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European Journal of Heart Failure 2001 3(6):671-677; doi:10.1016/S1388-9842(01)00192-1
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© 2001 European Society of Cardiology

Bradykinin infusion in chronic cardiac failure and the effects of captopril

S.M. Maguirea, D. McAuleyb, C. McGurkb, A.G. Nugentb, G.D. Johnstonb and D.P. Nichollsa,*

a Department of Medicine, Royal Victoria Hospital Belfast BT12 6BA, UK
b Department of Therapeutics, The Queen's University of Belfast Belfast, UK

* Corresponding author. Tel.: +44-28-9089-4951; fax: +44-28-9026-3168


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Patients with chronic cardiac failure (CCF) have abnormal vascular responses. Bradykinin (BK) is thought to contribute to the vasodilator effects of ACE inhibitors, but the effect of BK itself in patients with CCF has not been examined.

Methods: We studied the responses to infused BK at 10, 30 and 100 pmol min–1 in patients with CCF (n=10) and controls (n=10). The slope of the dose-response curve was used for comparisons between the groups. Forearm blood flow (FBF) was measured by venous occlusion plethysmography.

Results: Following BK, vasodilatation was observed in both groups as the slopes were positive in all, but the difference between the groups was not significant (P=0.77). The study was repeated with the co-administration of 4 µmol min–1 of NG-monomethyl L-arginine (L-NMMA). The vasodilator response to BK was reduced in both groups, and the effect was somewhat greater in the patient group (P=0.23). The vasodilator response to the endothelium-independent vasodilator sodium nitroprusside was slightly less in the patient group (P=0.08). The patients only then underwent repeat infusion of BK before and after a single oral dose of captopril 12.5 mg or placebo. Following captopril, the vasodilator response to BK was unchanged when compared to placebo (difference between slopes, P=0.53).

Conclusions: BK produces dose-dependent vasodilatation in both patients with CCF and controls; there was no difference in the responses, which were antagonised by L-NMMA and therefore in part NO (endothelium)-dependent. The responses were also unchanged after administration of an ACE inhibitor (captopril).

Key Words: Heart failure • Bradykinin • Vascular Changes • ACE Inhibitors

Received September 15, 2000; Revised March 19, 2001; Accepted May 10, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
In 1928 Frey et al. identified a hypotensive agent in human urine, later named kallikrein [1]. Kallikrein is an enzyme found in plasma and various tissues. Bradykinin (BK) is formed by the actions of plasma kallikrein on a high molecular weight and a low molecular weight precursor, and BK is itself metabolised by kininase I and kininase II. Kininase II is identical to angiotensin converting enzyme (ACE) [2], which has a higher affinity for BK as a substrate than for angiotensin I [3]. BK causes vasodilatation in man [4] both through direct effects on the vascular smooth muscle (endothelium independent) [5] and also through endothelium-dependent actions [6], and it is possible that some of the vasodilator effect of ACE inhibitors may be due to BK [7].

Studies in normal volunteers and in patients with hypertension have confirmed that at least part of the action of ACE inhibitors may be due to BK [8–10]. In contrast, studies on the effects of BK itself in patients with chronic cardiac failure (CCF) are few [11]. The data regarding the contribution of BK are conflicting, despite the fact that since the publication of the first CONSENSUS trial [12], ACE inhibitors are now standard therapy in this condition [13]. Circulating plasma levels of BK increase in normal subjects after ACE inhibition [14], whereas in patients with CCF they remain unchanged [15].

