Download - 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
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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.
ª 2010 Adis Data Information BV. All rights reserved. High Blood Press Cardiovasc Prev 2010; 17 (3)
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
Antihypertensive Drugs and the Renin-Angiotensin System 113
ª 2010 Adis Data Information BV. All rights reserved. High Blood Press Cardiovasc Prev 2010; 17 (3)
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]
Antihypertensive Drugs and the Renin-Angiotensin System 115
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