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

Abstract

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). 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 AT(1) and ACE-blockade before acute non-resuscitated 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.