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Cardiovascular Research 1999 44(3):595-600; doi:10.1016/S0008-6363(99)00234-5
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Effects of brain natriuretic peptide on forearm vasculature: comparison with atrial natriuretic peptide

Kim van der Zander, Alphons J.H.M Houben*, Abraham A Kroon and Peter W de Leeuw

Department of Internal Medicine, University Hospital Maastricht, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands

* Corresponding author. Tel.: +31-43-387-7005; fax: +31-43-387-5006 BHO{at}sint.azm.nl

Received 12 May 1999; accepted 9 July 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: The aim of the present study was to determine the vasoactive effects of brain natriuretic peptide (BNP) as compared to those of atrial natriuretic peptide (ANP) in normal man. Methods: Ten healthy male subjects (median age 21 (20–23) year) were studied twice. In the first study equimolar doses (1, 3, and 10 pmol/dl/min) of both BNP and ANP (in random order and double blind) were infused into the brachial artery of the non-dominant arm with a 1-h wash-out period in between. In the second study two BNP (n=5) or ANP (n=5) dose–response curves were performed in order to assess the repeatability of the BNP/ANP infusions. To this end, BNP and ANP were infused in the same equimolar doses as in the first protocol. Forearm blood flow (FBF) was determined by venous occlusion plethysmography before and during infusions. Results: BNP increased the FBF ratio (infused/contralateral arm) by 6%, 17%, and 48%, respectively (p<0.05), while ANP increased the FBF ratio by 4%, 58%, and 133% (p<0.001). The slopes of the BNP dose–response curves differed significantly from those of the ANP curves (18.1 versus 43.2; p=0.022). No differences were observed between the repeated dose–response curves of either BNP or ANP. Conclusions: The present data demonstrate that BNP induces a dose-dependent vasodilatation in man. On a molar basis, however, this vasodilatation is significantly less than the vasodilatation induced by ANP. These differences may be related to differences in natriuretic-peptide-receptor affinity. Furthermore, our data show that the vasoactive effects of both BNP and ANP are repeatable in time.

KEYWORDS Natriuretic peptide; Blood flow; Hemodynamics; Vasoconstriction/dilation; Hormones


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP), two members of the family of natriuretic peptides, stimulate sodium excretion by the kidney. BNP is mainly produced in the ventricles of the heart [1], while ANP is secreted from the atria. However, the mechanisms controlling the release of ANP and BNP may be different for the two peptides. This is corroborated by the finding that intravascular saline loading acutely increases the plasma concentrations of ANP without any effect on plasma BNP concentrations [2]. On the other hand, increased BNP levels are associated with left ventricular hypertrophy (LVH), and reduced cardiac output [3]. Hence, BNP may be an marker for LVH or left ventricular dysfunction [4]. It may be, therefore, that BNP levels more reflect long-term intravascular volume status rather than momentary volume changes.

ANP and BNP not only stimulate natriuresis and diuresis, but also cause vascular relaxation. While the renal effects of these two peptides when given in equimolar doses seem to be comparable [5–7], little is known about their relative potencies at the level of the vascular wall. In fact, the hemodynamic effects of BNP are somewhat contradicting. For instance, in chronic heart failure systemic infusion of BNP results in a fall in blood pressure, systemic vascular resistance, and pulmonary capillary wedge pressure [6]. On the other hand, studies in both hypertensive patients and healthy subjects reveal no effects of BNP on blood pressure, cardiac output or systemic vascular resistance [5,8]. This difference in results could be related, however, to the BNP levels which were reached.

All previously described effects of BNP and ANP have been derived mainly from animal and human experiments using systemic infusions, although local vascular effects of ANP have been reported as well, the direct vascular effects of BNP have been studied in less detail. In vitro studies suggest that BNP exerts its biological effects through the same pathway as ANP does, i.e. the natriuretic peptide receptor A (NPR-A). However, the affinity of BNP for this receptor is less than that of ANP [9,10]. Because of this difference in affinity, we suspected that ANP will cause a greater degree of vasodilatation than BNP when given in equimolar doses in man. The aim of the present study was, therefore, to compare the local vascular effects of BNP to those of ANP in healthy men. In addition, we wanted to determine the repeatability of the effects of BNP and ANP.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Subjects
Experiments were performed in ten healthy male volunteers, with a median age of 21 (interq. range 20–23) years. One week prior to the measurements, subjects followed an ad libitum salt diet, which resulted in a median 24-h urinary sodium excretion of about 140 mmol. They were asked to refrain from smoking and coffeine or alcohol containing beverages for at least 12 h before the experiments, which started at 8 a.m. after an overnight fast.

