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Indian Journal of Pharmacology 2003; 35: 139-145

EDUCATIONAL FORUM
NEUTRAL PEPTIDASE INHIBITORS

NEUTRAL PEPTIDASE INHIBITORS: NEW DRUGS FOR HEART FAILURE

I. BASURAY
Interventional Electrophysiology & Device Therapy, Arrhythmia Service; Division of Cardiology,
St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Manuscript Received: 29.7.2002

Revised: 23.10.2002

Accepted: 26.1.2003

ABSTRACT

Once it sets in, the left ventricular dysfunction is a continuous process ultimately leading to end stage
heart disease. End stage heart disease has a high mortality despite the presence of a number of treatment
modalities, as most of them are sub optimal. Thus despite considerable advancement in therapy, the
overall prognosis remains dismal. This has spurred the search for newer agents that can effectively
attenuate the aberrant physiological changes evident in heart failure. Early research in heart failure
treatment had made it evident that unloading the heart should be a primary consideration if the progress
of the aberrant physiology is to be attenuated. Subsequently it became evident that opposing the aberrant
neurohormonal stimulation, to achieve unloading is associated with a better outcome. Thus ACE
(angiotensin converting enzyme) inhibitors, which unload the heart by reducing the formation of
angiotensin II; have a better effect on mortality & morbidity, than the combination of nitrates and
hydralazine. This is despite the fact that both the latter mentioned drugs are very potent venous and
arteriolar dilator, respectively. Certain recent studies, albeit small ones, conducted in the last few years
have shown natriuretic agents which promote diuresis by augmenting body's defense against the abnormal
neurohormonal milieu evident in heart failure might have a better effect on long term prognosis than the
symptomatically more effective diuretics. These studies have lead to the development of novel agents
that not only block the over stimulated renin-angiotensin system but also augment the natriuretic peptide
system, the body's defence against the abnormal neurohormonal milieu that is evident in heart failure.
This article reviews the clinical pharmacology of novel agents that augments the natriuretic peptide
system in the body and their potential as new agents in the armamentarium of drugs for heart failure.

KEY WORDS

Cardiac failure

natriuretic peptides

neutral endopeptidase inhibitors

Introduction
Treatment of heart failure till date has at best been
symptomatic, with very little effort being made to
reverse the pathology. The introduction of the ACE
inhibitors in the treatment of heart failure was the
first successful attempt to achieve symptomatic well
being along with attenuation of aberrant biochemical
changes that accompany failure. It has been
appreciated that certain commonly used anti-failure
medications which induce symptomatic relief quite
effectively may either do not change (e.g. digitalis1 )
or even worsen the biochemical anomalies of heart
failure (e.g. loop diuretics) and thus provide the
patient with little or even adverse mortality benefits.
Correspondence: I. Basuray
e-mail: indranill.basuray@utoronto.ca

An illustration in this context is the use of frusemide,

a loop diuretic, in heart failure. Although it causes
diuresis and reduces the pulmonary capillary wedge
pressure, it does so at the cost of producing a
manifold increase in renin. This chemical released
from the kidney amongst other places, is an adverse
biochemical marker in heart failure 2 . It has now
become evident that an increase in such adverse
markers correlate with a poor mortality and
morbidity. Thus, in the hope of producing a
symptomatic benefit and reversing the pathology,
there is a determined effort world over, to generate
drugs that effectively alter the aberrations of
neurohormonal milieu that accompany ventricular
failure. A group of drugs presently undergoing

