ReVIewS

Novel therapeutic targets for hypertension

Ludovit Paulis and Thomas Unger
abstract | Despite the existence of established, effective therapies for hypertension, new methods of blood
pressure and cardiovascular risk reduction are still needed. Novel approaches are targeted towards treating
resistant hypertension, improving blood-pressure control, and achieving further risk reduction beyond blood-
pressure lowering. Modulation of the renin–angiotensin–aldosterone system (RAAS) provides the rationale
for current antihypertensive therapies, including the relatively new agents eplerenone and aliskiren. Novel
targets for antihypertensive therapy are also likely to be RAAS-related. The stimulation of angiotensin II type 2
receptors, or supplementation with renalase, could counteract the effects of angiotensin II type 1 receptor
stimulation or catecholamine release. Combined angiotensin-converting-enzyme and neutral endopeptidase
blockade decreases blood pressure, but is associated with a high incidence of angioedema. Aldosterone
synthase inhibitors might improve tolerability in aldosterone antagonism. A (pro)renin-receptor blocker could
prevent the deleterious angiotensin-independent actions of renin that are not inhibited by aliskiren. Finally,
new minimally invasive surgical procedures have revived the concept of renal denervation, and could be a
therapeutic option for patients with resistant hypertension. All of these strategies are exciting prospects, but
which of them will prove valuable in clinical setting remains to be discovered.
Paulis, L. & Unger, T. Nat. Rev. Cardiol. 7, 431–441 (2010); published online 22 June 2010; doi:10.1038/nrcardio.2010.85

Introduction
Hypertension is an important risk factor for cardio­
vascular morbidity and mortality. this condition
accounts for, or contributes to, 62% of all strokes and 49%
of all cases of heart disease and is the most prevalent con­
trollable disease in developed countries, affecting 20–50%
of adult populations. 1 the number of patients with
hypertension is likely to increase in the future, particu­
larly in transitional economies. Despite great advances
in the treatment of hyper tension, the cardiovascular
risk of patients with this condition remains increased.2
several studies and subgroup analyses indicate that low­
ering blood pressure below the currently recommended
target values (140/90 mmHg, or 130/80 mmHg if the
patient has diabetes)3 might have a negative impact on
mortality (invest4 and the aCCorD study5). However,
these target values are very challenging to achieve due
to insufficient diag nosis, ineffec tive treatment, or
low patient adherence to medical therapy, with only
5–30% of patients with hypertension achieve adequate
blood­pressure control.6
three main goals exist for an innovation in anti­
hypertensive therapy; to treat resistant hypertension, to
improve blood­pressure control, and to achieve further
risk reduction (beyond blood­pressure control) by tar­
geting the functional, metabolic, and structural altera­
tions associated with hypertension. various strategies
are being initiated to achieve these goals. the most
competing interests
T. Unger declares an association with the following company:
Vicore Pharma. See the article online for full details of the
relationship. L. Paulis declares no competing interests.
innovative of these is the search for novel targets and the
development of compounds with novel properties that
could prove to be superior to conventional therapy. this
review gives an overview of advances that have been
made during the past decade in targeting the renin–
angiotensin–aldosterone system (raas), which offers
the most promising opportunities for the identification
of novel targets in hypertension.
Physiology of the RAAS
the raas plays a crucial role in the regulation of blood
pressure, and its pharmacological inhibition is a key
aspect of the current approach to reducing the risk of
cardiovascular events. the raas cascade starts with
the release of renin into the circulation from the juxta­
glomerular cells of the kidney. renin secretion is stimu­
lated by several factors, including na+ load in the distal
tubule, β­sympathetic stimulation, or reduced renal per­
fusion. active renin in the plasma cleaves angiotensino­
gen (produced by the liver) to angiotensin i, which is
then converted by circu lating and locally expressed
angiotensin­converting enzyme (aCe) to angiotensin ii.
most of the effects of angiotensin ii on the raas are
Center for
exerted by its binding to angiotensin ii type 1 receptors Cardiovascular
(at1r), leading to arterial vasoconstriction, tubular and Research, Charité-
Universitätsmedizin,
glomerular effects—such as enhanced na+ reabsorption Hessische Strasse
or modulation of glomerular filtration rate—and promo­ 3–4, 10115 Berlin,
tion of inflammation, hypertrophy, and fibrosis in the Germany (l. Paulis,
T. Unger).
heart, kidneys, and arteries.7 additionally, together with
other stimuli such as adrenocorticotropin, antidiuretic Correspondence to:
T. Unger
hormone, catecholamines, endothelin, serotonin, thomas.unger@
and levels of mg2+ and K+, at1r stimulation leads to charite.de

