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.
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
J
J
Schumacher
M R
MR
Puchakayala
K
K
Binkowski
W
W
Eichler
A
A
Dendorfer
K-F
KF
Klotz
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