effects of antihypertensive drugs on the renin-angiotensin system in essential hypertension

Effects of Antihypertensive Drugs on theRenin-Angiotensin System in Essential HypertensionFranco Rabbia, Elisa Testa, Silvia Totaro, Giannina Leotta, Elena Berra, Michele Covella, Valeria Milazzo,Cristina Di Stefano and Franco Veglio

Hypertension Unit, Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

1. V Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

1.1 Calcium Antagonists (Calcium Channel Blockers) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

1.2 Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

1.3 a1-Adrenoceptor Antagonists (a1-Blockers) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

2. R Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

2.1 b-Adrenoceptor Antagonists (b-Blockers) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

2.2 Centrally Acting Antihypertensive Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

2.3 ACE Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

2.4 Angiotensin II Type 1 Receptor Antagonists (Angiotensin Receptor Blockers) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

2.5 Direct Renin Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Abstract A standardized approach to antihypertensive pharmacological therapy taking into account the patho-

physiological mechanism of hypertension is not yet available. Laragh and colleagues have proposed amodel

based on the concept that the two final determinants of blood pressure are the volume status and the renin-

angiotensin-aldosterone system. This model allows patients to be divided into two categories based on

plasma renin activity (<0.65 or >0.65 ng/mL) and with a different primary target for a specific therapy. In

Laragh’s opinion, all antihypertensive drugs could be divided into two groups according to their mechanism

of action: drugs that block the activity of the renin-angiotensin system (R drugs, such as b-adrenoceptorantagonists [b-blockers], ACE inhibitors, angiotensin II type 1 receptor antagonists [angiotensin recep-

tor blockers] and centrally acting antihypertensive drugs) or drugs that increase renal sodium excretion

(V drugs, such as diuretics, a-adrenoceptor antagonists [a-blockers] or calcium channel blockers). This

article reviews the mechanisms underlying this antihypertensive drug classification.

Received for publication: 23 June 2010; accepted for publication: 15 July 2010.

Keywords: Laragh’s hypothesis, essential hypertension, renin-angiotensin system, cardiovascular drugs,

antihypertensive therapy.

The so-called ‘essential hypertension’ had been described by

Page[1] as a ‘mosaic’ of heterogeneous mechanisms contributing to

the elevation of blood pressure (BP). A standardized stepped-care

approach to antihypertensive treatment is advocated for all patients

without complications. In the actual ‘individualized’ approach to

antihypertensive drugs, treatment is chosen taking into account

age, race, co-morbidities, cost and potential adverse effects. Other

information that may increase the likelihood of selecting an effi-

cacious drug by matching its mechanism of action with the under-

lying pathophysiological disturbance is not available.[2]

REVIEWARTICLEHigh Blood Press Cardiovasc Prev 2010; 17 (3): 109-115

1120-9879/10/0003-0109/$49.95/0

ª 2010 Adis Data Information BV. All rights reserved.

An alternative framework for personalization of antihyper-

tensive drug therapy was proposed by Laragh and colleagues

several years ago.[3] Their ‘vasocostriction-volume analysis’ is

based on the concept that the renin-angiotensin-aldosterone

system determines BP levels by regulating vascular tone and

intra-arterial volume.[3] In particular, the two final determi-

nants of BP are the sodium ions (or volume factor), which

sustain the pervasive volume factor, and the calibre of the ar-

terioles (the renin-vasoconstrictor factor), which is regulated

long term by renal renin release. Accordingly, all human hyper-

tensive disorders compose a spectrum of abnormally high renin

sodium products: at one extreme of the spectrum there are

hypertensive patients with the highest renin activity in the blood

and the lowest blood volumes, and at the other extreme there

are the so-called ‘low-renin’ hypertensive patients, character-

ized by a very high sodium volume status that suppresses renal

renin release.

