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Journal of Cardiovascular Pharmacology and

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DOI: 10.1177/1074248410368277

2010 15: 257 originally published online 14 May 2010J CARDIOVASC PHARMACOL THERKatherine C. Wu and Gary Gerstenblith

Review: Update on Newer Antihypertensive Medicines and Interventions

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Review

Update on Newer AntihypertensiveMedicines and Interventions

Katherine C. Wu, MD,1 and Gary Gerstenblith, MD1

Abstract

The incidence and prevalence of systemic hypertension are reaching global epidemic proportions. Despite a diverse pharmacologicarmamentarium of agents to treat high blood pressure, suboptimal control remains a significant problem in as many as 43% ofpatients and this rate has not significantly improved over the past 2 decades. There are a variety of factors contributing to thisincluding patient nonadherence due to complex drug regimens and medication side effects, undertreatment, and treatment

resistance. There, thus, remains a need to develop novel agents and approaches to antihypertensive therapy that facilitateattainment of optimal blood pressure levels. This monograph will review a number of new pharmacologic targets andinterventions as well as a novel method of drug delivery to patients.

Keywords

hypertension, antihypertensives, drug effects, reninangiotensin system

It is estimated that as many as 1 in 3 adults in the United States

have high blood pressure.1,2 Hypertension significantly

increases the risk of myocardial infarction, stroke, heart failure,

and end-stage renal disease. It thereby reduces overall life

expectancy, accounting for close to 60 000 deaths per year1 and

significant, lifelong disability for others. The direct and indirect

costs of hypertension are expected to approach $74 billion in

2009.1 Despite public health awareness and a multitude of

existing treatments, achievement of optimal blood pressure

control has minimally improved over the past 20 years and

remains relatively low at 43%.3,4 In many patients with hyper-

tension, adequate control may require 2 or more agents that tar-

get various blood pressure regulatory systems, thereby more

effectively and physiologically reducing blood pressure.5,6

This results, in part, from the fact that the regulation of vascular

tone and fluid balance is complex and involves many, often

interrelated, pathways. The most important of these regulatory

systems are the reninangiotensinaldosterone system

(RAAS), the endothelin system, and the natriuretic peptides

and kinin system. Although components of RAAS are targeted

by such widely used antihypertensives as angiotensin-

converting enzyme inhibitors (ACEIs) and angiotensin recep-

tor blockers (ARBs), there remains a role for the development

of therapeutic options with novel targets. In addition, as non-

compliance contributes significantly to uncontrolled blood

pressure, new drug delivery mechanisms, or agents that target

more than one pathway in a single pill could be important ther-

apeutically. This article will review newer drug classes and

approaches to treating hypertension, several of which are still

in development.

Nebivolol

Nebivolol is a third-generation b-adrenergic receptor blocker

that has been available in Europe for a decade but was only

Food and Drug Administration (FDA)approved for hyperten-

sion treatment in the United States, in 2007.7-9 Compared to

traditional b-blockers, it has a fundamentally different bio-chemical structure. Although there were potentially favorable

effects in patients with angina and heart failure as well,7,10,11

recently the FDA panel unanimously decided to deny approval

to expand the drugs treatment indications to include chronic

heart failure in the United States. Nebivolol is lipophilic and

hence readily metabolized by the liver and able to reach all

compartments of the body. It is very highly cardioselective,

with 4 times higher affinity for b1 receptors as compared to

metoprolol. It lacks both intrinsic sympathomimetic activity

and membrane stabilizing activity. In addition, it does not

appear to increase insulin resistance. Similar to carvedilol, it

also has direct vasodilator properties. However, the mechan-isms of this differ and are instead mediated via stimulation of

endothelial nitric oxide synthase activity, which results in

increased nitric oxide bioavailability and decreased oxidative

1 Division of Cardiology, Department of Medicine, Johns Hopkins University,

Baltimore, MD, USA

Corresponding Author:

Katherine C. Wu, Division of Cardiology, Johns Hopkins Hospital, 600 N.

Wolfe Street/Carnegie 568, Baltimore, MD 21287, USA

Email: [email protected]

Journal of Cardiovascular

Pharmacology and Therapeutics

15(3) 257-267

The Author(s) 2010

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stress. Thus, nebivolol has the ability to improve endothelial

dysfunction in addition to b-receptor blockade.

The agent undergoes extensive first-pass hepatic metabo-

lism by cytochrome P450 2D6 (CYP2D6), which yields multi-

ple active metabolites. Although there is no effect clinically,

how quickly the drug is metabolized is determined by genetic

polymorphisms of 2D6. In extensive metabolizers, nebivolols

half-life is 12 hours compared to 19 hours in slow metabolizers.