Furthermore, none of the subjects had used any medication (including non-steroidal anti-inflammatory drugs) in the two weeks prior to the measurements.

The study was approved by the Medical-Ethics Committee of the Maastricht University Hospital, and all participants gave written informed consent. The investigations conform with the principles outlined in the Declaration of Helsinki [11].

2.2 Experimental design
All volunteers were studied twice with a 2-week interval. The order of the experiments was randomised. Subjects were studied in supine position in a quite, temperature-controlled room (mean temp. 24.1±0.2°C). A 20-gauge catheter was inserted into the brachial artery of the non-dominant arm (under local anaesthesia, 1% lidocaine): for infusion of drugs and monitoring of blood pressure. Forearm volume was measured by water displacement; drug infusion rates were normalised to 100 ml forearm tissue.

In the first study, forearm vascular reactivity to repeated dose–response curves of ANP (n=5) or BNP (n=5) was studied. In the second study, forearm vascular reactivity to infusion of equimolar doses of both ANP and BNP was studied. These infusions were performed in random order and in a double blind fashion. The two studies were performed according to a similar experimental design.

Equimolar peptide doses of 1, 3, and 10 pmol/100 ml forearm/min were used in both studies, which was based on data obtained in pilot experiments as well as on data from literature [12]. Each dose was infused for 5 min. Forearm blood flow (FBF) was determined simultaneously in both arms using ECG-triggered venous occlusion plethysmography (ID-Plethysmograph, University of Maastricht, The Netherlands), as described in detail previously [13]. Blood pressure was measured intra-arterially using a Hewlett Packard 78205C monitor. Heart rate was derived from the ECG.

Basal measurements of blood pressure, heart rate, and FBF were obtained 15 min after insertion of the arterial catheter. Following another 15 min the first dose–response curve was determined, with FBF being recorded continuously from 2 min before until the end of infusion of BNP/ANP. The mean value of the last minute of each dose (0, 1, 3, and 10 pmol/dl/min) was used for the analyses. Before the next infusion of BNP/ANP, there was a 1-h recovery period in order to allow forearm blood flow (FBF) to return to baseline values.

All signals were stored on the hard disk of a personal computer by means of a custom built data acquisition system.

2.3 Drugs
All solutions were freshly prepared in 5% glucose immediately before infusion. ANP and BNP were obtained from Clinalfa (Ethifarma Nederland BV, The Netherlands).

2.4 Statistics and calculations
For each measurement of FBF the ratio between the infused arm and the contralateral arm was calculated. This ratio corrects for all systemic factors that affect the regulation of blood flow in both arms (e.g. changes in blood pressure, level of arousal, hormonal changes, etc.), and is stable during the day [14]. Furthermore, it ensures that the direct effects of locally infused substances on forearm blood flow can be assessed [15]. For each separate dose of drug the percentage change in FBF ratio (relative to pre-infusion values) was calculated. This calculated value is less influenced by possible changes in FBF [15].

Besides calculation of ANP/BNP dose–response curves for each individual, also individual concentration–response curves were calculated by correcting the dose for FBF at the time of infusion [16]. The slopes of both the dose–response and the concentration–response curves were calculated individually by linear regression of the percentage change in FBF ratio during the three doses of ANP/BNP. These slopes summarise each individual response to the three doses in one number. Statistically, this calculation will avoid the problem of repeated measures between the three doses.

Since the distribution of the FBF data within the group was not normal, data are presented as median values with interquartile ranges. Friedman's test (non-parametric two-way ANOVA) was used for analysis of multiple related samples (within one visit) and Wilcoxon paired sign test for paired analysis (between visits and within one visit). When appropriate, the Bonferroni correction was used for multiple comparisons. Values of p below 0.05 were considered statistically significant.

