Download Effect of angiotensin-converting enzyme inhibition

Clinical Science (1992) 83, 143-147 (Printed in Great Britain)
I43
Effect of angiotensin-converting enzyme inhibition on
plasma brain natriuretic peptide levels in patients with
heart failure
Chim C. LANG, Joseph G. MOTWANI, Abdul R. RAHMAN, Wendy J. COUTIE
and Allan D. STRUTHERS
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, U.K.
(keceived 2 December 1991/3 April 1992; accepted 14 A p r i l 1992)
1. The aim of this study was to examine the effect of
captopril, an angiotensin-converting enzyme inhibitor,
on plasma levels of human brain natriuretic peptidelike immunoreactivity (hBNP-li) in patients with
congestive heart failure.
2. Six male patients (aged 52-74 years) with mild to
moderate congestive heart failure were studied on two
occasions in the semi-recumbent position. After a
30 min rest, patients were randomized to receive oral
tablets of either captopril (6.25 mg followed by 25 mg
2 h later) or placebo in a single-blind manner. Plasma
hBNP-li, atrial natriuretic peptide-like immunoreactivity (ANP-li) and angiotensin II-like immunoreactivity (ANG II-li) levels and blood pressure were
measured.
3. Baseline plasma hBNP-li and ANP-P levels in
these patients with mild to moderate congestive heart
failure were 13.5 f 3.2 pmol/l and 50.9 f 11.8 pmol/l,
respectively. In 11 healthy male subjects aged 20-23
years, the peripheral plasma hBNP-li and ANP-li
levels were 1.3 f 0.2 pmol/l and 5.6 f 1.7 pmol/l, respectively. In all patients, captopril decreased the
plasma ANG II-li level (from 24.3f8.1 to
6.6 f 3.2 pmol/l, P < 0.05) and mean arterial blood
pressure (from 92 f 3 to 80 f 3 mmHg, P < 0.05).
Compared with placebo, captopril treatment was
associated with significant reductions in plasma
hBNP-li (from 14.3 f 3.0 to 12.8 f 2.1 pmol/l,
P<O.O5) and in plasma ANP-li (from 53.9f1.11 to
36.8 f 7.6 pmol/l, P <0.05) levels.
4. Our results show that in patients with heart
failure, acute inhibition of angiotensin-converting
enzyme with captopril results in falls in both plasma
hBNP-li (10% fall) and ANP-B (32% fall) levels. Our
results do not support a major role for angiotensinconverting enzyme in the metabolism of human brain
natriuretic peptide in heart failure, although a minor
role cannot be excluded since the fall in the plasma
ANP-P level was greater than the fall in the
plasma hBNP-li level. However, the fall in the
plasma hBNP-li level is most probably related to the
changes induced in intra-cardiac volume/pressure by
the angiotensin-converting enzyme inhibitor.
INTRODUCTION
Brain natriuretic peptide (BNP) is a novel
natriuretic peptide that was first isolated from the
porcine brain [l]. BNP has striking similarity with
atrial natriuretic peptide (ANP) both in amino acid
sequence and in biological actions [l-31, and has
either 26 or 32 amino acid residues: porcine (p)
BNP-26 and pBNP-32, respectively [4]. Although
originally isolated from the brain, BNP is also
synthesized and secreted into the circulation from
the porcine heart [S]. Rat BNP (rBNP), a 45-amino
acid residue peptide, has also been isolated from the
heart [6].
Until recently, information on BNP in man has
been scarce, mainly because human BNP (hBNP)
immunoreactivity was not detected with early antisera that were raised against pBNP or rBNP.
However, the complementary DNA sequence encoding for the hBNP precursor, hBNP (1-108), was
recently elucidated [7]. Since then hBNP has been
isolated from the human atrium and found to
comprise 32 amino acid residues, which are identical
with the sequence (77-108) of the hBNP precursor.
Furthermore, hBNP-like immunoreactivity (hBNPli) has now been detected in plasma [8,9] and
found to be grossly elevated in patients with congestive heart failure (CHF) [9]. Although there is
much interest in the control of synthesis and biological actions of BNP, the metabolism of BNP has
been little studied, at least in man. We have previously shown that degradation by neutral endopeptidase is an important pathway for BNP metabolism in patients with CHF [lo]. However, a
recent study in uiuo in rats has indicated that
angiotensin-converting enzyme (ACE) may also
Key words: angiotensin-converting enzyme inhibition, atrial natriuretic peptide, brain natriuretic peptide, congestive heart failure.
