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March 2006

Role of Angiotensin II in Cardiovascular Disease


Therapeutic Implications of More Than a Century of
Research
Carlos M Ferrario

The Hypertension and


Vascular Disease Center,
Wake Forest University
School of Medicine,
Winston Salem,
North Carolina,
USA
Correspondence to:
Dr Carlos M Ferrario
The Hypertension and
Vascular Disease Center,
Wake Forest University
School of Medicine,
Winston Salem,
NC 27157-1032,
USA
Tel: +1 336 716 5819
Fax: +1 336 716 6644
E-mail: cferrari@wfubmc.
edu
Accepted for publication
24th January 2006
JRAAS 2006;7:3-14

Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems

Abstract
More than a century of research on the reninangiotensin system (RAS) has uncovered the
widespread involvement of angiotensin II
(Ang II) in the pathophysiology of
cardiovascular diseases. A number of
outcomes-based mega trials utilising hard
clinical endpoints have revealed beneficial
effects of angiotensin receptor antagonists
(AIIAs/ARBs) in patients with hypertension,
heart failure, diabetic nephropathy, and
post-myocardial infarction (MI). The results
of these studies not only emphasise the
importance of Ang II in the pathophysiology
of these diseases but have provided the basis
for an evidence-based approach for the use of
AIIAs in clinical practice. It is hoped that the
next 100 years of research into the RAS will
uncover hitherto unimaginable therapeutic
opportunities.

converting enzyme (ACE) inhibitors, which inhibit


the synthesis of Ang II via ACE, have furthermore
contributed greatly to expand our vision of the
role of the RAS in cardiovascular and renal disease,
as well as revealing the existence of alternate
enzymatic pathways, angiotensin peptides, and
mechanisms by which this system regulates
blood pressure (BP) and tissue perfusion both
in normal and disease conditions. The AIIAs,
in particular, have proven particularly useful in
delineating the pathophysiological role of Ang II
in cardiovascular diseases. This is because these
agents specifically block Ang II formed from
both ACE and non-ACE (e.g., cardiac chymase)
sources and also do not impede the additional
beneficial haemodynamic and metabolic actions
of other biologically active peptides such as
bradykinin and angiotensin-(1-7) [Ang-(1-7)].

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Keywords:
Hypertension,
Cardiovascular
disease,
Diabetes mellitus,
Angiotensin II
antagonists,
ACE inhibitors,
Stroke,
Heart failure,
Post myocardial
infarction,
Diabetic
nephropathy

Introduction
When the Finnish physiologist Robert Tigerstedt
and his student, Per Gunnar Bergman, discovered
the first component (renin) of the renin-angiotensin
system (RAS) at the end of the 19th century, neither
the audience nor the investigators appreciated
the impact their discovery would ultimately have
on our understanding of cardiovascular disease
and how to treat it. Now, more than 100 years
later, we are beginning to fully unravel the
central and complex role of angiotensin II (Ang
II) not only in co-ordinating the physiological
hormonal cascade regulating renal function,
fluid and electrolyte balance, and blood pressure
but also in mediating a wide spectrum of
pathophysiological processes.
Research on the actions of Ang II has documented
the participation of this peptide across the
continuum of cardiovascular disease, including
hypertension, cardiac failure, and coronary heart
disease, post-myocardial infarction (MI) as well
as diabetic nephropathy. A considerable body of
research on the therapeutic benefits of blocking
Ang II in the management of these diseases has
come of age. Experimental studies and clinical
utilisation of both angiotensin II antagonists
(AIIAs), which selectively block the actions of
Ang II at its AT1 receptor, as well as angiotensin-

This article summarises our current understanding


of the pathological role of Ang II in a wide variety
of cardiovascular, renal and other diseases, and
reviews the considerable body of research that
has accumulated regarding the clinical benefits
of selective blockade of the AT1 receptor in the
treatment of hypertension, heart failure, and
target organ damage.
The Human Ang II System
The RAS has a remarkable history spanning more
than 100 years (Table 1). Beginning with the
discovery of renin in crude extracts of kidney
in 1898, RAS research has been punctuated
at regular intervals by some of the greatest
advances in cardiovascular medicine, including,
for example, the introduction of ACE inhibitors
and AIIAs.
Our current understanding of the basic
components of this intricate regulatory system
is summarised in Figure 1. The acid protease
renin, released into the circulation from the
renal cortical juxtaglomerular apparatus and also
released locally in other tissues (e.g., brain, heart,
blood vessels), generates angiotensin I (Ang I)
from the angiotensinogen precursor primarily
synthesised and released from the liver. Ang I
is then cleaved by ACE into Ang II, the principal
effector of the RAS with a variety of physiological
and pathophysiological actions. Formation of

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Table 1
Milestones in the history of the renin-angiotensin system.
Year

Investigators

Finding

1898

Tiegerstedt and Bergman

Demonstrated pressor substance in renal extracts (renin)

1934

Goldblatt et al.

Renal artery constriction produced hypertension in dogs

1940 Page and Helmer Braun-Menendez et al.



1952

Skeggs et al.

1954

Skeggs et al.

Independently showed that renin was peptidase producing pressor


hormone (angiotonin/ hypertensin)
Angiotensin isolated from blood
Identification of Ang I and Ang II
Identification of ACE
Amino acid sequence of Ang II
Synthesis of Ang II

1958

Gross

Ang II releases aldosterone

1971

Pals et al.

Saralasin, the 1st peptide AIIA

1972

Engel et al.

Teprotide, the 1st peptide ACE inhibitor

1975

Schelling et al.

Ang II shown to stimulate cell growth in 3T3 cells

1977

Cushman et al.

Captopril, the 1st non-peptide ACE inhibitor

1988

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1956 Skeggs et al.



Elliott and Peart; Skeggs et al.; Schwyzer et al.

Carini or Duncia

First non-peptide AIIAs identified

1989 Chiu et al.; Whitebread et al.; Chappell et al.



1991
1992
2000

Identification of non-peptide AIIAs


Identification of Angiotensin (1-7)

Murphy et al.; Sasaki et al.; Iwai et al.

