Download Water and sodium regulation in chronic heart failure: the role of

Cardiovascular Research 51 (2001) 495–509
www.elsevier.com / locate / cardiores
Review
Water and sodium regulation in chronic heart failure: the role of natriuretic
peptides and vasopressin
a,
a,b
a
Paul R. Kalra *, Stefan D. Anker , Andrew J.S. Coats
a
Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6 LY, UK
b
¨ Centrum for Molecular Medicine, Berlin,
Department of Cardiology, Franz-Volhard-Klinik ( Charite´ , Campus Berlin-Buch) at Max Delbruck
Germany
Received 15 November 2000; accepted 26 March 2001
Keywords: Heart failure; Natriuretic peptide; Vasoconstriction / dilation; Antihypertensive / diuretic agents
1. Introduction
Chronic heart failure (CHF) is a complex syndrome
characterised by objective evidence of ventricular dysfunction and associated clinical symptoms [1]. Activated
neurohormonal mechanisms play an important role in the
maintenance of circulatory homeostasis. They can be
divided into the vasoconstrictive, sodium retaining and the
opposing vasodilatory, natriuretic systems. Vasoconstrictive
and sodium retentive actions are provided by the renin–
angiotensin–aldosterone system, the sympathetic nervous
system, vasopressin, thromboxane and endothelin [2–5].
Initially, in patients with heart failure, these act as important compensatory mechanisms maintaining blood pressure and adequate tissue perfusion. However, prolonged
activation of these systems has deleterious effects on
haemodynamics and directly on the heart itself. Enhanced
vasoconstriction and fluid retention result in adverse
loading conditions in the failing ventricle, whilst high
levels of angiotensin II directly induce cardiac myocyte
necrosis and adversely alter the myocardial matrix structure [6–9]. Angiotensin II also potentiates sympathetic
drive by direct stimulation and by impairing its control by
the baroreceptors [10].
In view of these adverse effects, it might be anticipated
that measurement of plasma levels of neurohormones
would be a helpful adjunct during prognostic assessment
and even in the tailoring of therapy in CHF. Several
studies have demonstrated an impaired prognosis in patients with CHF who have elevated plasma levels of
norepinephrine and endothelin-1 [11,12]. Cardiac cachexia
*Corresponding author. Tel.: 144-207-351-8127; fax: 144-207-3518733.
E-mail address: [email protected] (P.R. Kalra).
is a wasting condition that occurs in a significant percentage of patients with CHF, and is associated with a
particularly poor prognosis [13]. This group appears to
have marked neurohormonal abnormalities, with patients
demonstrating elevated levels of norepinephrine and a
reduction in plasma sodium concentration [14]. However,
drugs that reduce plasma catecholamine levels are not
necessarily associated with an improved prognosis, suggesting that the mechanisms involved in blunting the
effects of the sympathetic nervous system are much more
complex [15]. This may result, at least in part, from the
fact that activation of the sympathetic nervous system can
be expressed in several different ways and only a small
proportion of catecholamines released at the synapse spill
over into the circulation.
The natriuretic peptide system, nitric oxide and vasodilatory prostaglandins provide counter-regulatory vasodilatation and natriuresis [16–18]. In humans, the natriuretic
peptide family consists of at least three structurally related
polypeptides. Over the last two decades our understanding
of their role in CHF has been greatly enhanced. In patients
with CHF, measurement of plasma natriuretic peptide
levels is increasingly used to aid diagnosis, assess prognosis and tailor therapy [19–21].
Despite advances in the pharmacological treatment of
CHF the prognosis remains poor. Although suppression of
the renin–angiotensin–aldosterone and sympathetic nervous systems reduce morbidity and mortality in CHF
[22,23], great potential still exists to further manipulate the
activated neurohormonal systems.
The control of sodium and water regulation is achieved
by a series of complex interactions occurring between
several different systems. For example, renal sympathetic
Time for primary review 28 days.
0008-6363 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 01 )00297-8
496
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
nerves, atrial natriuretic peptide (ANP) and angiotensin II
modulate renal juxtaglomerular renin release [24–26]. In
addition, vasopressin, norepinephrine and angiotensin II
facilitate the release of ANP [27–29]. However, ANP is
able to modulate the renal effects of vasopressin [30]. A
full review of these important systems is beyond the scope
of this article, and therefore we have chosen to focus on
the role of the natriuretic peptide system and vasopressin
in the pathophysiology of human CHF. Although they
function in opposition, there are exciting prospects for
their therapeutic manipulation in CHF. As such we will
review their respective diuretic and antidiuretic actions,
before discussing their role in current and future clinical
practice.
2. Mechanisms involved in sodium and water
homeostasis in chronic heart failure (Fig. 1)
The maintenance of circulatory integrity has, perhaps,
the most dominant influence on renal sodium and water
excretion [31]. Afferent sensing mechanisms involved in
Fig. 1. The role of natriuretic peptides and vasopressin in sodium and water regulation in CHF. Arterial under-filling results in the activation of
high-pressure mechanoreceptors and subsequent nonosmotic release of vasopressin. Acting through two different receptors, vasopressin enhances
vasoconstriction and decreases water clearance. Increased atrial stretch and ventricular volume overload stimulate the myocardial secretion of ANP and
BNP. These circulating peptides enhance natriuresis and diuresis, together with vasodilatation. The exact role of CNP in CHF remains unclear. (GFR,
glomerular filtration rate; Na 1 , sodium; NPR, natriuretic peptide receptor).
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
salt / water homeostasis can be sub-divided into high-pressure and low-pressure mechanoreceptors. High-pressure
receptors are located in the left ventricle, carotid sinus,
aortic arch and in the renal juxtaglomerular apparatus
[32–34]. These receptors respond to decreases in arterial
pressure, peripheral vascular resistance or renal perfusion
by appearing to stimulate reflexes that result in the
activation of the sympathetic and the renin–angiotensin–
aldosterone systems and the non-osmotic release of vasopressin. Low-pressure receptors are primarily found within the atria. These react to volume expansion or increased
stretch by enhancing the release of atrial and brain
natriuretic peptides. In CHF it appears that the highpressure receptors override the low-pressure receptors
since sodium and water retention occur despite elevated
atrial pressures [35]. However, the mechanisms involved in
neurohormonal activation in CHF appear to be much more
complicated, as these patients also exhibit blunted baroreflex responses [36].
3. The natriuretic peptide family
In 1981 de Bold and colleagues discovered ANP,
identifying the heart as an endocrine organ and stimulating
the search for related peptides [37]. Although brain
natriuretic peptide (BNP) was first discovered in porcine
brain [38], it soon became apparent that it was particularly
concentrated within the myocardium [39]. Since then
extensive evaluation has led to a greater understanding of
the role that these two peptides play in maintaining
circulatory homeostasis. C-type natriuretic peptide (CNP)
was discovered in 1990 [40] and although less is known
regarding its physiological role it appears to have a much
wider tissue distribution.
3.1. Structure
The three natriuretic peptides share a 17-amino acid ring
closed by a disulfide bond between two cysteine residues.
ANP is produced as a precursor protein that is cleaved to
produce a 98-amino acid N-terminal fragment and the
biologically active C-terminal 28-amino acid peptide [41].
The gene coding ANP is also expressed in the kidney,
where different processing of the precursor protein results
in the formation of a 32-amino acid protein — urodilatin
[42]. Similarly, in humans, BNP is produced as a propeptide, with cleavage resulting in the production of the
active 32-amino acid peptide (a different molecule to
urodilatin) and an N-terminal fragment [43]. Two mature
forms of CNP exist [44]. The higher molecular weight
CNP-53 predominates in tissues, whereas the 22-amino
acid peptide (CNP-22) is found mainly in plasma and
cerebrospinal fluid [45,46]. Most of the data on the
biological effects of CNP relate to the 22 amino-acid form.
497
3.2. Receptors and metabolism ( Fig. 2 a)
The physiological actions of the natriuretic peptides are
primarily mediated through interactions with natriuretic
peptide receptors (NPR) [47]. Binding of the appropriate
natriuretic peptide to the receptor results in the activation
of intracellular particulate guanylate cyclase, enabling the
formation of cyclic guanosine monophosphate (cGMP),
which in turn is thought to mediate the biological effects of
the peptides.
Three types of NPR (A, B and C) have been identified in
human tissues. Unfortunately their nomenclature does not
correspond to their interaction with the natriuretic peptides.
NPR-A has greater affinity for ANP and BNP, whereas
NPR-B is more specific for CNP [48]. The third, NPR-C,
lacks the guanylate cyclase domain and is thought to act as
a clearance receptor, and is one of two mechanisms by
which natriuretic peptides are catabolised [49]. Following
binding of a natriuretic peptide to the NPR-C, the resulting
receptor–ligand complex undergoes endocytosis and subsequent lysosomal hydrolysis. The second mechanism
involves cleavage of the natriuretic peptide molecule by
neutral endopeptidase, an enzyme with a wide tissue
distribution [50].
Receptors for the natriuretic peptides have been demonstrated within the kidney [51,52]. Recent studies in rats
have confirmed NPR-A, -B and -C mRNA expression in
all segments of the nephron, although levels varied at
different sites [53]. NPR-A mRNA was most abundant in
cells of the glomerulus, proximal and distal tubules, whilst
NPR-B mRNA was less abundant in all nephron fractions
studied. In this study NPR-C had the least expressed
mRNA in the glomerulus and tubules. In contrast, Itoh et
al. found glomerular mRNA expression for NPR-C was
greater than that for NPR-A and –B [54]. In addition, they
demonstrated a reversible reduction in the glomerular
mRNA for all three receptors in response to dehydration.
Immunohistochemistry has demonstrated staining for NPRB on papillary and medullary capillaries, glomeruli and
renal arteries in rat kidneys [55].