We have previously shown that patients with CCF have abnormal vascular responses [16]. We therefore set out to assess the contribution of BK to these observed responses by comparing the effects of infused BK on forearm blood flow in patients with CCF and in matched control subjects. In addition, patients were studied whilst on an ACE inhibitor, captopril, or placebo.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Subjects
Ten patients with compensated CCF were studied. All had a history of hospital admission for pulmonary oedema on at least one occasion but had been clinically stable for three months prior to study. All patients had a cardiothoracic ratio on a chest radiograph greater than 0.5, and had a mean left ventricular ejection fraction (LVEF) of 26% (range 14–40%) as measured by echocardiogram or gated blood pool scanning. The full demographic details of the patients and control subjects are summarised in Table 1. Six patients were in sinus rhythm at the time of study and four in atrial fibrillation with a relatively constant ventricular response. All patients were receiving loop diuretics and either lisinopril or enalapril as part of their treatment (mean dose of frusemide or equivalent was 58 mg, range 40–80 mg). ACE inhibitors, aspirin and long acting nitrates were omitted for 48 h prior to study and captopril and digoxin for 24 h (see section 4). Exclusion criteria included a history of diabetes (fasting glucose>7.0 mmol l–1), hypercholesterolaemia (cholesterol>6.2 mmol l–1) or hypertension (BP>160/90 mmHg), as these factors alone could affect the vascular responses. In addition, all patients and controls were non-smokers.


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  		Table 1 Clinical and biochemical characteristics of patient and control subjects [mean (S.E.M.) unless otherwise stated].

 
Ten healthy volunteers acted as controls and were considered to be normal on the basis of history, examination, ECG, routine laboratory analysis and cardiopulmonary exercise testing. All subjects gave written informed consent for all procedures. The study was approved by the local Ethics Committee of the Queen's University of Belfast.

2.2. Procedures
Studies were carried out in the morning in a temperature-controlled laboratory (24–26°C). Following an overnight fast during which time alcohol and caffeine-containing beverages were prohibited, subjects were asked to rest supine with the arms on supports slightly above the level of the heart. The subjects then underwent cannulation of the non-dominant brachial artery under local anaesthesia (1% lignocaine, Antigen Pharmaceuticals, Roscrea, Ireland), using a 27-gauge steel needle (Cooper's Needle Works, Birmingham) connected to an 18-gauge epidural line. After a period of 30 min during which physiological saline was infused at a rate of 0.5 ml min–1 to allow blood flow to stabilise, resting forearm blood flow (FBF) was measured using venous occlusion plethysmography. An indium-gallium strain gauge was placed around the widest part of the forearm (approximately two-thirds the distance from the wrist to the elbow). The alloy is liquid above 16°C and changes electrical resistance when stretched. The gauge was connected to a pre-amplifier as one limb of a Wheatstone bridge (model SPG16, Medasonics, Mountainview CA, USA) and the output connected to a chart recorder (Vasculab model R12B, Medasonics, Mountainview CA, USA). The 1% calibration button on the pre-amplifier corresponded to a 1% increase in forearm volume, and the recorder gain adjusted to give a 1-cm vertical deflection.

An occlusion cuff was placed at the wrist and congestion cuff above the elbow. The wrist cuff was inflated to above systolic pressure (200 mmHg) for 30 s prior to the measurements. The congestion cuff was inflated rapidly to a pressure between venous and arterial (40 mmHg) during each measurement (between 5 and 10 s). The average of five consecutive measurements was used and the tracings were analysed by a single independent observer (DPN) without knowledge of the clinical status of the subject. Forearm blood flow was expressed as ml min–1 100 ml–1 forearm volume. Measurements were carried out simultaneously in both arms to demonstrate that no systemic absorption of study drug had occurred.

Each subject with heart failure was studied on two occasions separated by 7–10 days, control subjects were studied only once. The first day of the study was similar for both patients and controls and consisted of the following. Using a constant rate infusor, BK (Sigma Chemical Co., Poole, Dorset) was infused intra-arterially at doses of 10, 30 and 100 pmol min–1 for 3 min at each dose, as previously described [11]. Measurement of FBF was carried out during the last 30 s of each drug infusion. In order to assess the endothelial contribution to the vasodilation produced, the infusions were repeated while NG-monomethyl-L-arginine (L-NMMA) at 4 µmol min–1 was co-infused. In order to assess the direct (endothelium independent) response, the inorganic nitrate sodium nitroprusside (SNP, David Bull Laboratories, Australia) was infused at doses of 3, 6, 9 and 12 nmol min–1 for 3 min at each dose. The order of the BK and SNP infusions was randomised by an independent observer. All drugs were prepared on the morning of study using physiological saline. Care was taken to ensure that photo-degradation of SNP did not occur.