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I. BASURAY

clinical trials that effectively fit in such criteria are the

neutral peptidase inhibitors. These are a group of
chemicals that inhibit the degradation of atrial
natriuretic peptide (ANP) and related neurohormones which are released by the body as a
compensatory mechanism to reverse the
pathophysiological state present in heart failure there
by causing an increase in the levels and activities of
these hormones. This article intends to review the
recent evidences gathered from clinical trials that
point to the possible role of these agents, as a group
will play as future drugs for heart failure. This review
will also discuss the role of novel designer drugs;
that combine ACE inhibition with peptide inhibition,
all as one molecule to treat heart failure.
Physiological role of natriuretic peptides in heart
failure: A review of the physiological role of the
natriuretic peptides would be in order to understand
the pharmacodynamics of the neutral peptidase
inhibitors. Three natriuretic peptides, the atrial (ANP),
the brain (BNP) and the C type natriuretic peptide (CNP)
have been identified in humans 3 . ANP is a 28 amino
acid peptide stored predominantly in the right atrium
and is believed to be coupled to mechanoreceptors,
and released upon atrial distension, as observed in
cardiac failure. Accumulated evidence from the past
one decade points to the crucial role played by this
peptide in inducing vasodilatation, promoting natriuresis
and miscellaneous other functions including counteracting the pathological role played by catecholamines,
the arginine-vasopressin, renin-angiotensinaldosterone system [RAAS]4 . RAAS is known to be
significantly augmented as part of body's mechanism
to counter fall in cardiac output in heart failure. This
becomes counter productive as water & sodium
retention occurs, causing an overt increase in the
afterload to the failing ventricle. BNP is structurally
similar to ANP and is stored mainly in the ventricles5 .
The ventricular filling pressure coordinates its release
and is functionally similar to ANP. CNP is a potent
vasodilator and is postulated to have a regulatory role
on the RAAS. The natriuretic peptides are degraded in
the body by a ubiquitous enzyme called neutral
endopeptidase (NEP)6 , found in many organs and
tissues. These include the kidneys, brain and lungs7 .
Experimental evidence in lower mammals, initially 8 and
later in humans, have corroborated the finding that
inhibition of these enzymes produce a sustained
increase in plasma ANP level9.

A large body of accumulated data supports the fact

that ANP therapy in heart failure is accompanied by
favourable hemodynamic responses. Prolonged
infusion of ANP in heart failure patients belonging to
class III or IV is associated with a two fold increase
in urine flow rate and an almost four fold increase in
sodium excretion10 . In severe heart failure patients,
similar infusions have produced an increase in
cardiac output with a concomitant decrease in
pulmonary capillary wedge pressure (PCWP),
plasma renin levels and pulmonary vascular
resistance11 . BNP has similar effects as ANP12 ; it
reduces the pulmonary capillary wedge pressure and
systemic vascular resistance and also initiates a
sustained natriuresis producing up to a 10 fold
increase in sodium excretion. Interestingly, this
biochemical also fosters favourable changes in the
neurohormonal milieu. While suppressing plasma
aldosterone levels, it increases ANP secretions.
These profiles of diuresis, vasodilatation and
neurohormonal suppression make the natriuretic
peptides, a potentially attractive treatment modality
for heart failure patients.
However, it is obviously ostensible that the therapeutic
potential of natriuretic peptides are considerably
attenuated in chronic heart failure patients because
of the need to give them, as intravenous infusions.
Thus, treatment of chronic LV failure necessitates the
development of orally active long acting analogues
or agents that block the metabolism of endogenously
generated natriuretic peptides. The development of
NEP inhibitors, is thereby a step to meet the latter
end.
Orally active natriuretic peptidase inhibitors:
Candoxatril and ecadotril are the two highly specific
inhibitors of NEP presently undergoing trials as future
drugs for heart failure. Both these agents are
prodrugs metabolised in the body to active
congeners. Candoxatril is activated in the liver to
candoxatrilat, the active metabolite, while ecadotril
is converted to its active congener, S-thiorphan.
While candoxatril has undergone the largest number
of trials amongst drugs in this group, experience with
ecadotril is limited to a few trials till date. Patients
with mild heart failure infused with candoxatrilat, the
active molecule of candoxatril, have both diuresis
and natriuresis13 . However, in severe heart failure
patients these actions are considerably lessened,

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NEUTRAL PEPTIDASE INHIBITORS

probably due to decreased renal perfusion 1 4 .