3.3. Natriuretic peptide release
The prime stimulus for ANP secretion is an increase in
atrial stretch, which occurs during intravascular volume
expansion [56]. Acute heart failure is a good model for
this, where rapid increases in atrial filling pressures result
in the elevation of plasma ANP levels [57]. Some controversy still exists with respect to the major site of
myocardial BNP synthesis in humans. Although significant
BNP immunoreactivity and gene expression have been
demonstrated in the ventricular myocardium of subjects
with CHF, they have also been found in atrial tissue under
normal conditions [58,59]. Luchner et al. evaluated the
differential atrial and ventricular expression of myocardial
BNP during evolution of heart failure in dogs [60]. Early
498
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
Fig. 2. (a) The natriuretic peptide receptor (NPR) is a transmembrane protein with several important domains. Intracellular particulate guanylate cyclase is
normally under the inhibition of the kinase homology domain. When an appropriate natriuretic peptide binds to the external domain of the NPR, (ANP or
BNP to NPR-A, CNP to NPR-B), this inhibition is released enabling the formation of cyclic guanosine monophosphate (cGMP) from guanosine
triphosphate (GTP). The resulting intracellular elevation of cGMP is thought to mediate the biological effects of the peptides. Following binding of the
natriuretic peptide to NPR-C (clearance receptor), the resulting receptor-ligand complex undergoes endocytosis and subsequent lysosomal hydrolysis.
(Amended from Levin E.R., Gardner D.G., Samson W.K. Natriuretic peptides. N Engl J Med 1998;339:321–328). (b) In the kidney the vasopressin V2
receptors (V2 -r) are located on the basolateral membrane of collecting duct cells. Binding of vasopressin (VP) to the receptor results in the activation of
adenylate cyclase and subsequent generation of intracellular cyclic adenosine monophosphate (cAMP). The net biological effect, a decrease in water
clearance, is achieved by ‘shuttling’ of aquaporin-2 water channels from cytoplasmic vesicles to the apical membrane, where they facilitate the movement
of water down the osmotic gradient. Aquaporin-2 water channel synthesis is also increased.
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
left ventricular dysfunction was characterised by a selective increase in levels of atrial BNP and BNP mRNA
expression, in association with elevated circulating levels
of plasma BNP. On progression to overt heart failure there
was a further increase in atrial BNP and BNP mRNA
expression, together with a further increase in plasma BNP.
At this point ventricular levels of BNP and BNP mRNA
were also elevated.
A volume-related pattern of release has been proposed
for BNP since its plasma levels increase during chronic
sodium dietary loading whilst its levels decrease during
fluid removal in patients undergoing haemodialysis
[61,62]. Furthermore BNP mRNA expression in the right
atrium is positively correlated with mean right atrial
pressure and ANP mRNA in subjects undergoing cardiac
surgery, which has led to the suggestion that atrial pressure
may also be an important regulatory mechanism [63].
Much less is known regarding the haemodynamic
factors responsible for CNP release. However, in vitro
studies have demonstrated marked augmentation of CNP
secretion from cultured cells by many important vasoactive
mediators. These include cytokines and neurohormones
important in the pathogenesis of chronic heart failure, such
as tumour necrosis factor, lipopolysaccharide and both
ANP and BNP [64,65]. More data are required to determine the in vivo significance of these findings.
3.4. Plasma and urine levels of natriuretic peptides
Plasma ANP and BNP concentrations are markedly
elevated in CHF and the magnitude of increase correlates
to the severity of heart failure [19,66–68]. This has led
several investigators to examine the use of plasma natriuretic peptide assays to aid in the diagnosis of CHF
[69,70]. In these studies plasma BNP level within the
normal range had an exceedingly high negative predictive
value. It has therefore been suggested that plasma BNP
could be useful as a screening tool — a value in normal
range virtually excluding CHF. Further studies have con-
499
firmed the prognostic significance of plasma natriuretic
peptides (Table 1). These have included subjects with CHF
[71,72], post-myocardial infarction [73] and even a cohort
selected purely on the basis of age [74]. In each of these
clinical scenarios, BNP was found to be an independent
prognostic indicator when assessed by multivariate analysis. Several theories have been postulated as to why BNP
appears to be a better predictor of prognosis than ANP in
CHF. These have included its ability to more accurately
reflect regional wall stress within the ventricle or perhaps
result from differences in gene regulation or metabolic
clearance for ANP and BNP [73]. Whether this is influenced by the enhanced expression of atrial BNP, as
demonstrated by Luchner et al. in early canine heart
failure, remains uncertain [60].
Plasma ANP levels have been suggested to be elevated
in coronary disease independent of left ventricular enlargement [75], and show a significant fall post successful
percutaneous transluminal coronary angioplasty. Postmyocardial infarction plasma BNP levels seem also to
relate to infarct artery patency, irrespective of left ventricular ejection fraction, being significantly lower in patients
with TIMI 3 flow [76].
Several studies have failed to demonstrate elevation of
plasma CNP in CHF above the basal levels found in
normal man [77,78]. Interestingly, however, both myocardial and urinary levels of CNP are significantly increased
in this condition [77,79]. In the study by Mattingly et al.
both CNP-22 and CNP-53 were found in the urine,
whereas only CNP-22 has been demonstrated in human
plasma [79]. Mean urinary concentrations of CNP were
250 to 750 times the concentrations for ANP and BNP, and
were much higher than expected from glomerular filtration
alone. The presence of CNP in human kidney has been
confirmed in the epithelial cells of all tubular segments
[79]. In addition, neutral endopeptidase, the enzyme responsible for natriuretic peptide breakdown, is abundant in
the brush border of the proximal renal tubular cell and
therefore these findings suggest that the increase seen in
Table 1
Relation between plasma natriuretic peptide levels and prognosis as assessed by univariate and multivariate analysis in a variety of studies with different
inclusion criteria
Study
Tsutamoto [71]
n
Inclusion criteria
85
Follow-up
LVEF ,45%
2 years
Variables
Omland [73]
131
AMI
Median
1293 days
Tsutamoto [72]
290
Median 812
days
Wallen [74]
541
Asymptomatic or
minimally
symptomatic LV
dysfunction
Aged 85 years
ANP
BNP
ANP
N-ANP
BNP
ANP
BNP
5 years
BNP
Prognostic significance
Univariate (P)
Multivariate (P)
,0.0001
,0.0001
,0.0001
0.0002
,0.0001
,0.0001
,0.0001
NS
,0.0001
0.45
0.99
,0.001
0.088
,0.0001
0.002
n, numbers of subjects; LVEF, left ventricular ejection fraction; AMI, acute myocardial infarction; LV, left ventricle; N-ANP, N-terminal ANP; NS,
non-significant.
500
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
urinary CNP in CHF is more likely to represent enhanced
renal production as opposed to filtration. Definitive proof
is, however, still required.
Borgeson et al. studied the effects of acute intravascular
overload in dogs [80]. This has haemodynamic effects
similar to acute heart failure. They found that whilst there
was the expected rise in plasma ANP, there was no
significant increase in plasma BNP and CNP levels. In
contrast there was a marked increase in urinary CNP but
not ANP or BNP. It thus appears that there is a differential
release of natriuretic peptides from the myocardium and
kidney during acute volume overload.
3.5. Biological effects of the natriuretic peptides
In humans the majority of data available regarding the
biological effects of natriuretic peptides relates to ANP and
BNP. These peptides appear to have very similar effects
promoting vasodilatation, natriuresis and diuresis, together
with inhibition of renin and aldosterone release
[37,38,81,82].
3.5.1. Natriuresis and diuresis
The natriuretic and diuretic actions of ANP and BNP
appear to be due to several mechanisms. An increase in
glomerular filtration rate (GFR) is thought to arise from an
increase in pressure within the glomerular capillaries
caused by afferent arteriolar vasodilatation and efferent
arteriolar vasoconstriction [83]. Filtration may be further
enhanced as a result of the increase in the effective area for
filtration, occurring as mesangial cells relax in response to
natriuretic peptide induced elevations in intracellular
cGMP [84]. This is an opposite effect to that caused by
angiotensin II, which induces contraction of mesangial
cells. In addition, ANP may actually alter the distribution
of intrarenal blood flow thereby changing medullary
haemodynamics and promoting natriuresis [85].
In normal man, infused ANP results in enhanced
electrolyte excretion and diuresis that cannot be accounted
for solely by the increase in GFR, suggesting that it may
act on renal tubules directly [86]. The major effect seems
to be in the collecting duct, where it directly inhibits
sodium reabsorption through a cation channel on the apical
membrane of the collecting duct cells in the inner medulla
[87,88]. The natriuretic and diuretic response to infused
ANP is of rapid onset, and therefore it is likely that the
early phase of natriuresis and diuresis is a result of direct
actions as opposed to being secondary to the inhibition of
renin or aldosterone release [89,90].
Additional mechanisms may further contribute to the
inhibition of sodium and water transport by natriuretic
peptides. ANP antagonizes the actions of vasopressin,
thereby inhibiting water transport in the collecting ducts
[91]. Angiotensin II usually promotes renal tubular sodium
and water transport, an effect again inhibited by ANP [92].
Infused ANP and BNP inhibit the release of renin and
aldosterone in normal man [90,93]. The exact mechanisms
involved remain uncertain, although ANP has also been
shown to directly inhibit renin release from cultured renal
juxtaglomerular cells [94]. Inhibition of aldosterone release
could potentially occur by several distinct mechanisms,
including direct effects of the natriuretic peptides on the
adrenal glomerulosa [95] or secondary to renin inhibition
[81]. Hunt et al. demonstrated that ANP significantly
inhibited angiotensin-II-induced aldosterone secretion, during concomitant infusions of the natriuretic peptides and
angiotensin-II in normal man [96]. Although BNP tended
to suppress this response to angiotensin-II, it did not reach
significance.