To examine the repeatability of the effects of both hormones, the Bland–Altman method was applied [17].


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
The baseline clinical characteristics of the ten male study participants are summarised in Table 1. Median urinary sodium output in the 24 hours prior to the first study was 139 (111–172) mmol, and prior to the second study 143 (91–196) mmol, indicating that salt intake of the subjects was not significantly different between the two experiments.


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  		Table 1 Characteristics of the ten study participants

 
3.1 Blood pressure and heart rate
MAP and HR did not change during any of the studies (Table 2), indicating that the local infusions of BNP or ANP had no systemic hemodynamic effects.


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  		Table 2 Heart rate and mean arterial pressure of the subjects at the beginning and end of the two studiesa

 
3.2 Study 1: Repeatability of the effects of BNP/ANP
The median slopes of the two dose- or concentration–response curves, were comparable both for BNP and for ANP (p>0.05). Using the Bland–Altman approach, the mean difference in individual slopes of repeated dose–response curves for BNP is 5.5 (95% confidence interval (C.I.) –22.6 to 33.7) and 0.8 (C.I. –6.5 to 8.2) for ANP. The mean difference in maximum percentage change in FBF of repeated infusions is 16.0% (C.I. –77.0 to 109.0) for BNP and –6.9% (C.I. –19.5–5.6) for ANP.

3.3 Study 2: Comparison of the effects of BNP and ANP on forearm blood flow
Since there was no evidence for a time-treatment interaction, the data from the randomised infusions were pooled for the analysis.

The three doses of BNP increased FBF ratio by 6% (interq. range –4–23), 17% (–3–33), and 48% (7–87), respectively, relative to baseline (Friedman; p<0.05; Fig. 1). The percentage change in baseline FBF ratio for ANP was 4% (interq. range –5–19), 58% (20–93), and 133% (54–173), respectively (Friedman; p<0.001; Fig. 1). In Table 3 the absolute flow (FBF) values and FBF ratio at baseline and after each dose of BNP/ANP are summarised.


Figure 1
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  		Fig. 1 Vasoreactivity of forearm (muscle) vasculature to local BNP and ANP infusions (i.a.) (expressed as percent change in FBF-ratio (infused/contralateral arm)). Data are presented as median and interquartile range. Both BNP and ANP caused significant dilatation (p<0.05). * p<0.05 BNP versus ANP.

 

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  		Table 3 Absolute FBF values and FBF ratio after each infused dosea

 
Post hoc analysis of the three doses separately revealed that at the highest dose (10 pmol/dl/min) the effects of BNP and ANP were significantly different (Wilcoxon; p=0.022; Fig. 1). The median slope of the regression line through the individual dose–response curves was 18.1 (interq. range 4.7–28.3) for BNP and 43.2 (19.8–60.8) for ANP (Wilcoxon; p=0.022; Fig. 2A). The median slope of the regression line through the concentration–response curves was 7.2 (interq. range 0.3–16.8) for BNP and 25.5 (12.9–40.8) for ANP (Wilcoxon; p=0.017; Fig. 2B).


Figure 2
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  		Fig. 2 Slope of the regression line through the individual dose–response curves (A) and the individual concentration–response curves (B) during BNP and ANP infusions. Data are presented as median and interquartile range. *P<0.05 BNP versus ANP.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The present data demonstrate that local BNP infusion in man induces a dose-dependent vasodilatation, which is significantly less than that induced by equimolar doses of ANP. Since the vasoactive effects of both BNP and ANP are repeatable in time, the difference between both peptides seems to be genuine and not due to some aspecific effect. Although we did not measure cardiac output, the design of the study and the use of FBF-ratio rather than absolute FBF values, make it extremely unlikely that the difference in effect between BNP and ANP can be explained by differential systemic effects of the two peptides. In addition, no changes in blood pressure and heart rate were apparent, which also argues against systemic effects of the agents.

Previous studies have shown that human BNP is able to relax human artery and vein tissue [18]. In healthy human beings and patients with chronic heart failure Nakamura et al. [19], using much higher doses than we did, also found a peripheral vasodilating effect of BNP.

