New insights in the pharmacological therapy of arterial

hypertension
Angel Cogolludo, Francisco Pérez-Vizcaı́no and Juan Tamargo

Purpose of review Abbreviations

Despite the large number of antihypertensive drugs ACE angiotensin-converting enzyme
available, their usefulness is limited due to low efficacy, side Ang angiotensin
ARB Ang II receptor type 1 blocker
effects, poor patient compliance and failure to reduce the AT1 Ang II receptor type 1
cardiovascular risk to the level of the general population. ECE endothelin-converting enzyme
NEP neutral endopeptidase
These limitations have stimulated the research and RAS renin–angiotensin system
development of new antihypertensive drugs, which we
briefly review herein. ß 2005 Lippincott Williams & Wilkins
Recent findings 1062-4821
Novel antihypertensive drugs under development include
new oral renin inhibitors, brain aminopeptidase A inhibitors,
angiotensin-converting enzyme 2 modulators, short-acting Introduction
L-type Ca2þ channel blockers, new T-type Ca2þ channel Hypertension is a major risk factor for cardiovascular
blockers, inhibitors of vascular NAD(P)H oxidase, diseases such as stroke, myocardial infarction, heart fail-
angiotensin-converting enzyme crosslink breakers, Rho ure, and end-stage renal disease [1]. Despite more than
kinase inhibitors, renal Naþ/Kþ ATPase inhibitors, 200 distinct drugs being able to lower blood pressure, less
potassium channel openers and drugs combining different than a third of treated hypertensives achieve a goal blood
mechanisms of action. pressure and almost 50% of patients discontinue new
Summary prescriptions within 6 months of therapy due to poor
Essential hypertension is a multifactorial and multigenic efficacy or intolerable side effects [2]. Moreover,
disorder, which means that various mechanisms contribute traditional drugs are unable to reduce the cardiovascular
to a greater or lesser extent to increasing blood pressure. risk of hypertensive patients to the level of the general
Drugs combining several mechanisms of action or population. These limitations stimulate the research and
combinations of antihypertensive drugs with those targeting development of new antihypertensive drugs. The goals
other risk factors may offer an alternative to reduce overall pursued with these drugs are summarized in Table 1.
cardiovascular risk. As we improve our understanding of In this article, we briefly review the new antihyper-
essential hypertension, it should be possible to develop tensive drugs under development (Table 2), focusing
safer and more effective antihypertensive drugs. The risk/ on their possible advantages compared with traditional
benefit ratio of these new existing antihypertensive drugs drugs.
will require long-term endpoint assessment studies.
Targeting the renin–angiotensin system
Keywords The renin–angiotensin system (RAS) plays a central role
antihypertensive drugs, blood pressure, renin–angiotensin in blood pressure control. Angiotensin (Ang) converting
system enzyme (ACE) inhibitors and Ang II receptor type-1
(AT1) blockers (ARBs) are widely used in the treatment
Curr Opin Nephrol Hypertens 14:423–427. ß 2005 Lippincott Williams & Wilkins. of hypertension and related cardiovascular disorders. In
an attempt to improve the efficacy of ACE inhibitors and
Department of Pharmacology, School of Medicine, Universidad Complutense, ARBs, new classes of antihypertensive agents are under
Spain
development.
Correspondence to Juan Tamargo, Department of Pharmacology, School of
Medicine, Universidad Complutense, Av/ Complutense s/n, 28040 Madrid, Spain
Tel: +34 91 3941472; fax: +34 91 3941472; e-mail: [email protected] Renin inhibitors
Renin catalyzes the first and rate-limiting step of the
Current Opinion in Nephrology and Hypertension 2005, 14:423–427
RAS. Renin inhibitors prevent the formation of Ang I and
Ang II without affecting kinin metabolism, so may offer a
therapeutic profile distinct from those of ACE inhibitors
and ARBs. Several renin inhibitors have been developed,
but they presented low potency, poor bioavailability, and
short duration of action after oral administration [3].
Aliskiren is an orally effective, nonpeptide, long-lasting
423
424 Pharmacology and therapeutics