nature reviews | cardiology volume 7 | auGust 2010 | 431

© 2010 Macmillan Publishers Limited. All rights reserved
reviews
Key points
■ Most current effective agents for blood-pressure control, and possible
future antihypertensives, are related to inhibition of the renin–angiotensin–
aldosterone system
■ The unmet needs for antihypertensive therapy include the treatment of
resistant hypertension, improving blood-pressure control, and achieving further
cardiovascular risk reduction
■ The efficacy of newly approved medications for high blood pressure
(aldosterone receptor blockers and renin inhibitors) still needs to be confirmed,
particularly in reducing mortality
■ Novel targets for antihypertensive therapy could include the angiotensin II
type 2 receptor, neutral endopeptidase, aldosterone synthase, renalase, the
(pro)renin receptor, and renal innervations
■ The development of hybrid molecules and fixed-dose combinations of existing
therapies are likely to prevail in future hypertension research
aldosterone release. aldosterone, in turn, promotes na+
and K+ excretion in the renal distal convoluted tubule
that, when excessive, can lead to left ventricular fibrosis,
arterial remodeling, and glomerulosclerosis.8
this classical concept of the raas provides a rationale
for the use of conventional therapies, such as aCe inhibi­
tors, at1r blockers, β­blockers, aldosterone antagonists,
and novel renin inhibitors in many cardiovascular condi­
tions. moreover, these classical targets are still attractive
for the development of new drugs in established classes
and in the search for novel approaches to disrupt the
raas, such as renal denervation, antiangiotensin ii
vaccination, or aldosterone synthase inhibition.
Current ‘gold standard’ therapy
aCe inhibitors and at1r blockers represent the back­
bone of current antihypertensive therapy. the beneficial
effects of these agents are attributed to the inhibition of
deleterious at1r stimulation and, therefore, prevention
of angiotensin ii­induced vasoconstriction, salt and
water retention, aldosterone and vasopressin release,
stimulation of the sympathetic nervous system, inflam­
mation, and stimulation of cell growth.7 large clinical
trials of patients with hypertension (for example, the
CaPP9 and stoP­210 studies), or high­risk patients with
evidence of vascular disease or diabetes plus one other
cardiovascular risk factor (HoPe11), have demonstrated
that aCe inhibitors are at least noninferior to conven­
tional standard therapy (β­blockers, diuretics, or calcium
antagonists) or provide additional benefit when given in
addition to standard background treatment. the years
following these trials saw the introduction of selective
at1r blockers that could possibly extend therapeutic
benefits beyond the effects of aCe inhibition by prevent­
ing a reactive increase in angiotensin ii or aldosterone
and leaving the angiotensin ii type 2 receptor (at2r)
unopposed for ongoing angiotensin ii stimulation. the
liFe,12 value,13 and ontarGet14 trials demonstrated
that at1r blockers were noninferior when compared
with β­blockers, calcium antagonists, or aCe inhibitors,
respectively, for the reduction of cardiovascular morbid­
ity and mortality in patients with hypertension or those
at high risk for cardiovascular events. moreover, in the
432 | AUGUST 2010 | volUme 7
© 2010 Macmillan Publishers Limited. All rights reserved
ontarGet study,14 telmisartan was better tolerated
than ramipril. Both aCe inhibitors and at1r antago­
nists also reduced the incidence of new­onset diabetes
mellitus.15,16 the possibility that at1r blockers with
peroxisome­proliferator­activated­receptor­γ activat­
ing properties, such as telmisartan, might provide better
protection from new­onset diabetes and cardiovascular
disease than agents that block at1r activation alone is
currently under investigation.17,18
to date, 16 aCe inhibitors and seven at1r blockers
have been approved for clinical use in various countries
(imidapril and cilazapril are not available in the us).19–21
the most­recent newcomers to these groups are imidapril
(in Phase iii trials in the us, approved in Japan) and azil­
sartan (prodrug formulation in Phase iii trials) (table 1).
the high number of aCe inhibitors and at1r blockers on
the market leaves little space open for additional agents
with the same mechanism. However, the evidence­based
efficacy of these compounds represents a gold standard
against which innovative drugs will have to compete.
New discoveries in the RAAS
Discoveries made in the past decade have widened the
search for possible therapeutic targets in hypertension
beyond the classical raas pathway. in 2002, the dis­
covery of the (pro)renin receptor (P)rr was reported by
nguyen and colleagues.22 this receptor binds renin and
prorenin, thereby increasing the enzymatic activity of
renin and unmasking the enzymatic activity of prorenin,
which was previously thought to be an inactive precursor.
thus, the catalytic efficiency of renin (that is, plasma
renin activity [Pra]) depends on its concentration and
that of prorenin, and also on the level of activation of
these enzymes. moreover, binding to (P)rr by renin or
prorenin was shown to elicit angiotensin i­independent
effects, including the activation of promyelocytic zinc
finger (PlZF),23 protein­phosphatidylinositol­3­kinase
(Pi3­K) and, eventually, mitogen­activated protein kinases
(maPKs) with subsequently enhanced protein synthesis,
cell proliferation, and decreased apoptotic activity.24,25
Further downstream in the raas cascade, angiotensin­
converting activity is affected not only by aCe, but also
by chymase, carboxypeptidase, cathepsin G, and tonin.
in addition to catalyzing the conversion of angiotensin i
to angiotensin ii, aCe also controls the inactivation of
bradykinin, which has nitric oxide (no)­dependent
vasodilative activity.7 Furthermore, a novel vasopeptidase,
the neutral endopeptidase (neP), has been shown to
cleave several vasoconstritive (angiotensins i and ii, and
endothelin) and vasodilative (natriuretic peptides and
kinins) substances.26 as with aCe inhibition, neP inhi­
bition could represent a new strategy to achieve blood
pressure reduction.
Finally, advances have been made in the investiga­
tion of effects mediated by other angiotensin receptors,
particularly at2r,27 which mediates effects such as anti­
proliferation, regression of cardiovascular remodeling,
and vasodilation that oppose at1r activation. 28 the
roles of the type 3 and type 4 angiotensin receptors, which
were discovered in the early 1990s, have not yet been
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Table 1 | Angiotensin-targeting agents*
compound (trade name) company (location)
Candesartan cilexetil (Atacand®) AstraZeneca (Sodertale Sweden)
Valsartan (Diovan®) Novartis (Summit, NJ)
Olmesartan medoxomil (Benicar®) Daiichi-Sankyo (Tokyo, Japan)
Imidapril (Tanatril®) Mitsubishi Tanabe Pharma
(Osaka, Japan)
Azilsartan kamedoxomil (TAK-491) Takeda Pharmaceuticals
(Osaka, Japan)
Azilsartan (TAK-536) Takeda Pharmaceuticals
(Osaka, Japan)
CYT006-AngQb Cytos Biotechnology
(Zurich-Schlieren, Switzerland)
PF-03838135 Pfizer (New York, NY)
Compound 21 Vicore (Gothenburg, Sweden)
*Compounds approved by the FDA20 and clinically investigated compounds listed by PhRMA126 as of 1st May 2010. Abbreviations: ACe, angiotensin-converting
enzyme; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; PPAR-γ, peroxisome proliferator-activated receptor gamma.
completely elucidated.19 these novel discoveries in the
physiology of the raas have stimulated some interesting
new therapeutic approaches, including blockade of the
(P)rr, at2r stimulation, and combined vasopeptidase
(neP plus aCe) inhibition (Figure 1).
Innovative targeting of angiotensin II
the idea of an anti­raas vaccination was first intro­
duced in the 1950s,29 but the early antirenin formula was
associated with severe autoimmune kidney disease. 30
the concept was revived in the 2000s by immunization
against angiotensin. some progress has been reported
with two antiangiotensin vaccines that advanced to clini­
cal testing.31–33 although, the antiangiotensin i vaccine,
PmD3117, showed some evidence for raas blockade, it
failed to lower blood pressure.31 However, CYt006, which
consists of an antiangiotensin ii antigenic peptide conju­
gated to a virus­like particle, lowered systolic blood pres­
sure by up to 21 mmHg in spontaneously hypertensive
rats and was well tolerated in a Phase i study.32 this
compound achieved a modest blood pressure reduction
(9/4 mmHg) in a Phase iia study.33
Possible advantages of the vaccination approach
include better patient compliance and the reported
ability of CYt006 to reduce blood pressure throughout
the whole day and to blunt its early morning surge.33 on
the other hand, the use of shorter dosing intervals in a
second study of CYt006 resulted in higher antibody
titers, but their affinity was reduced and the blood­
pressure response was attenuated.34 the use of CYt006
is, therefore, likely to be limited not only by safety con­
cerns, but also by insufficient blood­pressure reduction.
nevertheless, the research carried out on anti­raas
vaccinations could lead the way for the use of vaccinations
against other noninfectious pathologies.
AT2R agonists: stimulating the RAAS
Current therapeutic strategies are aimed at reducing del­
eterious stimulation of the at1r; less attention has been
nature reviews | cardiology
© 2010 Macmillan Publishers Limited. All rights reserved
reviews
Mechanism of action Phase
of development
AT1R blocker Approved (2000)
AT1R blocker Approved (2001)
AT1R blocker Approved (2002)
ACe inhibitor Phase III in USA;
approved in Japan
AT1R blocker with PPAR-γ activity Phase III
AT1R blocker with PPAR-γ activity Phase II
Antiangiotensin II antibody Phase II
AT1R blocker with PPAR-γ activity Preclinical
AT2R agonist Preclinical
paid to the at2r, which in many ways mediates actions
opposing at1r stimulation.7,35 the effect of at2r activa­
tion is modulated by its adaptor proteins. association of
this receptor with the PlZF promotes the activation of
Pi3­K and maPKs and, in turn stimulates cell prolifera­
tion, when growth factors (epidermal, insulin­like, fibro­
blast) are present.35 on the other hand, the at2r receptor
associates with phosphatases, inhibiting the maPKs,35
and the interaction between at2r and the 50 kDa at2r
binding protein (atBP50) promotes the cellular expres­
sion of the receptor and its antiproliferative proper­
ties.36 in addition, at2r stimulation activates the no/
cyclic guanosine monophosphate system and stimulates
phospholipase a2 with subsequent release of arachi­
donic acid.37 the resulting inhibition of cell growth and
proapoptotic actions,38 enhanced no formation in vas­
cular tissues,39 and attenuation of myointimal hyperplasia
after endothelial denudation40 may reduce undesired
neointimal growth, cardiac remodeling, or proliferative
retinopathy. at2r stimulation, therefore, represents an
exciting and innovative approach to the treatment of
cardiovascular disease continuum. not only would such
a strategy comprise the opposing effects of at1r, growth
factors and cytokines naturally, but its effects would be
more pronounced in pathological conditions where at2r
density is increased.28
the discovery of compound 21, a selective at2r
agonist with an oral bioavailability of 20–30%,41 intro­
duced the new concept of at2r agonistic therapy and
made direct investigation into the effects of at2r
stimulation possible. Compound 21 improved systolic
and diastolic function after experimental myocardial
infarction in rats.42 these effects were associated with
anti­inflammatory and antiapoptotic action, but were
not related to blood­pressure changes.42 in hypertensive
animals, however, acute infusion of compound 21 also
reduced blood pressure.43 Compound 21 has also been
reported to inhibit nuclear factor kappa B, activate
protein phosphatases, and to reduce the expression of
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Angiotensinogen Vasopeptidase inhibitors: beyond ACE inhibition