At present, three different natriuretic peptide receptors (NPR) have been described: NPR-A, NPR-B, and NPR-C [9,20]. The NPR-A and NPR-B are transmembrane guanylate cyclases, but the NPR-C is a short transmembrane protein which functions through intermediate G-proteins to inhibit adenylate cyclase and stimulate the phosphoinositol pathway. The latter has been called the clearance receptor, but binding to this receptor results in biological activity as well [9,20,21]. Both BNP and ANP are thought to act through the NPR-A. Activation of this receptor generates cGMP, which as second messenger activates Ca2+-activated and ATP-sensitive K+-channels, finally resulting in vasorelaxation [22,23].

The fact that BNP-induced vasodilatation is significantly less than that induced by equimolar doses of ANP could be explained by a difference in receptor-affinity. Cell culture experiments (human tissue cells) have shown that the affinity of BNP for NPR-A is 4–70 times less compared to ANP [9,10]. Consequently, BNP is ten-fold less potent than ANP at stimulating cGMP production via the NPR-A [9].

There is, however, a body of evidence in the literature that does not support the concept of lesser affinity of the NPR-A for BNP. For instance, Nakamura et al. [19] found no difference in forearm vasorelaxation between BNP and ANP in heart failure patients, which they explained by a downregulation of the NPR-A in these patients. However, when both ANP and BNP act via the same receptor, such a downregulation would effect the BNP-induced dilatation in a similar proportional manner. Moreover, Protter et al. [18] showed that human BNP and ANP are equipotent in relaxing isolated preconstricted human arteries. Also in cultured endothelial cells BNP and ANP show a similar dissociation constant and maximal binding capacity for the NPR-A [24], and both peptides are equipotent in stimulation of endothelial cGMP production [25]. BNP even induces a 20-fold greater release of CNP by endothelial cells than ANP [26]. The latter effect was in case of ANP completely and in case of BNP partly cGMP-mediated. Finally, Moritoki et al. [27] demonstrated in young (4 weeks old) animals that ANP-induced vasodilatation is partly mediated via nitric oxide. Hence, these findings suggest the possibility that BNP and ANP act partly through different mechanisms, as a result of which the dilatory effect of BNP may be less than that of ANP.

An alternative explanation may be that BNP, except for inducing vasodilation, also stimulates a vasoconstrictor mechanism. Although there are no data available to support such a hypothesis, it is well known that ANP can act as a vasoconstrictor. In previous studies we found that low doses of ANP into humans resulted in vasoconstriction of the microcirculation, most likely on the venular side [28]. A comparable observation has been made in renal studies. ANP dilates preglomerular (afferent) arterioles and constricts postglomerular (efferent) arterioles, thus causing an increased hydraulic pressure in the glomerular capillaries [29]. If BNP also has a dual action on the vasculature, the net effect of this peptide will depend on the balance between vasodilating and vasoconstrictor forces. Any difference in efficiency between BNP and ANP could thus depend on differences in this balance.

Plasma levels of BNP are lower than those of ANP in normal human subjects. In several disease states such as chronic heart failure (CHF) [30] and hypertension [31,32], in particular when LVH is present, levels of both peptides are elevated. Moreover, BNP levels frequently surpass plasma levels of ANP in severe CHF [7]. Thus, in view of our findings, it may be that BNP must increase to a greater extent than ANP in order to induce effective vasodilation, and maintain circulatory homeostasis.

In conclusion, our data demonstrate that both BNP and ANP induce vasodilatation of the forearm vasculature of healthy men. However, the effect of BNP is less potent in comparison with ANP. The difference in effect may be related to a difference in affinity for the natriuretic-peptide-receptor-A, or to a different balance in vasodilator and vasoconstrictor effects. Further studies are needed to elucidate the mechanisms of action of BNP.

Time for primary review 29 days.


   Acknowledgements
 
The authors thank Monique Fuss-Lejeune and Ellen Lambrichs for their accurate experimental assistance. The SWOL foundation is gratefully acknowledged for financial support.


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

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