BJA Advance Access originally published online on February 20, 2006
British Journal of Anaesthesia 2006 96(4):437-443; doi:10.1093/bja/ael030
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Effects of candesartan and enalaprilat on the organ-specific microvascular permeability during haemorrhagic shock in rats
1Department of Anaesthetics, Guy's and St Thomas' NHS Foundation Trust London, UK
2Department of Anaesthetics, University of Luebeck Germany
3Institute of Experimental and Clinical Pharmacology and Toxicology, University of Luebeck Germany
*Corresponding author: Department of Anaesthetics, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK. E-mail: jan.schumacher{at}gstt.sthames.nhs.uk
Accepted for publication December 20, 2005.
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Abstract |
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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 (AT1-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 AT1 and ACE-blockade before acute nonresuscitated HS significantly increased EB extravasation in the rat ileum by 53 and 66%, respectively.
Conclusion. This observation of increased microvascular albumin extravasation should be borne in mind for any interventional use of candesartan or enalaprilat during circulatory stress.
Keywords: ACE-inhibitor, enalaprilat; AT1-receptor antagonists, candesartan; extravasation; heart, ischaemia; protein, albumin
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Introduction |
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Angiotensin II is an important vasoconstrictor during hypovolaemia and has been suggested to contribute to shock-induced ischaemic organ damage.1 Therefore, pharmacologic blockade of the renin–angiotensin-system (RAS), initially using angiotensin-I-converting enzyme (ACE) inhibitors, is under investigation.2–5 Experimental studies showed that specific AT1 receptor blockade might enhance local organ perfusion during hypovolaemia more effectively, while having less effect on the systemic haemodynamic values compared with ACE-inhibitors. Aneman and colleagues6 found that candesartan given before acute hypovolaemia ameliorated mesenteric hypoperfusion in a pig model and Yilmaz and colleagues,7 using valsartan, presented similar results. The administration of candesartan before hypovolaemic shock failed to preserve porcine hepatic and renal circulation, but maintained mesenteric and jejunal mucosal perfusion.8 Because ACE is identical to kininase-II, which inactivates bradykinin (BK) and related kinins, potentiation of kinins might be responsible for the permeability effects of ACE-inhibitors.9 Experimental data show that during acute ACE-inhibition plasma extravasation is mediated by BK and substance P and that albumin extravasation from postcapillary venules can be found in murine stomach, small and large intestine, pancreas, urinary bladder, trachea and skin increasing 2- to 7-fold as a result of stimulation of tachykinin NK1 and bradykinin B2 receptors.10 AT1 receptor antagonists produce a concentration dependent inhibition of angiotensin II induced vasoconstriction without promoting BK accumulation.11 Therefore, the transcapillary shift of plasma fluid and proteins may be assumed to be less pronounced in this sort of RAS-antagonism. However, AT1 receptor blockade can also be associated with angioedema.12
During circulatory shock and cellular hypoxia, enhanced capillary permeability is associated with alterations in interstitial matrix composition and may contribute to target organ damage.13 Maintenance of physicochemical characteristics of the interstitial compartment is an important factor in regulating the delivery of vital nutrients including oxygen to the cell mass and the removal of waste products from the cellular compartments. As a consequence of major changes in capillary permeability, local tissue oedema may develop with an impairment of substrate exchange, leading to microcirculatory failure and organ damage.14
The pathology of fluid resuscitated haemorrhagic shock (HS) is divided into the first phase of hypoperfusion/ischaemia and the second phase of the reperfusion injury. Only limited data are available concerning microvascular damage during blockade of the RAS and HS before fluid resuscitation and reperfusion. The aim of our study was to determine the changes in capillary permeability with consecutive plasma extravasation in various organ tissues during acute severe unresuscitated HS, in the presence of ACE-inhibition by enalaprilat or AT1 receptor blockade by candesartan.