Elimination is via both urinary and fecal routes. It is contrain-

dicated in severe hepatic dysfunction and the starting dose

requires reduction in patients with severe renal insufficiency

or moderate liver impairment.

Compared to placebo, 12-week therapy with nebivolol

reduces diastolic blood pressure by an additional 5 to 8 mm

Hg and systolic blood pressure by 2 to 7 mm Hg in patients

with mild-to-moderate hypertension.12 In another trial of

stages I-II hypertensive African American patients, nebivolol

monotherapy significantly reduced diastolic and systolic pres-

sures by an additional 2 to 7 mm Hg compared to placebo in a

dose-dependent manner.13 Greater than 50% of the patients

responded to treatment, which is noteworthy, given the data

suggesting reduced effectiveness of traditional b-blockers in

African Americans.

Nebivolol has also been compared to otherb-blockers and

antihypertensive drug classes. Its antihypertensive effects are

similar to those of atenolol, bisoprolol, and metoprolol9,14,15

Compared to ACEIs and ARBs, there is equivalent or some-

what greater blood pressure lowering.16-18 Response rates

are similar between nebivolol and calcium channel blockers.19

Its adverse effects are similar to those of other traditional

b-blockers and nebivolol is generally well tolerated. There are

nonsignificant mild elevations of serum glucose levels, low-

density lipoproteins (LDL), and triglycerides and nonsignifi-

cant mild reductions in high-density lipoproteins (HDL).13,20

Erectile function is reported to be unaffected and even poten-

tially improved.9

There are as yet, however, no large outcome trials of nebi-

volol in hypertension, specifically in comparison to other

agents. This is necessary, given the concern raised from

meta-analyses regarding increased cardiovascular morbidity and

mortality in hypertensive patients treated with b-blockade.7,21,22

Hence, usingb-blockers as a class first-line agents to treat hyper-

tension is generally not favored except in those circumstances

wherein other properties of the b-blocker, for example, its

anti-ischemic or secondary prevention benefits are desired. The

future role that nebivolol will play in the decision making

regarding which drugs to use in which hypertensive patients

remains to be determined.

Direct Renin Inhibitors

The RAAS plays a critical role in the pathogenesis of hyperten-

sion. Agents such as ACEIs, ARBs, and aldosterone receptor

antagonists target various RAAS components (Figure 1) and

are effective at reducing blood pressure and hypertensive com-

plications. However, such agents act relatively downstream in

the pathway and thus do not completely inhibit RAAS, because

negative feedback loops lead to a compensatory rise in plasma

renin concentration and subsequent elevations in plasma renin

activity and angiotensin II levels, the so-called RAAS escape

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin-I

Angiotensin IIAngiotensin-II

Renin

Angiotensin II

receptors

Angiotensin-II

receptors

ACE

Renin inhibitors

_

ACEI_

ARBs_

KIDNEY

Adrenal Gland

Aldosterone release

Aldosterone

receptors

Aldosterone

receptors

Aldosteronereceptorblockers

_

Angiotensin breakdown

products

Angiotensin breakdown

products

NEPinhibitors

_

ANP released

from heart

ANP released

from heart

NEPinhibitors

Inhibit ANPbreakdown

Figure 1. The reninangiotensin system and the sites of inhibition by renin-inhibitors, angiotensin-converting enzyme inhibitors (ACEIs),angiotensin receptor blockers (ARBs), aldosterone-receptor blockers, and neutral endopeptidase (NEP) inhibitors.

258 Journal of Cardiovascular Pharmacology and Therapeutics 15(3)

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phenomenon. Because the negative feedback suppression of

angiotensin II on renin is disrupted by ACEI and ARB therapy,

there is a compensatory rise in plasma renin and angiotensin

I levels. Moreover, alternate, tissue-based, angiotensin-

converting enzyme (ACE) -independent pathways are activated

to convert angiotensin-I to angiotensin-II. Although the hemo-

dynamic effects of RAAS escape result primarily from higherangiotensin-II levels, increased plasma renin may also contrib-

ute via a direct vascular toxic effect.23 Hence, patients treated

with ACEI and ARB may not achieve adequate blood pressure

control with those agents alone. However, rigorous studies with

robust clinical outcomes are ultimately required to adequately

compare antihypertensive regimens to one another, despite

theoretical advantages and concerns.24

The incomplete blockade of RAAS with individual agents

alone spurred further interest in combining therapies (dual-

RAAS blockade) that inhibit different components of the

RAAS pathway, thus potentially diminishing the effects of the

escape phenomenon. Interrupting the RAAS cascade at its first-rate limiting step is potentially ideal because all downstream

components would more effectively be suppressed. Renin con-

trols the first and rate-limiting step of the RAAS and is secreted

by the juxtaglomerular cells of the kidney. It cleaves specifi-

cally and solely to angiotensinogen, which ultimately leads to

angiotensin-II formation and subsequent angiotensin-II type 1

receptor-mediated vasoconstriction and aldosterone release.