Cloned AT1 receptor

Iwai and Inagami

AT1 receptor subtypes cloned

Donoghue et al.

Cloning and characterisation of ACE2

Angiotensinogen

Inactive
fragments

Bradykinin

Renin

Renin Inhibitor

ACE Inhibitor

ACE

Ang II

PD123319

AT2R
?

Losartan

AT1R

ACE2

Ang I
NEP

Cell
membrane

Ang-(1-7)

ACE2

Ang-(1-9)
Ang-(1-5)

AT1-7R

Cardiac, vascular, and


renal effects

Mas

Figure 1
Key components of the renin-angiotensin system cascade and potential steps to block the system. Angiotensinogen
represents the starting point in the production of Ang II. Through the actions of the enzyme renin, Ang I is generated, which
is subsequently converted to Ang II by the second proteolytic enzyme ACE. AIIAs block the action of Ang II (generated by ACE
and alternative pathways) at the level of the AT1 (but not AT2) receptor. Specific blockers of the AT2 receptor (e.g. PD 123319)
are available for experimental but not clinical use. ACE inhibitors block only Ang II generated by ACE and also inhibit the
breakdown of other peptides such as bradykinin. Ang-(1-7) and Ang-(1-9) also form part of the RAS and may have important
biological activities. Ang-(1-9) is generated from Ang I through the actions of ACE2, whereas Ang-(1-7) is formed from Ang I
via the action of several tissue-specific endopeptidases (NEP) or from Ang II via ACE2. Ang-(1-7) may form part of a feedback
control mechanism, permitting a balance between the pressor-trophic effects of Ang II and the opposing depressor-antitrophic
effects of Ang-(1-7).

Ang II can be reduced by agents that inhibit ACE


[e.g. the ACE inhibitors (ACE-Is) such as captopril
and enalapril].
Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems

Ang II interacts with at least two classes of


angiotensin (AT) receptor on target tissues: these
have been designated AT1 and AT2. These receptors
are typical polypeptide (360 amino acid) proteins
with seven transmembrane domains. The majority

of the physiological actions of Ang II, including


vasoconstrictive effects, stimulation of aldosterone
secretion from the adrenal gland, retention of salt
and water, and growth stimulation are mediated
by the AT1 receptor (Table 2).1-4 AT1 receptors
are ubiquitously distributed throughout the body,
including blood vessels, heart, kidney, adrenal
gland, liver, brain and lung and can be blocked
by AIIAs.

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Table 2
Key pharmacological effects of Ang II mediated by activation of AT1 or AT2 receptors.
AT1

AT2

Vasoconstriction (via NO, intracellular Ca ,


and superoxide) and BP
2+

Inflammation (via NFB)


Cell growth and proliferation (via c-fos, c-myc, c-jun)
Anti natriuresis
Increased atherogenicity (via OxLDL)
Modulation of sympathetic nervous system activity
renal blood flow

Foetal tissue development


Vasodilatation (via bradykinin and NO)
and BP
Inflammation (via NFB)
Growth inhibition (VSMC, endothelial cell,
cardiomyocyte, cardiac fibroblast, via
MAP kinases)
Improvement in cardiac function
(LVEDV, LVESV and EF) and decrease in
chronotropic effect

myocardial contractility
arrhythmias

Vascular cell differentiation

PAI-1

Extracellular matrix composition

sympathetic activity

Apoptosis (via MAP kinases)

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endothelin release

NO = nitric oxide, NFB = nuclear factor kappa-B, OxLDL = oxidised low-density lipoprotein, MAP = mitogen-activated
protein, VSMC = vascular smooth muscle cell, LVEDV = left ventricular end diastolic volume, LVESV = left ventricular end
systolic volume, EF = ejection fraction, PAI-1 = plasminogen activator inhibitor-1.
Information extracted from Silverstein RL et al.1; Wagenaar LJ et al.2; Nicholls et al.3 and Schiffrin EL.4

Another Ang II receptor (AT2), which might


possess counter-regulatory actions against the
AT1 receptor, has also been described and can
be blocked by selective AT2 antagonists such as
PD 123319. AT2 receptors mediate a wide variety
of actions, including vasodilatation, inhibition of
cell growth, cell differentiation, and apoptosis
(Table 2). Although freely expressed during foetal
development, AT2 receptor expression at birth
is reduced, thereby allowing the AT1 receptor to
predominate. Several pathological states, including
ischaemic heart disease, dilated cardiomyopathy,
and atrial fibrillation, are associated with
increased AT2 receptor expression. Indeed, some
investigations suggest that the observed beneficial
effects of AIIAs might involve inhibition of Ang
II at the AT1 receptor plus stimulation of the
unblocked AT2 receptor.
In addition to the classical pathways of the RAS
described above, recent evidence suggests that
other novel angiotensin peptides may also be
generated (Figure 1). These peptides, including
Ang-(1-7) and Ang-(3-8) (Ang IV), may also have
important biological activities.5

Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems

Another pathway has also been recently


described. In this pathway, the non-biologically
active peptide Ang-(1-9) is generated from
Ang I through the actions of ACE2, the first
human homologue of ACE, whereas Ang(1-7) is formed from Ang I via the action of
several tissue-specific endopeptidases (NEP)
or from Ang II via ACE2. Ang-(1-7) can also
undergo subsequent metabolism by ACE to
another peptide Ang-(1-5), with no known
biological activity. As described above, Ang
II achieves its biological actions by binding
to AT1 or AT2 receptors; on the other hand,

Ang-(1-7) produces its biological effects such


as vasodilatation, natriuresis, diuresis, and
antitrophic effects by interacting with a non
AT1/AT2 receptor. Ang-(1-7) is the endogenous
ligand for the G-protein-coupled receptor mas,
the stimulation of which leads to production
of nitric oxide (NO) and prostacyclin (PGI2).
Recently, we showed that in cultured rat
neonatal myocytes, the anti-hypertrophic
actions of Ang-(1-7) were mediated by the
coupling of the peptide to the mas receptor.6
It is now becoming clear that Ang-(1-7) may
form part of a feedback control mechanism
for the RAS in which this peptide regulates,
in an opposing manner, the actions of Ang
II. Together, Ang-(1-7) and ANG-II thereby
function in a ying-yang manner, permitting a
balance between the pressor-trophic effects of
Ang II and the opposing depressor-antitrophic
effects of Ang-(1-7).