After each infusion, a wear-off period was allowed so that the FBF could return to baseline. The period permitted depended on the elimination half-life of the substance infused. Following bradykinin alone this was 25 min, following L-NMMA at 30 min and SNP at 20 min. Between different drug doses and during wear-off periods physiological saline was infused at a rate of 0.5 ml min–1.

In a second study, following these initial observations, the patients (but not the controls) received a single dose of either captopril 12.5 mg or placebo. The tablets were prepared as capsules and administered in a double-blind manner by an independent observer so that the investigator was not aware of the drug identity. The observer then checked the blood pressure of the patient at 30-min intervals for a total of 120 min to ensure that no adverse effects occurred. Sixty min after tablet administration, FBF was measured at baseline and following repeat infusion of BK, as above. A week later the study was repeated using the other treatment. Patients were asked to recommence their usual medication after the first study day and to discontinue it before the second study day, as before.

2.3. Statistical analysis
The average of five consecutive measurements of FBF was used for statistical analysis in all cases. In order to simplify the analysis, to reduce the number of tests, and to reduce baseline variability, the four doses of BK given on each occasion (0, 10, 30 and 10 pmol min–1) were regarded as a simple dose-response curve, and the slope of the curve calculated. The slope was then used for comparisons. Direct comparisons were made using Student's paired t-test or independent t-test as appropriate, having established that the data formed a normal distribution. In the presence of more than two variables, a two-way ANOVA was used. In both cases, the significance level chosen was P<0.05. Results are presented as mean±S.E.M.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The demographic characteristics of the patient and control groups are shown in Table 1. There were no significant differences between the groups except for a significant difference in systolic and diastolic blood pressure (P=0.01 and P=0.02 respectively). Baseline FBF before any treatment was lower in patients than in control subjects (Table 2), but the difference was not significant (P=0.103). After each active drug infusion, the FBF fell to baseline level before the next infusion was commenced (Table 2), and no significant differences between patients and controls were observed. At no time was there any change in FBF in the contralateral (control) arm to suggest systemic effects of the infused drugs.


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  		Table 2 Basal forearm blood flow (ml min–1 100 ml–1) at various stages of the first study

 
BK produced vasodilation in both patients and controls, as the slopes of the dose-response curves were all positive. The slope was similar in the two groups (patients 0.0755±0.0194; controls 0.0829±0.0155, P=0.77). Fig. 1 shows the changes in FBF from baseline with the three doses of BK, in patients and in controls. With co-administration of L-NMMA, the BK dose-response slopes were significantly reduced (patients 0.0155±0.0091, P=0.03 compared to preceding baseline, controls 0.0535±0.0118, P=0.004). Whilst the reduction in slope appeared to be greater in the patient group, the difference between the groups was not significant (P=0.23). The changes in blood flow in patients and controls are shown in Fig. 2a,b respectively.


Figure 1
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  		Fig. 1 Change in FBF from baseline in response to infusion of bradykinin in patients and control subjects (mean and S.E.M.). There was no significant difference between the groups.

 


Figure 2
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  		Fig. 2 Change in FBF from baseline in response to bradykinin before and during co-infusion of L-NMMA in patients (a) and controls (b) (mean and S.E.M.). The flow increase before is the same as in Fig. 1. There is significant attenuation of the increase by co-infusion of L-NMMA 4 µmol l–1 (P<0.05 at each dose level of bradykinin).

 
During infusion of SNP, FBF increased in both groups, as the slopes were all positive. The response appeared to be less in the patients (slope 0.0072±0.001, controls 0.0104±0.0014) but the difference was not significant (P=0.08; Fig. 3).


Figure 3
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  		Fig. 3 Change in FBF from baseline in response to SNP in patients and control subjects (mean and S.E.M.).

 
In the second study, the FBF in the patients on the two separate study days before administration of any drug was somewhat greater in the patients about to receive captopril (3.61±0.51 vs. 2.53±0.18 ml 100 ml–1 min–1; P=0.051). Following placebo there was a small apparent increase in FBF from 2.53±0.18 to 3.52±0.65 ml 100 ml–1 min–1 (P=0.29) whereas after captopril there was no significant change (3.61±0.51 to 3.38±0.46 ml 100 ml–1 min–1). The dose-response curves to BK (slopes) continued to show vasodilatation but were unchanged after captopril administration (P=0.53 see Fig. 4).


