Documente Academic
Documente Profesional
Documente Cultură
March 2006
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.
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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-
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Table 1
Milestones in the history of the renin-angiotensin system.
Year
Investigators
Finding
1898
1934
Goldblatt et al.
Skeggs et al.
1954
Skeggs et al.
1958
Gross
1971
Pals et al.
1972
Engel et al.
1975
Schelling et al.
1977
Cushman et al.
1988
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Carini or Duncia
Donoghue et al.
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
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).
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Table 2
Key pharmacological effects of Ang II mediated by activation of AT1 or AT2 receptors.
AT1
AT2
myocardial contractility
arrhythmias
PAI-1
sympathetic activity
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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
Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems
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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
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.
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Table 3
Involvement of the renin-angiotensin system in health and disease.
Certainly/probably Involved
Possibly Involved
Suppressed
Pregnancy
Renin-secreting tumours
Nephrotic syndrome
Mineralocorticoid hypertension
Angiotensinogen-secreting tumours
Aortic coarctation
Gordons syndrome
Renovascular hypertension
Phaeochromocytoma
Liddles syndrome
Malignant hypertension
Haemorrhage
Raynauds phenomenon
Essential hypertension
Cancerous proliferation
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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Myocardial infarction
Chronic renal failure with hypertension
Diabetes insipidus
Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems
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
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
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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
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])
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
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
All-cause mortality
OPTIMAAL
Valsartan
Val-HeFT
Heart failure
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RENAAL
Type 2 diabetics with nephropathy
VALIANT
All-cause mortality
VALUE
Candesartan CHARM Alternative Heart failure, ACE inhibitor intolerant Composite: CV death or hospital admission
for CHF
CHARM Preserved
Heart failure, LVEF 0.40
CHARM Added
Heart failure + ACE inhibitors
SCOPE
Elderly hypertensives
IDNT
Type 2 diabetics with nephropathy
Irbesartan
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
14
Atenolol
12
10
Losartan
8
6
4
2
0
0
Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems
16
Atenolol
6
5
Losartan
4
3
2
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.
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Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems
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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).
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Intention-to-treat analysis
Per-protocol analysis
50
40
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
Journal of
the ReninAngiotensinAldosterone
System
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
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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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Journal of
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System
Including other
Peptidergic Systems
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19. Nicholls MG, Robertson JI. The renin-angiotensin system
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21. Alderman MH, Ooi WL, Cohen H, Madhavan S,
Sealey JE, Laragh JH. Plasma renin activity: a risk factor
for myocardial infarction in hypertensive patients. Am J
Hypertens 1997;10:1-8.
22. Pitt B, Poole-Wilson PA, Segal R et al. Effect of
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25. Wachtell K, Hornestram B, Lehto M et al. Cardiovascular
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Journal of
the ReninAngiotensinAldosterone
System
Including other
Peptidergic Systems
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