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Animals
This investigation was performed in accordance with governmental animal protection laws and the experiments were officially approved by the German governmental animal care and use committee (No. 22/o/22). We investigated 38 male Sprague–Dawley rats (median 310.5 g, range 250–375 g, age 56–63 days; Harlan Winkelmann, Germany). The animals were allowed to acclimate for a minimum of 5 days after arrival at the laboratory. They were maintained on alternating 12 h/12 h light/dark cycles, housed at 22°C (45% relative humidity) with free access to water and standard maintenance-diet (1320 Altromin, Lage-Lippe, Germany). No animal showed symptoms of respiratory infection.
General anaesthesia
We induced general anaesthesia by i.m. administration of pentobarbital (90 mg kg–1; Sanofi, Ceva, Hannover, Germany). Ten minutes later, the animals received S-ketamine i.m. (50 mg kg–1, Parke Davis/Pfizer, Karlsruhe, Germany). The animals were then placed on a heating pad in the supine position and breathed oxygen spontaneously via an insufflation mask until tracheostomy was completed. After tracheostomy the tracheal tube was connected to a small animal respirator (HSE Schuler, Typ 811, H. Sachs Electronics, Freiburg, Germany) and the lungs were ventilated with 100% oxygen at a rate of 75–90 bpm, tidal volume was set to keep the arterial partial pressure of carbon dioxide at 35 mm Hg. Arterial blood gases were analysed by an ABL 500 (Radiometer, Copenhagen, Denmark). Anaesthesia was maintained with pentobarbital and S-ketamine. Basal fluid demand was covered by continuous infusion of Ringer's solution (lactate free) at a rate of 5 ml kg–1 h–1.
Animal preparation and haemodynamic measurements
A portex catheter (o.d. 0.61 mm) was inserted in the jugular vein under sterile conditions. The right carotid artery was exposed and cannulated with PE-50 polyethylene tubing. Mean arterial pressure (MAP) and heart rate (HR) were monitored via a pressure transducer (Isotec-healthdyne Cardiovascular, Marietta, GA, USA). After instrumentation of the two vessels skin in the cervical region was sutured. After thoracotomy a perivascular ultrasonic flow probe (T106, Transonic Instruments, Ithaca, NY, USA) was wrapped around the proximal ascending aorta. MAP, HR and cardiac output [CO (determined ultrasonographically)] were continuously recorded. Body core temperature was measured via a rectal probe and maintained at 37°C with an overhead heating lamp and an underlying heating element.
Study protocol
Enalaprilat was dissolved in a vehicle solution (1 mg in 950 µl of phosphate buffered saline and 50 µl 1 M Na2CO3). Candesartan was also dissolved in an identical vehicle solution. Animals were randomized to receive i.v. bolus doses of enalaprilat (ENA, 1 mg kg–1), candesartan (CAND, 30 µg kg–1) or placebo (vehicle solution as described above) and were randomly allocated to shock or normovolaemic control groups. Figure 1 illustrates the study protocol.
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After preparation and instrumentation a stabilization period of 30 min was allowed. The animals received either enalaprilat, candesartan or vehicle i.v. at the end of the stabilization period. Haemorrhage was performed in the appropriate subgroups 20 min later by removing blood via the arterial line at a constant rate over 10 min, until CO was reduced to 50% of its baseline value. Animals were left in this critical state for the following 30 min. Animals in the control subgroups remained haemodynamically unchanged over the observation period.