Thus, inhibiting renin activity should block RAAS at its source

of activation and thus provide more complete suppression of its

downstream components, compared to other strategies.

Development of oral renin inhibitors was limited for a num-

ber of years due to its low bioavailability because of significanthepatic first-pass effects, as well as a short duration of action

and low antihypertensive potency.25,26 In March 2007, aliski-

ren was the first direct renin inhibitor to be approved by the

US FDA for the treatment of essential hypertension as mono-

therapy or in combination with other agents. It was designed

using molecular-modeling techniques and crystal structure

analysis.27,28 It is a nonpeptide, low-molecular-weight renin

inhibitor which is still poorly absorbed (2.5% bioavailability)

but is minimally metabolized and slowly excreted. It thus

reaches a peak plasma concentration within 1 to 3 hours

following oral administration. The accumulation half-life is

*24 hours and steady state plasma levels are attained in 7 to

8 days. The drug is primarily eliminated in the feces as unme-

tabolized drug and


5/12

fibroblasts, and cardiomyocytes. Receptors for endothelin are

widely distributed to varying degrees in many tissues and each

cells response to endothelin varies, accounting for its multipli-

city of action. Its vasoactive effects are mediated via interac-

tion with 2 specific receptor subtypes, endothelin A (ETA

)

and endothelin B (ETB; Figure 2). The receptors have varying

affinity for each of the 3 closely related isoforms of endothelin,

ET-1, ET-2, and ET-3. Endothelin A has a >100-fold increased

binding affinity for ET-1 than for ET-3. Endothelin-B has equal

affinity for all 3 isoforms. Vascular tone is believed to be

mediated via activation of ETA receptors found in vascular

smooth muscle cells, which results in endothelins vaso-

constrictive response. This effect is counterbalanced by ETBstimulation, which results in the release of vasodilatory

endothelial-derived substances such as nitric oxide and prosta-

cyclin. Endothelin receptors are also found abundantly in renal

collecting duct cells and their stimulation regulates sodium

reabsorption.41 Hence, the physiologic regulation of blood

pressure is controlled, in part, by the equilibrium between ETAand ETB receptor stimulation and endothelins multiple path-

ways affecting vascular tone and natriuresis.

Much of what is known about the biologic effects of

endothelin is derived from research with endothelin antago-

nists. There has been a particularly large focus on the potential

therapeutic benefits of such agents on pulmonary arterial

hypertension, currently the only licensed clinical indication for

endothelin receptor antagonists, which will not be reviewed

here. However, several clinical trials also studied patients with

essential hypertension.40 In 1998, bosentan, a mixed ETA and

ETB receptor antagonist, was first compared with enalapril and

placebo in the treatment of 293 patients with mild-to-moderate

essential hypertension.42 Following 4 weeks of therapy, bosen-

tan significantly reduced the primary end point, diatolic blood

pressure, by 5.7 mm Hg, compared to the 1.8 mm Hg decline

seen with placebo. The antihypertensive effect of bosentan was

similar to that of enalapril therapy which resulted in a 5.8 mm

Hg decline in diastolic blood pressure. This occurred without

evidence of reflex tachycardia or of sympathetic nervous sys-

tem or RAAS activation, which can characterize the response

to vasodilators. Although relatively well tolerated and safe,

*7% of the bosentan-treated patients experienced asympto-

matic elevations of liver transaminases to greater than twice the

upper limit of normal, which normalized after discontinuing

the therapy. This effect appeared somewhat dose dependent.