The vasoconstriction-volume model helps to identify, in in-

dividual patients, two different primary targets for a specific

therapy: (i) the sodium volume factor identified by a plasma

renin activity (PRA) <0.65 ng/mL; and (ii) the renin factor oc-

curring in medium- and high-renin patients and identified by a

PRA >0.65 ng/mL. In the opinion of Laragh and colleagues,[3]

an initial antisodium volume therapy is appropriate for low-

renin patients, by using a diuretic, an a-adrenoceptor antag-

onist (a-blocker) or a calcium channel blocker (CCB), that re-

duce BP by increasing direct or indirect renal sodium excretion

(V drugs). Conversely, b-adrenoceptor antagonists (b-blockers),ACE inhibitors, angiotensin II type 1 receptor antagonists

(angiotensin receptor blockers [ARBs]) and centrally acting anti-

hypertensive drugs, which lower BP by reducing or blocking the

activity of the renin-angiotensin system (R drugs), are the most

effective drugs in high-renin states, and have little or no effect on

BP in overt low-renin patients. This article reviews the mechan-

isms underlying this antihypertensive drug classification.[4]

1. V Drugs

1.1 Calcium Antagonists (Calcium Channel Blockers)

CCBs, selective inhibitors of calcium influx in depolarized

smooth muscle, have been recognized as useful agents in the

treatment of hypertension, ischaemic heart disease and as anti-

arrhythmic agents. Over the years, different types of calcium

channels have been identified, but all available CCBs interact

with the same calcium channel, the L-type voltage-gated plas-

ma membrane channel, which is the best characterized and the

most important member of the class. Calcium channels facil-

itate the influx of extracellular calcium ions into the cell, the

subsequent release from intracellular sources, and the activa-

tion of contractile proteins. Conversely, blockade of the L-type

channels by CCBs causes vascular relaxation and a decrease

in myocardial contractile activity.[5] Classification of the var-

ious subtypes of CCBs is based on their chemical structures.

Dihydropyridine CCBs exert their hypotensive action mainly

by causing a decrease in peripheral resistance due to arterial

vasodilatation, whereas non-dihydropyridine CCBs lower BP

mainly by causing a decrease in cardiac output.[6]

There are several data[7] supporting the evidence that the

antihypertensive efficacy of CCBs is inversely related to pre-

treatment PRA. Low-renin hypertensive subjects have a greater

hypotensive response to CCBs than high-renin subjects. Thus,

CCBs are considered by some authors as first-line drugs espe-

cially in older and low-renin patients.[7]

There seems to be a relationship between low-renin essential

hypertension and various abnormalities of calciummetabolism,

suggesting that the hormonal control of calcium metabolism is

linked to the renin system activity as well as to the pathophysio-

logy of the hypertensive process.[8] Moreover, Resnick et al.[9]

demonstrated that the range of PRA in essential hypertension

shows a continuous negative correlation with the serum mag-

nesium level and a positive correlation with the serum ionized

calcium level. The initial level of serum ionized calcium predicts

the BP response to nifedipine, as does the initial PRA.

Essential hypertensive subjects with a low-renin profile, low

ionized calcium levels and elevated 1,25-dihydroxy vitamin D

levels show a better response to nifedipine, an enhanced sensi-

tivity to the BP effects of dietary salt loading and have sig-

nificantly lower BP values in response to oral calcium

supplementation. Hypertensive subjects with the opposite me-

tabolic profile (high-renin activity, high serum ionized calcium

and low 1,25-dihydroxy vitamin D levels) are relatively in-

sensitive to the BP effects of both dietary salt loading and ni-

fedipine, and show no significant hypotensive response to

calcium supplements.[10]

These results suggest that low-renin hypertension is more

critically dependent on extracellular calcium than the high-

renin type and demonstrate that both levels of serum ionized

calcium and PRA may predict the sensitivity of BP to calcium

channel blockade.[10]

The CCBs have a wide spectrum of effects on the kidney.

First, by causing vasodilatation of the afferent renal arter-

ioles,[11] dihydropyridinic CCBs cause an increase in intra-

glomerular pressure that may be associated with an increase

in renal blood flow. Acute felodipine administration causes

110 Rabbia et al.

ª 2010 Adis Data Information BV. All rights reserved. High Blood Press Cardiovasc Prev 2010; 17 (3)

significant diuresis and natriuresis by a direct inhibitory effect

on net renal tubular sodium and water reabsorption.[12] A mild

natriuretic effect, probably at the renal tubular level, may ex-

plain why theCCBs, although potent vasodilators, do not cause

fluid retention.[5] CCBs – mostly of the dihydropyridinic type –

cause an increase in renin release, although less than ACE in-

hibitors or ARBs. The rise in renin that occurs following the

administration of CCBs may result from reflex sympathetic

stimulation, natriuretic effects or direct effects on calcium de-

pendent renin regulatory pathway[13] (table I).