Table 1. Goals of the new antihypertensive agents A inhibitor EC33, given intravenously, inhibits brain
aminopeptidase A and the formation of Ang III and
1. Interfere with the mechanisms involved in the genesis and
maintenance of elevated blood pressure reduces blood pressure for up to 24 h in DOCA-salt rats
2. Better blood pressure control over 24 h [9,10]. Thus, brain aminopeptidase A inhibitors represent
3. Greater protection against organ damage associated with a potential antihypertensive treatment.
hypertension
4. Effects on other cardiovascular risk factors
5. More effective prevention of cardiovascular disease Angiotensin-converting enzyme 2 modulators
6. Safer and better tolerated ACE2 is a carboxypeptidase with specificity, tissue distri-
bution, and function distinct from those of ACE [11,12].
ACE2 hydrolyses Ang I into Ang-(1–9), Ang II into Ang-
Table 2. New antihypertensive drugs under development (1–7) and bradykinin into [des-Arg9]-bradykinin, but
does not convert Ang I into Ang II, being insensitive
1. Modulation of the RAS
Oral renin inhibitors: aliskiren to ACE inhibitors [11,12]. In addition, ACE2 appears to
Brain aminopeptidase A inhibitors: RB150 be a negative regulator of ACE in the heart and kidney. It
ACE2 modulators can be speculated that ACE2 plays a role in the regulation
Angiotensin receptor blockers: pratosartan, TAK-536
2. Ca2þ channel blockers: clevidipine, S-amlodipine, KYS05001 of blood pressure by counterbalancing the potent vaso-
3. Inhibitors of vascular NAD(P)H oxidase: apocynin, pefabloc, constrictor effects of Ang II [11]. If so, ACE2 stimulation
S17834, PR-39, p91ds-tat would be synergistic, or additive, to ACE inhibitors/ARBs
4. AGE crosslink breakers: alagebrium
5. Rho kinase inhibitors: Y-27632, fasudil, hydroxyfasudil, KI-2309 in inducing vasodilation and lowering blood pressure
6. Drugs with multiple mechanisms of action [13]. By contrast, ACE2 inhibition might become useful
ACE/NEP inhibitors in the treatment of symptomatic hypotension. The
ECE/NEP inhibitors: SLV-306
NO-releasing drugs: NO-sartans, NO-releasing statins development of specific ACE2 antagonists and agonists
(NCX 6550, NCX 6553) would allow us to understand the pathophysiological
AT1 and ETA receptor antagonists: MS-248360, BMS-248360 role of ACE2 and its role in the modulation of blood
7. Naþ/Kþ ATPase inhibitors: PST 2238
8. Potassium channel openers: iptakalim pressure.
RAS, renin–angiotensin system; ACE, angiotensin-converting enzyme;
AGE, advanced glycosylation end-products; NEP, neutral endopepti- Calcium channel blockers
dase; ECE, endothelin-converting enzyme; NO, nitric oxide; AT1, Ang II Patients undergoing surgical interventions often develop
receptor type 1. hypertensive episodes that require a rapid control of
blood pressure. Clevidipine is an ultrashort-acting L-type
Ca2þ channel dihydropyridine antagonist [14]. In hyper-
renin inhibitor that in experimental models reduces tensive patients after coronary artery surgery, clevidipine
blood pressure as effectively as valsartan or benazeprilat infusion produces a rapid arteriolar vasodilatation and a
[4]. In hypertensive patients, once-daily oral doses of dose-dependent decrease in blood pressure that, in con-
aliskiren (150–640 mg) decrease plasma Ang I and II trast to sodium nitroprusside, is not associated with an
levels for 48 h and its antihypertensive efficacy and increase in heart rate, cardiac index or cardiac filling
tolerance is similar to enalapril [5], losartan [6] and pressures. Clevidipine has a high clearance (0.06 l/min/
irbesartan [7]. In mildly sodium-depleted normotensives kg), a small volume of distribution (0.19 l/kg) and is
a combination of aliskiren, 150 mg/daily, plus valsartan, rapidly metabolized by ester hydrolysis to inactive
80 mg/daily, lowers blood pressure at least as effectively metabolites (half-life < 1 min), which translates into a
as higher dose (300 and 160 mg/daily, respectively) rapid cessation of its effects. These characteristics make
monotherapy [8]. Thus, aliskiren is the first orally active clevidipine a drug of choice to reduce blood pressure in
renin inhibitor and provides a true alternative to ACE cardiac surgery.
inhibitors and ARBs for hypertension and other cardio-
vascular and renal diseases. Azelnidipine and S-amlodipine (the only vasoactive
enantiomer of amlodipine) are two new L-type Ca2þ
Brain aminopeptidase A inhibitors antagonists producing long-lasting antihypertensive
Aminopeptidase A hydrolyzes Ang II to Ang III (Ang 2– effects with lesser reflex tachycardia. KYS05001 is a
8). Intracerebroventricular injection of both angiotensins new selective T-type Ca2þ channel blocker nearly equi-
causes similar pressor responses. The intracerebroventri- potent to mibefradil [15].
cular injection of EC33, a specific aminopeptidase A
inhibitor, blocks the formation of brain Ang III and the Inhibitors of vascular NAD(P)H oxidase
pressor response of intracerebroventricular Ang II in hyper- Oxidative stress is implicated in the pathogenesis of
tensive rats, suggesting that the conversion of Ang II hypertension. NAD(P)H oxidase is the major source of
to Ang III is a prerequisite to increasing blood pressure superoxide anion in blood vessels and its expression
[9]. RB150, a prodrug of the specific aminopeptidase and activity are modulated by Ang II acting via AT1
 Pharmacological therapy of arterial hypertension Cogolludo et al. 425