In addition, Ang-(1-7) may also contribute to


the antihypertensive effects of both ACE-Is and
AIIAs.5 By preventing ACE-mediated peptide
degradation and increasing Ang I availability,
ACE inhibition elevates Ang-(1-7). AIIAs also
increase Ang-(1-7) by increasing the availability
of Ang I (via blockade of AT1-mediated negative
feedback on renin) and promoting conversion
of Ang II to Ang-(1-7) via increased ACE2
expression/activity.
Pharmacological Modulation of RAS
ACE-Is and AIIAs represent the principal
pharmacologic methods of inhibiting the
RAS. However, other types of agents capable
of blocking the RAS are available, including
aldosterone receptor blockers (e.g., eplerenone)
and renin antagonists (e.g., aliskiren).

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between Ang II and the AT1 receptor present
on target tissues; this includes, for example, the
afferent and efferent arterioles of the kidney,
vascular smooth muscle, and zona glomerulosa
of the adrenal gland. AIIAs block the action of
Ang II regardless of its site of origin (ACE or nonACE pathways) and, furthermore, do not produce
changes in the metabolism of other biologically
active peptides (e.g., bradykinin) which can
contribute to development of adverse events (e.g.,
cough) seen with ACE-Is.
Aldosterone Antagonists
Spironolactone, a non-selective aldosterone
antagonist, and eplerenone, both antagonise the
effects of aldosterone at its receptor and have
demonstrated clinical benefits in patients with
hypertension, heart failure, and nephropathy.
The addition of eplerenone to standard medical
therapy may also represent an interesting new
strategy to improve mortality and morbidity
particularly in post-MI patients with LV systolic
dysfunction and heart failure.

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ACE Inhibitors
Initially introduced as antihypertensive agents,
ACE-Is have demonstrated clinical efficacy in
the treatment of a wide range of cardiovascular
and renal diseases, including heart failure, acute
MI, chronic renal failure, and sclerodermal renal
crisis. ACE-Is arose from early studies performed
in the 1960s showing that components of venom
from the Brazilian arrowhead viper (Bothrops
jararaca) inhibited kinase II, an enzyme involved
in the degradation of bradykinin and later found
to be identical to ACE. Analogues of the nonpeptide fraction of snake venom (teprotide),
which inhibited ACE, were found to lower BP
in hypertensive patients and produce beneficial
effects in heart failure patients. Subsequent research
revealed that ACE inhibition could be achieved
by succinyl amino acids (e.g., carboxyalkanoyl
and mercaptoalkanoyl derivatives), a finding that
ultimately led to the discovery of captopril, the
first orally active, competitive ACE-I. Since that
time, a plethora of ACE-Is have been developed
(enalapril, lisinopril, benazepril, quinapril,
ramipril, fosinopril, moexipril and spirapril) that
share a common structural moiety that interacts
with the zinc ion in the ACE active site.
Angiotensin II Antagonists
AIIAs represent the newest class of drugs
introduced to treat hypertension. However, since
their initial introduction, AIIAs have demonstrated
clinical efficacy in treating left ventricular
hypertrophy (LVH), heart failure, diabetic
nephropathy, and post-MI.7-18

Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems

The development of AIIAs began in the early


1970s with pharmacologic studies of several
peptide analogues of Ang II such as saralasin,
sarcosine,1 isoleucine8 Ang II, and other
substitution of amino acids at the C-terminal
end of the Ang II molecule. Although potent
Ang II antagonists, these compounds retained
significant partial agonist activity and had to be
administered intravenously, thereby precluding
their clinical use.
Chemists subsequently
synthesised a series of non-peptide AIIAs
based on the imidazole and imidazole-5-acetic
acid structures and, in an elegant series of
molecular manipulations, developed losartan,
the first orally active, selective, and potent nonpeptide AIIA. Losartan is metabolised to two
derivatives EXP 3174, which is more potent
than losartan at blocking the AT1 receptor,
and the intermediate metabolite EXP 3179,
which has low affinity for the AT1 receptor and
may possess anti-inflammatory and platelet
anti-aggregatory effects independent of the
AT1 receptor. By employing losartan or its
metabolites as a molecular model, chemists
have since synthesised a wide range of AIIAs
(valsartan, irbesartan, eprosartan, telmisartan,
candesartan, and olmesartan).
The clinical effects of the AIIAs arise primarily from
their ability to selectively block the interaction

Renin Inhibitors
Burton and colleagues described the first renin
inhibitor in 1980, but the substrate analog of
angiotensinogen they identified lacked potency
and specificity. In the years to follow, a variety
of renin inhibitors were synthesised based on
substitution of various non-hydrolyzable residues
of the scissile bond cleaved by renin. However,
limited oral absorption and brief duration of
biologic action diminished the clinical usefulness
of these agents. Monoclonal antibodies against
renin have also been used as molecular probes to
study the RAS but have limited clinical utility.
Recently, the first orally active renin inhibitor
(aliskiren) has been reported to be effective
as an antihypertensive agent both in animals
and human subjects. In healthy volunteers,
oral aliskiren dose-dependently lowers Ang II
levels to a degree equivalent to that seen with
enalapril and, in patients with mild-to-moderate
hypertension, aliskiren was as effective as
irbesartan in lowering BP. However, whether
aliskiren treatment results in protection from
heart attack, stroke, and nephropathy remains
to be investigated.