Northridge et al., in a recent trial 1 5 compared
candoxatril in oral doses of 200-400 mg as monotherapy in mild heart failure patients in a double-blind
clinical trial, with 20 mg frusemide. Severe heart
failure patients could not be included in the trial since
a diuretic free period of two weeks, as required in
the study design, could not be enforced in them.
Monotherapy with candoxatril induced diuresis,
natriuresis and kaluresis compared to frusemide.
While a greater decrease in systolic blood pressure
was documented with NEP inhibitors, the heart rate,
diastolic blood pressure and the functional class of
the patients remained similar to baseline studies.
Plasma renin activity, a negative prognostic factor in
chronic heart failure, showed a two fold increase
following the first dose of frusemide, with a four-fold
rise later on. Therapy with candoxatril was not
associated at any stage with any discernable
increments in plasma renin activity. Treadmill
exercise capacity, an important prognostic marker
in heart failure, registered an increase of 12+3.5 sec
after 200 mg candoxatril twice a day and a rise of
35+3.1 sec after 400 mg of the drug twice daily for
9 days. However, frusemide treated patients in the
same period, recorded a decreased exercise
capacity by 30+2.6 sec. The same group in an earlier
study also documented a 40% decrease in
pulmonary capillary wedge pressure using
candoxatril compared to a 15% reduction with
frusemide2.
Experience with ecadotril as stated before is limited.
In a recent pilot safety study, though the drug
compared favorably with placebo, as far as shortterm safety and tolerance is concerned, its clinical
efficacy was shown to be disappointingly
negative 1 6 , 1 7 . Though this has been attributed
primarily to the study design, which was not geared
to observe this parameter, other factors like
inadequate dosing could have also played a role.
However, in earlier studies reported by Kahn et al.18
ecadotril administration to heart failure patients
resulted in a rise in plasma ANP, decrease in both
plasma renin activity and pulmonary capillary wedge
pressure.
Role of NEP inhibitors in heart failure: The first
line treatment for mild heart failure has been a
diuretic, which is usually combined with an ACE
inhibitor. While ACE inhibitor use is associated with

141

decreased hospitalization and death19 , the long term

effects of diuretics in heart failure, as far as mortality
and morbidity statistics go, are yet ill-defined. There
have been contradictory findings with diuretic trials
in mild and severe heart failure. Cowley et al.2 0
showed that moderately severe cardiac failure
patients put on frusemide at high doses (120 mg),
exhibited improved quality of life and better exercise
capacity. Few other uncontrolled studies too have
come to the same conclusion21 . However, Northridge
and colleagues, using low doses to treat mild heart
failure, have shown a decrease rather than an
increase in exercise capacity. These adverse effects
of diuretics on mild heart failure, with no evidence of
fluid retention, can be explained by detrimental
changes they induce including stimulation of the
RAAS mechanism, and a decrease in cardiac output
by ventricular unloading 15 . Though both these factors
exist even in severe heart failure patients treated
with diuretics, the decrease in congestion and
reduction of fluid overload achieved, produces
symptomatic benefits. Thus the pathophysiological
aberrations instead of getting attenuated; actually
worsens over a time period, leading to more severe
forms of heart failure. The end point of this vortex of
increasing failure ultimately makes the disease drugrefractory. Accumulated evidence for the past one
decade has confirmed the early elevation of NEP in
the progression of left ventricular dysfunction, even
before the onset of symptoms. There is considerable
evidence that indicate the fact that this increase is
beneficial; by preventing the activation of RAAS and
consequent salt and water retention, thus delaying
the initiation of pathological changes that continue
unabated leading to end stage cardiac failure 22 . Thus
it is hypothesized, but not actually proved that
initiation of diuretics at this stage, as is commonly
done nowadays, produces double harm; it not only
reduces the natriuretic peptide concentration but also
unleashes the RAAS from the inhibitory effect of
the endogenous NEP.
NEP inhibitors have a number of potential advantages
over conventional diuretics in the treatment of patients
with chronic heart failure since they do not activate
RAAS system. Ample evidence also suggests that
hemodynamic changes attained using these drugs
are decidedly better at least in cases of mild heart
failure when compared to diuretics. Extrapolation of
these results to more severe cases of cardiac failure

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I. BASURAY

Figure 1. Pathways showing the sites of drug action in heart failure.