Abbreviations: ACE, angiotensin-converting enzyme; ANG Il-li, angiotensin Il-like immunoreactivity; ANP, atrial natriuretic peptide; ANP-Ii, atrial natriuretic peptide
like immunoreactivity; BNP, brain natriuretic peptide; CHF; chronic heart failure; hBNP, human brain natriuretic peptide; hBNP-li, human brain natriuretic peptidelike
immunoreactivity; pBNP, porcine brain natriuretic peptide; rBNP, rat brain natriuretic peptide.
Correspondence: D r C.C. Lang, Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee D D I 9SY, U.K.
144
C. C. Lang et al.
have an important role in the metabolism of BNP
[ll]. We have therefore examined the effect of an
ACE inhibitor, captopril, on the plasma hBNP-li
level in patients with CHF.
After a 30 min semi-recumbent rest, venous blood
was removed for measurement of plasma ANP-li
and hBNP-li levels.
Sample handling
MATERIALS A N D METHODS
Patients and subjects
Six male subjects (aged 52-74 years) with mild to
moderate CHF (New York Heart Association Classification 11-111) were studied on 2 days at least 7
days apart. All had impaired left ventricular function (radionuclide ejection fraction <45%) and reduced exercise capacity and were on regular anticardiac failure therapy with the exception of ACE
inhibitors: diuretics (six), long-acting nitrates (four)
and calcium antagonists (four). All gave their voluntary written informed consent before participation
in this investigation, which was approved by the
hospital ethical committee.
Patients were requested to adhere to their normal
diet for the duration of the study and to maintain a
similar patterns of meals for the 24-28 h before each
investigational day. Patients were studied in the
morning having fasted overnight, and their morning
medication was withheld. Alcohol consumption was
not allowed for 36 h before the study, and cigarette
smoking was forbidden on the morning of the study.
Patients remained in the fasted state throughout the
study period on each investigational day.
As a control, 11 healthy male subjects aged 20-23
years were studied. All had normal plasma urea and
creatinine concentrations and a normal urinalysis.
None was taking any regular medication. All subjects were discouraged from taking vigorous exercise
and were given general advice to avoid large
changes in their sodium intake in the 5 days before
their study day.
Materials
Captopril (Capoten) was purchased from E. R.
Squibb and Sons Ltd, Hounslow, Middx., U.K.
Protocol
On reporting to the clinical laboratory at 08.30
hours, each patient was requested to rest semirecumbent on a bed, and an intravenous cannula
was placed in his forearm. At 09.00 hours, an oral
tablet of either captopril (6.25mg) or placebo was
administered in single-blind randomized fashion. A
further dose of either captopril (25mg) or placebo
was administered at 11.00 hours. Venous blood was
collected at 09.00 hours and at 13.00 hours for
measurement of plasma ANP-like immunoreactivity
(ANP-li), hBNP-li and angiotensin 11-like immunoreactivity (ANG 11-li) levels.
All healthy control subjects were studied in the
morning of each study day after an overnight fast.
Venous blood (10ml) was collected in chilled
tubes containing EDTA (potassium salt) and 4000
kallikrein inhibitory units of aprotinin (Trasylol;
Bayer U.K. Ltd, Newbury, Berks., U.K.) for
measurement of plasma ANP-li and hBNP-li levels.
Venous blood was also collected into lOml chilled
tubes containing a solution of 0.05 mol/l o-phenanthroline, 2 g of neomycin/l, 0.125mol/l EDTA and
2% (v/v) ethanol for measurement of the plasma
ANG 11-li level. These samples were centrifuged
immediately and plasma was stored at -70°C until
assay.
Analytical methods
Plasma hBNP-li was measured by r i a . after
plasma extraction as previously described by our
group [12] using a commercially available r i a . kit
(Peninsula Laboratories Inc., Belmont, CA, U.S.A.).