1.2 Diuretics

This category includes antihypertensive drugs that have a

primary natriuretic action on the kidneys (i.e. they reduce body

sodium and water content). In general, diuretics act by pre-

venting reabsorption of salt and water from renal tubular urine.

Thus, sodium and water content in the body decreases, leading

to a reduction in cardiac output and followed later by an auto-

regulatory reduction in total peripheral resistance, which

restores blood flow to a lower BP. Both subsequent changes can

contribute to the decrease in BP. Drugs in this class include the

thiazide and loop sulfonamide diuretics, and the potassium-

sparing agents, of which spironolactone represents the proto-

type.[14]

Diuretics differ in structure and mechanism or site of action

within the nephron. Loop diuretics primarily block chloride

reabsorption by inhibition of the Na+/K+/Cl- co-transport

system of the luminal membrane of the thick ascending limb of

Henle’s loop;[15] in addition, when given intravenously, they

cause rapid vasodilatation in addition to their diuretic ac-

tion.[16] Potassium-sparing agents act in the distal tubule to

prevent potassium loss: spironolactone and eplerenone com-

petitively inhibit aldosterone’s receptor, triamterene and

amiloride act directly on the epithelial sodium channel onwhich

aldosterone exerts its effects, thus preventing potassium secre-

tion. These drugs have a potent natriuretic-diuretic action

without causing potassium loss. The thiazide diuretics act

by inhibiting sodium and chloride co-transport across the

luminal membrane of the early segment of the distal convolut-

ed tubule, where 5–8% of the filtered sodium is normally

reabsorbed.[17]

It is important to understand that normally there is a re-

ciprocal relationship between PRA levels and BP. Thus, in

healthy individuals both a high BP and a salt excess suppress

renin secretion, whereas both a low BP and a lack of salt in-

crease renin secretion. All diuretics stimulate renin secretion by

reducing body sodium content and, therefore, lower blood

volume and BP. Loop diuretics stimulate PRA more than

thiazide diuretics for two reasons. First, they induce a greater

natriuresis. Second, they block chloride transport at the macula

densa sensor, which normally is a signal to suppress renin se-

cretion.[4] Over and above the stimulatory effects on renin levels

of a decrease in BP, the natriuresis induced by amiloride or

triamterene increases PRA levels also by turning off the tubular

detector control, which signals from the macula densa region of

the nephron to the afferent arteriole.[18] Spironolactone and

eplerenone, which are more selective aldosterone receptor

antagonists, release PRA from chronic suppression and cause a

reflex increase in aldosterone and PRA levels. Both natriusesis

and low BP contribute to this effect.

Renin and aldosterone responses to stimulatory and sup-

pressive agents may be similar in a qualitative sense but differ

quantitatively; diuretics, in fact, tend to increase PRA more

than aldosterone levels (thus lowering the aldosterone/plasma

renin activity ratio [ARR]).[13]

There is evidence that the antihypertensive effect of diuretics

is significantly related to pre-treatment PRA only. Therefore,

the greatest decrease in BP occurs in low-renin subjects. In

particular, some data show that diuretics are effective anti-

hypertensive agents in most patients with low- and normal-

renin isolated systolic hypertension.[19] Diuretics, and mostly

thiazides, have been considered as a potential cause of lack of

cardioprotection in different epidemiological studies. This ef-

fect may be attributable to the reflex activation of sympathetic

nervous system and/or renin secretion.[20]

Table I. Effects of drugs on plasma renin concentration (PRC), plasma renin

activity (PRA), plasma aldosterone concentration (PAC) and aldosterone/plasma renin activity ratio (ARR)

Drugs PRC PRA PAC ARR

Calcium channel blockers m m k k

Loop diuretics m m m k

Thiazide diuretics m m m k

Aldosterone receptor antagonists m m m k

Amiloride, triamterene m m m k

a1-Adrenoceptor antagonists (a1-blockers) = = =/k =/k

b-Adrenoceptor antagonists

(b-blockers)

k k k m

Centrally acting antihypertensive drugs k k k m

ACE inhibitors m m k k

ARBs m m k k

Aliskiren m k k k

ARBs= angiotensin II type 1 receptor antagonists (angiotensin receptor

blockers);m indicates increased;k indicates reduced; = indicates no change.

