Haemodynamic effects of an angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist during hypovolaemia in the anaesthetized pig

F. Ryckwaert*,1,2, P. Colson1,2, E. André1, P.-F. Perrigault1, G. Guillon2 and C. Barberis2

1 Faculté de Médecine, Université-Montpellier I, Montpellier, France. 2 INSERM U 469, Montpellier, France*Corresponding author: Service d’anesthésie-réanimation, Hôpital Arnaud de Villeneuve, Avenue du Doyen Giraud, F-34295 Montpellier, France

Accepted for publication: May 15, 2002


    Abstract
 Top
 Abstract
 Introduction
 Results
 Discussion
 References
 
Background. Renin–angiotensin system antagonists, either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor (AT1) antagonists, may interfere with regulation of arterial pressure during anaesthesia. This study aimed to compare the haemodynamic profile of anaesthetized pigs, which were subjected to haemorrhage in the presence of the ACE inhibitor enalaprilat or the AT1 antagonist valsartan.

Methods. Thirty-six pigs were assigned randomly to placebo, enalaprilat or valsartan groups. After a 30-min period of stabilization following anaesthesia and injection of the study drug, the animals were bled in two equal steps of 20% of their estimated blood volume (20% BV and 40% BV).

Results. After bleeding of 20% BV, the mean arterial pressure (MAP) decreased significantly but similarly in each group (20–25%) but the placebo and the enalaprilat groups had a significant decrease in cardiac index (CI, 22% and 16%, respectively) without significant change in systemic vascular resistance (SVR). Conversely, in the valsartan group, SVR decreased significantly (23%, P<0.02 vs other groups) without significant change in CI (–4%). After bleeding of 40% BV, the CI decreased significantly compared with 20% BV in the three groups (19% in the placebo and enalaprilat groups, 14% in the valsartan group) but the MAP decreased significantly in the enalaprilat group only (23%). The SVR increased significantly in the placebo group (P<0.01 vs each of the other groups), but there were no differences in the change in SVR between the other groups.

Conclusion. Blockade of the renin–angiotensin system by either enalaprilat or valsartan leads to a similar decrease in arterial pressure during anaesthesia and haemorrhage but the haemodynamic profiles are quite different.

Br J Anaesth 2002; 89: 599–604

Keywords: arterial pressure, hypertension; complications, hypervolaemia; enzymes, angiotensin-converting enzyme, inhibition; model, pig; hormones, renin


    Introduction
 Top
 Abstract
 Introduction
 Results
 Discussion
 References
 
Renin–angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor (AT) antagonists, are increasingly used in the treatment of cardiovascular and other diseases.1 2 Because angiotensin II is involved in short-term regulation of arterial pressure, the blockade of its effect by inhibition of either angiotensin II production (ACE inhibitor) or the AT-receptor-mediated effect (AT antagonist) may interfere with arterial pressure regulation.36 During anaesthesia and surgery, arterial pressure may become angiotensin dependent.7 The anaesthesia-induced reduction in sympathetic tone may be counterbalanced by angiotensin II, especially when a reduction in intravascular volume is involved.8 Accordingly, arterial pressure may decrease markedly during general anaesthesia when angiotensin II action is impeded by an angiotensin II competitive inhibitor.911