Several recent clinical trials have examined darusentan, a

selective ETA receptor antagonist, which would be expected

to be pathophysiologically superior to combined ETA/ETBreceptor antagonist because the vasodilatory effects of ETBreceptor stimulation would not be suppressed. Phase II studies

in moderate and resistant hypertension were promising with a

dose-dependent decrease in blood pressure that was greater

than that achieved by bosentan.43 An initial phase III trial was

recently published in September 2009 and involved 379

patients with treatment-resistant hypertension already receiv-

ing at least 3 other antihypertensive agents.44 The primary end

point was a change in seated systolic and diastolic blood pres-

sure over 14 weeks of therapy. Darusentan significantly

reduced the systolic and diastolic blood pressures by an addi-

tional 10 mm Hg compared to placebo. This antihypertensive

effect was accompanied by a significantly increased fluid

ENDOTHELIALCELLENDOTHELIAL CELL

Endothelin-1

ECEETB

VASCULAR SMOOTH MUSCLE CELL

ETB

Big Endothelin-1

Increased NO

Vasoconstriction

ETA

KIDNEY

Vasoconstriction

Salt and water

retention

Vasodilation

Figure 2. The opposing effects of endothelin on endothelial and vascular smooth muscle cells are shown and are mediated by differentialresponse to endothelin-receptor (ETA and ETB) stimulations. Endothelin-converting enzyme (ECE) is found on endothelial cells and isresponsible for conversion of big endothelin-1 to endothelin-1, the predominant form of endothelin.


260



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retention, most likely related to the vasodilatory effects of

darusentan and that required higher doses of diuretics.

However, these results have since been supplanted by a

larger phase III trial in 849 resistant hypertension patients,

which failed to demonstrate a significant change in trough sys-

tolic and diastolic blood pressure at 14 weeks, the prespecified

primary endpoints, compared with placebo. Other secondaryend points were reportedly met and included changes in ambu-

latory blood pressure, percentage of patients reaching systolic

blood pressure goal, and change in estimated glomerular filtra-

tion rate. Nonetheless, because of the negative primary end

point results, the drugs sponsor anticipates that it will no lon-

ger develop the agent45 and it is currently unclear what role, if

any, endothelin-receptor antagonists will play in future studies

of systemic hypertension.

Vasopeptidase Inhibition

Neutral endopeptidase or neprylisin (NEP) is a zinc-dependentmetallopeptidase found on endothelial cells, vascular smooth

muscle cells, cardiac myocytes, renal epithelial cells, and fibro-

blasts.46 It is responsible for the degradation of natriuretic pep-

tides such as atrial natriuretic peptide (ANP; Figure 1), brain

natriuretic peptide (BNP), and C-type natriuretic peptide

(CNP). Atrial natriuretic peptide and BNP are released from the

myocardium in response to myocardial stretch, CNP is found in

the kidney, heart, lung, and vascular endothelium and released

in response to shear stress. Natriuretic peptides promote

natriuresis, diuresis, and vasorelaxation and are antiprolifera-

tive. However, NEP is also required for the metabolism of

angiotensin-II (Figure 1). Hence, NEP inhibitors used as mono-therapy induce natriuresis and potentially reduce blood pres-

sure because they increase circulating ANP levels. However,

this antihypertensive effect is offset variably by increased

angiotensin-II levels, which may explain the lack of net antihy-

pertensive effect seen in small human trials of NEP inhibitors

alone.47,48 This subsequently led to interest in developing

dual-acting compounds that could block both NEP and the gen-

eration or activity of angiotensin II.

The other 2 main enzyme regulators in RAAS are ACE and

endothelin-converting enzyme (ECE; Figure 2), both of which

are also zinc metallopeptidases. Neutral endopeptidase shares

similarities in structure and mechanism of action with ACE and

ECE. Hence, it has been possible to design molecules that

simultaneously target both ACE/NEP and NEP/ECE (dual

vasopeptidase inhibitors) as well as ACE/NEP/ECE (triple

vasopeptidase inhibitors).49 Such a multipronged approach

with a single molecule could theoretically improve antihyper-

tensive efficacy and compliance without the need for multiple

agents and complex dosing regimens.

Dual vasopeptidase inhibition has had limited success. By

inhibiting both ACE and NEP, there are synergistic effects with

greater blood pressure lowering not seen with selective inhibi-

tors alone.49,50 There is increased activity of the endogenous

vasodilator systems and decreased angiotensin-II production,

which result in greater hemodynamic and renal effects.

However, clinical trials of dual inhibition using the agent

omapatrilat were associated with an increased risk of angioe-

dema, compared to ACE-inhibition alone, approaching 2% to

6%.49-52 The mechanism for this is not completely delineated but

has caused the cessation of further development of omapatrilat.