Involvement of the RAS in Human


Health and Disease
During the course of evolutionary development,
the
RAS
has
undergone
considerable
modification and refinement, with the result that
this regulatory system has become intricately
involved in a wide range of physiological
and pathophysiological processes in multiple
tissues, organs, and syndromes.3 There is now
a growing body of evidence that enhancement
or suppression of the RAS plays a central
role in the etiology of a plethora of human
diseases (Table 3), including for example,
renin-secreting tumours, scleroderma renal

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Table 3
Involvement of the renin-angiotensin system in health and disease.
Certainly/probably Involved

Possibly Involved

Suppressed

Pregnancy

Early polycystic kidney disease

Sodium and fluid excess

Renin-secreting tumours

Nephrotic syndrome

Mineralocorticoid hypertension

Angiotensinogen-secreting tumours

Aortic coarctation

Gordons syndrome

Renovascular hypertension

Phaeochromocytoma

Liddles syndrome

Malignant hypertension

Connective tissue diseases

Syndrome of apparent mineralocorticoid excess

Haemorrhage

Raynauds phenomenon

Essential hypertension

Acute circulatory renal failure

Cancerous proliferation

Primary renin deficiency

Multiple organ failure

Pregnancy-associated hypertension

Hepatic cirrhosis
Addisons disease and related disorders
Anorexia nervosa, bulimia nervosa,
diuretic abuse, purgative abuse
Bartters syndrome and related disorders

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Vascular and cardiac remodelling

Myocardial infarction
Chronic renal failure with hypertension
Diabetes insipidus

Reproduced from Nicholls MG and Robertson JIS19 with permission.

Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems

In vivo and in vitro studies of the molecular


and cellular effects of Ang II and AIIAs have
also provided a wealth of data to demonstrate
the involvement of the RAS in cardiovascular
and renal diseases, including cardiac
hypertrophy/remodelling, cardiac arrhythmias,
endothelial dysfunction, vascular remodelling/
atherosclerosis, thrombus formation, platelet
aggregation, and nephropathy (Table 4).
However, the most convincing evidence of
the role of the RAS in cardiovascular disease
comes from studies in which blockade of AT1
receptors has been shown to positively impact
the morbidity and mortality outcomes of
cardiovascular diseases.

34.5

40
30
20
20

7.8

10
0

8.1

High

6.5

4.8
2.5

2.1

1.7

Moderate

Low

High
Normal
Low

Renin Level

Several lines of evidence are consistent with


a pathological role for Ang II in cardiac, renal
and vascular diseases. Stimulation of the RAS,
as evidenced, for example, by increased levels
of plasma renin activity (PRA) or Ang II, occurs
in numerous pathologic states including
hypertension,20 and epidemiological studies
have shown a clear association with increased
risk of cardiovascular events. For example, a
series of epidemiological studies by Alderman
and colleagues21 demonstrated that a low urinary
sodium and elevated plasma renin activity
represent an independent risk factor for MI and
cardiovascular and all-cause mortality. In patients
with hypertension, PRA level was found to be
independently and directly associated with the
incidence of MI, with a 2 unit increase in PRA
producing an overall 25% increase in MI incidence
(Figure 2).21

Mortality and Morbidity effects of


AIlAs Evidence from Randomised
Clinical Trials
A number of outcomes-based mega trials utilising
hard clinical endpoints (Table 5)7-9,11-17,22,23 have
evaluated the beneficial effects of AIIAs (losartan,
valsartan, candesartan and irbesartan) in patients
with hypertension, heart failure, diabetic
nephropathy and post-MI. The results of these
studies not only emphasise the importance of
Ang II in the pathophysiology of these diseases
but have provided the basis for an evidencebased approach for the use of AIIAs in actual
clinical practice.

MI Rate/1,000 Person years

crisis, malignant hypertension, cardiac failure,


and diabetic nephropathy.19

Risk Status
Figure 2
Relationship between renin activity and risk of myocardial
infarction in patients with hypertension.
Adapted from Alderman MH et al. Am J Hypertens
1997;10:1-8.21

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Hypertension
The Losartan Intervention For Endpoint reduction
(LIFE) trial demonstrated the ability of losartan
to regress LVH and improve cardiovascular
morbidity and mortality in patients with
mild-to-moderate essential hypertension and
a electrocardiographic documented cardiac
hypertrophy. 7 LIFE was a double-blind,
randomised, parallel group trial involving a
total of 9,193 hypertensive patients (aged 55 to
80 years). The LIFE trial population primarily
involved patients at high risk of cardiovascular
events, with most patients having a least one
other risk factor such as coronary heart disease
or diabetes. Patients with sitting BP between
160-200/95-115 mmHg and LVH randomly

received either a losartan-based or an atenololbased antihypertensive regimen for at least four


years and until 1,040 patients had a primary
cardiovascular event. An important aspect of
the LIFE trial was the fact that it was designed
to reflect the manner in which hypertension is
treated in actual clinical practice. That is, LIFE
employed antihypertensive regimens of multiple
medications including a thiazide diuretic and
a calcium channel blocker (CCB) or other
medication (in addition to losartan or atenolol)
to adequately control BP.
For a comparable reduction in BP LIFE
revealed that, in patients with hypertension
and LVH, a losartan-based regimen prevented

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Table 4
Involvement of renin-angiotensin system in cardiovascular and renovascular diseases, as evidenced by studies utilising AIIAs.
Cardiac remodelling
left ventricular mass
myocardial fibrosis
collagen synthesis (cell culture/animal models)
Arrhythmogenicity

new onset atrial fibrillation


QT dispersion

risk of stroke in hypertensive patients with LVH and atrial fibrillation


Endothelial Dysfunction
Improved endothelial function

extracellular superoxide dismutase in arterial wall, increasing the bioavailability of NO


Improved vasomotor function
intercellular adhesion molecule (ICAM-1) expression in endothelial cells

Vascular remodeling/atherosclerosis
vascular hypertrophy ( intima-media thickness)
Inhibition of LDL oxidation, Ox-LDL receptor expression, and Ox-LDL uptake
fatty streaks (non-human primates)
Inhibition of inflammation ( NFB activation, macrophage binding to endothelial cells, MCP-1 expression,
COX-2 mRNA expression and COX-2-dependent TxA2 and PGF2a generation in human endothelial cells [via losartan
metabolite EXP-3179])