Much of the information regarding the physiology and pathophysiology of the renin–angiotensin system during anaesthesia and surgery has been based on studies of ACE inhibitors. Many cardiovascular effects are shared by ACE inhibitors and AT antagonists, and this is particularly true with regard to the short-term actions of angiotensin II on arterial pressure regulation. ACE is a non-specific carboxypeptidase involved in the conversion of angiotensin I to angiotensin II and in the inactivation of central opioids, enkephalins and bradykinin, a potent vasodilator. Inactivation of angiotensin II formation is, nevertheless, accepted to be the main mechanism of ACE inhibition.1 AT antagonists have potential therapeutic interest:2 first, they should not induce the bradykinin-related side-effects of ACE inhibitors, such as cough, which occurs in 10–20% of patients receiving ACE inhibitors. Secondly, because they competitively block specific receptors (AT1), AT antagonists should suppress angiotensin II effects better than ACE inhibitors. Indeed, blockade of the converting enzyme favours other metabolic pathways leading to angiotensin II synthesis, especially the chymase pathway. However, the real importance of such converting-enzyme-independent angiotensin II synthesis is not well known. In addition, because the reduction in bradykinin breakdown caused by ACE inhibitors could participate in their therapeutic effect, AT antagonists may not provide a similar therapeutic profile. However, during AT1 blockade, AT2 receptors remain exposed to increasing levels of angiotensin II which could be a source of synergistic effects, as activation of AT2 receptors has the opposite effect to activation of AT1 receptors. Hence, stimulation of AT2 receptors by increasing levels of angiotensin synergistically augments the effects of AT1 receptor blockade.6 12 Thus, the differences between ACE inhibitors and AT antagonists in the blockade of the renin–angiotensin system might lead to some haemodynamic consequences following stimulation of the renin–angiotensin system.

Clinical recommendations for the treatment of hypotensive episodes after induction of anaesthesia do not discriminate between ACE inhibitors and AT antagonists any more than they ascertain the role of changes in either cardiac output (CO) or vascular resistance (VR) in the mechanisms of hypotension.9 11 13 Therefore, in an attempt to reveal differences between the two treatments, we compared the haemodynamic profile of anaesthetized pigs subjected to haemorrhage, and therefore dependent on the renin– angiotensin system for maintenance of arterial pressure, in the presence of a non-specific blockade of renin– angiotensin system with an ACE inhibitor and in the presence of a specific blockade of AT1 receptors.

Materials and methods
Animals and preparation
Experiments were performed on female commercial farm-bred piglets (2–3 months, 15–22 kg). The study was approved by the Animal Care and Use Committee of our institution.

The animals were fasted except for water ad libitum for 12 h before induction of anaesthesia. The animals were premedicated with i.m. ketamine 20 mg kg–1, midazolam 0.5 mg kg–1 and atropine 2 mg. An i.v. catheter was placed in an ear vein and lactated Ringer’s solution was infused at a rate of 1 ml kg–1 h–1 using an i.v. infusion pump. Anaesthesia was induced with thiopental 2–3 mg kg–1. The animal’s trachea was intubated and the lungs ventilated mechanically with 1% isoflurane in 100% oxygen, keeping the end-tidal isoflurane concentration at 0.8–1.0 MAC and the end-tidal carbon dioxide pressure between 35 and 40 mm Hg (Datex Lab., Ultima).

A branch of the external carotid artery was cannulated to measure mean arterial pressure (MAP). A thermodilution pulmonary artery catheter was placed via a jugular vein to measure the central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP). CO was determined by thermodilution using a separate central venous injection catheter, as the average of three consecutive measurements. Cardiac index (CI), indexed stroke volume (iSV) and indexed systemic VR (iSVR) were calculated using the following formulae:

CI = CO/body weight (ml kg–1)

iSV = CI/heart rate (ml kg–1)

iSVR = (MAP–CVP)/CI (IU kg)

Temperature was measured in the pulmonary artery and was maintained using a heating blanket. After surgical preparation, piglets were allowed to stabilise for 30 min. At the end of the stabilization period, baseline measurements of heart rate (HR), MAP, PCWP, CI, iSV and iSVR were performed. At this time, the animals were assigned to the study groups.

Animal groups and experimentation
Preliminary studies
First, two animals were studied without any haemorrhage or injection protocol in order to estimate the potential drift effect over the time of the study experiment. No significant fluctuation was seen during the 90-min procedure. The maximum variation was less than 10% at any time for any variable: 7% for MAP, 1% for HR, 3% for CI and 7% for iSVR.