As mentioned earlier, urodilatin, a 32-amino acid peptide, is produced in the kidney from a precursor protein
[42]. Although its in vivo role in humans has yet to be
fully clarified, exogenous urodilatin promotes both natriuresis and diuresis at doses lower than those demonstrated with ANP [97].
It is apparent that the natriuretic peptides tend to
antagonise the biological effects of the renin–angiotensin–
aldosterone system. However, angiotensin II itself and
angiotensin-converting enzyme (ACE) inhibitors also influence circulating natriuretic peptide levels. Angiotensin
II infused to increase arterial blood pressure and systemic
vascular resistance in healthy volunteers increased plasma
concentrations of ANP but not BNP or CNP [98]. In
contrast, Wiese and colleagues demonstrated an increase in
BNP mRNA expression in isolated human atrial and
ventricular myocardium in response to angiotensin II [99].
ACE inhibitors have been shown to decrease both circulating ANP and BNP in patients post-myocardial infarction
[100,101]. Furthermore, increased vasodilator therapy, in
the form of diuretics and ACE inhibitors, can also reduce
BNP measurements to the normal range in patients with
CHF [102]. However, Vantrimpont et al. failed to demonstrate a reduction in plasma ANP during chronic treatment
with ACE inhibitors in subjects with asymptomatic left
ventricular dysfunction post-myocardial infarction [103].
Whether the reduction of circulating natriuretic peptides
purely reflects the documented beneficial effects of ACE
inhibitors on left ventricular remodelling and dilatation or
are a consequence of a more direct effect is not fully
elucidated. A study in rats has confirmed that losartan, an
angiotensin receptor antagonist, can inhibit angiotensin
II-stimulated ANP secretion [104]. In addition, combined
use of losartan and an endothelin receptor antagonist
almost completely blocked volume–load-induced N-terminal ANP release, suggesting a more direct role for endothelin and angiotensin II in volume–load induced ANP
secretion.
3.5.2. The role of natriuretic peptides in CHF — data
from experimental models and small studies of human
CHF
The exact extent of natriuretic peptide-induced natriuresis and diuresis in CHF remains somewhat unclear.
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
3.5.2.1. ANP In healthy dogs infused ANP resulted in
marked natriuresis and diuresis, accompanied by a reduction in mean arterial and right atria pressures without a
change in heart rate [105]. Renin secretion was suppressed
whilst GFR and renal plasma flow increased. In contrast,
when ANP was infused in dogs with CHF it merely
resulted in a small reduction in mean arterial pressure
without affecting other haemodynamic variables or renin
concentration. There was no change in natriuresis or
diuresis.
Intravenously infused ANP was found to have little
effect in patients with CHF, whereas in controls it resulted
in the expected natriuresis and diuresis [90,106]. Despite
this, other favourable effects such as an improvement in
haemodynamics and inhibition of neurohormonal activation still occurred. Therefore a degree of renal ANP
resistance appears to occur in CHF. Downregulation of
natriuretic peptide receptors has been demonstrated on
peripheral smooth muscle cells and platelets of patients
with CHF [107,108] and in the renal medulla in a rat
model of CHF [109], and may occur secondary to the
elevated plasma ANP levels seen in CHF. Alternatively it
might result from vasoconstrictor-induced NPR downregulation, which has been demonstrated in cultured rat vascular smooth muscle cells with both angiotensin and vasopressin [110]. Whether a similar downregulation of
receptors occurs in the human kidney, thereby accounting
for this apparent renal resistance to natriuretic peptides in
CHF, remains uncertain. Alternative mechanisms may well
be involved, including a decrease in the sodium delivery to
the collecting tubules, where the major natriuretic effect of
the peptides is exerted. Evidence supporting this has come
from a rat model of CHF [111], where the administration
of an angiotensin II receptor antagonist, which increases
sodium delivery to the distal nephron, restores renal
responsiveness to exogenous ANP. An interesting recent
study by Misono has demonstrated that binding of ANP to
its receptor is dependent on local chloride concentration,
with a reduction in chloride decreasing binding [112]. This
effect could not be overcome by excess ANP. Since
chloride concentrations in the renal tubules are tightly
coupled with sodium and water transport, Misono proposes
that chloride-mediated feedback plays a role in ANPinduced natriuresis in states such as CHF where high
circulating levels of ANP are found. Thus, persistent ANPinduced natriuresis would consequently result in a reduction in tubular chloride concentration, which below a
certain threshold would result in inhibition of ANP binding
to its receptor. Further studies evaluating this hypothesis
are required. Other work, however, demonstrated that the
renal effects were preserved when exogenous ANP was
given as a bolus dose [113].
3.5.2.2. BNP Whilst early studies of ANP in human
CHF have been somewhat disappointing those with BNP
have held more promise. Twenty patients with severe CHF
were randomized in a double-blind, placebo-controlled
501
trial to receive incremental infusions of human BNP or
placebo [114]. Infusion of incremental BNP was associated
with favourable haemodynamic and natriuretic effects.
More recently Abraham et al. have studied the haemodynamic, neurohormonal and renal effects of infused BNP
in patients with decompensated heart failure [115]. They
confirmed the beneficial haemodynamic responses, including reductions in both cardiac preload and systemic
vascular resistance, which occurred without an associated
reflex tachycardia. Although there was a fall in mean
arterial pressure there were no significant changes in GFR
or renal blood flow. This preservation of renal haemodynamics may relate to the documented renal vasodilating
properties of the natriuretic peptides [116]. The natriuretic
response was blunted in some of the patients with CHF
[115]. Indeed the best predictor of natriuretic response to
BNP was distal tubular sodium delivery, as assessed by
lithium clearance. This supports the data mentioned above
regarding the renal responsiveness to exogenous ANP in
rats with CHF [111]. However, the finding that enhanced
natriuresis occurs in response to higher concentrations of
infused BNP in compensated CHF patients [117], suggests
that the action of natriuretic peptides in CHF is more
complex.
A recent study in a canine model of CHF demonstrated
that repeated short-term administration of subcutaneous
BNP resulted in an improvement in cardiovascular haemodynamics [118]. If confirmed in humans, this might
provide a novel therapeutic method for the chronic administration of BNP in CHF.
There are several potential reasons why studies with
infused BNP in CHF appear to be encouraging, whilst
those with ANP have been a disappointment. Human BNP
has a significantly prolonged plasma half-life [119], which
may be a reflection of a relative resistance to metabolism
by neutral endopeptidase [120]. Differences in study
design may have influenced the results of the earlier
studies with ANP [114]. Most studies with ANP did not
administer the full human ANP peptide chain and it is
feasible that the analogues used may have reduced biological effects when compared to the endogenous peptide.
Several of the studies used infusions over relatively short
time-periods, which may not have been adequate to
achieve steady-state plasma levels. Furthermore, most of
the patients in the ANP studies were not taking ACE
inhibitors. In view of the fact that angiotensin II enhances
cGMP degradation, ACE inhibitors or angiotensin receptor
blockers may enhance the biological effects of natriuretic
peptides [111,121].
3.5.2.3. CNP The renal actions of CNP have been less
extensively investigated and from the few completed
studies findings are inconsistent. Hunt et al. infused CNP
into healthy volunteers to achieve plasma levels greater
than those found in pathological states, but they were
unable to demonstrate a natriuretic response, although
there was a decrease in plasma aldosterone levels [122].
502
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
However, a further study showed enhanced natriuresis in
response to a bolus of CNP [123]. This was associated
with significant elevations of both ANP and BNP, perhaps
resulting from competition for clearance mechanisms. In
comparison to ANP and BNP, CNP has a much shorter
plasma half-life at approximately 2.6 min [122]. It remains
uncertain how plasma levels of CNP relate to in vivo tissue
levels. Of particular interest, CNP is located at high
concentration in the vascular endothelium and its receptor,
NPR-B, in the adjacent vascular smooth muscle [124].
CNP is therefore in prime position to influence vascular
regulation. Indeed in a study by Davidson et al., looking at
forearm blood flow, CNP inhibited the vasoconstrictive
effect of angiotensin I but not angiotensin II [125]. This
suggests that CNP may act as an inhibitor of local vascular
ACE, although the exact mechanisms involved are undetermined.
3.5.3. Other biological effects of the natriuretic peptides
The natriuretic peptides have many other important
actions in addition to their vasodilatory and renal effects.
In healthy human subjects, low dose ANP infusion results
in enhanced vascular permeability and a subsequent reduction of plasma volume [126]. In vitro studies have also
shown that natriuretic peptides inhibit vascular smooth
muscle and endothelial cell proliferation [127–129]. In
addition, in cultured aortic smooth muscle cells ANP and
CNP inhibit plasminogen activator inhibitor-1 mRNA
expression in response to various stimuli [130]. This has
led some to speculate that the natriuretic peptides may be
involved in the response to vascular injury. Evidence in
support of this has come from in vivo studies in rabbits,
which have shown that an infusion of exogenous CNP can
inhibit intimal thickening after injury to the carotid artery
[131,132].
A recent study has also shown that the natriuretic
peptides, and ANP in particular, are powerful lipolytic
agents both in situ in human adipose tissue and in vitro in
isolated fat cells [133]. Studies have also confirmed that
human adipose tissue expresses NPR messenger RNA
[134]. The clinical relevance of this is uncertain and
requires further evaluation particularly in the setting of
cachexia and heart failure where patients demonstrate
significant loss of adipose tissue [135]. Our group has
preliminary data showing a significant positive correlation
between plasma levels of ANP and BNP to plasma
concentrations of tumour necrosis factor, independent of
left ventricular dimensions, in patients with CHF [personal
communication, M. Rauchhaus]. In addition, cachectic
CHF patients had higher BNP levels. A mechanistic
relationship for these findings remains unclear and it is
feasible that both natriuretic peptides and tumour necrosis
factor are merely markers of disease severity. This area
deserves more extensive evaluation and as such we are
undertaking further studies. Furthermore, how or whether
exogenous infused natriuretic peptides influence plasma
and myocardial cytokine levels remains to be seen.