Natriuretic peptidase

Kininogen

Angiotensinogen
Renin

Kininogenase
Angiotensinogen I
ACE

Angiotensinogen II

Bradykinin
NEP

Inactive
metabolite
ACE inhibitors

Inactive
metabolite
NEP inhibitors

Vasoactivepeptidase inhibitors

Facilitates:
Inhibits:

is not undesirable; as presently we have some, though

not extensive data advocating their efficacy in such
states. More extensive studies are warranted with
subjects in New York Heart Association class III or
IV to collect supporting data. It is also important to
realise that these group of patients are really in need
of more effective pharmacological agents to control
heart failure. Failure of appropriate pharmacological
measures to treat such patients makes it inevitable
in clinical practice to go for invasive alternatives like
biventricular pacing.

left ventricular preload, such patients are in most need

of diuresis. Thus there is a built-in self regulation; any
event like dehydration or diuresis that decreases
preload would automatically decrease natriuretic
peptide secretion and their diuretic effect, so that the
dehydration is not exacerbated. Dehydration is an
important adverse effect of diuretics that restrict their
use in heart failure patients. However there is a flip
side to this phenomenon; this may be also the cause
of the rather nonsustained action of these drugs, when
given to heart failure patients.

An additional unique property present in these drugs

could be of clinical importance. The effects of NEP
inhibitors are caused by potentiation of endogenous
natriuretic peptides, so their action depends on the
secretion of such peptides. It has thus been
hypothesised but not proved that NEP inhibitors would
be most effective in patients with high peptide
secretion. As the peptide secretion is related to high

To summarise, the use of NEP inhibitors at various

stages of heart failure, results in an equitable or even
better hemodynamic changes but not at the cost of
adverse neurohormonal stimulation. The role of these
drugs in more severe form of heart failure alone or
in combination, though appears to be promising, is
yet to be tested by clinical trials.

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NEUTRAL PEPTIDASE INHIBITORS

143

Table 1. Combined NEP and ACE inhibitors (vasoactivepeptidase inhibitors) and their inhibitory activity in various phases of studies.
Agent

Study phase

ACE Ki (nmol/L)

NEP Ki (nmol/L)
9

Omapatrilat (BMS186716)

III

Sampatrilat (UK81252)

II

1.2

Fasidotril (BP1.137)

II

9.8

5.1

MDL 100,240 (active metabolite MDL 100,173)

0.08

0.11

Z13752A

3.2

1.8

BMS189921
Mixanpril (active metabolite RB105)

II

12

63

Preclinical

4.2

1.7

ACE = angiotensin-converting enzyme; Ki = inhibitory constant; NEP = neutral endopeptidase.

Table 2. Clinical trials showing efficacy of omapatrilat in varying severity of heart failure.
Heart failure
(NYHA Class)

No of patients

Treatment

Findings

II-IV27

369

Omapatrilat 2.5, 5, 10, 20,

and 40 mg/day

Dose-dependent reduction in PCWP,

SBP/DBP, and SVR, and improvement in
NYHA class

II and III2 8

48

Omapatrilat 2.5, 5-10, 20-40

mg/day

Dose-dependent improvement in functional

status and LVEF
Dose-dependent reduction in SBP/DBP
Significant reduction in predose serum BNP,
epinephrine, and aldosterone.