receptors [16
]. In experimental models, NAD(P)H Vasopeptidase inhibitors

oxidase inhibitors (Table 2) decrease superoxide produc- Agents that simultaneously inhibit ACE and neutral
tion, increase nitric oxide production and partially restore endopeptidase (NEP) represent an attractive concept
endothelium-dependent relaxation, reduce neointimal in the treatment of hypertension. Omapatrilat was a vaso-
formation and lower blood pressure [16
,17,18]. Most peptidase inhibitor that produced a greater antihyperten-
of these compounds, however, are not specific for the sive effect than losartan, amlodipine and lisinopril [26].
NAD(P)H oxidases and peptide inhibitors (PR-39, Since omapatrilat was not approved because of an increa-
p91ds-tat) cannot be administered orally, limiting their sed incidence of angioedema, the development of this
clinical application. class of agents has been strongly discouraged. An alterna-
tive approach is to develop endothelin-converting enzyme
Angiotensin-converting enzyme crosslink (ECE)–NEP inhibitors. SLV-306, a NEP/ECE inhibitor
breakers that reduces endothelin-1 levels, has therapeutic potential
Abnormal collagen cross-linking due to the formation of in hypertension and heart failure [27].
advanced glycosylation end-products (AGEs) contributes
to increased cardiovascular stiffness, a predictor of Nitric oxide-releasing drugs
adverse cardiovascular events in the elderly and patients Drugs combining an antihypertensive molecule with a
with hypertension or diabetes. Alagebrium is a new drug nitric oxide donor group have been developed to improve
that catalytically breaks established AGE cross-links. In the efficacy and safety profile of ‘native’ drugs. Hybrid
aged, hypertensive and diabetic animals, alagebrium drugs combining an ARB and a nitric oxide donor (i.e.
reduces systolic pressure and aortic stiffness, slows nitric oxide sartans) antagonize the effects of Ang II with
pulse-wave velocity, improves ventricular diastolic potency similar to that of losartan or captopril in spon-
distensibility and cardiac output, ameliorates diabetic taneously hypertensive rats [28]. Nitric ester derivatives
nephrosclerosis and reduces urinary protein excretion of pravastatin (NCX 6550) and fluvastatin (NCX 6553)
[19
,20]. In elderly patients, alagebrium improves arterial show enhanced antiproliferative and antiinflammatory
compliance, reduces systolic blood pressure and is well activity, having potential application in disorders associ-
tolerated. Studies in elderly patients with isolated systolic ated with endothelial dysfunction and vascular inflam-
hypertension, heart failure and diabetic nephropathy are mation [29].
in progress [19
].
Dual AT1 and ETA receptor antagonists
Rho kinase inhibitors Endothelin-1 exerts potent vasoconstrictor and prolifera-
Vascular smooth muscle contraction is controlled by free tive effects in vascular smooth muscle cells. The anti-
cytosolic Ca2þ concentration ([Ca2þ]i) and the Ca2þ hypertensive benefit of ECE inhibitors and specific ETA
sensitivity of the contractile proteins [21]. Ca2þ sensit- and ETB receptor antagonists, however, appears limited.
ization of the contractile proteins is mainly signaled by Preclinical evidence shows that dual AT1 and ETA
the RhoA/Rho kinase pathway which regulates the receptor antagonists (Table 2) present good oral bioavail-
degree of phosphorylation of myosin light chain ability and exhibit a broader spectrum of antihyperten-
(MLC) by phosphorylating MLC phosphatase, maintain- sive activity than individual AT1 or ETA receptor
ing force generation [21–23]. antagonists [30].