Another dual ACE/NEP inhibitor, ilepatril (AVE-7688), has

undergone phase II testing in patients with mild-to-moderatehypertension and was found to lower blood pressure more effec-

tively than losartan and had a reduced, 1.07%, incidence of

angioedema.53 Phase IIb/III clinical trials are underway.

The increased rate of angioedema associated with dual

ACE/NEP inhibition is postulated to be due to inhibition of

aminopeptidase P (APP) which along with ACE inhibits the

breakdown of substance P and bradykinin, with possibly only

a minor contribution specifically from NEP inhibition. Thus,

a combined ARB and NEP inhibitor is postulated to be safer

with a lower probability of angioedema because APP and ACE

levels would not be affected. The pharmacokinetics of such an

agent were recently tested in preclinical studies and in healthyvolunteers.54 It was found to be well tolerated in humans with

no serious adverse effects, but additional longer term clinical

studies are required to determine the incidence of angioedema

and its efficacy in patients with hypertension. Dual NEP/ECE

inhibition has also been studied, predominantly in heart failure.

However, in this patient population, such inhibitors failed to

reduce systemic blood pressure,55 and hence either triple

ACE/NEP/ECE inhibition or concomitant therapy with ACEI

or ARBs is needed.

Triple ACE/NEP/ECE inhibitors are still in preclinical devel-

opment and their toxicity profiles are currently unknown.46,49

The advantage of such agents is in the potential for reducingpolypharmacy. However, the broad targeting of such drugs may

predispose to adverse effects because many other downstream

enzymatic pathways could be affected. Careful, objective eva-

luation of this pharmacologic class is needed but may be war-

ranted, given their theoretical benefits.

Antihypertensive Effects of Novel Progestins

The Womens Health Initiative reported an increased risk of

cardiovascular disease in those receiving postmenopausal

estrogen and progesterone replacement therapy (hormone

replacemant therapy [HRT]). This resulted in changes in the

guidelines for prescribing HRT and decreased use.56 However,

a significant number of women experience major unacceptable

symptoms associated with estrogen deficiency accompanying

menopause, in addition to the increased cardiovascular risk

of the postmenopausal state itself. Hence, alternative strategies

for hormone therapy have been developed. A novel progestin,

drospirenone, was synthesized from 17-a spironolactone, an

aldosterone-receptor blocker (Figure 1) which has a high-

affinity for aldosterone receptors57,58 and which is used for the

treatment of hypertension. It has both antialdosterone and anti-

androgenic effects and could thus reduce salt and water reten-

tion and hence cause less weight gain and hypertension, as

compared to traditional HRT. Drosperinone is rapidly and

Wu and Gerstenblith 261

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completely absorbed and metabolized following oral ingestion.

Metabolism is independent of the cytochrome P450 system.

Peak serum concentration is achieved within 1 hour of admin-

istration and steady state is achieved in 10 days. Elimination

half-life is 30 hours and excretion of the drugs metabolites are

via the feces and urine. Contraindications include severe renal

insufficiency or acute renal failure.Drosperinone has been studied in postmenopausal women

with stages I-II hypertension in 2 clinical trials of relatively

short duration (8 and 12 weeks).59,60 There were statistically

significant reductions, on the order of 3 mm Hg to 5 mm Hg,

in both 24-hour ambulatory and clinic blood pressures com-

pared to placebo. The drug was generally well tolerated with

an adverse event rate of 6.9%. Dizziness was the most common

adverse event at 4% compared to 2% in placebo. There was no

clinically significant increase in serum potassium values.

Drosperinone currently is approved for moderate to severely

abnormal vasomotor function and atrophic vulva. It is unlikely

to be effective as a single antihypertensive agent, given itsrather modest blood pressure-lowering ability. However, its

mechanism of action may support its use in postmenopausal

women with hypertension, though more extensive efficacy and

studies comparing it with other HRT options are needed.57,61

Hypertension Vaccines

A significant deterrent to optimal blood pressure control is

patient noncompliance with medications, the rate of which may

approach as high as 55% at 3 years following initiation of an

antihypertensive therapy.62 Hence, the concept of a vaccine

that eliminates the need to take medications is an attractiveoption and has been explored since the 1950s.63 Vaccine efforts

have targeted components of RAAS. Initial preclinical efforts

were either ineffective in reducing blood pressure or required

an immunologic adjuvant that is toxic to and prohibited for use

in humans.

Recent attempts at vaccine development are directed at

inducing an immunological response and autoantibody produc-

tion against endogenous angiotensin-I or angiotensin-II.63

PMD3117 consists of a 12-amino-acid analog of angiotensin-

I, which is coupled to the carrier, keyhole limpet hemocyanin,

and adsorbed onto the adjuvant, aluminium hydroxide.64 Pre-

clinical experiments documented a reduction in blood pressure.