like aCe, neP is a membrane­bound metalloproteinase
that cleaves vasoactive substances. Because neP sub­
Renin strates can be either vasodilatory or vasoconstrictive, the
1
effect of neP inhibition on blood pressure in experimen­
Inactive Inactive tal and clinical settings is quite variable.46 the potential
peptide peptide
Angiotensin I of neP as a target for antihypertensive therapy comes
mainly from the opportunity to design combined aCe
and neP (vasopeptidase) inhibitors or combined at1r
2 blocker and neP inhibitors in one molecule (table 2).
6 ACE, chymase,
NEP carboxypeptidase, early studies with vasopeptidase inhibitors were
tonin, cathepsin C encouraging. omapatrilat reduced blood pressure in
stroke­prone spontaneously hypertensive rats,47 in deoxy­
corticosterone acetate (DoCa)–salt hypertensive rats44
Natriuretic and salt­sensitive rats48 as well as in individuals with
Bradykinin Angiotensin II
peptides mild­to­moderate hypertension.49 in addition, sampa­
trilat was shown to lower blood pressure in patients
4 3 with hypertension.50 larger trials of omapatrilat, such
BKR AT2R AT1R (P)RR
5 as overture,51 and oCtave,52 confirmed that com­
bined aCe and neP inhibition might be effective in the
8
NO Aldosterone treatment of hypertension and heart failure, but also vali­
7 dated concerns about the higher incidence of angioedema
with combined therapy than with aCe inhibition alone.
Vasodilation Vasoconstriction
Antifibrosis Collagen synthesis Both, the advantage and the limitation of vasopeptidase
Apoptosis Antiapoptosis inhibition could be associated with the simultaneous
Natriuresis ROS generation
Anti-inflammation Na+ and water retention
interference with aCe and neP. although use of aCe
and neP inhibitors might offer some benefit beyond the
already established favorable effect of aCe inhibition,
the colocalization of their targets on the same cell mem­
Figure 1 | The renin–angiotensin–aldosterone system: vasoactive balance and
brane means that the most prominent effects are likely to
targets for antihypertensive therapy. Blood pressure and cardiovascular remodeling be seen on their mutual targets—the kinins46—which may
are modulated through the balance of vasoconstricting and growth-promoting account for the higher incidence of angioedema in the trials
stimuli on the one hand, and vasodilating and antifibrotic stimuli on the other. with combined neP and aCe inhibitors. the question
Renin cleaves angiotensinogen to angiotensin I and its activity is enhanced by remains as to whether future formulations of aCe and neP
binding to the (P)RR, which also triggers angiotensin-independent signaling. inhibitor, with better safety profiles, can be developed.
Angiotensin I is converted by ACe to angiotensin II, which exerts its effects by
binding to the AT1R and AT2R. ACe also converts bradykinin into an inactive form.
Aldosterone: revisiting an old target
Bradykinin can bind to the endothelial BKR leading to NO-mediated vasodilation
and associated effects. Bradykinin is also cleaved by NeP, which inactivates aldosterone-receptor antagonists
natriuretic peptides and other vasoactive substances. established and possible as a downstream effector of angiotensin ii, and mediator
therapeutic targets include (1) Renin inhibition; (2) ACe inhibition; (3) AT1R of some of its unfavorable effects, aldosterone represents a
blockade; (4) AT2R stimulation; (5) (P)RR blockade; (6) NeP inhibition; logical therapeutic target. in fact, the aldosterone­receptor
(7) aldosterone-receptor blockade or aldosterone-synthase inhibition; (8) NO– blocker spironolactone has been used for decades. not
cGMP stimulation. Abbreviations: ACe, angiotensin-converting enzyme; AT1R, only is spironolactone effective in lowering blood pres­
angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; BKR, bradykinin
sure,53 but has been shown to reduce mortality in patients
receptor; cGMP, cyclic guanosine monophosphate; NeP, neutral endopeptidase;
with severe heart failure when combined with background
NO, nitric oxide; (P)RR, (pro)renin receptor; ROS, reactive oxygen species.
treatment (including aCe inhibitors, loop diuretics, and
digoxin).54 the importance of antialdosterone treatment
the inflammatory cytokines interleukin­6 and tumor is highlighted by the fact that primary aldo steronism
necrosis factor in primary fibroblasts.44 these results might be more common than previously thought,
indicate that pharmacological stimulation of the at2r particularly among black patients with resistant hyper­
might not only be beneficial in hypertension, but also in tension.55–57 However, there is still a surprising shortage
associated pathologies with an inflammatory component, of well­controlled blood­pressure trials of spironolactone.
such as myocardial fibrosis, atherosclerosis, myocardial another major disadvantage of spironolactone is its poor
infarction, or myocarditis. on the other hand, long­ selectivity for mineralocorticoid receptors, which leads
term activation of at2r might also reduce angiogenesis to progesterone­dependent and testosterone­dependent
and has been hypothesized to have contributed to the adverse effects, such as loss of libido, menstrual irregu­
nonsuperiority of at1r blockers over aCe inhibitors.45 larities, painful enlargement of the breasts, impotence,
Future results on the effects of at2r agonists in various and gynecomastia.
cardiovascular conditions, including hypertension are, the interest in aldosterone as a target for anti­
therefore, highly anticipated. hypertensive therapy was revived with the introduction