Second, the efficacy of the renin–angiotensin system blockade with either the AT1 antagonist valsartan (Novartis Pharma, Basle, Switzerland) or the ACE inhibitor enalaprilat (Merck Sharp Dohme Chibret Laboratory, Paris, France) had been assessed through the inhibition of the agonist-induced increase in MAP. The agonists were angiotensin II and angiotensin I for enalaprilat and valsartan respectively, at a dose that increased MAP by at least 20%. We expected inhibition of the angiotensin-induced increase in MAP 90 min after the injection of the renin–angiotensin system blocker (which was the time required for the whole procedure) to be at least 50%. At a dose of 0.06 mg kg–1, the inhibitory effect of enalaprilat on the arterial pressure response to injection of angiotensin I was 84%, 90%, 67% and 57% at 30, 60, 90, 120 min after the injection, respectively. Similarly the inhibitory effect of valsartan 3 mg kg–1 on the arterial pressure response to injection of angiotensin II was 75%, 56%, 50% and 43% at 30, 60, 90 and 120 min after the injection, respectively.

Study protocol
Thirty-six animals were assigned randomly to placebo, enalaprilat or valsartan groups. Injection consisted of a 10 ml sodium chloride solution for the placebo. Enalaprilat 0.06 mg kg–1 was dissolved in 10 ml sodium chloride solution, and valsartan 3 mg kg–1 in 10 ml distilled water. The piglets were allowed to stabilize for a 30-min period before being bled in two equal steps. Twenty percent of the calculated blood volume (BV) (based on a BV of 70 ml kg–1) was removed over a 5-min period for each step.

Measurements consisted of HR, MAP, PCWP, CI, iSV and iSVR. After injection and after each stepped bleed, the animals were allowed to stabilize for 30 min and then measurements were collected 30 min after the injection and 30 min after each of the bleeds.

At the end of the experiment, the animals were killed with a central venous bolus injection of potassium chloride 40 mmol during deepened anaesthesia (MAC 2%).

Statistical analysis
Results are expressed as median [25%, 75% interquartile range] because some data were not normally distributed. Overall effects were evaluated by the Friedman test (within group) and Kruskal–Wallis analysis of variance (between groups). In the case of significant differences, further comparisons were made using Wilcoxon (within group) and Mann–Whitney U (between groups) tests. A value of P<0.05 was considered significant but the Bonferroni– Dunn procedure was used for correction of multiple comparisons when appropriate. A post-hoc power estimate (PHPE) with a confidence interval of 95% was performed when a statistically significant difference was observed between groups.


    Results
 Top
 Abstract
 Introduction
 Results
 Discussion
 References
 
The 36 animals were assigned randomly as follows: 13 placebo, 11 enalaprilat and 12 valsartan. Baseline values for HR, MAP, PCWP, iSVR, CI, and iSV are shown in Table 1. The end-tidal isoflurane concentration was 0.95% [0.8, 1.1] with no significant variation between groups or periods of measurement.


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Table 1 Haemodynamic data at baseline. Values represent median (interquartile range)
 
Effects of injection
Injections of placebo, enalaprilat or valsartan had no significant effect on MAP, PCWP, iSVR, CI and iSV. The haemodynamic profile was similar in each group, except for HR which after injection of valsartan decreased by 8% [3, 14] from baseline (P=0.022).

Effects of 20% BV haemorrhage (Fig. 1)
At the first bleed (20% BV), decreases in MAP from baseline were: 25% [21, 29] (P=0.002), 22% [19, 35] (P=0.003) and 25% [8, 33] (P=0.005) for the placebo, enalaprilat and valsartan groups, respectively. No significant difference was found between groups.

The decrease in MAP was associated with a decrease in CI in the placebo and enalaprilat groups: 22% [10, 29] (P=0.002) and 16% [4, 21] (P=0.005), respectively, and a decrease in iSVR in the valsartan group (23% [15, 28]) (P=0.002).

In the valsartan group, changes in CI and iSV from baseline were not statistically significant (–4% [+6, –15], and 1.0% [+6.8, +1.2], respectively), but were significantly different from changes in the placebo group (P<=0.014, PHPE>0.90). The changes in iSVR were not significant in the placebo or enalaprilat groups, but were in the valsartan group (P<=0.016, PHPE>0.60). Changes in HR were not statistically significant in any group.