The RhoA/Rho kinase pathway is upregulated in hyper- Modulation of renal NaR/KR-ATPase

tensive patients [22–25]. Selective Rho kinase inhibi- Adducin gene mutations and increased levels of
tors induce vascular smooth muscle relaxation, lower endogenous ouabain-like factor are associated with hy-
blood pressure and inhibit cardiovascular remodeling pertension and upregulation of the renal Naþ/Kþ-
and endothelial dysfunction in hypertensive animal ATPase [31]. In preclinical studies, PST 2238 selectively
models [22–24]. In hypertensive patients they improve antagonizes the increased blood pressure and renal Naþ/
endothelial dysfunction, normalize the production of Kþ-ATPase activity induced by endogenous ouabain-like
superoxide, reduce peripheral vascular resistance and factor or present in Milan hypertensive rats [32]. Hence,
inhibit the development of coronary and cerebral vasos- PST 2238 might be useful in hypertensive patients with
pams [22–25]. Therefore, Rho kinase is a promising an impairment renal sodium excretion.
therapeutic target in essential hypertension.
KR channel modulation
Drugs with multiple mechanisms of action Activation of Kþ channels induces membrane hyperpol-
Due to the multiple pathophysiological factors involved arization, decreases [Ca2þ]i and produces arteriolar relax-
in essential hypertension, drugs combining different ation and blood pressure reduction [33]. Several
mechanisms of action may offer advantages over drugs endogenous vasodilators exert their effects through acti-
with a single mechanism. vation of Kþ channels. In animal models, elevated blood
426 Pharmacology and therapeutics