Antihypertensive Drugs and the Renin-Angiotensin System 111


1.3 a1-Adrenoceptor Antagonists (a1-Blockers)

a1-Adrenoceptors are located post-synaptically and mediate

vasoconstriction through endogenously releasednorepinephrine.[5]

Until 1987, prazosin was the only selective a-blocker available,but other agents are now available.[15] By blocking sympathetic

influence on vascular smooth muscle, these agents act as both

arterial and venous vasodilators.[20] Peripheral resistance falls

without major changes in cardiac output, partly because of a

balance between a decrease in venous return (preload) and a

modest reflex sympathetic stimulation (consequence of vaso-

dilatation).[15]

The a1-adrenergic blockers have little or no clinical effect on

glomerular filtration rate and renal blood flow[21] even if renal

vascular resistance is reduced.[22] a-Blockers promote natriur-

esis. This effect facilitates and sustains their antihypertensive

action and thereby makes them especially effective for lowering

BP in low-renin, high-sodium volume hypertensive patients.[14]

Few data are available on a-blockers; however, chronic pra-

zosin or doxazosin administration does not promote substan-

tial changes in PRA.[14,23-25]

2. R Drugs

There are four ways to reduce the activity of the renin-

angiotensin system in humans: the reduction of renin release

(b-blockers), the direct inhibition of the activity of renin (alis-

kiren), the inhibition of the ACE activity (enzyme that converts

the inactive decapeptide angiotensin I to the active hormone

angiotensin II) [ACE inhibitors] and the competitive ant-

agonism of ATII receptors (ARBs).

2.1 b-Adrenoceptor Antagonists (b-Blockers)

For many years, b-adrenergic blocking agents have been the

second most popular antihypertensive drugs after diuretics.

The competitive inhibition of b-blockers on b-adrenergic ac-

tivity produces numerous effects on functions that regulate BP,

causing a reduction in cardiac output (by 15–20%) and heart

rate, possibly a decrease in central sympathetic nervous outflow,

a pre-synaptic blockade that inhibits catecholamine release,

and a probable decrease in peripheral vascular resistance.[15]

b-Adrenergic neural activity directly stimulates kidney

b1-receptors to increase renin secretion. Thus, renin levels us-

ually fall promptly after b-blocker therapy, reflecting a suppres-sion of renin release from the juxtaglomerular cells due to a

reduction in the processing of pro-renin to active renin.[26]

b-Blockers suppress kidney renin secretion, thereby lowering

PRA and plasma angiotensin II (Ang II) formation by about

75%.[4,23] b-Blockers represent the first way to reduce the ac-

tivity of the renin-angiotensin system in humans.

b-Blockade consistently suppresses aldosterone too. The

suppression of Ang II levels is comparable with that produced

during ACE inhibition. However, by reducing pro-renin pro-

cessing to renin, b-blockers do not stimulate renin secre-

tion, unlike ACE inhibitors and ARBs. This unique action of

b-blockers has important implications for the treatment of

cardiovascular disease.[26] However, because they only suppress

renin secretion through the renal b-receptor, renin levels may

not be completely suppressed by their action.[14] Medium- and

high-renin hypertensive subjects seem to respond more con-

sistently than those with low renin.[26]

In general, b-blockers have little or no clinical effect on

glomerular filtration rate or renal blood flow, renal vascular

resistance, urinary sodium or potassium excretion, free-water

clearance or body fluid composition.[22]

2.2 Centrally Acting Antihypertensive Drugs

Stimulation of a2-receptors in the CNS reduces peripheral

sympathetic activity and hence produces vasodilatation. Clas-

sical centrally acting drugs, such as clonidine and a-methyl-

dopa, are efficacious antihypertensives. Central imidazoline

(I1)-receptor represents a target for centrally acting agents:

moxonidine and rilmenidine are considered to be moderately

selective I1-receptor stimulants, while clonidine is a mixed

agonist. The imidazoline (I1)-agonists also cause peripheral

sympathetic inhibition, triggered at the level of central nervous

imidazoline receptors, which are predominant in the anterior

ventro-lateral medulla.[20]