4. Vasopressin
Vasopressin is synthesised in the hypothalamus as a
pre-pro hormone, before being transported along axons to
the neuronal terminals in the neurohypophysis, where it is
stored in secretory granules. It is subsequently released
into the circulation by exocytosis, in response to both
osmotic and nonosmotic stimuli [34].
Many patients with CHF have water retention in excess
of sodium with resulting hyponatraemia, and this finding is
associated with a significantly impaired prognosis [136].
Although increased thirst in CHF can lead to increased
water intake, this in itself cannot fully explain the hyponatraemia [137]. Several studies have confirmed an increase in plasma levels of vasopressin in patients with
CHF [4,138,139]. It therefore appears that elevated plasma
levels of vasopressin occur in patients with CHF despite
the associated atrial distension, hyponatraemia and low
osmolality, which would usually inhibit its release in
normal subjects. This is thought to occur as a result of
non-osmotic release of vasopressin.
Non-osmotic release of vasopressin results from disturbances in circulatory homeostasis detected by the highpressure mechanoreceptors described earlier [32–34]. Arterial under-filling results in a release in the inhibition of
the hypothalamus from neuromodulatory impulses. This
results in enhanced vasopressin synthesis and release.
4.1. Vasopressin receptors and water channels ( Fig. 2 b)
Vasopressin exerts its biological effects via interactions
with specific receptors, of which there are two distinct
types, V1 and V2 . Binding of vasopressin to the V1 receptor
results in activation of the phosphoinositide pathway and
mobilisation of cytosolic calcium [140]. The V1 receptor
has two subtypes: V1a is located on a number of cell types
including vascular smooth muscle and V1b is present in the
anterior pituitary [141,142]. Activation of V1a results in
enhanced vasoconstriction and contributes to the maintenance of vascular tone in normal subjects [143]. In dogs
with experimental heart failure antagonism of this receptor
is associated with a decrease in systemic vascular resistance and an increase in cardiac output [144].
The V2 receptors are primarily located on the basolateral
membrane of collecting duct cells in the kidney [140].
Binding of vasopressin to these receptors results in the
activation of adenylate cyclase and subsequent generation
of intracellular cyclic adenosine monophosphate. The main
biological effect of vasopressin in the kidney, a decrease in
water clearance, is achieved by the resulting ‘shuttling’ of
aquaporin-2 water channels from cytoplasmic vesicles to
the apical surface of the collecting duct where they are
inserted [145]. At the apical membrane these water channels facilitate water transport across the collecting duct
cells in response to the osmotic gradient generated by the
counter-current concentrating system. In addition vasopres-
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
sin actually increases aquaporin-2 water channel synthesis
[146].
Vasopressin has other effects in the kidney, including
increasing the reabsorption of urea in the final portion of
the inner medullary collecting duct thereby maintaining
medullary hypertonicity and sodium in the cortical segment [147,148].
4.1.1. The role of vasopressin in CHF — data from
experimental models and small studies of human CHF
Recent improvements in the understanding of the functional significance of vasopressin in CHF have been
achieved by the development of specific V2 receptor
antagonists. In a rat model of heart failure the administration of a V2 antagonist resulted in a reduction of aquaporin2 protein in the collecting duct [149]. Further animal
studies have confirmed that antagonism of the V2 receptor
results in the anticipated increase in water excretion, with
an associated decrease in urinary osmolality [144,149,150].
Studies in humans have produced similar results. Abraham et al. demonstrated that the administration of an oral
selective V2 receptor antagonist to patients with CHF
significantly increased urine flow and plasma sodium
concentration [151]. There was an associated reduction in
urine osmolality, therefore confirming an increase in
solute-free water clearance.
The effect of vasopressin on renal physiology in patients
with CHF may be more complicated than initially appreciated. Eisenman et al. have demonstrated that low dose
vasopressin can actually restore urine output in patients
with the hepatorenal syndrome and in anuric patients with
end-stage heart failure [152]. Indeed some studies in
animals have shown that after volume expansion, the
administration of vasopressin actually results in diuresis
[153]. Eisenman et al. speculate that this diuretic effect
occurs directly through stimulation of the V1 receptor
located in renal epithelial cells and indirectly by enhancing
ANP release [152].
5. Clinical trials involving natriuretic peptides and
vasopressin antagonism in CHF
5.1. Natriuretic peptides
5.1.1. Therapy guided by plasma natriuretic peptide levels
As mentioned earlier, plasma measurements of ANP and
BNP have been used to assist in the diagnosis of CHF and
in subsequent prognostic assessment [19,20]. Recent evidence suggests that measurements of BNP may be useful
in guiding the tailoring of conventional therapy. Troughton
et al. compared conventional drug therapy intensified to
reduce plasma amino terminal BNP levels to within normal
range against therapy directed by standard clinical assessment, in patients with symptomatic CHF [21]. The investigators hypothesised that titration of therapy guided by
plasma BNP levels would prove to be superior, since
503
plasma BNP concentrations are related to ventricular filling
pressures and wall stress [154,155]. In addition, previous
studies have confirmed that plasma BNP levels fall when
left ventricular filling pressure is reduced by vasodilator
therapy with ACE inhibitors and diuretics [154,156]. They
demonstrated that there were fewer total cardiovascular
events (death, hospital admission or heart failure decompensation) in the BNP-guided therapy group than in the
clinical group. At 6 months 27% of patients in the BNPguided group had suffered a first cardiovascular event in
comparison to 53% in the clinical group (P50.034).
However, the use of BNP to titrate therapy was a relatively
complicated process and resulted in the BNP group
receiving slightly higher doses of ACE inhibitors and
diuretics. Of particular note, the use of spironolactone was
significantly increased in the BNP-guided group.
5.1.2. Vasopeptidase inhibition
In order to potentiate the beneficial circulatory and renal
effects of the natriuretic peptide family in CHF, investigators have looked at methods of impairing their breakdown. Initial studies in hypertension and CHF using
inhibitors of neutral endopeptidase, the enzyme involved in
natriuretic peptide catabolism, revealed limitations due to
increased activation of the renin–angiotensin–aldosterone
system [157–159]. This led onto the development of
vasopeptidase inhibitors, molecules simultaneously inhibiting neutral endopeptidase and ACE. This combines the
established benefits of ACE inhibition with the potential
benefits of enhancing the natriuretic peptide system. Animal studies with omapatrilat, a recently developed vasopeptidase inhibitor, have shown benefits in CHF models
[160].
The efficacy of omapatrilat in human CHF has now been
confirmed. McClean et al. demonstrated improvements in
functional status, left ventricular performance, together
with a reduction in blood pressure after 12 weeks of
treatment with the drug [161]. Omapatrilat also resulted in
an enhanced natriuresis and a reduction in total blood
volume. Despite the decrease in systemic blood pressure
and blood volume, renal function was preserved. The
recently published IMPRESS study compared the effects
of omapatrilat with lisinopril (an ACE inhibitor) with
primary end-point being improvement in exercise testing at
week 12 [162]. Secondary end-points included death and
comorbid events indicative of worsening heart failure. In
this study there were no significant differences in principal
end-points. However, there were fewer cardiovascular
system adverse events (combined data) in the omapatrilat
group and although individual cardiovascular end-points
related to worsening heart failure did not reach significance, the results favoured omapatrilat in each case.
Some concerns have been voiced over the side-effect
profile of omapatrilat. The IMPRESS study demonstrated
an excess of gastrointestinal side-effects when compared to
the lisinopril group [162]. Of more concern has been the
rarer, but potentially life-threatening, angioedema. The
504
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
0.7% rate found with omapatrilat [163] is in excess of the
0.34% documented with ramipril [164]. The higher rate
found with omapatrilat in IMPRESS maybe an untoward
side-effect of the drug itself or possibly relate to differences in the population groups studied [165]. This study
included significant numbers of black participants, a group
known to have a higher rate of angioedema associated with
ACE inhibitors compared to Caucasians [166]. Unfortunately there is currently no data available on sub-group
analysis from IMPRESS, and as such it remains uncertain
as to whether the excess rate of angioedema found with
omapatrilat is specific to the drug itself or as a consequence of the populations studied. Further clinical studies,
with much larger numbers of patients, are required to
establish mortality and morbidity end-points and safety
data in order to properly assess the place of omapatrilat in
current clinical practice. The relatively small numbers of
patients recruited (573) and short length of follow-up (24
weeks) in IMPRESS [155] demonstrate current limitations
of clinical studies on vasopeptidase inhibition in CHF,
when compared to established studies confirming benefits
of ACE inhibitors. For example, the SAVE Trial investigating the benefits of captopril in patients with reduced left
ventricular function, recruited 2231 patients followed-up
for an average of 42 months [167]. In addition, it remains
uncertain how the result of enhancement of natriuretic
peptide levels will influence their other biological properties in clinical practice.
5.1.3. Intravenous recombinant human BNP
Although intravenous natriuretic peptide administration
is not practical in the outpatient management of patients
with CHF, it may be beneficial during acute deterioration.
Nesiritide, a recombinant human BNP, has recently been
studied in two randomised trials involving patients hospitalised with decompensated CHF [168]. The first was a
double-blind efficacy study and demonstrated a significant
improvement in haemodynamic function and clinical status
when compared to placebo. Nesiritide infusion resulted in
a dose-related decrease in pulmonary capillary wedge
pressure, which was associated with a decrease in systemic
vascular resistance and increase in cardiac index. Although
there was a decrease in systolic blood pressure there was
no associated reflex tachycardia. In the comparative study
nesiritide was compared with standard intravenous agents,
(including dobutamine and nitrates), which served as
controls for clinical efficacy and adverse events. Improvements in clinical status were similar between the groups.
