437-443
Main Authors: Schumacher, J, Puchakayala, M.R., Binkowski, K, Eichler, W, Dendorfer, A, Klotz, K.-F.
Format: Article
Language:English
Subjects:
ACE-inhibitor
ACE-inhibitor, enalaprilat
albumin
Anesthesia
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Angiotensin II Type 1 Receptor Blockers - pharmacology
Angiotensin-Converting Enzyme Inhibitors - pharmacology
Animals
AT1-receptor antagonists
AT1-receptor antagonists, candesartan
Benzimidazoles - pharmacology
Biological and medical sciences
candesartan
Capillary Permeability - drug effects
Coloring Agents
enalaprilat
Enalaprilat - pharmacology
Evans Blue
extravasation
Extravasation of Diagnostic and Therapeutic Materials - etiology
heart
heart, ischaemia
Hemodynamics - drug effects
Ileum - blood supply
ischaemia
Kidney - blood supply
Lactic Acid - blood
Male
Medical sciences
Oxygen Consumption - drug effects
protein
protein, albumin
Rats
Rats, Sprague-Dawley
Renin-Angiotensin System - drug effects
Shock, Hemorrhagic - physiopathology
Tetrazoles - pharmacology
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Summary:To counteract the contribution of angiotensin II to shock-induced ischaemic organ damage pharmacologic blockade of the renin–angiotensin-system (RAS) is currently under investigation. To evaluate potential side-effects of RAS blockade regarding capillary leak, we studied alterations in microvascular permeability in various organs during haemorrhagic shock (HS) in rats pretreated with candesartan (AT1-receptor antagonism) or enalaprilat (ACE-inhibition). Thirty-eight instrumented and anaesthetized animals received either candesartan, enalaprilat or placebo. Within each of the three groups 6–7 animals were exposed to HS and 6 animals of each group served as normovolaemic controls. After 30 min of shock, 50 mg kg−1 Evans blue (EB) was injected i.v. followed by a distribution period of 20 min. Exsanguination was performed with saline, before harvesting organs to quantify albumin-bound EB extravasation. To reduce cardiac output from 37.5 (1.3) to 20.4 (1.1) ml min−1 [mean (sem)] in the shock groups, withdrawal of 4.0 (0.25) ml [mean (sem)] blood was necessary. Simultaneously mean arterial pressure decreased from 77.5 (3.2) to 36.1 (2) mm Hg. Serum lactate increased significantly from 1.3 (0.1) to 3.5 (0.24) mmol litre−1. Treatment with candesartan increased EB extravasation in the kidney in normovolaemic controls. Specific AT1 and ACE-blockade before acute nonresuscitated HS significantly increased EB extravasation in the rat ileum by 53 and 66%, respectively. This observation of increased microvascular albumin extravasation should be borne in mind for any interventional use of candesartan or enalaprilat during circulatory stress.
ISSN:0007-0912
1471-6771
DOI:10.1093/bja/ael030