However, a subsequent phase II clinical trial failed to show a

similar blood pressure response in humans, although immuno-

logic activity was documented and there was biochemical evi-

dence of RAAS inhibition.64 It was postulated that higher titers

might be required to induce a sustained antihypertensive effect.

Modifications to the vaccine with a change in its adjuvant have

been made and additional clinical trials are underway.63

A second vaccine recently tested in humans is Cyt006-

AngQb, which targets angiotensin-II.65,66 It is composed of

an angiotensin-II-derived peptide conjugated to recombinant

virus-like particles originating from the RNA-phage Qb. In

phase I trials, the vaccine was well tolerated and generated a

strong immunogenic response to angiotensin-II. In a small,

randomized placebo-controlled phase IIa trial of 72 patients

with mild-to-moderate hypertension, Cyt006-AngQb was well

tolerated, with no serious side effects and no safety issues.

After a single dose of the vaccine, all patients generated an

immune response to angiotensin-II. Following second and third

injections at 4 and 12 weeks, respectively, the half-life approxi-

mated 4 months, which supports a treatment regimen of a fewtimes per year. At the 300 mg dose, there were average reduc-

tions of 4 to 9 mm Hg in daytime diastolic and systolic blood

pressures and 13 to 25 mm Hg decrease in the early morning

blood pressure surge, compatible with attenuation of RAAS sti-

mulation. The effect on early morning blood pressure was

unexpected and may be unique to the vaccine, due to the slow,

steady rise in antibody production compared to the peaks and

troughs of oral agents. Although these initial results are promis-

ing, they reflected secondary analysis of a very small number

of patients. There also remain unanswered safety concerns.67

In regulating fluid and electrolyte balance, RAAS has benefi-

cial physiologic effects that aid the bodys ability to maintainhemodynamic homeostasis in the setting of various stresses.

Importantly, its rapid activation is vital in situations such as

shock, trauma, and severe dehydration. Although arguably,

antihypertensive medications that inhibit RAAS would also

theoretically blunt the bodys response to such insults,

vaccine-induced circulating antibodies to angiotensin-II have

much longer half-lives, as long as 17 weeks, and cannot be eas-

ily reversed by mere withdrawal of therapy, as is the case with

oral medications.67 In addition, even in the setting of milder

degrees of salt and volume depletion, inhibiting RAAS could

lead to dangerous levels of hyperkalemia and renal failure.67

There are also theoretical concerns regarding the triggeringof autoimmune disease by repeated injections of an endogen-

ous peptide linked to virus-like particles. Furthermore, much

larger clinical trials of longer duration are needed to confirm

the antihypertensive effects and safety as well as whether there

are associated end-organ benefits to vaccination.

Treatment of Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a strong, independent predic-

tor of the development of hypertension and the severity of both

disorders are directly related.6,68-71 Although not fully eluci-

dated, the relationship between sleep-disordered breathing and

elevated blood pressure is thought to occur via various neuro-

hormonal mechanisms. Periodic apnea with hypoxemia and

hypercapnia cause surges of sympathetic nervous system acti-

vation and parasympathetic withdrawal, which repetitively

increase blood pressure.69,71 Blood pressures as high as 240/

130 mm Hg have been recorded in patients at the end of apneic

spells.71,72 Obstructive sleep apnea is also associated with

aldosterone excess, which increases oxidative stress and

inflammation.69,73 Obesity itself, which is commonly associ-

ated with OSA, appears to independently activate the sympa-

thetic nervous system and stimulate RAAS.69,74

The most effective treatment for OSA is continuous positive

airway pressure (CPAP) administered via nasal mask.73


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Continuous positive airway pressure therapy results in acute

reductions in blood pressure and sympathetic activity during

the sleep cycle.71,72 Data supporting long-term benefits of

CPAP in hypertensive patients are less definitive, primarily

because there are relatively few well-designed, longitudinal-

controlled trials.71,73 Many studies were of short follow-up

duration and failed to include true placebo-control groups,rather than sham CPAP (application of the nasal mask without

concomitant pressure) which was subsequently shown to

increase blood pressure.73,75,76 Trial end points were often spot

blood pressure measurements taken at variable times of day,

rather than 24-hour ambulatory blood pressure recordings.71,73 In addition, many of the study patients were either normo-