This led the authors to suggest that nesiritide may be
helpful in the short-term management of decompensated
patients with heart failure, particularly since it avoids the
tachycardia associated with dobutamine therapy and the
tolerance experienced with nitrate infusions.
examining the use of vasopressin antagonists in human
heart failure. Selective inhibition of the V1 receptor led to
immediate improvement in haemodynamic parameters in
patients with baseline elevations in plasma vasopressin
[169]. This, however, was only a transient response and
data on long-term responsiveness and benefits are not
available. V2 receptor antagonism in patients with CHF has
been performed with an orally active molecule — WAYVPA-985. In a randomised, placebo-controlled study administration of this antagonist resulted in increased solutefree water excretion with resulting elevation of serum
sodium concentration [151]. In addition there was a
reduction in urinary aquaporin-2 levels, suggesting that the
enhanced diuresis may well be secondary to a reduction in
aquaporin-2 production and mobilisation.
Combined V1 and V2 receptor antagonists offer the
potential advantages of reduced vasoconstriction together
with enhanced solute-free water excretion. This may be
particularly applicable for hyponatraemic patients with
CHF, a group with significantly impaired prognosis.
Conivaptan (YM087) is an orally active combined V1a / V2
receptor antagonist. An early study has confirmed its
efficacy and tolerability in six patients with severe CHF
[170]. Administration of the drug resulted in an increase in
serum sodium concentration. This was associated with a
decrease in urine osmolality and increases in urine output
and free-water clearance. Larger studies are required to
assess its long-term safety, efficacy and clinical benefit.
6. Conclusions
Improvements in the understanding of neurohormonal
activation in CHF have confirmed the importance of the
balance between the vasoconstricting, sodium-retaining
systems and those involved in vasodilatation and natriuresis. These systems interact to maintain circulatory
integrity. However, as heart failure progresses enhanced
sodium and water retention contributes to the debilitating
symptoms experienced by patients and adversely effect
myocardial performance.
Therapeutic manipulation of neurohormones is now a
feasible and exciting prospect in the treatment of CHF.
Early clinical data are encouraging for vasopeptidase
inhibitors, molecules combining inhibition of ACE and
neutral endopeptidase, and intravenous recombinant human
BNP. Vasopressin receptor antagonism results in enhanced
diuresis in both animal models and humans. Further data
are required on the long-term efficacy and safety of these
treatments prior to their implementation in routine clinical
practice.
Acknowledgements
5.2. Vasopressin receptor antagonists
Currently there are only a limited number of studies
PR Kalra is supported by Wessex Heartbeat. SD Anker
is supported with a postgraduate fellowship of the Max
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
¨
Delbruck
Centrum for Molecular Medicine, Berlin, Germany. AJS Coats is supported by the Viscount Royston
ˆ Holiday and
Trust Fund. We thank Philip Kalra, Sian
Aidan Bolger for critically reading the manuscript and
Justin Kirk-Bayley for his assistance with the figures.
[21]
[22]
References
[1] The Task Force on Heart Failure of the European Society of
Cardiology. Guidelines for the diagnosis of heart failure. Eur Heart J
1995;16:741–751.
[2] Genest J, Granger P, De Champlain J, Boucher R. Endocrine factors
in congestive heart failure. Am J Cardiol 1968;22:35–42.
[3] Mancia G. Sympathetic activation in congestive heart failure. Eur
Heart J 1990;11(Suppl. A):3–11.
[4] Szatalowicz VL, Arnold PE, Chaimovitz C et al. Radio immunoassay of plasma arginine vasopressin in hyponatraemic patients with
congestive heart failure. New Engl J Med 1981;305:263–266.
[5] Pacher R, Stanek B, Hulsmann M et al. Prognostic impact of big
endothelin-1 plasma concentrations compared with invasive haemodynamic evaluation in severe heart failure. J Am Coll Cardiol
1996;27:633–641.
[6] Packer M. The neurohormonal hypothesis: a theory to explain the
mechanism of disease progression in heart failure. J Am Coll
Cardiol 1992;20:248–254.
[7] Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones
regulating cardiovascular function in patients with severe congestive
heart failure and their relation to mortality. For the CONSENSUS
Trial Study Group. Circulation 1990;82:1730–1736.
[8] Tan LB, Jalil JE, Pick R et al. Cardiac myocyte necrosis induced by
angiotensin II. Circ Res 1991;69:1185–1195.
[9] Weber KT. Extracellular matrix remodelling in heart failure: a role
for de novo angiotensin II generation. Circulation 1997;96:4065–
4082.
[10] Grassi G, Cattaneo BM, Servavalle G et al. Effects of chronic ACE
inhibition on sympathetic nerve traffic and baroreflex control of the
circulation. Circulation 1997;96:1173–1179.
[11] Cohn J, Levine TB, Olivari MT et al. Plasma norepinephrine as a
guide to prognosis in patients with chronic congestive heart failure.
New Engl J Med 1984;311:819–823.
[12] Pousset F, Isnard R, Lechat P et al. Plasma endothelin-1 is a strong
prognostic marker in chronic heart failure. Eur Heart J 1997;18:254–
258.
[13] Anker SD, Ponikowski P, Varney S et al. Wasting as independent risk
factor for mortality in chronic heart failure. Lancet 1997;349:1050–
1053.
[14] Anker SD, Chua TP, Ponikowski P et al. Hormonal changes and
catabolic / anabolic imbalance in chronic heart failure and their
importance for cardiac cachexia. Circulation 1997;96:526–534.
[15] Anker SD. Catecholamine levels and treatment in chronic heart
failure. Eur Heart J 1998;19(Suppl. F):F56–F61.
[16] Edwards BS, Zimmermann RS, Burnett JC. Atrial natriuretic factor:
physiological actions and implications in congestive heart failure.
Cardiovasc Drugs Ther 1987;1:89–100.
[17] Dzau VJ. Renal and circulatory mechanisms in heart failure. Kidney
Int 1987;31:1402–1416.
[18] Habib F, Dukta D, Crossman D, Oakley CM, Cleland JG. Enhanced
basal nitric oxide production in heart failure: another failed counterregulatory vasodilator mechanism? Lancet 1994;344:371–373.
[19] Burnett Jr. JC, Kao PC, Hu DC et al. Atrial natriuretic peptide
elevation in congestive heart failure in the human. Science
1986;231:1145–1147.
[20] Omland T, Aarsland T, Aakvaag A, Lie RT, Dickstein K. Prognostic
value of plasma atrial natriuretic factor, norepinephrine, and epi-
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
505
nephrine in acute myocardial infarction. Am J Cardiol 1993;72:255–
259.
Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls
MG, Richards AM. Treatment of heart failure guided by plasma
aminoterminal natriuretic peptide (N-BNP) concentrations. Lancet
2000;355:1126–1130.
Australia / New Zealand Heart Failure Research Collaborative
Group. Randomised, placebo-controlled trial of carvedilol in patients
with congestive heart failure due to ischaemic heart disease. Lancet
1997;349:375–380.
The SOLVD Investigators. Effect of enalapril on survival in patients
with reduced left ventricular ejection fraction and congestive heart
failure. New Engl J Med 1991;325:293–302.
Vander AJ. Control of renin release. Physiol Rev 1967;47(3):359–
382.
Kurtz A, Bruna RD, Pfeilschifter J, Taugner R, Bauer C. Atrial
natriuretic peptide inhibits renin release from juxtaglomerular cells
by a cGMP-mediated process. Proc Natl Acad Sci USA
1986;83:4769–4773.
Keeton TK, Pettinger WA, Campbell WB. The effects of altered
sodium balance and adrenergic blockade on renin release induced in
rats by angiotensin antagonism. Circ Res 1976;38:531–539.
Cargill RI, Coutie WJ, Lipworth BJ. The effects of angiotensin II on
circulating levels of natriuretic peptides. J Clin Pharmac
1994;38:139–142.
Inoue M, Kimura T, Ota K. Effect of vasopressin on atrial
natriuretic peptide release and renal function in dogs. Am J Physiol
1988;255:E449–E455.
Rankin AJ, Wilson N, Ledsome JR. Effects of autonomic stimulation on plasma immunoreactive atrial natriuretic peptide in the
anaesthetized rabbit. Can J Physiol Pharmacol 1987;65:532–537.
Dillingham MA, Anderson RJ. Inhibition of vasopressin action by
atrial natriuretic factor. Science 1986;231:1572–1573.
Schrier RW. Pathogenesis of sodium and water retention in highoutput and low-output cardiac failure, nephrotic syndrome, cirrhosis
and pregnancy. New Engl J Med 1988;319:1065–1072.
Gilmore JP. Contribution of baroreceptors to the control of renal
function. Circ Res 1964;14:301–317.
Schrier RW, Berl T. Mechanism of effect of alpha adrenergic
stimulation with norepinephrine on renal water excretion. J Clin
Invest 1973;52:502–511.
Shrier RW, Berl T, Anderson RJ. Osmotic and non-osmotic control
of vasopressin release. Am J Physiol 1979;236:F321–F332.
Martin Sc P-Y, Schrier RW. Sodium and water retention in heart
failure: pathogenesis and treatment. Kidney Int 1997;51(Suppl.
59):S57–S61.
Ponikowski P, Chua TP, Piepoli M et al. Augmented peripheral
chemosensitivity as a potential input to baroreflex impairment and
autonomic imbalance in chronic heart failure. Circulation
1997;96:2586–2594.
de Bold AJ, Borenstein HB, Veress AT, Sonnenberg HA. A rapid
and potent natriuretic response to intravenous injection of atrial
myocardial extract in rats. Life Sci 1991;28:89–94.
Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic
peptide in porcine brain. Nature 1988;332:78–81.
Saito Y, Nakao K, Itoh H et al. Brain natriuretic peptide is a novel
cardiac hormone. Biochem Biophys Res Commun 1989;158:360–
368.
Sudoh T, Minamino N, Kangawa K, Matsuo H. C-type natriuretic
peptide (CNP): a new member of the natriuretic peptide family
identified in porcine brain. Biochem Biophys Res Commun
1990;168:863–870.
Shields PP, Glembotski CC. Regulation of atrial natriuretic factor
(99–126) secretion from neonatal rat primary atrial cultures by
activators of protein kinases A and C. J Biol Chem 1989;264:9322–
9328.
Schulz-Knappe P, Forssmann K, Herbst F, Hock D, Pipkorn R,
Forssmann WG. Isolation and structural analysis of ‘urodilatin’, a
506
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
new peptide of the cardiodilatin-(ANP)-family, extracted from
human urine. Klin Wochenshcr 1988;66:752–759.
Sudoh T, Maekawa K, Kojima M, Minamino N, Kangawa K,
Matsuo H. Cloning and sequence analysis of cDNA encoding a
precursor for human brain natriuretic peptide. Biochem Biophys Res
Commun 1989;159:1427–1434.
Tawaragi Y, Fuchimura K, Tanaka S, Minamino N, Kangawa K,
Matsuo H. Gene and precursor structures of human C-type natriuretic peptide. Biochem Biophys Res Commun 1991;175:645–651.
Stingo AJ, Clavell AL, Heublein DM, Wei CM, Pittelkow MR,
Burnett Jr. JC. Presence of C-type natriuretic peptide in cultured
human endothelial cells and human plasma. Am J Physiol
1992;263:H1318–H1321.
Togashi K, Kameya T, Kurosawa T, Hasegawa N, Kawakami M.
Concentrations and molecular forms of C-type natriuretic peptide in
brain and cerebrospinal fluid. Clin Chem 1992;38:2136–2139.
Chinkers M, Garbers DL. The protein kinase domain of the ANP
receptor is required for signalling. Science 1989;245:1392–1394.
Suga S, Nakao K, Hosoda K et al. Receptor selectivity of natriuretic
peptide family, atrial natriuretic peptide, brain natriuretic peptide,
and C-type natriuretic peptide. Endocrinology 1992;130:229–239.
Almeida FM, Suzuki M, Scarborough RM, Lewicki JA, Maack T.
Clearance function of type C receptors of atrial natriuretic factor in
rats. Am J Physiol 1989;256:R469–R475.
Soleilhac JM, Lucas E, Beaumont A et al. A 94-kDa protein,
identified as neutral endopeptidase-24.11, can inactivate atrial
natriuretic peptide in the vascular endothelium. Mol Pharmacol
1992;41:609–614.
Oehlenschlager WF, Baron DA, Schomer H, Curie MC. Atrial and
brain natriuretic peptides share binding sites in the kidney and heart.
Eur J Pharmacol 1989;161:159–164.
¨ S, Jamison RL, Myers BD, Pratt RE. Identification of
Canaan-Kuhl
‘B’ receptor for natriuretic peptide in human kidney. Endocrinology
1992;130:550–552.
´
Grandclement
B, Morel G. Ultrastructural characterization of atrial
natriuretic peptide receptors (ANP-R) mRNA expression in rat
kidney cortex. Biol Cell 1998;90:213–222.
Itoh K, Nonoguchi H, Shiraishi N, Tomita K. Gene regulation of
atrial natriuretic peptide A, B, and C receptors in rat gomeruli. Exp
Nephrol 1999;7:328–336.
Bonhomme MC, Grove KL, Caron S et al. Immunolocalization of
natriuretic peptide receptor B in the rat kidney. J Am Soc Nephrol
1998;9:1777–1786.
Dietz JR. Release of natriuretic factor from rat heart-lung preparation by atrial distension. Am J Physiol 1984;247:R1093–R1096.
Zimmerman RS, Edwards BS, Schwab TR, Heublein DM, Burnett
Jr. JC. Cardiorenal-endocrine dynamics during and following volume expansion. Am J Physiol 1987;252:R336–R340.
Mukoyama M, Nakao K, Hosoda K et al. Brain natriuretic peptide
as a novel cardiac hormone in humans: evidence for an exquisite
dual natriuretic peptide system, atrial natriuretic peptide and brain
natriuretic peptide. J Clin Invest 1991;87:1402–1412.
Wei CM, Heublein DM, Perella MA et al. Natriuretic peptide system
inhuman heart failure. Circulation 1993;88:1004–1009.
Luchner A, Stevens TL, Borgeson DD et al. Differential atrial and
ventricular expression of myocardial BNP during evolution of heart
failure. Am J Physiol 1998;274:H1684–H1689.
Lang CC, Coutie WJ, Khong TK, Choy AMJ, Struthers AD. Dietary
sodium loading increases plasma brain natriuretic peptide levels in
man. J Hypertens 1991;9:779–782.
Lang CC, Choy AMJ, Henderson IS, Coutie WJ, Struthers AD.
Effect of haemodialysis on plasma levels of brain natriuretic peptide
in patients with chronic renal failure. Clin Sci 1992;82:127–131.
Doyama K, Fukumoto M, Takemura G et al. Expression and
distribution of brain natriuretic peptide in human right atria. J Am
Coll Cardiol 1998;32:1832–1838.
Suga S, Itoh H, Komatsu Y et al. Cytokine-induced C-type nat-
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]
[85]
riuretic peptide (CNP) secretion from vascular endothelial cells –
evidence for CNP as a novel autocrine / paracrine regulator from
endothelial cells. Endocrinology 1993;133:3038–3041.
Nazario B, Hu RM, Pedram A, Prins B, Levin ER. Atrial and brain
natriuretic peptides stimulate the production and secretion of C-type
natriuretic peptide from bovine aortic endothelial cells. J Clin Invest
1995;95:1151–1157.
Dickstein K, Larsen AL, Bonarjee V et al. Plasma proatrial natriuretic factor is predictive of clinical status in patients with
congestive heart failure. Am J Cardiol 1995;76:679–683.
Gottlieb SS, Kukin ML, Ahern D, Packer M. Prognostic importance
of atrial natriuretic peptide in patients with chronic heart failure. J
Am Coll Cardiol 1989;13:1534–1539.
Motwani JG, McAlpine H, Kennedy N, Struthers AD. Plasma brain
natriuretic peptide as an indicator for angiotensin-converting-enzyme-inhibition after myocardial infarction. Lancet 1993;341:1109–
1113.
McDonagh TA, Robb SD, Murdoch DR et al. Biochemical detection
of left-ventricular systolic dysfunction. Lancet 1998;351:9–13.
Cowie MR, Struthers AD, Wood DA et al. Value of natriuretic
peptides in assessment of patients with possible new heart failure in
primary care. Lancet 1997;350:1349–1351.
Tsutamoto T, Wada A, Maeda K et al. Attenuation of compensation
of endogenous cardiac natriuretic peptide system in chronic heart
failure. Circulation 1997;96:509–516.
Tsutamoto T, Wada A, Maeda K et al. Plasma brain natriuretic
peptide level as a biochemical marker of morbidity and mortality in
patients with asymptomatic or minimally symptomatic left ventricular dysfunction: comparison with plasma angiotensin II and
endothelin-1. Eur Heart J 1999;20:1799–1807.
Omland T, Aakvaag A, Bonarjee VVS et al. Plasma brain natriuretic
peptide as an indicator of left ventricular systolic function and
long-term survival after acute myocardial infarction: comparison
with plasma atrial natriuretic peptide and N-terminal proatrial
natriuretic peptide. Circulation 1996;93:1963–1969.
Wallen T, Landahl S, Hedner T, Nakao K, Saito Y. Brain natriuretic
peptide predicts mortality in the elderly. Heart 1997;77:264–267.
Klinge R, Jørgensen B, Thaulow E, Sirnes PA, Hall C. N-terminal
proatrial natriuretic peptide in angina pectoris: impact of revascularization by angioplasty. Int J Cardiol 1999;68:1–8.
Uusimaa P, Ruskoaho H, Vuolteenaho O et al. Plasma vasoactive
peptides after acute myocardial infarction in relation to left ventricular dysfunction. Int J Cardiol 1999;69:5–14.
Wei CM, Heublein DM, Perrella MA et al. Natriuretic peptide
system in human heart failure. Circulation 1993;88:1004–1009.
Totsune K, Takahashi K, Murakami O, Satoh F, Sone M, Mouri T.
Elevated plasma C-type natriuretic peptide concentrations in patients
with chronic renal failure. Clin Sci 1994;87:319–322.
Mattingly MT, Brandt RR, Heublein DM, Wei C, Nir A, Burnett Jr.
JC. Presence of C-type natriuretic peptide in human kidney and
urine. Kidney Int 1994;46:744–747.
Borgeson DD, Stevens TL, Heublein DM, Matsuda Y, Burnett JC.
Activation of myocardial and renal natriuretic peptides during acute
intravascular volume overload in dogs: functional cardiorenal responses to receptor antagonism. Clin Sci 1998;95:195–202.
Burnett Jr. JC, Granger JP, Opgenorth TJ. Effects of synthetic atrial
natriuretic factor on renal function and renin release. Am J Physiol
1984;247:F863–F866.
Atarashi K, Mulrow PJ, Franco-Saenz R. Effect of atrial peptides on
aldosterone production. J Clin Invest 1985;76:1807–1811.