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of the selective mineralocorticoid­receptor blocker,
eplerenone. in several clinical trials, eplerenone was
at least noninferior to amplodipine,58 enalapril,59 and
lo sartan 60 in reducing blood pressure. in addition,
eplerenone lowers blood pressure in patients with hyper­
tension61 and reduces all­cause mortality in patients with
heart failure when added to conventional therapy.62 the
data comparing eplerenone with spironolactone are
still insufficient. the sexual adverse effects are less pro­
nounced with eplerenone than with spironolactone, but
both drugs can cause hyperkaliaemia,63 and higher doses
of eplerenone than spironolactone are required to achieve
the same blood­pressure­reducing effect.64
aldosterone-synthase inhibitors
another innovative approach toward aldosterone antago­
nism is to inhibit the formation of aldosterone itself. this
strategy prevents a reactive increase in aldosterone levels
that could activate pathways not antagonized by receptor
blockade. Currently, there are several investigational sub­
stances with this mechanism of action targeted toward
the treatment of hypertension and heart failure (table 3).
First, the proof of concept of this idea was demonstrated
with the effect of FaD286 (novartis; Basel, switzerland),
an enantiomere of fadrazol that was shown to have an
inhibitory effect on aldosterone synthase (also know as
CYP11B2). FaD286 lowered blood pressure in rats over­
expressing renin and angiotensinogen65 (although the
onset of this effect was slow, starting from week 7) and in
wistar rats with cerebrospinal fluid enriched with na+.66
FaD286 also ameliorated cardiac and renal target­organ
damage.65,67 second, sPP2745 (speedel Pharmaceuticals;
Basel, switzerland) is claimed to suppress aldosterone
levels, have a good specificity, offer protection to the
cardiac, renal, and vascular systems, and be compatible
with conventional therapy.68
From a clinical point of view, the goal for the
aldosterone­synthase inhibitors is to be noninferior
to and better tolerated than eplerenone or spirono­
lactone. the safety and tolerability studies are encour­
aging; FaD286 protected myocardium comparably
to spironolactone and normalized the redox status of
the left ventricle in rats after myocardial infarction.69
However, some of the effects of mineralocorticoid­
receptor blockers might not be mediated by the inhibi­
tion of aldosterone, but also by the action of cortisol on
these receptors, which can be activated by an altered
redox state.70 thus, the expectations about the efficacy
of aldosterone­synthase inhibitors in conditions with low
aldosterone levels could be questioned.
Renin: a newly established target
renin is the catalyst of the rate­limiting step in the raas
cascade and was, therefore, the first logical target for
raas inhibition. However, the concept of renin inhibi­
tion was superseded by aCe inhibition as a result of the
greater bioavailability and potency of aCe inhibitors and
because they are easier to synthesize. the observed rise in
renin during both aCe inhibition and at1r blockade71
means that the idea of renin inhibition is still an attractive
nature reviews | cardiology
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reviews
Table 2 | Novel NeP inhibitors with or without AT1R blocking action
compound company (location) Mechanism of action Phase of
development
Ilepatril; Sanofi-Aventis (Paris, France) NeP inhibitor Phase III
AVe-7688
LCZ696 Novartis (Basel, Switzerland) Combined AT1R blocker Phase II
and NeP inhibitor
Daglutril Solvay (Brussels, Belgium) Combined AT1R blocker Phase II
and NeP inhibitor
VNP489 Novartis (Basel, Switzerland) Combined AT1R blocker Phase I
and NeP inhibitor
Abbreviations: AT1R, angiotensin II type 1 receptor; NeP, neutral endopeptidase.
option. with the introduction in 2007 of the first­in­class
selective renin inhibitor, aliskiren, renin became the most­
recent target established for antihypertensive therapy.
aliskiren is well tolerated and has a dose­dependent effect
on Pra, concentration of angiotensins i and ii,72 and
blood pressure.73 in head­to­head comparisons, aliskiren
was noninferior to at1r blockers,73 aCe inhibitors,74
hydrochlorothiazide,75 and atenolol76 for blood­pressure
reduction. nevertheless, high doses (300 mg) of aliskiren
were required to achieve similar blood­pressure reduction
comparable with that of losartan (100 mg).73 the limit­
ing factor might be the relatively low bioavailability of
aliskiren (2–7%).72 therefore, the development of other
agents in this class is expected, with four new compounds
pending (table 3). the most advanced formulation,
sPP635, underwent a Phase iia study in 2007. this com­
pound was well­tolerated and lowered blood pressure by
17.9/9.8 mmHg (systolic/diastolic) after 4 weeks.77
although there is sufficient evidence for the non­
inferiority of aliskiren for blood­pressure reduction when
compared with conventional therapies, it remains to be
demonstrated that this blood­pressure reduction will be
reflected by respective reduction in other risk factors (for
example, left ventricular hypertrophy, atherosclerosis, and
proteinuria) and, most importantly, in cardiovascular
morbidity and mortality. although renin inhibition is
associated with a reactive rise in plasma renin concen­
tration78 that could negate the effects, the increase in
plasma renin concentration might not be as excessive as
originally thought. apparently, there are always enough
aliskiren molecules available to inhibit renin even when
its concentration is elevated.79 moreover, a meta­analysis
of eight clinical trials showed that aliskiren treatment does
not lead to blood­pressure rises any more frequently than
other antihypertensive medication.80
The (pro)renin receptor: new possibilities
renin mediates both angiotensin­dependent and
angiotensin­independent effects, the latter is at least partly
controlled through the binding of renin to the newly dis­
covered (P)rr.22 the unfavorable results of (P)rr stimu­
lation include the upregulation of transforming growth
factor­β1, plasminogenactivator inhibitor­1, fibronectin
and collagens,81 enhanced protein synthesis, cell prolif­
eration, and decreased apoptosis.24 all currently available
methods of raas inhibition leave the (P)rr pathway,
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Table 3 | Modulators of aldosterone or renin action*