Although the principal actions of clonidine are linked to its

centrally mediated suppression of sympathetic activity, the in-

hibition of the renin axis may also contribute to its anti-

hypertensive effect. Although the quantitative importance

of this latter action is not clear, it can be observed an initial

suppression of the vasoconstriction mediated by the renin-

angiotensin system, followed by a long-term antihypertensive

action due to the suppression of aldosterone.[27]

Renin secretion decreases because b-adrenergic signals to thejuxtaglomerular cells are reduced; b-blockers and centrally

acting antihypertensive drugs are the only classes of anti-

hypertensive drugs that persistently lower PRA levels.[14,23]

High-renin patients experience significantly greater BP de-

crements than low-renin patients.[14]

A further characteristic of these drugs is their ability to

decrease BP without producing sodium retention.[28] The

112 Rabbia et al.


central a2-adrenergic agonists have little or no clinical effect

on glomerular filtration rate and renal blood flow; how-

ever, renal vascular resistance is reduced. Urinary sodium

and potassium excretion and body fluid composition are

unchanged.[22]

2.3 ACE Inhibitors

Three chemically different classes of ACE inhibitors have

been developed, classified by the ligand of the zinc ion of

ACE,[15] with different pharmacological profile and clinical

efficacy.[29]

ACE inhibitors lower BP by reducing the circulating levels of

Ang II, thereby removing the direct vasoconstriction induced

by this peptide. Because ACE inhibitors block only Ang II

production via the classical pathway, there could be additional

effects of ARBs. Other effects are likely to contribute to their

antihypertensive effect, such as a decrease in aldosterone se-

cretion, which may cause natriuresis or at least a lack of renal

sodium retention, reactive to the BP fall.

ACE inhibitors induce a significant decrease in plasma

aldosterone concentration and an increase in PRA levels[23]

because, by preventing the formation of Ang II, they impair the

immediate feedback suppression of Ang II on renal renin se-

cretion. Similar to ARBs, though, by reactively secreting more

renin, the blockade of Ang II formation can be overcome, thus

resulting in a partial escape of ACE inhibition and a rise in

BP.[14] In particular, it has been shown that Ang II virtually

disappears from the circulation at peak of initial ACE inhibi-

tion. In long-term therapy, however, Ang II levels in plasma

become again measurable and often close to pre-therapeutic

levels.[30]

ACE inhibitors, by promoting dilatation of both afferent

and efferent renal arterioles, could be expected to reduce intra-

glomerular pressure and hence to lessen the rate of excretion of

albumin. ACE inhibitors are also known to blunt sympathetic

activity.[11]

2.4 Angiotensin II Type 1 Receptor Antagonists

(Angiotensin Receptor Blockers)

The Ang II receptor was found to have two major subtypes.

The type 1 (AT1) receptor mediates most of the physiological

roles of Ang II (including vasoconstriction, stimulation of

aldosterone release and sympathetic nerve activity, promotion

of cell growth, matrix deposition and inflammation).[15,31]

Agents that selectively block the AT1 receptor have been syn-

thesized and are now available for clinical practice.

ARBs displace Ang II from its specific AT1 receptor, an-

tagonizing all of its known effects and resulting in a dose-

dependent fall in peripheral resistance, together with a little

change in heart rate or cardiac output.[32] As a consequence of

the competitive displacement, circulating levels of Ang II in-

crease. At the same time, the blockade of the renin-angiotensin

mechanism is more complete, by including any Ang II that

is generated through pathways that do not involve ACE (in-

cluding the serine proteinase chymase).[15]

The increased Ang II is shunted to the AT2 receptor, fa-

vouring vasodilatation and attenuation of unfavourable vas-

cular remodelling.[33] ARBs and ACE inhibitors are the most

important renin-angiotensin system blockers in use. The biol-

ogy of the system suggests some differences between the two

types of drugs. For example, ACE inhibitors do not affect Ang

II generation by non-ACE pathways, whereas ARBs antag-

onize all AT1 receptors effects. Conversely, ACE inhibitors

affect both AT1 and AT2 receptors equally, whereas ARBs

inhibit AT1 receptors and stimulate AT2 receptors. This

characteristic might contribute with a different potential of

each class of drugs in the protection of patients from stroke.[34]