Evans blue analysis
We used the tissue concentration of Evans blue (EB) as a marker for plasma extravasation. Complete and tight binding of the dye to serum albumin, and its complete extraction by formamide has been validated in the past.15–18 After 30 min of shock 50 mg kg–1 body weight EB (C.I.23960, Ch. K2561269, Merck KgaA, Darmstadt, Germany) were injected i.v. Exactly 20 min later, the right atrium of the heart was incised for exsanguination of the animal and evacuation of perfusate and dye. Immediately afterwards a 20 G cannula was placed into the apex of the left ventricle with its tip pointing into the aorta and the circulatory system was perfused with 0.9% NaCl containing heparin (100 U ml–1) until the fluid leaving the right atrium was clear. The applied perfusion volume was four times the calculated blood volume (7.46 ml per 100 g body weight19) of the individual animal. To optimize this technique, we inflated a pressurized infusion bag until a perfusion pressure of 40 mm Hg in the carotid artery was established. This previously described20 pressure controlled procedure allowed a standardized antegrade body perfusion in all animals. The exsanguination resulted in an immediate cardiac arrest. The animals were dissected and the heart, lungs, spleen, kidneys, liver, ileum, right gluteus maximus muscle and a part of the shaved skin were removed. Additionally, the lungs were perfused via the pulmonary artery with 10 ml of heparinized saline. Tissues were rinsed in saline, gently blotted and weighed. One half of each tissue was dried by incubation at 60°C for 48 h. EB was extracted from the remaining portion of tissue by incubation in pure formamide (4 ml g–1 tissue) (F-7503, Sigma Aldrich Chemie, Germany) at room temperature for 48 h. The supernatant was removed from the tissues and read against a formamide blank at 620 nm (Spectrophotometer, Beckmann DU 7400, Germany). Absorbance was compared with a standard curve of 0.05–50 µg ml–1 EB in formamide. Extravasation is expressed as microgram EB per gram dry tissue.
Statistical analysis
According to the guidelines of the governmental animal care and use committee, we were obliged to choose the smallest possible sample size for statistical testing. Data are expressed as mean (SEM). Intergroup comparisons were performed using Kruskal–Wallis H-test with post hoc analysis using the Mann–Whitney U-test. For intragroup comparisons we used the Friedman-test and the Wilcoxon-test for post hoc analysis. Probability values <0.05 were considered to show significance.
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We found no differences in baseline haemodynamic values between the six groups of animals (Table 1). The administration of enalaprilat and candesartan induced a significant reduction of MAP at 70 min in groups ENA-CTRL, CAND-CTRL, compared with the placebo group CTRL. This MAP reduction was similar in enalaprilat and candesartan treated animals.
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P<0.05 compared with ENA-HS 60 min. 
P<0.05 compared with CAND-CTRL 70 min. 
P<0.05 compared with CAND-HS 60 minFor animals in the haemorrhagic shock groups HS, ENA-HS and CAND-HS withdrawal of 4.0 (0.3) ml [mean, (SEM)] blood resulted in a 50% reduction of CO. This haemorrhage volume amounts to 17.4% of the calculated total blood volume according to:19 blood volume=7.46 ml per 100 g body weight. HR was minimally affected, MAP values showed a significant reduction by 40–50%.
Effects of haemorrhage on serum lactate
In all haemorrhaged animals blood lactate levels showed a significant increase (Table 2). Bicarbonate and base excess values differed significantly at the end of the shock period.
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Effects of haemorrhage on organ-specific extravasation of albumin-bound EB
After haemorrhage, in animals without RAS blockade, a general tendency of EB extravasation was observed, which was significant in the kidney and lungs (Table 3).
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Effects of RAS blockade on organ-specific extravasation of albumin-bound EB
RAS blockade in the CTRL groups resulted in an increased EB extravasation in the kidney and this was significant only in the CAND group. A trend towards increased hepatic EB extravasation was observed in CAND treated animals.
Effects of RAS blockade on organ-specific extravasation of albumin-bound EB during HS
After haemorrhage there was a significant increase in ileal EB extravasation in the CAND (66%) and in the ENA (53%) treated animals compared with the CTRL group. This effect did not differ between the treatments (Table 3).
A tendency of reduced cardiac EB extravasation was seen in both the drug treated animals.
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Discussion |
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In this investigation, the impact of unresuscitated haemorragic shock on organ-specific capillary leak after pretreatment with RAS antagonists was studied. The pathology of fluid resuscitated HS is divided into the first phase of hypoperfusion/ischaemia and the second phase of the reperfusion injury. Only limited data are available concerning microvascular damage during RAS blockade and HS before fluid resuscitation and reperfusion.