Effects of 40% BV haemorrhage (Fig. 1)
Thirty min after the second bleed (40% BV), decreases in MAP from baseline in the placebo, enalaprilat and valsartan groups were 29% [24, 41] (P=0.002), 43% [32, 54] (P=0.003) and 32% [19, 48] (P=0.005), respectively. The MAP decreased significantly from the 20% BV haemorrhage in the enalaprilat group only (23% [17, 28]) (P=0.005). No significant difference in the decrease in MAP was found between the groups (P=0.203).

The decrease in MAP was associated with a significant decrease in CI and iSV from baseline in all groups but the decrease in iSV was significantly lower in the valsartan group than in the placebo group (P=0.002, PHPE>0.95).

The changes in iSVR from baseline were significantly different between the placebo (+10.3% [+1.2, +19.4]) and valsartan groups (–23.3 [–40.2, –5.1]) (P=0.006, PHPE>0.85) and between the placebo and enalaprilat groups (–4.7% [–16.4, +3.4]) (P=0.010, PHPE>0.65) as a result of an increase in iSVR from the first bleed in the placebo group by 12% [2, 20] (P=0.007), while no significant change was found in the enalaprilat and valsartan groups (1.9% [–7.3, 3.3], –2.1% [–11.9, +23.9], respectively).

The increase in HR from baseline was 35% [15, 61] (P=0.002), 28% [–8, +63] (P=0.047) and 18% [+4, +31] (P=0.012) for the placebo, enalaprilat and valsartan groups, respectively. No significant difference in the increase in HR was found between groups (P=0.221).


    Discussion
 Top
 Abstract
 Introduction
 Results
 Discussion
 References
 
Although MAP appeared to be influenced similarly by both treatments during anaesthesia and hypovolaemia, the results show that renin–angiotensin system antagonists interfere with the haemodynamic determinants of arterial pressure (i.e. CO and VR) in quite different ways. While the ACE inhibitor induced a proportional decrease in MAP and CO, selective AT1 blockade was associated with a vasodilatation and a preservation of CO and SV.

It is well accepted that, in conscious mammals, a moderate reduction (20–30%) in BV has little effect on MAP (less than 10% reduction), which is completely unaffected by inhibition or blockade of the combined effects of the two major hormones, angiotensin and vasopressin.14 15 In the present study, the first haemorrhage (20% BV) induced a 20–25% decrease in MAP in all three groups. This important fall in MAP, larger than described in previous studies,14 15 can be related to anaesthesia. Below 20–30% blood loss, the carotid sinus reflex control should have maintained MAP,14 15 but under anaesthesia the baroreflex is blunted.16 Even in the placebo group, the MAP decrease is 25% while the HR increased by 5%, suggesting that the slope of the baroreflex response to change in carotid sinus pressure is decreased. In anaesthetized animals, the arterial pressure is more sensitive to haemorrhage because of autonomic blockade.17 18

During anaesthesia and before bleeding, injection of placebo, enalaprilat or valsartan had no effect on MAP, which indicates that maintenance of arterial pressure is not dependent on the renin–angiotensin system.7 After loss of 20% BV, MAP decreased similarly in the three groups (20–25%). Moreover the MAP, HR, CI and iSVR varied in the same way in the enalaprilat and placebo groups. The absence of vasoconstriction and the lack of significant differences between the enalaprilat and placebo groups in their haemodynamic profile may suggest that the renin– angiotensin system is not stimulated. However, the haemodynamic profile is completely different in the valsartan group: the MAP decrease is explained by the decrease in VR while CO and SV are unaffected. The ‘paradoxical’ vasodilatation observed when AT1 is blocked in the context of haemorrhage suggests that the renin– angiotensin system is indeed activated. With selective AT1 blockade, angiotensin, released in response to the hypovolaemia-induced stimulation of the renin–angiotensin system, may be available to activate AT2. There is some evidence that angiotensin can act to physiologically antagonize its own hypertensive effects by causing relaxation of some vascular beds.6 12 Activation of AT2 has been proposed to counteract the effects of the AT1 subtype.19 Scheuer and Perrone have demonstrated, in anaesthetized rats using AT1 and AT2 antagonists, that the AT2 receptor mediates a vasorelaxation response to angiotensin.20 Furthermore, the counteracting effects of AT1 and AT2 could account for the lack of effect in the placebo group. Nevertheless, a greater angiotensin level in the valsartan group cannot be ruled out, because selective AT1 blockade decreases the angiotensin-induced feedback regulation of renin release.2123