Plasma samples (1mi) were acidified with 1 ml of
0.1% trifluoroacetic acid and passed through SepPak C,, cartridges (Amersham International Ltd,
Amersham, Bucks, U.K.). The cartridges were preactivated with buffer (4 ml) containing 60% (w/v)
acetonitrile/O.l% trifluoroacetic acid and buffer containing 0.1% trifluoroacetic acid. After each aliquot,
the cartridges were washed with 0.1% trifluoroacetic
acid (10ml) and the BNP was eluted with 3ml of
60% (w/v) acetonitrile/O.l% trifluoroacetic acid solution. The eluate was evaporated under vacuum and
the precipitate was resuspended in 2 5 0 ~ 1of BNP
assay buffer. The anti-hBNP-32 antibody used was
generated against synthetic hBNP-32 (Peninsula
Laboratories). The antibody showed the following
cross-reactivities: hBNP-32, 100%; rBNP-32, 0.04%;
rBNP-45 and pBNP-26, 0%; a-human ANP (1-28),
0%; angiotensin 11, endothelin-1 and vasopressin,
0%. A portion (100~1)of reconstituted BNP extract
was incubated in duplicate with 1 0 0 ~ 1of antihBNP-32 antibody, which had been reconstituted
with 13ml of r.i.a. buffer, at 4°C overnight. Then
"'1-hBNP-32 (between 10000 and 20000 c.p.m.)
was added, mixed and incubated at 4°C overnight.
Standard curves were constructed with standard
hBNP-32 (Peninsula Laboratories) in r.i.a. buffer
over a concentration range of 0.5-128 pg/tube. Precipitation was with 1 0 0 ~ of
1 diluted goat anti-rabbit
IgG serum and 1 0 0 ~ 1of diluted normal rabbit
serum. Precipitates were allowed to form for 2 h at
room temperature before 0.5ml of r i a . buffer was
added. The pellets were separated by centrifugation
at 1700g for 20min, supernatant was removed and
the radioactivity in the pellets was counted in a
LKB C h i y-counter. The plasma hBNP-li level was
estimated by direct comparison with the standard
I45
Angiotensiwconverting enzyme inhibition and brain natriuretic peptide
curve and was corrected for percentage extraction.
The intra-assay and interassay coefficients of
variation for this assay in patients with CHF
(n =9) were 5.8% and 14.8%, respectively. The range
of percentage recoveries for radiolabelled
12%hBNP-32 with this assay was 57481.4%.
Plasma ANP-li level was measured by r i a . after
plasma extraction by the method of Richards et al.
[13]. The intra-assay and interassay coefficients of
variation for this assay were 4.9% and 7.8%, respectively. The plasma ANG 11-li level was measured by r.i.a. after Sep-Pak C18 cartridge extraction
by the method of Morton & Webb [14]. In brief,
the extraction process involved the cartridges being
pretreated with methanol ( 5 ml) and then water
( 5 ml). Plasma (5 ml) was then passed through the
cartridge under gentle vacuum. After washing with
water (5ml), angiotensin I1 was eluted from the
column with aqueous 20% (v/v) methanol (2ml).
The extracts were then dried and redissolved in Tris
buffer (50mmol/l; pH 7.5). The normal range of the
plasma ANG 11-li level with this assay is 2.911.5 pmol/l.
Haemodynamic parameters
Heart rate was displayed continuously on an
ECG oscilloscope (Adult Monitor 78351A, HewlettPackard, Boblingen, Germany) and blood pressure
was recorded by a semi-automatic sphygmomanometer (Dinamap Vital Signs Monitor; Critikon,
Tampa, FL, U.S.A.).
Statistical analysis
The effect of captopril on the neuroendocrine and
haemodynamic parameters was tested by analysis of
variance followed by multiple-range testing using
the Statgraphics softwear package (Statistical
Graphics Corporation Inc, Rockville, MD, U.S.A.).
All data are presented as means+SEM, and a P
value of less than 5% was considered as statistically
significant.