Thrombus formation and platelet aggregation


platelet aggregation
platelet shape change (early phase of platelet activation) induced by Ang II and TxA2 analogue
PAI-1
tissue factor (initiates coagulation via factor VII)
Impact on risk factors
new onset diabetes mellitus
albuminuria
Molecule-specific effects
serum uric acid with losartan but not other AIIAs
Modulation of peroxisome proliferator-activated receptor- (PPAR) through partial agonist activity (telmisartan, irbesartan,
and losartan at high concentrations)

Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems

Renal effects
proteinuria in type 2 diabetes and non-diabetic nephropathy
TGF- in type 2 diabetes mellitus and chronic allograft nephropathy
oxidative stress and proinflammatory state of the kidney
Preservation of glomerular and tubulointerstitial structure (rats)
pore size of glomerular membrane (rats)

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more cardiovascular morbidity and death
than an atenolol-based regimen.
Losartan
produced a 13% relative risk reduction in the
composite primary endpoint of cardiovascular
mortality, stroke (fatal and non-fatal), and MI
(HR 0.87, p=0.021), an effect primarily due to
a 25% reduction in the risk of fatal and nonfatal stroke (Figure 3, p=0.001).7 The potential
public health impact of including losartan as

part of a combination antihypertensive therapy


regimen for patients with high BP and LVH is
substantial. For example, when the benefits of
losartan over atenolol in preventing stroke are
applied to that fraction of the European Union
population who meet LIFE eligibility criteria,
it was estimated that using losartan in patients
with hypertension and LVH would prevent
125,000 first strokes over a 5.5 year period.24

Table 5
AIIA endpoint trials in patients with heart failure, hypertension, type 2 diabetes, or post-MI.
AIIA

Trial

Patient Population

Endpoints

Losartan

ELITE II

Heart Failure

All-cause mortality


LIFE
Hypertensives with LVH

Composite: CV mortality, stroke


(fatal and non-fatal), MI

All-cause mortality

OPTIMAAL

Post-MI with LVD

Composite: doubling of serum creatinine,


ESRD, mortality

Valsartan
Val-HeFT
Heart failure

All-cause mortality, combined mortality


and morbidity

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RENAAL
Type 2 diabetics with nephropathy

VALIANT

Post-MI with LVD

All-cause mortality

VALUE

Hypertensives at high risk

Composite: cardiac morbidity and mortality

Candesartan CHARM Alternative Heart failure, ACE inhibitor intolerant Composite: CV death or hospital admission

for CHF

CHARM Preserved
Heart failure, LVEF 0.40

Composite: CV death or hospital admission


for CHF


CHARM Added
Heart failure + ACE inhibitors

Composite: CV death or hospital admission


for CHF

SCOPE
Elderly hypertensives

Major CV events (composite: CV mortality,


non-fatal MI, non-fatal stroke)

IDNT
Type 2 diabetics with nephropathy
Irbesartan

Composite: doubling of serum creatinine,


ESRD, mortality

ELITE II = Losartan Heart Failure Survival Study22; LIFE = Losartan Intervention for Endpoint Reduction7; OPTIMAAL = Optimal
Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan14; RENAAL = Reduction of Endpoints in NIDDM with the
Angiotensin Antagonist Losartan16; Val-HeFT = Valsartan Heart Failure Trial23; VALIANT = The VALsartan In Acute myocardial
iNfarcTion 15; VALUE = Valsartan Antihypertensive Long-term Use Evaluation study8; CHARM = Candesartan in Heart FailureAssessment of Reduction in Mortality and Morbidity11-13; SCOPE = Study on Cognition and Prognosis in the Elderly9;
IDNT = Irbesartan Diabetic Nephropathy Trial17

Primary composite of CV death,


stroke and MI

Fatal and non-fatal stroke

14

Atenolol

12
10

Losartan

8
6
4

Adjusted Risk Reduction


13.0%, p=0.021
Unadjusted Risk Reduction 14.6%, p=0.009

2
0
0

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Including other
Peptidergic Systems

Proportion of patients with


first event (%)

Proportion of patients with


first event (%)

16

Atenolol

6
5

Losartan

4
3
2

Adjusted Risk Reduction


24,9%, p=0.001
Unadjusted Risk Reduction 25.8%, p=0.0006

1
0

6 12 18 24 30 36 42 48 54 60 66
Study Month

6 12 18 24 30 36 42 48 54 60 66
Study Month

Figure 3
Impact of a losartan-based regimen compared with an atenolol-based regimen on the primary composite endpoint (CV death,
stroke, and MI) and fatal/non-fatal stroke in hypertensive patients with LVH in the LIFE study.
Adapted from Dahlof B et al. Lancet 2002;359:995-1003.7

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Importantly, the cardiovascular and stroke benefits
of a losartan-based regimen were accompanied
by an excellent tolerability profile. Patients
receiving a losartan-based regimen experienced a
significantly lower discontinuation rate as a result
of all serious adverse events (p<0.0001), drugrelated adverse events (p<0.001), and serious drugrelated adverse events (p=0.006) compared with
patients receiving an atenolol-based regimen.