compound (trade name) company (location) Mechanism of action Phase
of development
Aldosterone
eplerenone (Inspra®) Pfizer (New York, NY) Aldosterone-receptor blocker Approved (2002)
LCI699 Novartis (Basel, Switzerland) Aldosterone-synthase inhibitor Phase II
SPP2745 Speedel Pharmaceuticals (Basel, Switzerland) Aldosterone-synthase inhibitor Phase 0
FAD286 Novartis (Basel, Switzerland) Aldosterone-synthase inhibitor Preclinical
Renin
Aliskiren (Tekturna®, Rasilez®) Novartis and Speedel Pharmaceuticals Renin inhibitor Approved (2007)
(Basel, Switzerland)
SPP635 Speedel Pharmaceuticals (Basel, Switzerland) Renin inhibitor Phase I
SPP676 Speedel Pharmaceuticals (Basel, Switzerland) Renin inhibitor Phase I
SPP1148 Speedel Pharmaceuticals (Basel, Switzerland) Renin inhibitor Phase I
VTP2799 Vitae Pharmaceuticals (Fort washington, PA) Renin inhibitor Phase I
SPP1234 Speedel Pharmaceuticals (Basel, Switzerland) Renin inhibitor Preclinical
*Compounds approved by the FDA20 and clinically investigated compounds listed by PhRMA126 as of 1st May 2010.