Rats are frequently used as models for HS and two types of indirect shock control have been described. One model withdraws blood until the arterial blood pressure is reduced to a certain value.21 22 In the other, a fixed blood volume is removed.23 24 Gainer and colleagues25 reported that survival rates from constant-volume studies are less reproducible and literature indicates that even in repeated experiments comparison of different investigators can be difficult. Therefore, investigations on HS in the presence of drugs acting on vascular resistance, require a model of arterial pressure independent shock control. In hypovolaemic shock, decreased CO reduces the delivery of oxygen and other nutrients to the tissues. This in turn reduces the metabolism of virtually all cells of the body, leading to multiple types of cellular damage. In our investigation the reduction of CO by 50% was achieved by a mean total blood loss of 4.0 ml. This strong reduction of oxygen delivery of the tissues generated a significant increase in plasma lactate, a base deficit and a decrease in bicarbonate indicating a succesful performance of desired shock level.
In this study enalaprilat was used for ACE-inhibition and candesartan for AT1 receptor blockade. Enalaprilat is the primary active diacid metabolite of enalapril and has a faster onset than its prodrug. The angiotensin AT1 receptor antagonist candesartan displays more than 1000-fold higher affinity for the angiotensin II, type AT1 receptor than for the AT2 subtype. Its receptor affinity is higher than that of losartan and the binding is unsurmountable.26 The significant MAP reduction after drug administration was equivalent in the 1 mg kg–1 dosage of enalaprilat and the 30 µg kg–1 dosage of candesartan treated groups. Dosages were chosen according to haemodynamic experience in our laboratory27 and of other investigators.6 Because of the long plasma half-lives of the drugs even in rats28 29 a continuous infusion was not necessary during the 80-min observation period. In addition, the drugs were administered under invasive haemodynamic monitoring to accurately identify onset times and blood pressure reductions.
To determine the alteration of capillary permeability, we used tissue concentration of EB as a marker for albumin extravasation. Complete and tight binding of the dye to serum albumin, and its complete extraction by formamide has been validated in the past.15–18 According to the heterogeneity of capillary permeability and perfusion determinants under normal conditions, EB bound albumin varies 
10-fold from one organ to another. The distribution of EB in the various tissues of our control animals corresponds to published data.13
Maintenance of the interstitial compartment's physicochemical characteristics is of crucial importance for the adequate delivery of vital nutrients including oxygen to the cell mass. Well known consequences of major changes in capillary permeability are local tissue oedema formation with impairment of substrate exchange, leading to organ damage.14
Alterations of capillary permeability may occur during various disease processes: Spontaneously hypertensive rats have been described to be susceptible for a selective BK related increase in renal capillary permeability,30 furthermore, antihypertensive drugs are known to induce capillary permeability disturbances.31 Additionally, in experimental models designed to imitate cerebral,32 coronary,33 mesenteric,34 renal35 or skeletal muscle hypoperfusion,36 it has been established, that plasma extravasation into the interstitial space, and cellular oedema, contribute to aggravation of microcirculatory disturbances.13
We found a tendency to increased capillary permeability in the kidney of normovolaemic rats after acute ACE-inhibition with enalaprilat and a significant capillary leak with candesartan. In this context it has been hypothesized, that AT2 receptor stimulation by elevated angiotensin II levels during AT1 blockade may activate the Kinin–Kallikrein system37 or induce BK production.38 This might explain clinical reports of angioedema development in the presence of AT1 receptor blocker treatment.12