RESULTS
All results are shown in Table 1.The baseline plasma
hBNP-li and ANP-li levels in the patients with
CHF were 13.5 f3.2 pmol/l and 50.9 f 11.8 pmol/l,
respectively. By comparison, the peripheral plasma
hBNP-li and ANP-li levels in the healthy control
subjects were 1.3 f0.2 pmol/l and 5.6 f1.7 pmol/l,
respectively. These plasma hBNP-li levels compared
well with two previously quoted values for plasma
hBNP-li levels in normal subjects, 0.9 pmol/l and
1.5pmol/l [8,9]. The values in our patients with
CHF also corresponded well with those previously
quoted for patients with CHF [9].
Table 1. Effect of captopril on plasma hBNP-li, ANP-li and A N G
Il-li levels and mean arterial blood pressure in patients with CHF
(n=6). Values are means+sEn. Statistical significance (analysis of variance): *P <0.05 versus placebo. Sampler were taken at baseline immediately
before oral tablets of either captopril (6.25mg) or placebo (Omin) and at
+240min thereafter. A further oral dose of either captopril (24mg) or
placebo was administered at 120min.
+
Baseline (Omin)
After captopril
( 240min)
Plasma hBNP-li level (pmol/l)
Placebo
Captopril
12.7 f 2.8
14.3 k 3.0
l2.6f 3. I
12.8 f2.1*
Plasma ANP-Ii level (pmol/l)
Placebo
Captopril
47.9f 12.1
53.9* 11.1
59.6 f 15.8
36.8 f7.6*
Plasma ANG Il-li level (pmol/l)
Placebo
Captopril
18.9k4.8
24.3 k8.I
17.8 & 5. I
6.6 f 3.2*
88+3
92f3
86+6
80 f 3*
Mean arterial blood
pressure (mmHg)
Placebo
Captopril
+
In all patients, captopril decreased plasma ANG
11-li levels (Table 1). This was accompanied by a
significant fall ( P <0.05) in mean arterial blood
pressure. Both plasma ANP-li and hBNP-li levels
were decreased by captopril ( P <0.05 and P <0.05,
respectively).
DISCUSSION
The metabolism of BNP remains poorly defined
in man. On the basis of the remarkable structural
similarity between ANP and BNP, it could be
assumed that these peptides share common metabolic pathways. However, recent studies suggest that
this assumption is only partially justified. Presently
there are at least two important pathways of metabolism for ANP: degradation by the enzyme neutral
endopeptidase (EC 3.4.24.1 1, endopeptidase 24.11,
atriopeptidase) and binding to ANP-C or ANPclearance (non-guanylate-cyclase-linked) receptors
[15,16]. In this regard, Vogt-Schaden et al. [17]
have previously shown that kidney neutral endopeptidase is capable of cleaving pBNP, thus suggesting
an important role for neutral endopeptidase in the
metabolism of BNP. Whereas the enzyme cleaves
ANP .mainly at one site ( C y ~ ' ~ ~ - P h1,e PBNP
'~~
appears to be cleaved at several different sites [17].
We have recently shown that candoxatril, an orally
available neutral endopeptidase inhibitor, is capable
of increasing endogenous plasma hBNP-li levels in
CHF, thus indicating an important role also for
neutral endopeptidase in the metabolism of BNP in
man [lo]. The role of ANP-C receptor binding in
the metabolism of BNP in man remains controversial. Mukoyama et al. [18] have recently
shown that BNP is retained in the circulation
146
C. C. Lang et al.
longer than ANP in man, i.e. the half-times of
plasma disappearance of hBNP were longer than
those of ANP [18]. They attributed this to a lower
(about 7%) binding affinity of hBNP to ANP-C
receptors than that of ANP [MI. In a preliminary
study, we have also provided evidence that BNP is
not metabolized appreciably by ANP-C receptors in
patients with heart failure [19].
The present study was designed to examine the
effect of ACE inhibition on plasma hBNP-li levels
in patients with CHF. Already there is a body of
circumstantial evidence pointing to an interaction
between ACE inhibition and ANP. Initial studies in
vitro suggested that ACE inhibitors slowed the
metabolism of ANP [20]. Animal experiments in
oioo have shown either enhancement or no change
in ANP-induced natriuresis after inhibition of ACE
[21-231. Studies in normal or hypertensive man are
divided as to whether the endogenous plasma ANP
level is raised [24], lowered [25] or unchanged [26]
by ACE inhibitors. In heart failure, ACE inhibitors
seem more often to cause a fall in plasma ANP
levels [27]. These results suggest that the observed
changes in plasma ANP levels are not specific to
ACE inhibition and may reflect changes in
haemodynamics during therapy with ACE inhibitors. This is particularly true in our study, since
captopril treatment was associated with a significnt
fall in systemic arterial blood pressure (and probably intra-cardiac pressure/volume [ZS]), which in
turn will reduce the secretion of ANP.