II-IV29

573

Omapatrilat 10 mg/day
titrated to 40 mg/day Vs
lisinopril 5 mg/day titrated
to 20 mg/day

Significant benefit of composite end points

of death, hospitalization, discontinuation of
study treatment for worsening heart failure

SBP=systolic blood pressure; DBP=diastolic blood pressure; SVR=systemic vascular resistance; LVEF-left ventricular ejection fraction

Future directions: While the salutary effect of ACE

inhibitors in heart failure, in general, and NEP
inhibitors in particular, in changing adverse
neurohormonal milieu per se remains unquestioned,
efforts are in progress to develop a chimeric
molecule; called vasopeptidase inhibitors, combining
both these properties23 . Figure 1 depicts the site of
action of such drugs. Such molecules (Table 1),
would have both the advantage of antagonising the
RAAS and added natriuresis and diuresis of NEP
inhibitors. In principle it is also expected to have
both the tremendous mortality and morbidity benefits
as ACE inhibitors with potent anticongestive powers
of loop diuretics, but devoid of their adverse effects.

Clinical trials with omapatrilat, the combined ACE and

NEP inhibitor has indeed shown it to have better
natriuretic and humoral (decrease in renin) effects
than the ACE inhibitor lisinopril24 . If the mortality
among two recently concluded trials are compared
omapatrilat exhibited a significant decrease in
mortality when compared to 20 mg/d of lisinopril25 .
In the just concluded joint International Society and
European Society of Hypertension meet; the results
of the massive OCTAVE trial, that compared
Omapatrilat to Enalapril, another ACE inhibitor was
announced. This trial tested; omapatrilat Vs enalapril
in25-27 hypertensive patients recruited from 3298 sites
in 12 countries26 . Though the trial did not have any

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I. BASURAY

heart failure patient as such but the fact that

omapatrilat was a more effective antihypertensive
than enalapril clearly positions the drugs to be more
effective in attenuating changes that lead to frank
heart failure than enalapril. Omapatrilat was found
to have the same side effect profile as Enalapril,
other than the incidence of Angioedema was
decidedly more (3.1 times more). This has raised
some concern, with FDA withholding its approval for
this particular agent. There has however been a
number of other trials that has compared the efficacy
of omapatrilat in heart failure. These are summarized
in Table 2 27-29 .

4.

Wei CM, Heublein DM, Perella MA, Lerman A, Rodeheffer

RJ, McGregor CG, et al. Natriuretic peptide system in
human heart failure. Circulation 1993;88:1004-9.

5.

Yasue H, Yoshimura M, Sumida H, Kilkuta K, Kugiyama K,

Jougasaki M, et al. Localization and mechanism of
secretion of B-type natriuretic peptide in comparison with
those of A-type natriuretic peptide in normal subjects and
patients with heart failire. Circulation 1994;90:195-203.

6.

Stephenson SL, Kenny AJ. The hydrolysis of alpha-human

atrial natriuretic peptide by pig kidney microvillar
membranes is initiated by endopeptidase-24.11. Biochem
J 1987; 243:183-7.

7.

Ronco P, Pollard H, Galceran M, Delauche M, Schwartz

JC, Verroust P. Distribution of enkephalinase (membrane
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8.

Shepperson NB, Barclay PL, Bennett JA, Samuels GM.

Inhibition of neutral endopeptidase (E.C.3.4.24.11) leads
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Richards M, Espiner E, Frampton C, Ikram H, Yandle T,

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Conclusion
With the elucidation of the neurohumoral mechanism
of heart failure, the realization has dawned that
effective therapy, against these hormonal changes
appropriately modifies the course of heart failure with
apparent decrease in both mortality and morbidity.
The RAAS has been decidedly one of the most
important culprits, in the progressive down hill course
of an untreated heart failure. Similarly secretion of
NEP is one of the few positive responses of the body
against the self destructive neurohormonal
stimulation that is active in heart failure. Thus a
treatment modality that effectively attenuates the
former and potentiates the latter would indeed be a
major pharmacological progress. Preliminary results
with such drugs like NEP inhibitors and Omapatrilat
conform to the above expectation. However, given
the fact that medical practice at the present time is
exclusively evidence based, larger studies with these
drugs are warranted to confirm or negate our positive
experience with these agents 30 .
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