with its undesirable effects, unopposed. even aliskiren
does not prevent the interaction between the (P)rr recep­
tor and its ligands.82 on the other hand, aliskiren reduced
(P)rr expression in transgenic renin­overexpressing rats83
and might, therefore, still reduce (P)rr stimulation.
the organoprotective concept of (P)rr blockade is
supported by studies using a peptide that corresponds to
the ‘handle’ region of prorenin and inhibits the binding
of prorenin to the (P)rr. this peptide reduced nephro­
pathy in diabetic rats,84 and cardiac fibrosis in stroke­
prone spontaneously hypertensive rats.85 the protein
also reduced cardiac fibrosis, hypertrophy, and creati­
nine levels, and improved left ventricular function in
spontaneously hypertensive rats given a high­salt diet.86
the effect was, however, absent or attenuated when renin
levels were high, possibly because the prorenin receptor
was already saturated by renin molecules.87 although
this finding could indicate that the conditions suitable
for (P)rr inhibitory therapy are limited, it is hoped that
designing a nonpeptide inhibitor of (P)rr could result in
favorable raas inhibition with simultaneous blockade
of angiotensin­independent prorenin effects, that might
prove particularly beneficial in high­risk patients, such as
those with diabetes.
Renalase: a novel target
renalase, a novel kidney­related peptide, was discovered
after an extensive search for unrecognized kidney­related
signaling proteins that might impact cardiovascular
health.88 renalase is the first known circulating amine
oxidase in plasma that metabolizes catecholamines.88 the
plasmatic activity of renalase itself is undetectable under
basal conditions, but can be provoked by the release or
infusion of catecholamines.89 although renalase is also
expressed in the heart, skeletal muscle, and liver, the
kidney seems to be the major source of circulating renal­
ase because no compensatory rises in reduced renalase
levels are observed among patients with end­stage renal
failure or in subnephrectomized rats.88,89
the concept that renalase might be involved in the regu­
lation of blood pressure is supported by the fact that the
downregulation, or knock­out, of renalase is associated
with elevated blood pressure.90,91 moreover, two single­
nucleotide polymorphisms (rs2576178 and rs2296545)
are associated with essential hypertension in a northern
Han Chinese population, one of which has possible func­
tional impact.92 these data indicate that increasing renal­
ase concentration could reduce blood pressure, and that a
population of patients with hypertension (and a renalase
deficiency or renalase polymorphism) could exist, for
whom such a treatment would be particularly effective.
recombinant renalase has been shown to dose­
dependently lower blood pressure, heart rate, and
contractility 88 and to protect the myocardium against
ischemia–reperfusion injury.93 However, more studies are
needed to assess whether renalase could become a real
therapeutic target. a deeper understanding of renalase
physiology is also needed, particularly its crosslink with
other vasoactive systems. metabolism of the renal vaso­
dilator, dopamine, by renalase could raise safety concerns94
and limit its therapeutic potential.
Invasive treatment with renal denervation
the kidneys play an important role in the regulation of
blood pressure. the regulatory actions of the kidneys are
controlled by hemodynamic load, neurohumoral modula­
tors, and renal sympathetic activity. the latter, depending
on the level of its activation, affects the juxtaglomerular
apparatus and renin secretion, renal tubules, and na+
excretion as well as the afferent arterioles and renal blood
flow.95 modulation of these mechanisms could be achieved
by the ablation of renal nerves, which would also remove
efferent innervations leading to reduced sympathetic
outflow from the posterior hypothalamic area.96
the surgical removal of renal nerves attenuated hyper­
tension in a variety of experimental models, including
spontaneously hypertensive rats; borderline hypertensive
rats; Goldblatt 1 kidney 1 clip and Goldblatt 2 kidney 1

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Table 4 | Other novel compounds for arterial hypertension*

compound company (location) Mechanism of action Phase
(trade name) of development
Diltiazem HCL, extended- Biovail Laboratories (Mississagua, Calcium-channel blocker Approved (2000)
release (Tiazac®) ON, Canada)
Nebivolol (Bystolic®) Forest Laboratories (New York, NY) β-blocker with NO-potentiating effects Approved (2007)
Clonidine, controlled Addrenex Pharmaceuticals (Durham, Centrally acting α2 adrenergic agonist Preregistration
release NC) and Sciele Pharma (Atlanta, GA)
Darusentan Gilead Sciences (Foster City, CA) endothelin A receptor antagonist Phase III for resistant
hypertension
estradiol plus Bayer Schering Pharma Hormone therapy Phase III
drospirenone (Angeliq®)‡ (Berlin, Germany)
Monoxidine Solvay (Brussels, Belgium) Imidazoline-receptor blocker Phase III
Tadalafil eli Lilly (Indianapolis, IN) Phosphodiesterase 5 inhibitor Phase II§
TBC3711 encysive Pharmaceuticals endothelin A receptor antagonist Phase II for resistant
(Pfizer; New York, NY) hypertension
PS433540 Pharmacopeia (Ligand; Combined AT1R and endothelin A Phase II
San Diego, CA) receptor blocker
Lercanidipine, modified Forest Laboratories (New York, NY) Calcium-channel antagonist Phase II
release
ADX415 Sciele Pharma (Atlanta, GA) Centrally acting α2 adrenergic agonist Phase II
PL3994 Palatin Technologies (Cranbury, NJ) Natriuretic peptide receptor agonist Phase II
Sapropterin (Kuvan®) ||
BioMarin Pharmaceuticals (Novato, CA) Tetrahydrobiopterin analogue Phase II
AR9281 Arête Therapeutics (Hayward, CA) Soluble epoxidehydrolase inhibitor Phase IIa