With regard to BNP, there has only been one
previous study examining the interaction of ACE
inhibition and BNP, and that was in animals.
Infusing 12’I-pBNP into anaesthetized rats,
Vanneste et al. [ll] showed that degradation of
pBNP was reduced not only by phosphoramidon, a
neutral endopeptidase inhibitor, but also by captopril. They concluded that ACE could play a physiological role in the inactivation of BNP. In the
current study, the endogenous plasma hBNP-li level
did not increase but actually decreased after therapy
with the ACE inhibitor. It is worth noting that the
decrease in the plasma ANP-li level (32% of baseline) was greater than the decrease in the plasma
hBNP-li level (10% of baseline) after captopril treatment. The underlying mechanism(s) for our findings
is unclear, although there may be several possible
explanations of this. First, it is likely that the
haemodynamic changes caused by captopril may
have reduced BNP secretion and that this overcomes any small coincidental effect of ACE inhibition on BNP clearance. Therefore, although our
results do not support a major role for ACE in the
metabolism of BNP in heart failure, a minor role
cannot, however, be excluded. The stimulus for
BNP secretion in man remains unclear, but evidence
from recent studies does suggest that BNP secretion
is related to intra-cardiac volume/pressure changes
[l2, 281. Ideally, one would have used a dose of
captopril that does not alter intra-cardiac pressure/
volume, although such a dose of captopril may be
diffcult to identify in patients with CHF without
invasive measurements of cardiac filling pressures.
On the other hand, it might be worth repeating this
experiment in healthy subjects in whom no important changes in intra-cardiac pressures would be
expected from ACE inhibition. A second possible
explanation is that the effect of ACE on BNP
metabolism may be species-specific. This is likely
because the amino acid sequence of BNP varies as
much as 50% among different species [l, 5-71, in
striking contrast to ANP where the structure is
highly conserved between species [29]. It is possible
that differences in amino acids are responsible for
tertiary structural modulation that can regulate the
recognition of ACE-specific cleavage site and thereby influence the efficiency of the enzyme. Finally, it
is worth noting the difference in the study design
between our study and that of Vanneste et al. [ll].
Whilst Vanneste et al. [ll] examined the effect of
captopril on steady-state concentrations of infused
12%BNP and its degradation on the stopping of
the infusion, we have only examined the effect of
captopril on endogenous plasma hBNP-li levels.
Ideally, one would formally examine the effect of
captopril on infused hBNP and its clearance, but
hBNP is not freely available for human administration. Clearly, further studies are required to examine the role of ACE in BNP metabolism in man.
In summary, we have shown that captopril
caused significant reductions in both plasma ANP-li
and hBNP-li levels in patients with CHF, although
the reduction in the plasma ANP-li level was
greater than the fall in the plasma hBNP-li level in
these patients. There was also a significant fall in
mean arterial blood pressure and the plasma ANG
11-li level. Our results do not support a major role
for ACE in the metabolism of hBNP, but they
cannot exclude a minor role for ACE in the metabolism of hBNP. In support of the latter possibility
is our observation that the fall in the plasma ANP-li
level was greater than the fall in the plasma
hBNP-li level. However, the fall in the plasma
hBNP-li level is likely to be mainly related to the
changes in intra-cardiac volume/pressure induced by
the ACE inhibitor.
ACKNOWLEDGMENTS
C.C.L. was supported by the British Heart Foundation. J.G.M. was supported by the Scottish
Hospital Endowments Research Trust. We are
grateful to Dr J. J. Morton of the MRC Blood
Pressure Unit, Western Infirmary, Glasgow, U.K.,
for performing the angiotensin I1 assay. We thank
Miss F. Zaccarini for typing the manuscript.
Angiotensin-converting enzyme inhibition and brain natriuretic peptide
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