A recent report30 has suggested that atenolol,


one of the most widely prescribed beta-blockers
worldwide, may not represent the most appropriate
reference drug in hypertension trials because of a
lack of demonstrable superiority of cardiovascular
mortality and morbidity benefits compared to
placebo or other antihypertensive drugs. On the
other hand, the value of atenolol in the prevention
of stroke death was amply demonstrated in the
landmark study of Systolic Hypertension in the
Elderly Program (SHEP), in which the combination
of atenolol with chlorthalidone resulted in a 37%
decrease in the occurrence of strokes. Additional
evidence of the benefits of an atenolol-based
therapy is found in results from the International
Verapamil Trandolapril Study (INVEST), where
similar outcomes were obtained in patients
receiving an atenolol-based strategy compared
with those receiving verapamil.31 The inclusion of
atenolol in the LIFE trial is further justified in light
of the recent findings of a comprehensive metaanalysis32 demonstrating that reducing BP using
beta-blocker/diuretic regimens is associated with
substantial cardiovascular outcomes benefits.
This analysis showed that patients who received
a beta-blocker (alone or in combination with
diuretic) demonstrated a 26% risk reduction in
all cardiovascular events (p<0.001), a 19% risk
reduction in cardiovascular death (p=0.001), 34%
risk reduction in stroke (p<0.001), and a 20% risk
reduction in coronary heart disease (p<0.001).
These cardiovascular benefits are consistent with
the general recognition of beta-blockers as a firstline treatment for hypertension, as outlined by
the 7th report of the Joint National Committee
on Prevention, Detection and Evaluation, and
Treatment of High Blood Pressure, the European
Society of Hypertension/European Society of
Cardiology, and NICE.

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A subgroup analysis of LIFE25 involving


hypertensive patients with LVH and a history of
atrial fibrillation (n=342) also showed that losartan
was more effective than the atenolol-based strategy
in lowering the risk of the primary composite
endpoint (cardiovascular mortality, stroke and
MI) as well as stroke and cardiovascular death. A
losartan-based regimen resulted in a significantly
lower incidence of the primary composite
endpoint (HR=0.58, p=0.009), cardiovascular
death (HR=0.58, p=0.048), and stroke (HR=0.55,
p=0.039). However, the incidence of MI was
similar in the two groups (HR=1.49, p=0.392).

formation, platelet aggregation, and risk factors


for stroke.

The therapeutic advantage of losartan over


atenolol observed in LIFE most likely arises from
blockade of the deleterious effects of Ang II
mediated by AT1 receptors as well as from possible
molecule-specific effects such as a reduction in
serum uric acid levels and inhibition of platelet
aggregation.26 Although LIFE was not designed
to evaluate the mechanism(s) by which losartan
exerts its anti-stroke effect, several sub-analyses
of LIFE data reveal that at least part of the stroke
benefit in favour of losartan may be explained
by effects on left ventricular mass index, urinary
albumin/creatinine ratio, and, possibly, the
specific ability of the molecule to reduce serum
uric acid levels, and the anti-thrombotic actions
of the molecule.27-29

Journal of
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Including other
Peptidergic Systems

Losartan produced a greater regression in LVH


compared with atenolol29 and this effect could
have contributed approximately 32% of the
advantage of a losartan-based therapy over an
atenolol-based therapy on the primary composite
endpoint. LIFE data also showed that losartan
reduced albuminuria to a greater degree than
atenolol for the same degree of reduction in BP,
an effect that potentially could have contributed
to approximately 20% of the outcome difference
in favour of losartan.27 Another sub-analysis of
LIFE data revealed that differences in serum uric
acid levels between the losartan and atenolol
study groups may also have contributed to the
benefit of losartan on the primary composite
endpoint (death, MI or stroke).28 In addition
to effects on left ventricular mass, serum uric
acid, and urinary albumin, an abundance of
experimental and clinical data (Table 4) suggest
the potential for losartan to impact stroke risk
through a variety of mechanisms, all independent
of BP. These include, for example, effects on
cardiac remodelling, vascular remodelling,
atherosclerosis, endothelial function, thrombus

The Study on Cognition and Prognosis in


the Elderly (SCOPE) also found that an AIIA
(candesartan)-based regimen resulted in a
significant 27.8% risk reduction in non-fatal stroke
compared with usual antihypertensive treatment
in elderly hypertensive patients (p=0.04).9
However, the primary endpoint (CV death,
non-fatal MI, or non-fatal stroke), or secondary
endpoint measures of all stroke, fatal stroke,
MI, cardiovascular mortality, and percentage
of patients with cognitive decline or dementia
showed no significant differences between
study groups. A small difference in BP (3.2/1.6
mmHg in favour of candesartan) may explain
the reduction in non-fatal stroke observed in
patients receiving candesartan.
The Valsartan Antihypertensive Long-term
Use Evaluation (VALUE) study evaluated the
hypothesis that, for an equivalent degree of BP
lowering, the AIIA valsartan would be more
effective than the CCB amlodipine in preventing

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cardiac morbidity and mortality.8 Hypertensive
patients at high risk of cardiac events (n=15,245)
were randomised to receive valsartan (80 to 160
mg daily) or amlodipine (5 to 10 mg daily). After
a median follow-up of 4.2 years, no differences
between the two groups occurred with respect
to the primary composite endpoint of cardiac
morbidity and mortality or all-cause mortality,
although fewer patients in the amlodipine group
experienced an MI (HR=1.19, p<0.02). As with the
SCOPE study above, the BPs achieved in the two
study groups were dissimilar, particularly during
the first six months of therapy. For example,
fewer valsartan-treated patients than amlodipinetreated patients achieved the combined systolic
and diastolic target BP of < 140/90 mmHg (56%
vs. 62%, respectively).

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Heart Failure
Evidence consistent with a central role of Ang
II in the pathophysiology of heart failure comes
from three large, randomised double-blind trials
Losartan Heart Failure Survival Study (ELITE
II), Valsartan Heart Failure Trial (Val-HeFT),
and Candesartan in Heart Failure Assessment of
Reduction in Mortality and Morbidity (CHARM).

CHARM-Added involved patients with ejection


fractions of 40% taking optimum doses of
ACE-I; CHARM-Alternative involved heart failure
patients with ejection fractions < 40% who
were ACE-I intolerant; and CHARM-Preserved
involved patients with symptomatic failure and
preserved systolic function (ejection fraction
> 40%).11-13 Each study compared candesartan to
placebo as add-on therapy to conventional heart
failure treatments such as beta-blockers, diuretics,
digitalis, and ACE-Is if appropriate. Results from
the individual CHARM-Added and CHARMAlternative trials revealed that candesartan
significantly impacted the primary composite
endpoint as well as its individual components and
total mortality. However, in CHARM-Preserved,
the composite endpoint and cardiovascular death
were not significantly different between groups,
although candesartan did reduce admissions for
heart failure.