NCX-899 Merck (New York, NY) and NicOx NO-releasing enalapril Phase I
(Valbonne, France)
Naproxcinod NicOx (Valbonne, France) NO-releasing COX inhibitor Phase I
*Compounds approved by the FDA20 and clinically investigated compounds listed by PhRMA126 as of 1st May 2010. ‡Angeliq®is currently approved for the
treatment of menopausal symptoms. §Tadalafil (as Adcirca®; eli Lilly, Indianapolis, IN) was approved for pulmonary arterial hypertension in 2009. ||Kuvan®is
currently approved for the treatment of phenylketonuria. Abbreviations: AT 1R, angiotensin II receptor type 1; COX, cyclo-oxygenase; NO, nitric oxide; PAH,
pulmonary arterial hypertension.

clip rats; DoCa­salt hypertensive rats; and obese hyper­
tensive dogs.95 additionally, renal denervation also attenu­
ated the development of heart failure after coronary­artery
ligation in rats.97 However, the translation of this concept
into humans was compromised by the poor risk:benefit
ratio, which was the result of high operative morbidity
and mortality.98,99
a percutaneous, catheter­based radiofrequency abla­
tion method for renal sympathetic denervation has been
developed and assessed in a cohort study of 45 treated
patients with resistant hypertension.100 the results were
impressive; renal norepinephrine spillover after the proce­
dure was reduced by 47%, mean office blood pressure was
reduced by 27/17 mmHg and the proportion of patients
whose average systolic blood pressure did not drop by
>10% between day and night decreased by 50% at the
12­month follow­up.100 the adverse events reported in
this study include one renal­artery dissection and one
femoral­artery aneurysm without further complica­
tions.100 additionally, schlaich and colleagues reported
the case of a patient with uncontrolled hypertension in
whom renal ablation reduced left ventricular hypertrophy
in addition to sympathetic tone and blood pressure. 101
although further studies are required to confirm the long­
term safety and efficacy of this procedure, particularly the
risk of catheter­induced atherosclerotic complications or
reinervation,95 minimally invasive percutaneous ablation
of renal nerves has some potential for the treatment of
patients with resistant hypertension.
Other possible targets
this review does not claim to be exhaustive and all­inclu­
sive. many other promising drugs, targets, and approaches
in the treatment of hypertension are emerging. attempts
are being made to overcome drug tolerance, no resis­
tance, and the adverse effects associated with currently
available no­donor therapy. no­donors with decreased
susceptibility to free radicals or with enhanced cardio­
selectivity are being developed, and approaches to direct
targeting of soluble guanylate cyclase (sGC) or to increase
cGmP concentration by phosphodiesterase inhibition are
being considered. no­donors with a thiol group might be
less prone to tolerance development and could enhance
the antiremodelling potential of no.102 one such agent,
la419, was even reported to prevent left ventricular
hypertrophy, without affecting blood pressure, suggesting
either increased tissue specificity or effects beyond blood
pressure reduction.103 another possible method of enhanc­
ing no delivery would be the modulation of existing
molecules by adding an no­releasing moiety 104 (table 4).
no­independent sGC stimulators, such as BaY
41­2272 or BaY 41­8543, reduced blood pressure and

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© 2010 Macmillan Publishers Limited. All rights reserved
reviews

Table 5 | Fixed-dose combinations investigated, or approved since 2000, for arterial hypertension
compound (trade name) company (location) Mechanism of action Phase of
development
eprosartan mesylate and Solvay Pharmaceuticals AT1R blocker and thiazide diuretic Approved (2001)
hydrochlorothiazide (Teveten®) (Allschwil Switzerland)
Olmesartan medoxomil and Daiichi Sankyo (Tokyo, Japan) AT1R blocker and thiazide diuretic Approved (2003)
hydrochlorothiazide (Benicar HCT®)
Amlodipine besylate and Pfizer (New York, NY) Calcium-channel antagonist Approved (2004)
atorvastatin calcium (Caduet®) and HMG-CoA reductase inhibitor
Amlodipine besylate and Daiichi Sankyo (Tokyo, Japan) Calcium-channel antagonist Approved (2007)
olmesartan medoxomil (Azor®) and AT1R blocker
Aliskiren and hydrochlorothiazide Novartis (Basel, Switzerland) Direct renin inhibitor and thiazide Approved (2008)
(Tekturna HCT®) diuretic
Amlodipine and valsartan and Novartis (Basel, Switzerland) Calcium-channel antagonist, AT1R Approved (2009)
hydrochlorothiazide (exforge HCT®) blocker and thiazide diuretic
Valsartan and aliskiren (Valturna®) Novartis (Basel, Switzerland) AT1R blocker and renin inhibitor Approved (2009)
Telmisartan and amlodipine Boehringer Ingelheim AT1R blocker and calcium-channel Approved (2009)
besylate (Twynsta®) (Ingelheim, Germany) antagonist
Ramipril and hydrochlorothiazide King Pharmaceuticals ACe inhibitor and thiazide diuretic Approved (2009; not
(Altace HTC®) (Cary, NC) available in the US)
Lisinopril and carvedilol (Coreg CR®) GlaxoSmithKline ACe inhibitor and β-blocker/ Approved (2009; not
(Brentford, UK) α1-blocker available in the US)
CS-8635; olmesartan medoximil, Daiichi-Sankyo (Tokyo, Japan) AT2R antagonist, calcium-channel Preregistration
amlodipine, and hydrochlorothiazide antagonist, and thiazide diuretic
Azilsartan kamedoxomil and Takeda Pharmaceuticals AT1R blocker and thiazide diuretic Phase III
chlortalidone (Osaka, Japan)
Aliskiren and amlodipine Novartis (Basel, Switzerland) Renin inhibitor and calcium-channel Phase III
antagonist
Aliskiren and amlodipine and Novartis (Basel, Switzerland) Renin inhibitor and calcium channel Phase III
hydrochlorothiazide antagonist and thiazide diuretic
Lisinopril and pyridoxal phosphate Medicure (winnipeg, MB) ACe inhibitor and cardioprotective Phase II (on hold)
(cardoxal); MC4232 enzyme
*Compounds approved by the FDA20 and clinically investigated compounds listed by PhRMA126 as of 1st May 2010. Abbreviations: ACe, angiotensin-converting
enzyme, AT1R, angiotensin II receptor type 1; AT2R, angiotensin II receptor type 2; HMG-CoA; 3-hydroxy-3-methylglutaryl-coenzyme A.