The involvement of the renin–angiotensin system in control of arterial pressure is even more apparent at the second haemorrhage (40% BV). In the control group, although the decrease in MAP from baseline is 30%, the iSVR increases about 12% from the 20%-BV bleed, suggesting the involvement of a vasoconstrictor system. By contrast, in the enalaprilat group the overall decrease in MAP is 40% as a result of a similar decline between baseline and 20% BV, and between 20% BV and 40% BV, and the iSVR does not increase. Both results suggest a prominent role of angiotensin in the vasoconstrictor response in the placebo group.

In the enalaprilat group the decrease in arterial pressure appears to be volume dependent. This result is in agreement with the classic concept of the renin–angiotensin system as a circulating hormonal system involved in the regulation of arterial pressure during hypovolaemia.3 4 7 In the valsartan group, the overall decrease in MAP is about 30%, which is in the same range as in the placebo group, but without an increase in SVR. Conversely, the ‘paradoxical’ vasodilatation at 20% BV is still observed at 40% BV. Moreover, the decrease in CI and SV is moderate, observed mainly at 40% BV and is lower than in the placebo group. These effects on VR and CO were not observed in the enalaprilat group. The discrepancy between the two treatments on the determinants of arterial pressure reveals the importance of the specific angiotensin II receptors in mediating the effects of activation of the renin–angiotensin system. Besides the vasodilatory effect, AT2 stimulation may have some beneficial effect on myocardial function. AT1 blockade may have a positive effect on left ventricular filling when preload is low, by enhancing left ventricular diastolic function.6

Our experimental model has enabled us to demonstrate the different effects of ACE inhibitors and AT1 antagonists on arterial pressure regulation, and their effects on haemodynamic variables during anaesthesia and haemorrhage. However, short-term treatment and experiments in healthy young pigs cannot be extrapolated to long-term treatment in patients with cardiovascular disease. Nevertheless, the results suggest that further clinical studies that examine the consequences of the two treatments are warranted. The current recommendations for the use of vasoconstrictors in any case of hypotension following anaesthesia in patients treated with renin–angiotensin system antagonists, no matter what kind of renin–angiotensin system antagonist it is, may thus be too simplistic.13 24

In summary, the inhibition of the renin–angiotensin system by either the non-specific blockade of the two receptor subtypes, AT1 and AT2, with enalaprilat or by the specific blockade of AT1 with valsartan leads to two different haemodynamic profiles in response to hypovolaemia in the anaesthetized pig. The difference between the two forms of antagonism makes apparent the functions of the AT2 receptor. Further clinical studies are required to assess the clinical relevance of our findings to patients receiving long-term treatment for various indications.911 25


    Acknowledgements
 
The authors are grateful to Dr de Gasparo for helpful criticism and to Novartis Laboratories for generously providing valsartan, and Dr Scemama and Merck Sharp Dohme Chibret Laboratories for generously providing enalaprilat.



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Fig 1 Changes (%) from baseline (T0) in heart rate (HR), mean arterial pressure (MAP), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), indexed stroke volume (iSV) and indexed systemic vascular resistances (iSVR) changes after the first (20% BV) and second (40% BV) bleed in the three groups. Data are presented as median, interquartile range (boxes), 10–90% percentiles (bars), and range (circles). Values were compared within groups using a Friedman test then a Wilcoxon test: *P<=0.02 from baseline. Values were compared between groups using a Kruskal–Wallis analysis of variance (P<=0.015) then a Mann–Witney U test: {dagger}P<0.015 between the valsartan and placebo groups; #P=0.016 between the valsartan and enalaprilat groups; {ddagger}P=0.01 between the enalaprilat and placebo groups.

 

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