The first major randomised trial (ELITE) of an


AIIA in patients with heart failure revealed an
unexpected decrease in mortality in losartantreated versus ACE-I-treated patients.33 However,
ELITE II failed to confirm significant differences
between losartan and captopril groups with respect
to all-cause mortality or all-cause hospitalisation.
However, losartan was well tolerated, with
approximately 9.7% of patients taking losartan
discontinuing study medication due to adverse
experiences, compared with 14.7% of patients on
captopril (p<0.001).22
The Val-HeFT compared valsartan with placebo on
mortality and morbidity (resuscitated cardiac arrest,
hospitalisation for heart failure or administration
of an inotropic or vasodilator drug for > 4 hours).23
As with ELITE II, Val-HeFT studied patients with
NYHA class II-IV and ejection fractions less
than 40% but differed from ELITE II in that the
AIIA (valsartan) was administered twice daily, in
addition to usual therapy that included ACE-Is.
Although both study groups produced similar
effects on all-cause mortality, a significant 13.2%
decrease in the combined endpoint of all-cause
mortality plus morbidity was apparent in favour
of valsartan (p=0.009), an effect due primarily to
a 24% decrease in heart failure hospitalisations in
valsartan-treated patients (p<0.001).23 Valsartan
also significantly improved NYHA classification,
symptoms of heart failure, and health-related
quality-of-life assessments (p<0.05).
Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems

CHARM represents the most recent outcomes


trial in patients with heart failure.10 CHARM
was not a single study but a series of studies
carried out concurrently in three different
populations of patients with heart failure

Type 2 Diabetes and Renal Disease


Several AIIAs have been shown to slow the
progression of renal disease in patients with
type 2 diabetes and nephropathy. 16,17 The
Reduction of Endpoints in NIDDM with the
Angiotensin Antagonist Losartan (RENAAL)16
and Irbesartan Diabetic Nephropathy Trial
(IDNT)17 both studied the effect of an AIIA
on the time to first event of a composite
endpoint (doubling of the serum creatinine
concentration, ESRD or death).
RENAAL involved 1,513 patients with severe renal
disease that was likely to progress to dialysis
and compared losartan (50 or 100 mg once
daily) with placebo, in addition to conventional
antihypertensive treatment (i.e. CCBs, diuretics,
alpha blockers, beta-blockers, and centrally
acting agents).16 Over a follow-up period of 3.4
years, losartan resulted in a 16% risk reduction
in the composite endpoint (doubling of serum
creatinine concentration, end-stage renal disease
(ESRD), or death from any cause, Figure 4) and a
28% reduction in the risk of ESRD, compared with
placebo (p=0.002).
The renal protective effect of losartan was
estimated to produce an average delay of two
years in the need for dialysis or transplantation.
In addition, losartan significantly decreased
the level of proteinuria by approximately
35% compared with placebo-treated patients
(p<0.001) as well as decreased the risk
of first hospitalisation for heart failure by
approximately 32% (p=0.005).

The findings of RENAAL are consistent with a


substudy of LIFE trial involving 1,195 patients
with hypertension, LVH, and diabetes.34
A
losartan-based regimen was more effective
than an atenolol-based regimen in decreasing
cardiovascular morbidity and mortality as well
as mortality from all causes, despite similar
decreases in mean BP. A separate exploratory

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Intention-to-treat analysis

Per-protocol analysis

Risk reduction: 16%


p=0.024

50

40

Risk reduction: 22%


p=0.008

50

40

P
L

30

30
L
20

% with event

% with event

20

10

0
0

12

24

36

48

10

0
0

24

36

48

Months

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Months

12

Figure 4
Comparison of a losartan (L)-based versus placebo (P) regimen in addition to conventional antihypertensive treatment, on primary
composite endpoint in patients with type 2 diabetes and nephropathy enrolled in RENAAL.
Adapted from Brenner B et al. N Engl J Med 2001;345:861-9.16

post hoc analysis of LIFE also suggests that


losartan may better protect against cardiac death
from arrhythmias than atenolol.35

IDNT involved 1,715 hypertensive patients


with nephropathy due to Type 2 diabetes and
compared irbesartan (300 mg daily), amlodipine
(10 mg daily), and placebo (conventional
antihypertensive treatment) over a mean
treatment duration of 2.6 years.17 In patients
receiving irbesartan, the serum creatinine
concentration increased approximately 21% more
slowly (p=0.02) compared with the amlodipinetreated patients. In addition, irbesartan-treated
patients experienced a 20% lower risk of primary
composite endpoint of doubling of the baseline
serum creatinine concentration, development of
ESRD, or death from any cause versus placebo
(p=0.02) and a 23% lower risk versus amlodipine
(p=0.006). However, unlike RENAAL, IDNT did
not show a significant difference in the decline of
ESRD among study groups.

Journal of
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Including other
Peptidergic Systems

Post-MI
The therapeutic benefit of selective antagonism
of the AT1 receptor in post-MI patients has been
evaluated in two large trials. The Optimal Therapy
In Myocardial infarction with the Angiotensin II
Antagonist Losartan (OPTIMAAL)14 investigated
the hypothesis that losartan would be superior or
non-inferior to captopril in decreasing all-cause
mortality in high-risk patients after acute MI. An
ACE-I was chosen as an active comparator in this
study because of the documented benefits of this
class of drugs in improving survival and reducing
morbidity in patients with acute MI and cardiac
failure.
During a mean follow-up of 2.7 years, losartan
and captopril were found to produce similar