The initial responses to hypovolaemic circulatory shock are powerful sympathetic reflexes aimed at the maintenance of normal arterial pressure in the face of decreasing CO. Blood flow through the heart and brain is maintained essentially at normal levels, despite the fact that blood flow in many other areas might be decreased to as little as one-quarter of normal because of vasospasm.39 HS generates selective mesenteric ischaemia by producing a disproportionate mesenteric vasospasm that is mediated primarily by the renin–angiotensin axis.40 41 After this physiological response, shock might become progressive because of persistent mesenteric vasoconstriction and failure of the intestinal mucosal barrier. Angiotensin II as an important vasoconstrictor during hypovolaemia has been suggested to contribute to shock-induced organ damage1 so that experimental pharmacological blockade of the RAS to counteract mesenteric hypoperfusion is currently under investigation.6–8 42 Unfortunately, ACE-inhibitors are known to have the potential to increase albumin extravasation in various tissues by potentiation of kinins,9 10 43 whereas AT1 receptor antagonists lack BK accumulation. Therefore, the transcapillary shift of plasma fluid and proteins during normovolaemia can be assumed to be less, but no data have been available regarding capillary alterations during hypovolaemic shock. In particular, the transcapillary hydrostatic pressure gradients in different organ networks are not defined during HS shock in the presence of RAS blockade. In spontaneously hypertensive rats, Kanagawa and colleagues44 reported that administration of enalapril and candesartan significantly increased renal blood flow using a coloured dye-extraction microsphere technique. Both substances tended to increase splanchnic blood flows and no changes were observed in various other organs. However after HS our results showed increased renal albumin extravasation in the control and ENA groups only. This may be attributed to the fact that in the CAND group, where renal extravasation was already significantly increased during normovolaemia, there was no further increased extravasation after HS.
Aneman and colleagues6 demonstrated in a porcine model of acute haemorrhage that candesartan ameliorated the shock-induced reduction of mesenteric perfusion. Our results demonstrated that enalaprilat and candesartan increased EB extravasation in the ileum during HS by 53 and 66% respectively. This finding might be either a result of increased splanchnic blood flow or shock related systemic inflammatory mediator release or a combination of both, however our experimental model could not explain this difference.
The limitation of our study in this context may be attributed to the fact that capillary extravasation using net-filtration of albumin and not direct blood-flow is measured. Thus our results can be influenced by the flow-reduction phenomenon during HS, which may explain the small decrease in EB extravasation seen in the CTRL group. In the presence of a RAS blocker this phenomenon is ameliorated leading to increased extravasation. Using an experimental model that examines simultaneous microvascular flow and extravasation may differentiate these mechanisms, however such a model has not yet been established.
Furthermore, in the context of HS, specific AT1 receptor blockade did not prove superior to ACE-inhibition regarding microvascular permeability.
In addition, we observed an insignificant trend towards increased hepatic EB extravasation in CAND treated normovolaemic animals and a reduced cardiac EB extravasation in both the drug treated animals after HS. It remains unclear which definitive mechanisms are responsible for each organ-specific alteration.
General anaesthesia was administered identically to all the animals before intervention, thus any possible interactions with RAS blockers and physiological shock states would have equally influenced all six groups of animals. In addition ketamine probably reduced some of the cardiac depressant effects of anaesthesia.
In conclusion, our findings indicate that countermeasures against renin–angiotensin activation in the mesenteric circulation may exert a potential side-effect of increased albumin extravasation. The observed alterations of increased mesenteric capillary albumin extravasation should be borne in mind for any interventional use of candesartan or enalaprilat during circulatory stress. Further studies of simultaneous evaluation of microcirculatory flow and albumin leakage are needed to evaluate the physiological consequences of the observed albumin extravasation.
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Acknowledgments |
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The authors gratefully acknowledge the support of Dipl. Psych. Prof. Dr Hüppe, for the statistical analysis and Dunja Schumacher for her technical support (both affiliated to the Department of Anaesthetics, University of Luebeck). The authors wish to thank Dr F. Simmersbach (Astra Zeneca GmbH) for the generous gift of Candesartan and Dr A. Wöhrmann (MSD Sharp & Dome GmbH) for the generous gift of Enaprilat.
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