Effects of candesartan and enalaprilat on the organ-specific microvascular permeability during haemorrhagic shock in rats.
BACKGROUND
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 (AT(1)-receptor antagonism) or enalaprilat (ACE-inhibition).


METHODS
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.


RESULTS
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 AT(1) and ACE-blockade before acute non-resuscitated HS significantly increased EB extravasation in the rat ileum by 53 and 66%, respectively.


CONCLUSIONS
This observation of increased microvascular albumin extravasation should be borne in mind for any interventional use of candesartan or enalaprilat during circulatory stress.
Schumacher
J
J
Department of Anaesthetics, Guy's and St Thomas' Hospital and NHS Foundation Trust, Lambeth Palace Road, London SE1 7EH, UK. jan.schumacher@gstt.sthames.nhs.uk
Puchakayala
M R
MR
Binkowski
K
K
Eichler
W
W
Dendorfer
A
A
Klotz
K-F
KF
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002199:Capillary Permeability / Q000187:drug effects*; D004396:Coloring Agents; D015773:Enalaprilat / Q000494:pharmacology*; D005070:Evans Blue; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000209:etiology; D006439:Hemodynamics / Q000187:drug effects; D007082:Ileum / Q000098:blood supply; D007668:Kidney / Q000098:blood supply; D019344:Lactic Acid / Q000097:blood; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004396:Coloring Agents; D013777:Tetrazoles; D019344:Lactic Acid; D005070:Evans Blue; D015773:Enalaprilat; C081643:candesartan