5 Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression

pressure is associated with a downregulation of the b1 in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison
subunit (Kcnmb1) of large conductance Ca2þ activated with enalapril. Hypertension 2002; 39:E1–E8.
(BK) Kþ channels [34], while a gain-of-function mutation 6 Stanton A, Jensen C, Nussberger J, et al. Blood pressure lowering in essential
hypertension with an oral renin inhibitor, aliskiren. Hypertension 2003;
in the b1 subunit is associated with a low prevalence of 42:1137–1143.
diastolic hypertension [35]. These findings provide the 7 Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective
basis for therapeutic agents that specifically target the b1 renin inhibitor, provides dose-dependent antihypertensive efficacy and
placebo-like tolerability in hypertensive patients. Circulation 2005;
subunit. Iptakalim, a selective ATP-sensitive Kþ channel 111:1012–1018.
opener, produces long-lasting vasodilator effects without 8 Azizi M, Menard J, Bissery A, et al. Pharmacologic demonstration of the
altering heart rate, reverses hypertensive cardiovascular synergistic effects of a combination of the renin inhibitor aliskiren and the AT1
receptor antagonist valsartan on the angiotensin II–renin feedback interrup-
remodeling and reduces endothelin release from endo- tion. J Am Soc Nephrol 2004; 15:3126–3133.
thelial cells [36]. 9 Fournie-Zaluski MC, Fassot C, Valentin B, et al. Brain renin–angiotensin
system blockade by systemically active aminopeptidase A inhibitors: a
potential treatment of salt-dependent hypertension. Proc Natl Acad Sci
Combination therapy U S A 2004; 101:7775–7780.
An alternative in improving blood pressure control is to use 10 Reaux-Le Goazigo A, Iturrioz X, Fassot C, et al. Role of angiotensin III in
hypertension. Curr Hypertens Rep 2005; 7:128–134.
a fixed low-dose combination of two antihypertensives
11 Burrel L, Johnston C, Tikellis C, Cooper M. ACE2, a new regulator of the
acting through different mechanisms [1]. The polypill renin–angiotensin system. Trends Endocrinol Metab 2004; 15:166–169.
strategy selected six components (three antihyper- 12 Fleming I, Kohlstedt K, Busse R. New fACEs to the renin–angiotensin system.
tensives, a statin, folic acid and aspirin) to reduce cardi- Physiology 2005; 20:91–95.
ovascular risk by more than 80% [37]. Hypertension and 13 Yagil Y, Yagil C. Hypothesis: ACE2 modulates blood pressure in the mam-
malian organism. Hypertension 2003; 41:871–873.
hypercholesterolemia are the two most common cardio-
14 Nordlander M, Sjoquist PO, Ericsson H, et al. Pharmacodynamic, pharma-
vascular risk factors and less than 20% of patients with cokinetic and clinical effects of clevidipine, an ultrashort-acting calcium
both conditions reach the treatment goals. The combi- antagonist for rapid blood pressure control. Cardiovasc Drug Rev 2004;
22:227–250.
nation of atorvastatin and amlodipine is the first attempt
15 Lee YS, Lee BH, Park SJ, et al. 3,4-Dihydroquinazoline derivatives as novel
to treat hypertension or angina and dyslipidemia concur- selective T-type Ca2þ channel blockers. Bioorg Med Chem Lett 2004;
rently with a single pill, thus simplifying the treatment. 14:3379–3384.
This can be considered as the first version of a polypill. 16 Touyz RM. Reactive oxygen species, vascular oxidative stress, and redox

signaling in hypertension: what is the clinical significance? Hypertension
2004; 44:248–252.
This article focuses on the role of oxidative stress in hypertension-associated
Conclusion vascular damage and clinical trials investigating cardiovascular benefits of
Essential hypertension is a multifactorial and multigenic antioxidants.
disorder, which means that various mechanisms contri- 17 Jacobson GM, Dourron HM, Liu J, et al. Novel NAD(P)H oxidase inhibitor
suppresses angioplasty-induced superoxide and neointimal hyperplasia of rat
bute to a greater or lesser extent to increasing blood carotid artery. Circ Res 2003; 92:637–643.
pressure. As we improve our understanding of essential 18 Cai H, Griendling KK, Harrison DG. The vascular NAD(P)H oxidases as
hypertension, it should be possible to tailor the devel- therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 2003;
24:471–478.
opment of safer and more effective antihypertensive
19 Bakris GL, Bank AJ, Kass DA, et al. Advanced glycation end-product cross-
drugs. The risk/benefit ratio of these new existing anti-
link breakers: a novel approach to cardiovascular pathologies related to the
hypertensive drugs will require long-term endpoint aging process. Am J Hypertens 2004; 17:23S–30S.
Complete review of AGE cross-linking breakers, with special mention of alageb-
assessment studies. rium.
20 Susic D, Varagic J, Ahn J, et al. Crosslink breakers: a new approach to
Acknowledgements cardiovascular therapy. Curr Opin Cardiol 2004; 19:336–340.
The research of the authors is funded by grants from Ministerio de 21 Somlyo AP, Somlyo AV. Ca2þ sensitivity of smooth muscle and nonmuscle
Educación y Ciencia (SAF 2002/02304 and AGL2004-06685-C04-1) myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol
Rev 2003; 83:1325–1358.
and by Red Temática de Investigacı́ón Cardiovascular (RECAVA).
22 Lee DL, Webb RC, Jin L. Hypertension and RhoA/Rho-kinase signaling in the
vasculature: highlights from the recent literature. Hypertension 2004;
References and recommended reading 44:796–799.
Papers of particular interest, published within the annual period of review, have 23 Shimokawa H. Rho-kinase as a novel therapeutic target in treatment of
been highlighted as: cardiovascular diseases. J Cardiovasc Pharmacol 2002; 39:319–327.