Marin-Grez M, Fleming JT, Steinhausen M. Atrial natriuretic
peptide causes pre-glomerular vasodilatation and post-glomerular
vasoconstriction in rat kidney. Nature 1986;324:473–476.
Stockand JD, Sansom SC. Regulation of filtration rate by glomerular
mesangial cells in health and diabetic renal disease. Am J Kidney
Dis 1997;29:971–981.
Ziedel ML, Brenner BM. Actions of atrial natriuretic peptides on the
kidney. Semin Nephrol 1987;7:91–97.
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
[86] Weidman P, Hasler L, Gnadinger MP et al. Blood levels and renal
effects of atrial natriuretic peptide in normal man. J Clin Invest
1986;77:734–742.
[87] Gunning ME, Ballerman BJ, Silva P et al. Characterization of ANP
receptors in rabbit inner medullary collecting duct cells. Am J
Physiol 1988;255:F324–F330.
[88] Light DB, Schweibert EM, Karlson KH, Stanton BA. Atrial
natriuretic peptide inhibits a cation channel in renal inner medullary
collecting duct cells. Science 1989;243:383–385.
[89] Richards AM, Nicholls MG, Ikram H, Webster MWI, Yandle TG,
Espiner EA. Renal, hemodynamic, and hormonal effects of human
alpha atrial natriuretic peptide in healthy volunteers. Lancet
1985;1:545–549.
[90] Cody RJ, Atlas SA, Laragh JH et al. Atrial natriuretic factor in
normal subjects and heart failure patients: plasma levels and renal,
hormonal, and haemodynamic responses to peptide infusion. J Clin
Invest 1986;78:1362–1374.
[91] Dillingham MA, Anderson RJ. Inhibition of vasopressin action by
atrial natriuretic factor. Science 1986;231:1572–1573.
[92] Harris PJ, Thomas D, Morgan TO. Atrial natriuretic peptide inhibits
angiotensin-stimulated proximal tubular sodium and water reabsorption. Nature 1987;326:697–698.
[93] Holmes SJ, Espiner EA, Richards AM, Yandle TG, Frampton C.
Renal, endocrine, and hemodynamic effects of human brain natriuretic peptide in normal man. J Clin Endocrinol Metab
1993;76:91–96.
[94] Kurtz A, Bruna RD, Pfeilschifter J, Taugner R, Bauer C. Atrial
natriuretic peptide inhibits renin release from juxtaglomerular cells
by a cGMP-mediated process. Proc Natl Acad Sci USA
1986;83:4769–4773.
[95] Goodfriend TL, Elliott M, Atlas SA. Actions of synthetic atrial
natriuretic factor on bovine adrenal glomerulosa. Life Sci
1984;35:1675–1682.
[96] Hunt J, Espiner EA, Nicholls MG, Richards AM, Yandle G.
Differing biological effects of equimolar atrial and brain natriuretic
peptide infusions in normal man. J Clin Endocrinol Metab
1996;81:3871–3876.
[97] Saxenhofer H, Raselli A, Weidmann P et al. Urodilatin, a natriuretic
factor from kidneys, can modify renal and cardiovascular function in
men. Am J Physiol 1990;259:F832–F838.
[98] Cargill RI, Coutie WJ, Lipworth BJ. The effects of angiotensin II on
circulating levels of natriuretic peptides. J Clin Pharmacol
1994;38:139–142.
[99] Wiese S, Breyer T, Dragu A et al. Gene expression of brain
natriuretic peptide in isolated atrial and ventricular human myocardium: influence of angiotensin II and diastolic fiber length. Circulation 2000;102:3074–3079.
[100] Bonarjee VVS, Omland T, Nilsen DWT et al. Left ventricular
volumes, ejection fraction, and plasma proatrial natriuretic factor
(1–98) after withdrawal of enalapril treatment initiated early after
myocardial infarction. Br Heart J 1995;73:506–510.
[101] Motwani JG, McAlpine H, Kennedy N, Struthers AD. Plasma brain
natriuretic peptide as an indicator for angiotensin-converting
enzyme inhibition after myocardial infarction. Lancet
1993;341:1109–1113.
[102] Murdoch DR, McDonagh TA, Byrne J et al. Titration of vasodilator therapy in chronic heart failure according to plasma brain
natriuretic peptide concentration: randomized comparison of the
hemodynamic and neuroendocrine effects of tailored verses empirical therapy. Am Heart J 1999;138:1126–1132.
[103] Vantrimpont P, Rouleau JL, Ciampi A et al. Two-year time course
and significance of neurohumoral activation in the Survival and
Ventricular Enlargement (SAVE) Study. Eur Heart J
1998;19:1552–1563.
[104] Leskinen H, Vuolteenaho O, Ruskoaho H. Combined inhibition of
endothelin and angiotensin II receptors blocks volume load-induced cardiac hormone release. Circ Res 1997;80:114–123.
507
[105] Riegger GA, Elsner D, Kromer EP et al. Atrial natriuretic peptide
in congestive heart failure in the dog: plasma levels, cyclic
guanosine monophosphate, ultrastructure of atrial myoendocrine
cells, and hemodynamic, hormonal, and renal effects. Circulation
1998;77:398–406.
[106] Crozier IG, Nicholls MG, Ikram H, Espiner EA, Gomez HJ,
Warner NJ. Haemodynamic effects of atrial peptide infusion in
heart failure. Lancet 1986;2:1242–1245.
[107] Tsutamoto T, Kanamori T, Morigami N, Sugimoto Y, Yamaoka O,
Kinoshita M. Possibility of downregulation of atrial natriuretic
peptide receptor coupled to guanylate cyclase in peripheral vascular beds of patients with severe chronic heart failure. Circulation
1993;87:70–75.
[108] Schiffrin EL. Decreased density of binding sites for atrial natriuretic peptide on platelets of patients with severe congestive heart
failure. Clin Sci 1988;74:213–218.
[109] Tsunoda K, Mendelsohn FAO, Sexton PM, Chai SY, Hodsman GP,
Johnston CI. Decreased atrial natriuretic peptide binding in renal
medulla in rats with chronic heart failure. Circ Res 1988;62:155–
161.
[110] Hirata Y, Emori T, Ohta K, Shichiri M, Marumo F. Vasoconstrictorinduced heterologous down-regulation of vascular atrial natriuretic
peptide receptor. Eur J Pharmacol 1989;164:603–606.
[111] Abassi ZA, Kelly G, Golomb E, Klein H, Keiser HR. Losartan
improves the natriuretic response to ANF in rats with high-output
heart failure. J Pharmacol Exp Ther 1994;268:224–230.
[112] Misono KS. Atrial natriuretic factor binding to its receptor is
dependent on chloride concentration: a possible feedback-control
mechanism in renal salt regulation. Circ Res 2000;86:1135–1139.
[113] Firth BG, Perna R, Bellomo JF, Toto RD. Cardiorenal effects of
atrial natriuretic factor administration in congestive heart failure:
natriuresis and diuresis without haemodynamic alterations. Am J
Med Sci 1989;297:203–208.
[114] Marcus LS, Hart D, Packer M et al. Hemodynamic and renal
excretory effects of human brain natriuretic peptide infusion in
patients with congestive heart failure: a double-blind, placebocontrolled, randomized crossover trial. Circulation 1996;94:3184–
3189.
[115] Abraham WT, Lowes BD, Ferguson DA et al. Systemic haemodynamic, neurohormonal, and renal effects of a steady-state
infusion of human brain natriuretic peptide in patients with
haemodynamically decompensated heart failure. J Card Fail
1998;4:37–44.
[116] Dunn BR, Ichikawa I, Pfeffer JM, Troy JL, Brenner BM. Renal
and systemic hemodynamic effects of synthetic atrial natriuretic
peptide in anesthetized rat. Circ Res 1986;59:237–246.
[117] Yoshimura M, Yasue H, Morita E et al. Hemodynamic, renal, and
hormonal responses to brain natriuretic peptide infusion in patients
with congestive heart failure. Circulation 1991;84:1581–1588.
[118] Chen HH, Grantham JA, Schirger JA, Jougasaki M, Redfield MM,
Burnett Jr. JC. Subcutaneous administration of brain natriuretic
peptide in experimental heart failure. J Am Coll Cardiol
2000;36:1706–1712.
[119] Holmes SJ, Espiner EA, Richards AM, Yandle TG, Frampton C.
Renal, endocrine, and haemodynamic effects of human brain
natriuretic peptide in normal man. J Clin Endocrinol Metab
1993;76:91–96.
[120] Smith MW, Espiner EA, Yandle TG, Charles CJ, Richards AM.
Delayed metabolism of human brain natriuretic peptide reflects
resistance to neutral endopeptidase. J Endocrinol 2000;167:239–
246.
[121] Raya TE, Lee RW, Westhoff T, Goldman S. Captopril restores renal
hemodynamic responsiveness to atrial natriuretic peptide in rats
with heart failure. Circulation 1989;80:1886–1892.
[122] Hunt PJ, Richards AM, Espiner EA, Nicholls MG, Yandle TG.
Bioactivity and metabolism of C-type natriuretic peptide in normal
man. J Clin Endocrinol Metab 1994;78:1428–1435.
508
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
[123] Igaki T, Itoh H, Suga S et al. C-type natriuretic peptide in chronic
renal failure and its action in humans. Kidney Int
1996;49(Suppl.):S144–S147.
[124] Komatsu Y, Nakao K, Itoh H, Suga S, Ogawa Y, Imura H. Vascular
natriuretic peptide. Lancet 1992;34:622.
[125] Davidson NC, Barr CS, Struthers AD. C-type natriuretic peptide:
an endogenous inhibitor of vascular angiotensin-converting enzyme
activity. Circulation 1996;93:1155–1159.