tensive or had well-controlled blood pressure at the beginning

of the study.71,73 In such patients, net reductions of*2 mm Hg

have been observed, which are modest but statistically signifi-

cant.71,73 Few studies have exclusively studied patients with

hypertension; one such study reported a 10 mm Hg decrease

in systolic and diastolic blood pressures and was characterizedby longer CPAP use and more severe OSA.77 In an observa-

tional study of refractory hypertensive patients with OSA,

CPAP treatment for 2 months was associated with an 11 mm

Hg reduction in 24-hour systolic blood pressure, with a decline

in nocturnal systolic blood pressure of 14 mm Hg.78

The existing data suggest modest and heterogeneous blood

pressure responses to CPAP that are patient specific. The most

benefit may be derived by individuals in whom (a) OSA is

more severe (particularly those with prominent complaints

of daytime somnolence); (b) blood pressure is harder to con-

trol; and (c) CPAP compliance is high.71,73 However, addi-

tional well-designed, longer term randomized trials areneeded to further define the role of OSA therapy in reducing

the risk of developing hypertension and treating patients with

hypertension.

Baroreflex Stimulation

It has long been known that the carotid sinus baroreceptor

reflex plays a significant role in blood pressure homeostasis

and modulation of autonomic tone. Arterial stretch receptors

in the carotid sinuses and aortic arch are exquisitely sensitive

to arterial stretch. As blood pressure increases, baroreceptor

activity rises in proportion to the rate of change in arterial pres-

sure. Impulses are propagated to the central nervous system,

which results in increased parasympathetic tone in the heart

and reduced sympathetic activation of the heart, kidneys, and

peripheral vasculature, causing blood pressure to fall.

The concept of carotid nerve stimulation arose in the 1950s

and 1960s.79 It originated from the notion that artificially

increasing nerve activity from the carotid sinus to the brain

stem would be interpreted as a rise in arterial blood pressure

and lead to neural signaling that reduced blood pressure and

heart rate. Several initial devices using carotid sinus electrical

stimulation were tested in animals and humans but faced

numerous technical problems, including uncomfortable extra-

neous muscle and nerve stimulation, nerve damage, and

difficulties with communication between an external antenna

and the implanted receiver. Recent technological advances can

theoretically overcome many of these limitations.

The newest carotid sinus stimulator device now under-

going clinical trials is the Rheos System (CVRx, Mineapolis,

Minnesota).71,79,80 It received an investigational device exemp-

tion from the FDA in 2006. Electrodes are placed on both car-otid arteries and the leads are attached to a pulse generator that

is implanted subcutaneously near the clavicle. Surgical implan-

tation under general anesthesia is required. The device is fully

programmable, which facilitates individualized parameter set-

tings. It was first tested in a small group of 11 patients under-

going elective carotid surgery as a proof-of-concept study.

The device resulted in significant reductions in blood pressure

(18 + 26 mm Hg systolic and 8 + 12 mm Hg diastolic) in a

voltage-dependent manner. Maximal blood pressure reductions

were seen using 4.4 + 1.2 volts (23 + 24 mm Hg systolic and

16 + 10 mm Hg diastolic). Ongoing trials sponsored by the

manufacturer80,81

include the device-based therapy in hyper-tension trial (DEBuT-HT), device-based therapy in hyperten-

sion extension trial (DEBuT-HET), and the Rheos pivotal

trial. Device-based therapy in hypertension trial is a multicen-

ter European study examining the safety and efficacy of Rheos

in 45 patients with refractory hypertension. Results of a sub-

study of 21 DEBuT-HT patients have recently been reported,

which investigated whether chronic baroreceptor stimulation

resulted in changes in cardiac autonomic regulation, as

reflected by heart rate variability and heart rate turbulence, and

whether there was a corresponding effect on blood pressure.82

Measurements were made at 1 month after device implantation

with the stimulator turned off and compared with measure-ments made after 3 months of activated electrical stimulator

therapy. There were significant declines in office blood pres-

sures (185 + 31/109 + 24 mm Hg to 154 + 23/95 +

16 mm Hg), which were associated with significant changes

in heart rate variability and heart rate turbulence, supporting

decreased sympathetic and increased parasympathetic activity

in actively treated patients. The main results of the safety stud-

ies, DEBuT-HT, and the related longer term follow-up study,

DEBuT-HT, are yet to be published. Also in progress is the

Rheos Pivotal Trial which is a randomized, double-blind trial

of 300 patients aiming to demonstrate clinically significant,

sustained reductions in office systolic blood pressures up to 1

year. Although the initial data were promising, the results of

these ongoing studies will be required to better define the clin-

ical role of baroreceptor stimulation.