secondary alterations in experimental hypertension.105,106
the sGC activator, cinaciguat (BaY 58­2667), which has
a similar hemodynamic profile to organic nitrates, 107
reduced preload and afterload in patients with acute heart
failure108 and is currently in a Phase iib clinical study for
this indication.
the phosphodiesterase inhibitors have been associated
with improvements in functional class and exercise capac­
ity among patients with pulmonary hyper tension,109,110
and reductions in systemic blood pressure in healthy
individuals.111 in addition, these agents have been shown
to prevent the development of pulmonary hypertension
and target­organ damage, and improve survival in
animal models.112–115 although blood­pressure reduction
induced by tadalafil has been reported to be relatively low
(–1.6/0.8 mmHg),111 a Phase ii study of this agent for the
treatment of hypertension is ongoing and an application
for approval for this indication is pending.
endothelin­receptor blockers, such as darusentan, are
currently approved for the treatment of pulmonary hyper­
tension.116 in the Heat­Htn117 and Dar­201118 studies
and another blinded randomized trial,119 darusentan was
more effective than placebo for blood­pressure reduc­
tion in patients with stage ii hypertension or resistant
hypertension. on the other hand, in the Heat­HF120 and
eartH121 trials, darusentan failed to improve heart failure,
and hemodynamics or left ventricular remodeling.
other substances and strategies that have been
investigated for the treatment of hypertension include
the soluble epoxide hydrolase inhibitors,122 the pineal
hormone melatonin,123,124 and hormone­replacement
therapy in postmenopausal women with hypertension.125
Finally, several hybrid drugs or fixed­dose combinations
(table 5) for the treatment of arterial hypertension are
currently being investigated.
Conclusions
effective, evidence­based therapeutic regimens are cur­
rently available in the fight against arterial hypertension
and associated cardiovascular complications. However,
demand still exists for new, more­effective methods of
blood­pressure control and cardiovascular risk reduc­
tion. among the best­established agents in the treatment
of the cardiovascular disease continuum are those that
disrupt the raas. novel targets are, therefore, very likely
to emerge from new discoveries in this system.
all the potential approaches discussed in this review
have their pros and cons. the vaccination against

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 reviews

angiotensin represents an innovative method of oppos­
ing the raas and could improve 24 h blood­pressure
control and eliminate the problem of patient noncompli­
ance. However, such a vaccine might be limited either by
safety concerns or insufficient efficacy. Pharmacological
stimulation of at2r could counterbalance at1r stimu­
lation and reduce inflammation. However, the effects of
at2r stimulation on blood pressure have not yet been
fully elucidated. Combined aCe and neP blockade
decreases blood pressure, but is associated with a high
incidence of angioedema. aldosterone synthase inhibi­
tors could be better tolerated than spironolactone, yet
the question remains as to whether they are as effective
as spironolactone or as the more­selective eplerenone. a
(P)rr blocker could prevent the deleterious angiotensin­
independent actions of renin that are not inhibited by
aliskiren, and renalase could counteract the effects cat­
echolamine release. renal denervation could be a thera­
peutic option for patients with resistant hypertension, but
this is an invasive approach.
all these strategies, however, need to compete with
the well­established beneficial effects of current anti­
hypertensive therapies. moreover, in the light of the con­
stantly decreasing availability of funds for cardiovascular
research, the focus is shifting toward the investigation
of fixed­dose combinations of established drugs and to
design of hybrid molecules. the raas is most likely to
be the basis for the development of novel hybrid drugs
and fine tuning of fixed­dose combinations. However,
we cannot confidently predict which of the compounds
will be established as useful research tools and which will
make it into clinical practice.
Review criteria
This article is based on a comprehensive PubMed
database search. Full-text articles in english published
between 2005 and 2010 were searched for using
the terms “hypertension”, “high blood pressure” and
“treatment” to identify potential therapeutic targets.
The PubMed database was then searched for the
identified promising new targets: “renin inhibition”,
“aldosterone synthase inhibition”, “prorenin receptor”,
“neutral endopeptidase” or “neurilysine”, “renalase”,
“renal denervation”, “angiotensin II type 2 receptor” in
combination with “hypertension”, “target-organ damage”,
“remodeling”, or “heart failure”. The reference lists of
leading review articles identified during this search were
checked for additional publications.

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acknowledgments
L. Paulis was supported by the Marie Curie Intra-
european Fellowship (2009–237834) within the 7th
european Community Framework Program.
volume 7 | auGust 2010 | 441