Figure 4
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  		Fig. 4 Change in FBF from baseline in response to bradykinin in patients with CCF (n=10) following captopril 12.5 mg or matching placebo administered in random order on two separate study days (mean and S.E.M.).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In patients with CCF, the vascular responses are abnormal [16–21] with overall vasoconstriction [22]. It might be anticipated therefore that the vascular responses to vasodilator infusions such as BK would also be abnormal, but our study suggests that the vasodilator response to BK is preserved in patients with CCF. The co-administration of the NO synthase inhibitor L-NMMA significantly reduced the vasodilator effect of BK in both patients and controls, indicating a degree of endothelium dependence in both. The effect of L-NMMA infusion was somewhat greater in patients, possibly related to differences in expression of endothelial BK receptors [23]. The endothelium-independent responses to SNP were preserved, indicating that smooth muscle dysfunction is unlikely to be the cause of the reduced responses after L-NMMA. The vasodilator responses to BK, as measured by the slope of the dose-response curve, were not affected by the co-administration of a single low dose of ACE inhibitor (captopril 12.5 mg).

Investigations in animals suggest that BK mediated its effects on the vasculature both indirectly via the endothelium [6] and directly via vascular smooth muscle [4,5]. In normal man, vasodilatation in veins and resistance vessels following the administration of BK is at least partly endothelium-dependent [24,25]. Work on the superficial hand vein has demonstrated that infusion of L-NMMA inhibits the venodilator action of BK, but not that of glyceryl trinitrate (GTN) [26]. There is conflicting evidence for smooth muscle dysfunction in patients with CCF. Some investigators did not detect any abnormalities [18,19], whereas others including ourselves have demonstrated abnormal function [16,17,20,21]. This study suggests that there may be impaired smooth muscle function in patients with CCF, in keeping with our previous work in patients with CCF using GTN [16]. SNP is an endothelium-independent vasodilator acting directly on the vascular smooth muscle. It acts as a nitrate donor but does not require biotransformation within the smooth muscle cell as does GTN. As SNP acts differently to GTN, abnormal function may result from alterations in smooth muscle responsiveness rather than impaired production or function of NO. This could be due to alterations in intra-cellular cGMP function, or reduced activity of endothelium-derived hyperpolarising factor (EDHF) which hyperpolarises the smooth muscle cell membrane, and as a result sensitises it to the effects of NO and may also initiate relaxation. The exact identity and function of EDHF in patients with CCF has yet to be elucidated. Finally, previous studies have demonstrated an enhanced response to BK following a single oral dose of captopril, both in normal man [27] and in patients with CCF [9]. In the present study, the responses to BK were similar in patients and controls.

As with any study, there are limitations to the present work. We would have liked to study a greater number of subjects, but the tests were very time consuming. Only a single (low) dose of captopril was studied, and it is possible that higher doses would have produced significant effects on the BK responses [9]. The dose of captopril chosen for study was thought to be the minimum effective dose that would not produce marked systemic hypotension, which could affect the results in itself. Such a response was not observed in any of the patients, and the test infusions were well tolerated in both groups. All the patients were given ACE inhibitors as part of their routine treatment, and at the time the study was conducted, it was already unethical to fail to do so. Given the confounding role of drugs such as ACE inhibitors and aspirin in the vascular responses to infused BK, we attempted to minimise their influence as far as possible by withdrawing them before the study. Changes in tissue ACE activity may persist for weeks after discontinuing treatment, but it was not though to be ethical to withhold treatment for this length of time, and it was vascular reactivity that was the object of study. Aspirin irreversibly acetylates cyclo-oxygenase (COX) in platelets and elsewhere, but vascular endothelial COX regenerates within hours [28], so that a 48-h withdrawal period is sufficient to restore reactivity.

We have shown that the vascular responses to infused BK are preserved in patients with CCF, and that they were endothelium-dependent. The responses were unchanged after ACE inhibition and may contribute to the vascular effects of ACE inhibitors [29].


   Acknowledgements
 
We are grateful to Dr. C Patterson for advice on statistics.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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