of special interest


of outstanding interest 24 Hirooka Y, Shimokawa H, Takeshita A. Rho-kinase, a potential therapeutic
target for the treatment of hypertension. Drug News Perspect 2004; 17:523–
527.
1 2003 European Society of Hypertension–European Society of Cardiology
Guidelines for the Management of Arterial Hypertension. J Hypertension 25 Masumoto A, Hirooka Y, Shimokawa H, et al. Possible involvement of Rho-
2003; 21:1011–1053. kinase in the pathogenesis of hypertension in humans. Hypertension 2001;
38:1307–1310.
2 Jones JK, Gorkin L, Lian JF, et al. Discontinuation of and changes in treatment
after start of new courses of antihypertensive drugs: a study of a United 26 Corti R, Burnett JC Jr, Rouleau JL, et al. Vasopeptidase inhibitors: a new
Kingdom population. BMJ 1995; 311:293–295. therapeutic concept in cardiovascular disease? Circulation 2001;
104:1856–1862.
3 Stanton A. Therapeutic potential of renin inhibitors in the management of
cardiovascular disorders. Am J Cardiovasc Drugs 2003; 3:389–394. 27 Tabrizchi R. SLV-306. Curr Opin Investig Drugs 2003; 4:329–332.
4 Wood JM, Schnell CR, Cumin F, et al. Aliskiren, a novel, orally effective renin 28 Breschi MC, Calderone V, Digiacomo M, et al. NO-sartans: a new class of
inhibitor, lowers blood pressure in marmosets and spontaneously hyperten- pharmacodynamic hybrids as cardiovascular drugs. J Med Chem 2004;
sive rats. J Hypertens 2005; 23:417–426. 47:5597–5600.
 Pharmacological therapy of arterial hypertension Cogolludo et al. 427

29 Ongini E, Impagnatiello F, Bonazzi A, et al. Nitric oxide (NO)-releasing statin 34 Amberg GC, Santana LF. Downregulation of the BK channel beta1 subunit in
derivatives, a class of drugs showing enhanced antiproliferative and antiin- genetic hypertension. Circ Res 2003; 93:965–971.
flammatory properties. Proc Natl Acad Sci U S A 2004; 101:8497–8502.
35 Fernández-Fernández JM, Tomas M, Vazquez E, et al. Gain-of-function muta-
30 Kowala MC, Murugesan N, Tellew J, et al. Novel dual action AT1 and ETA tion in the KCNMB1 potassium channel subunit is associated with low
receptor antagonists reduce blood pressure in experimental hypertension. prevalence of diastolic hypertension. J Clin Invest 2004; 113:1032–
J Pharmacol Exp Ther 2004; 309:275–284. 1039.
31 Ferrandi M, Tripodi G, Salardi S, et al. Renal Na, K-ATPase in genetic 36 Wang H, Long CL, Zhang YL. A new ATP-sensitive potassium channel
hypertension. Hypertension 1996; 28:1018–1025. opener reduces blood pressure and reverses cardiovascular remodeling
32 Ferrari P, Ferrandi M, Torielli L, et al. Antihypertensive compounds that in experimental hypertension. J Pharmacol Exp Ther 2005; 312:1326–
modulate the Na–K pump. Ann N Y Acad Sci 2003; 986:694–701. 1333.
33 Nelson MT, Cheng H, Rubart M, et al. Relaxation of arterial smooth muscle by 37 Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than
calcium sparks. Science 1995; 270:633–637. 80%. BMJ 2003; 326:1419–1424.