Renal Nerve Ablation

From both preclinical and human studies, it has long been known

that renal sympathetic innervation plays an important pathophy-

siologic role in initiating and maintaining hypertension.83,84

Renal efferent nerve endings are found in the renal arteries, jux-

taglomerular apparatus, and renal tubules. Activation of the renal

nerves stimulates renin release, promotes sodium reabsorption,

and impairs renal perfusion. The renal sensory afferent nerves


263



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provide feedback regulation to the central nervous system,

specifically, the posterior hypothalamus, and thus directly con-

trol the level of sympathetic outflow to not only the kidneys but

also the heart and peripheral vasculature.

The potential therapeutic benefits of renal denervation on

blood pressure control were first observed from preclinical

experiments.83 The purpose of these studies using animal mod-els was originally to examine the pathophysiologic mechan-

isms by which the renal efferent and afferent nerves

contribute to normal and pathologic functioning of the kidneys

and other organs. It was generally noted in multiple models of

hypertension that bilateral renal denervation averted the devel-

opment of hypertension or significantly reduced its magni-

tude.85,86 This led to efforts to modulate renal innervations

surgically in patients to control blood pressure. Initial surgical

efforts involved surgical nephrectomy; thoracolumbar, abdom-

inal, or pelvic sympathectomy was plaqued by considerable

morbidity and mortality.83,84 Moreover, such approaches could

not guarantee uniform efficacy in functionally eliminatingrenal innervation and consequently, the effects on blood pres-

sure control were erratic.83 However, selective renal denerva-

tion remains an attractive therapeutic target. Recently, a

percutaneous, catheter-based approach was developed and

tested in a proof-of-concept and safety study in 45 patients with

resistant hypertension.84 A catheter (Symplicity by Ardian Inc,

Palo Alto, California) was advanced into each renal artery via

the femoral approach and radiofrequency ablation was per-

formed at 6 separate sites within each artery. The median pro-

cedure time was 38 minutes. One patient had a renal artery

dissection upon placement of the catheter, prior to radiofre-

quency treatment, and underwent successful renal stenting andwas withdrawn from the renal denervation protocol. There

were no other renovascular complications for 6 months post-

procedure and glomerular filtration rates were stable. Limited

efficacy data suggest long-term, persistent reductions of office

blood pressures in the 9 patients reaching the 12-month follow-

up at the time of the studys publication: systolic/diastolic

reductions of 14/10 + 4/3 mm Hg; 21/10 + 7/4;

22/11 + 10/5; 24/11 + 9/5; and27/17 + 16/11

at 1, 3, 6, 9, and 12 months postprocedure, respectively. Nota-

bly, the study documented a 47% reduction in postprocedure

noradrenaline spillover from the kidneys into the circulation,

supporting the effective denervation of the efferent renal sym-

pathetic nerves by the technique.

Although this initial report is promising, there are a number

of limitations and unanswered questions.84,87 Large rando-

mized trials that include a control group and which better stan-

dardize or control for concomitant medical therapy are needed.

In addition, not all patients in the study responded to the ther-

apy and this may be due to the variable causes of resistant

hypertension which were not well-defined or investigated.

Hence, a better defined target group of study patients is needed.

The effects on ambulatory blood pressure rather than office

blood pressure may better characterize the true benefits of the

therapy. Finally, this approach is not likely to be recommended

as a first-line therapy in the management of hypertension but

reserved for specific patient subgroups, yet to be defined, with

resistant hypertension.

Summary

Hypertension poses a growing public health dilemma of epi-

demic proportions. It is expected to affect 1.56 billion individ-uals worldwide by year 2025, both in developed and

developing countries.88 Although there are a number of effec-

tive treatments, the majority of patients do not achieve target

blood pressure for a variety of reasons, including insufficient

medication, true drug resistance, and noncompliance. There

remains a significant need to develop and thoroughly test new

agents and approaches to better control hypertension, in the

form of drugs that target multiple components of the pathways,

which control blood pressure and/or via novel drug delivery

such as vaccination.

Declaration of Conflicting Interests

The authors declared no conflicts of interest with respect to the author-

ship and/or publication of this article.

Financial Disclosure/Funding

The authors disclosed receipt of the following financial support for the

research and/or authorship of this article: Dr Wu is supported by the

Donald W. Reynolds Cardiovascular Research Center at Johns Hop-

kins University.

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