[126] Wijeyaratne CN, Moult PJA. The effect of a human atria natriuretic peptide on plasma volume and vascular permeability in
normotensive subjects. J Clin Endocrinol Metab 1993;76:343–346.
[127] Itoh H, Pratt RE, Dzau VJ. Atrial natriuretic polypeptide inhibits
hypertrophy of vascular smooth muscle cells. J Clin Invest
1990;86:1690–1697.
[128] Itoh H, Pratt RE, Ohno M, Dzau VJ. Atrial natriuretic polypeptide
as a novel antigrowth factor of endothelial cells. Hypertension
1992;19:758–761.
[129] Furuya M, Yoshida M, Hayashi Y. C-type natriuretic peptide is a
growth inhibitor of rat vascular smooth muscle cells. Biochem
Biophys Res Commun 1991;177:927–931.
[130] Bouchie JL, Hansen H, Feener EP. Natriuretic factors and nitric
oxide suppress plasminogen activator inhibitor-1 expression in
vascular smooth muscle cells. Arterioscler Thromb Vasc Biol
1998;18:1771–1779.
[131] Furuya M, Aisaka K, Miyazaki T et al. C-type natriuretic peptide
inhibits intimal thickening after vascular injury. Biochem Biophys
Res Commun 1993;193:248–253.
[132] Shinomiya M, Tashiro J, Saito Y et al. C-type natriuretic peptide
inhibits intimal thickening of rabbit carotid artery after balloon
catheter injury. Biochem Biophys Res Commun 1994;205:1051–
1056.
[133] Sengenes C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J.
Natriuretic peptides: a new lipolytic pathway in human adipocytes.
FASEB J 2000;14:1345–1351.
[134] Sarzani R, Dessi-Fulgheri P, Paci VM, Espinosa E, Rappelli A.
Expression of natriuretic peptide receptors in human adipose and
other tissues. J Endocrinol Invest 1996;19:581–585.
[135] Anker SD, Swan JW, Volterrani M et al. The influence of muscle
mass, strength, fatigability and blood flow on exercise capacity in
cachectic and non-cachectic patients with chronic heart failure. Eur
Heart J 1997;18:259–269.
[136] Lee WH, Packer M. Prognostic importance of serum sodium
concentration and its modification by converting-enzyme inhibition
in patients with severe chronic heart failure. Circulation
1986;73:257–267.
[137] Phillips PA, Rolls BJ, Ledingham JGG, Morton JJ, Forsling ML.
Angiotensin II-induced thirst and vasopressin release in man. Clin
Sci 1985;68:669–674.
[138] Riegger GA, Liebau G, Kochsiek K. Antidiuretic hormone in
congestive heart failure. Am J Med 1982;72:49–52.
[139] Goldsmith JR, Francis GS, Cowley AW, Levine T, Cohn JN.
Increased plasma arginine vasopressin levels in patients with
congestive heart failure. J Am Coll Cardiol 1983;1:1385–1390.
[140] Carmichael MC, Kumar R. Molecular biology of vasopressin
receptors. Semin Nephrol 1994;14:341–348.
[141] Riegger GAJ, Liebau G. The renin–angiotensin–aldosterone system, antidiuretic hormone and sympathetic nerve activity in an
experimental model of congestive heart failure in the dog. Clin Sci
1982;62:465–469.
[142] Bichet DG. Molecular and cellular biology of vasopressin and
oxytocin receptors and action in the kidney. Curr Opin Nephrol
Hypertens 1994;3:45–53.
[143] Bussien JP, Waeber B, Nussberger J et al. Does vasopressin sustain
blood pressure of normally hydrated healthy volunteers? Am J
Physiol 1984;246:H143–H147.
[144] Naitoh M, Suzuki H, Murakami M et al. Effects of oral AVP
receptor antagonists OPC-21268 and OPC- 31260 on congestive
[145]
[146]
[147]
[148]
[149]
[150]
[151]
[152]
[153]
[154]
[155]
[156]
[157]
[158]
[159]
[160]
[161]
[162]
heart failure in conscious dogs. Am J Physiol 1994;267:H2245–
H2254.
Nielsen S, Chou CL, Marples D, Christensen EI, Kishore BK,
Knepper MA. Vasopressin increases water permeability of kidney
collecting duct by inducing translocation of aquaporin-CD water
channels to plasma membrane. Proc Natl Acad Sci USA
1995;92:1013–1017.
Terris J, Ecelbarger CA, Nielsen S, Knepper MA. Long-term
regulation of four renal aquaporins in rat. Am J Physiol
1996;271:F414–F422.
Sands JM, Nonoguchi H, Knepper MA. Vasopressin effects on urea
and H 2 O transport in inner medullary collecting duct subsegments.
Am J Physiol 1987;253:F823–F832.
Reif MC, Troutman SL, Schafer JA. Sodium transport by rat
cortical collecting tubule. J Clin Invest 1986;77:1291.
Xu DL, Martin PY, Ohara M et al. Upregulation of aquaporin-2
water channel expression in chronic heart failure rat. J Clin Invest
1997;99:1500–1505.
Fujita H, Yoshiyama M, Yamagishi H et al. The effect of
vasopressin V1 and V2 receptor antagonists on heart failure after
myocardial infarction (Abstract). J Am Coll Cardiol 1995;25:234A.
Abraham WT, Oren RM, Crisman TS et al. Effects of an oral,
nonpeptide, selective V2 receptor vasopressin antagonist in patients
with chronic heart failure (Abstract). J Am Coll Cardiol
1997;29(Suppl. A):169A.
Eisenman A, Armali Z, Enat R, Bankir L, Baruch Y. Low-dose
vasopressin restores diuresis both in patients with hepatorenal
syndrome and in anuric patients with end-stage heart failure. J
Intern Med 1999;246:183–190.
Chan WY, Hruby VJ. Natriuretic action of neurohypophysial
peptides: effects of agonists and antagonists and implication of
natriuretic receptor. J Pharmacol Exp Ther 1988;246:597–602.
Richards AM, Crozier IG, Yandle TG, Espiner EA, Ikram H,
Nicholls MG. Brain natriuretic factor: regional plasma concentrations and correlations with haemodynamic state in cardiac
disease. Br Heart J 1993;69:414–417.
Magga J, Vuolteenaho O, Tokola H, Marttila M, Ruskoaho H.
B-type natriuretic peptide: a myocyte-specific marker for characterizing load-induced alterations in cardiac gene expression. Ann
Med 1998;30(Suppl. 1):39–45.
Murdoch DR, McDonagh TA, Byrne J et al. Titration of vasodilator therapy in chronic heart failure according to plasma brain
natriuretic peptide concentration: randomized comparison of the
hemodynamic and neuroendocrine effects of tailored verses empirical therapy. Am Heart J 1999;138:1126–1132.
Kentsch M, Otter W, Drummer C et al. Neutral endopeptidase
24.11 inhibition may not exhibit beneficial haemodynamic effects
in patients with congestive heart failure. Eur J Clin Pharmacol
1996;51:269–272.
Munzel T, Kurz S, Holtz J et al. Neurohormonal inhibition and
haemodynamic unloading during prolonged inhibition of ANF
degradation in patients with severe chronic heart failure. Circulation 1992;86:1089–1098.
Richards AM, Wittert GA, Crozier IG et al. Chronic inhibition of
endopeptidase 24.11 in essential hypertension: evidence for enhanced atrial natriuretic peptide and angiotensin II. J Hypertens
1993;11:407–416.
Trippodo NC, Fox M, Monticello TM, Panchal BC, Asaad M.
Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE
inhibition with captopril. J Cardiovasc Pharmacol 1999;34:782–
790.
McClean DR, Ikram H, Garlick AH et al. The clinical, cardiac,
renal, arterial and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure. J Am
Coll Cardiol 2000;36:479–486.
Rouleau JL, Pfeffer MA, Stewart DJ et al. Comparison of
P.R. Kalra et al. / Cardiovascular Research 51 (2001) 495 – 509
[163]
[164]
[165]
[166]
[167]
vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise
tolerance and morbidity in patients with heart failure: IMPRESS
randomised trail. Lancet 2000;356:615–620.
Messerli FH, Nussberger J. Vasopeptidase inhibition and angiooedema. Lancet 2000;356:608–609.
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G.
Effects of an angiotensin-converting enzyme inhibitor, ramipril, on
cardiovascular events in high-risk patients. The Heart Outcomes
Prevention Evaluation Study Investigators. New Engl J Med
2000;342:145–153.
Coats AJS. Omapatrilat — the ups and downs of an exciting but
complicated new drug. Int J Cardiol 2000;74:1–3.
Gibbs CR, Lip GY, Beevers DG. Angioedema due to ACE
inhibitors: increased risks in patients of African origin. Br J Clin
Pharmacol 1999;48(6):861–865.
Rutherford JD, Pfeffer MA, Moye´ LA et al. Effects of captopril on
509
ischemic events after myocardial infarction: results of the survival
and ventricular enlargement trial. Circulation 1994;90:1731–1738.
[168] Colucci WS, Elkayam U, Horton DP et al. Intravenous nesiritide, a
natriuretic peptide, in the treatment of decompensated congestive
heart failure. New Engl J Med 2000;343:246–253.
[169] Creager MA, Faxon DP, Cutler SS, Kohlmann O, Ryan TJ, Gavras
H. Contribution of vasopressin to vasoconstriction in patients with
congestive heart failure: comparison with the renin–angiotensin
system and the sympathetic nervous system. J Am Coll Cardiol
1986;7:758–765.
[170] Abraham W, Suresh DP, Wagoner LE, Haas GJ, Nelson C, BakkerArkema RG. Pharmacotherapy for hyponatraemia in heart failure:
effects of a new combined vasopressin V1A / V2 receptor antagonist, conivaptan (YM087) administered orally (Abstract). Eur Heart
J 2000;21:345.