When ARBs are administered, renin is released from the

kidney because of the removal of the feedback inhibition ofAng

II. ARBs therefore induce an increase in PRA together with a

reduction of plasma aldosterone concentration. The lack of any

PRA increase in a patient taking ACE inhibitors or ARBs is an

important piece of information for the physician, suggesting

that the drug is not efficacious.[14,23]

The plasma renin stimulation by ACE inhibitors or ARBs

provides some explanation on the reasons why the renin-

angiotensin-aldosterone system inhibitors are sometimes sub-

optimal or not effective.[35] Therefore, several investigators

have proposed to associate an ARB with an ACE inhibitor to

block the renin-angiotensin cascade at two sites and hence

obtain a greater and longer lasting blockade of the system.[30]

2.5 Direct Renin Inhibitors

Aliskiren, the first of a new class of orally effective non-

peptide renin inhibitors for the treatment of hypertension, is a

drug that targets the renin system at its point of activation.[36] It

was available in the US and, more recently, also in Europe.

Several peptide-like renin inhibitors have been previously syn-

thesized, but were not clinically usable.[37]

Aliskiren has been shown to lower BP effectively in hyper-

tensive patients (a dose-dependent effect with a persistence for

24 hours) both alone and in combination with other drugs;[38,39]

the antihypertensive effect of aliskiren monotherapy seems to



be comparable with that of ACE inhibitors, ARBs and other

antihypertensive agents at equipotent doses. However, its

antihypertensive efficacy is enhanced by drugs that trigger a

reactive increase in the PRA such as diuretic, ACE inhibitors

and ARBs.[40]

As for inhibition of the renin-angiotensin system by ACE

inhibitors or ARBs, aliskiren therapy is accompanied by a re-

active rise in plasma renin concentration; however, in contrast

to ACE inhibitors and ARBs, aliskiren reduces PRA.[41] Fur-

thermore, it appears that aliskiren induces a greater reactive

increase in renal renin secretion than ACE inhibitors or ARBs,

particularly when given in combination with them.[42,43] Re-

cently, Sealey and Laragh[43] proposed that the exaggerated

renin response may limit the ability of aliskiren to reduce BP

because Ang II generation might occur again (‘Ang II escape’),

possibly even at the levels above baseline, as has been described

before for ACE inhibitors. Furthermore, high levels of renin

will stimulate the recently discovered (pro) renin receptor, in-

ducing effects in an Ang II-independent manner. This rise can

be partly explained by the lack of a negative feedback, and

therefore provides a valuable, although indirect, measure of the

reduction of Ang II levels induced by aliskiren. It has also been

suggested that renin response may be due to other mechanisms,

such as the unloading of renal and extrarenal baroreceptors, the

direct action on the renin-secreting juxtaglomerular cell to in-

fluence pro-renin processing and renin release by a mechanism

independent of Ang II levels, and an effect on renin clearance.

Finally, some authors suggest that aliskiren may interfere with

the renin assay by binding to pro-renin and causing an over-

estimation of the renin concentration, causing an artifact.[41]

Other authors suggest that this renin increase is the con-

sequence of a combination of factors, including an assay arti-

fact; correcting for these phenomena the increase is lower than

previously thought. Furthermore, the higher circulating level of

renin and pro-renin seems to downregulate their receptor in a

greater manner.[44]

3. Conclusions

To believe that different patients respond selectively to either

a natriuretic, antivolume V-drug or an antirenin R-type anti-

hypertensive drug, according to the pathogenetic mechanism

understating the pressor state, would be a simplification. This

approach would reduce the use of multiple drugs, anti-

hypertensive costs and adverse effects, and offers patients ef-

fectiveness and compliance. Unfortunately, no studies have

demonstrated this hypothesis, and large controlled trials are

needed to confirm it.

Acknowledgements

This study was supported by Regione Piemonte, Ricerca Sanitaria

Finalizzata andMUR, 2008. The authors have no conflicts of interest that

are directly relevant to the content of this review.

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Correspondence: Dr Elisa Testa, HypertensionUnit, Department ofMedicine

and Experimental Oncology, University of Turin, Via Genova 3, 10126

Torino, Italy.

E-mail: [email protected]



effects of antihypertensive drugs on the renin-angiotensin system in essential hypertension

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