effects on all-cause mortality, sudden or


resuscitated cardiac death, and fatal/nonfatal reinfarction, although captopril therapy
was associated with significantly fewer
cardiovascular deaths (13.3% vs. 15.3% for
losartan, p=0.03). Consistent with the excellent
tolerability of the AIIA class of drugs in general,
losartan was better tolerated than captopril and
gave rise to significantly fewer discontinuations
(17% vs. 23%, respectively, p<0.0001).
Similar to the overall findings of OPTIMAAL,
VALsartan In Acute myocardial infarction
(VALIANT)15 also found that therapeutically
comparable doses of valsartan and captopril
produced similar mortality benefits in
patients at high risk for cardiovascular events
post-MI.
In this study, post-MI patients
received conventional therapy plus either
valsartan alone, valsartan plus captopril, or
captopril alone and were followed up for a
median of 24.7 months. The occurrence of
death from any cause was similar among
all three groups, with a hazard ratio of 1.00
(p=0.98) for valsartan group versus captopril
and 0.98 (p=0.73) for valsartan plus captopril
versus captopril. When the results of OPTIMAAL
and VALIANT are analysed together, it is clear
that AIIAs may be considered as suitable
alternatives to ACE-Is in patients with highrisk acute MI. 36
Conclusions What Does the Future
Hold?
More than a century of research on the RAS
has unveiled some of the most remarkable
advances in cardiovascular medicine. The
development of selective AIIAs, in particular,
has confirmed the pivotal role that Ang II plays
in development of a variety of cardiovascular

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and renal diseases, including hypertension,
cardiac failure, coronary heart disease and postMI, as well as diabetic nephropathy. However,
in many respects, we have only just begun to
reveal the intricate and diverse physiological
and pathophysiological underpinnings of this
remarkable regulatory system. Perhaps the
next 100 years of research will address many
unresolved issues on the mechanism of Ang
II-mediated cardiovascular and renal disease
and uncover hitherto unimaginable therapeutic
opportunities. In the shorter term, several
issues are worthy of further study.

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Advances in molecular genetic technology


have provided a powerful investigational tool
in cardiovascular research, and application
of this technology is expected to provide
further characterisation of the role of Ang II
in BP regulation, molecular mechanisms of
end-organ injury, and genetic components
of hypertension. All of the known genes
encoding the principal components of the
RAS, including angiotensinogen, renin, ACE,
ACE2, and AT1/AT2 and mas receptors, can
now be disrupted by gene targeting. This
line of research holds great promise for the
future, perhaps allowing generation of mice
with a humanised genome and identification of
background genes capable of modifying RAS
genes in vivo.

Peroxisome proliferator-activated receptors


(PPARs), a family of ligand-activated nuclear
receptors intimately involved in glucose and lipid
metabolism, may be involved in the development
of several chronic diseases, including diabetes,
obesity, atherosclerosis and cancer. There is also
evidence to suggest a role for PPAR in BP control,
as indicated by the fact that thiazolidinediones
decrease BP in man and animal models with
Type 2 diabetes or obesity. Recent studies in
vitro demonstrated that some AIIAs (telmisartan
and irbesartan) induce PPAR activity in cultured
mouse 3T3-L1 pre adipocytes and increase
mRNA levels for PPAR target genes (aP2 and
adiponectin). Although the effects of these agents
on human PPAR have yet to be determined, these
findings merit further study in man to determine
the clinical significance, if any, of the effects of
AIIAs on insulin sensitivity, glucose lowering, and
cardiovascular outcomes.

Ang-(1-7) serves as a feedback control mechanism


within the RAS and appears to be critically
involved in the control of tissue perfusion, cell
cell communication, development, and growth.
However, the mechanisms and potential clinical
benefits of boosting formation of Ang-(1-7)
remain to be delineated. Genomic studies are
also needed to determine the possible existence
of polymorphisms in the ACE2 gene or Ang-(1-7)forming enzymes.
While most of the cardiovascular effects of Ang
II occur via interaction with the AT1 receptor, we
are beginning to recognise that AT2 receptors
may also play a role in pathophysiological
processes. Further research is needed to
elucidate more clearly the role of AT2 receptors
in cardiovascular diseases and to examine the
potential clinical benefits of specifically targeting
the AT2 receptor.

Journal of
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Including other
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The clinical potential of other agents that impact


the RAS such as vasopeptidase inhibitors, renin
inhibitors, and aldosterone-receptor blockers
represent another area of intense research
interest. Aliskiren is a novel, orally effective
renin inhibitor that dose-dependently lowers
BP in hypertensive patients and appears to
have a tolerability profile similar to irbesartan
and placebo. Further research is needed to
assess whether blocking the RAS at its most
upstream point offers any clinical advantages
for cardiovascular protection.

Substantial clinical and epidemiological evidence


suggests that serum uric acid represents an
important risk factor for cardiovascular and
renal disease and should be carefully considered
when evaluating overall cardiovascular risk in
patients with hypertension. Post hoc analysis
of data from the LIFE trial raises the possibility
that a treatment-induced decrease in serum uric
acid may attenuate cardiovascular risk. Although
elevated levels of uric acid are associated with
deleterious effects on endothelial dysfunction,
oxidative metabolism, platelet adhesiveness,
haemorheology, and aggregation, further
research is needed to determine the pathogenic
mechanisms through which uric acid may
impact cardiovascular disease.
In addition,
it would be interesting to evaluate whether a
reduction in serum uric acid levels by lifestyle or
pharmacologic means would improve the longterm prognosis of patients with hypertension
and perhaps other cardiovascular diseases.
The confirmation in the LIFE trial that
atherothrombosis represented the majority of the
stroke events in the studied population implicates
an action of AIIAs in the mechanisms that
contribute to hyper-coagulation and thrombosis.
The selective effects of some AIIAs in reducing
the rate of platelet aggregation and inhibiting
inflammatory and atherogenic cytokines needs
further investigation since this may represent
a novel mechanism by which this treatment
approach reduces the risk of thrombotic and
embolic effects.
Acknowledgements
This article was supported by Merck & Co. Inc.,
Whitehouse Station, NJ. The author thanks Jan S.
Redfern, PhD, for writing and editorial support.
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Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems

March 2006

Volume 7
Number 1
14

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