STATE OF THE ART
Effects of Calcium Channel and Renin–Angiotensin
System Blockade on Intravascular and
Neurohormonal Mechanisms of Hypertensive
Vascular Disease
Yoshiko Mizuno1,2, Robert F. Jacob1,2 and R. Preston Mason1,2
Several classes of antihypertensive drugs have been shown to
improve vascular function through mechanisms other than reducing
blood pressure (BP) alone. Certain dihydropyridine calcium channel
blockers (CCBs) and inhibitors of the renin–angiotensin system (RAS)
increase nitric oxide (NO) bioavailability and decrease oxidative
stress, thereby improving endothelial activity and vascular function.
Pulse wave analyses have shown that these agents reduce the impact
of pressure wave reflections on central systolic BP (SBP), consistent
with a decrease in arterial stiffness. The complementary vascular
mechanisms of these drug classes suggest that combination therapy
may be effective for improving clinical outcomes. In animal model
Epidemiologic studies show that the risk of adverse cardiovascu-
lar outcomes increases progressively with increasing blood pres-
sure (BP), whereas clinical trials demonstrate that lowering BP
reduces such risk.1 All antihypertensive medications lower BP,
but specific drug classes have pleiotropic effects that may con-
tribute to cardiovascular risk reduction. The relative importance
of the degree of BP reduction vs. the mechanisms associated
with BP reduction remains the subject of considerable debate.2
The primary purpose of antihypertensive therapy is BP reduc-
tion, and this continues to be the accepted basis for their clinical
benefit. Developing a better understanding of the mechanisms
underlying hypertensive vascular disease, as well as the pleio-
tropic actions of antihypertensive agents, offers the potential for
more targeted therapy that reduces global cardiovascular risk.
A number of structural and functional mechanisms have been
identified in the pathogenesis of hypertensive vascular disease.
By releasing certain mediators such as nitric oxide (NO), the
vascular endothelium modulates vascular tone while protecting
against atherogenic and thrombotic processes.3 However, hyper-
tension, together with other cardiovascular risk factors, impairs
1Cardiovascular Division, Department of Medicine, Brigham and Women’s
Hospital, Harvard Medical School, Boston, Massachusetts, USA; 2Elucida
Research, Beverly, Massachusetts, USA. Correspondence: R. Preston Mason
(rpmason@elucidaresearch.com)
Received 17 April 2008; first decision 20 May 2008; accepted 24 July 2008;
advance online publication 28 August 2008. doi:10.1038/ajh.2008.258
© 2008 American Journal of Hypertension, Ltd.
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studies, combination calcium channel/RAS blockade has been
shown to be more effective in improving endothelial dysfunction
than treatment with drugs from either class alone. Furthermore,
results from recent clinical trials suggest a greater reduction in
central aortic SBP, pulse pressure, and cardiovascular events with
calcium channel/RAS blockade vs. β-blocker/diuretic therapy.
These studies support the potential benefit of combination calcium
channel and RAS blockade in the prevention and treatment of
cardiovascular disease.
Am J Hypertens 2008; 21:1076-1085 © 2008 American Journal of Hypertension, Ltd.
endothelial function and decreases the release of NO and vascu-
lar responsiveness to stimuli.4,5 In addition, the mechanical forces
inherent in hypertension activate neurohormonal mechanisms,
including the renin–angiotensin system (RAS), which modulates
endothelial and smooth muscle function and, ultimately, vessel
wall structure, in order to reestablish normal hemodynamic con-
ditions.6 Antihypertensive drugs may have class-specific mor-
phologic, hemodynamic, and physiologic effects that influence
the ­vascular disease process. This article reviews the underlying
mechanisms of hypertensive vascular disease, the therapeutic
effects of calcium channel blockers (CCBs) and agents that block
the RAS, and the potential benefits associated with combining
these drugs as a treatment regimen.
Central Vs. Peripheral Circulation
In Hypertensive Vascular Disease
When BP is measured conventionally over the brachial artery,
it is assumed that these measurements accurately reflect pres-
sures in the central circulation. This assumption is supported
by evidence that brachial BP parameters are powerful pre-
dictors of cardiovascular structural damage, morbidity, and
mortality.7,8 However, measures of central arterial pressure
may be stronger predictors of cardiovascular events as they
are directly influenced by vascular endothelial function.9,10
Central aortic pressure is determined by cardiac output and
peripheral vascular resistance, as well as by arterial stiffness
and the timing and magnitude of pressure wave reflections.11
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 Hypertensive Vascular Disease
The pressure wave in the aorta reflects the summation of a for-
ward wave generated by ejection of blood from the left ventricle
and a reflected wave arriving subsequently from the periphery
(Figure 1).10 Due to the elasticity of the central arteries, only a
portion of each stroke volume is delivered distally during sys-
tole, with the remainder delivered by elastic recoil of the aorta
during diastole.10 Increases in central arterial stiffness result in
the delivery of greater portions of each stroke volume during
systole. As a result, the velocities of both forward and reflected
waves increase, and the reflected wave returns earlier to the
aorta, thereby raising central aortic pressure and increasing
left ventricular load. Accordingly, central aortic stiffness con-
tributes directly to the generation of a wide pulse pressure with
higher systolic BP (SBP) and lower diastolic BP.
The mechanism by which central aortic stiffness contrib-
utes to higher pulse pressure was evaluated in patients with
uncomplicated systolic hypertension by calibrated tonometry
and pulsed Doppler.12 Hypertensive patients had significantly
higher pulse pressure than age- and gender-matched normo-
tensive controls, an effect attributed primarily to a higher char-
acteristic impedance (Zc). The Zc value represents the pressure
generated by the forward wave in the proximal aorta during
early systole before the return of the reflected wave. Unlike
pulse wave velocity, the sensitivity of Zc is amplified by a
decrease in lumen diameter. Pulse wave velocity and Zc values,
inserted into the water hammer (surge) equation, showed that
P2
160
SBP
AP
PP
120 P1
Aortic pressure (mm Hg)
MAP
DBP
80
AI = AP/PP
40
0
Systole Diastole
DN
Figure 1 | Components of central aortic pressure. In this typical aortic pulse
contour, P1 is the pressure peak caused by the forward flow wave; AP is the
late systolic augmentation pressure caused by return of the reflected wave
to the aortic root; and P2 is the pressure peak that results from summation
of the forward and reflected waves. DN is the dicrotic notch dividing systole
and diastole. The augmentation index (AI) is defined as the ratio of AP to pulse
pressure (PP). DBP, diastolic blood pressue; MAP, mean arterial pressure; SBP,
systolic blood pressure. Adapted with permission from ref. 11.
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STATE OF THE ART
mean effective aortic diameter was decreased in hypertensive
subjects as compared with normotensive controls. Thus, an
increase in pulse pressure is disproportionate to the increase
in mean arterial pressure in patients with systolic hypertension
due to increased Zc and reduced effective aortic diameter.
Endothelial Dysfunction In Cardiovascular
Disease: A Target For Combination Treatment
The endothelium is a continuous layer of cells that cover the
luminal vessel walls. These cells produce a variety of signaling
molecules that modulate vascular tone and inflammatory proc-
esses. Perhaps the most important molecule is NO, produced
by endothelial NO synthase (eNOS), an NAD(P)H-dependent
enzyme. Beyond vasodilation, NO inhibits smooth muscle
cell proliferation and migration, adhesion of leukocytes to
the endothelium, and platelet aggregation.13 Vascular injury,
metabolic disorders, and deficiencies in essential substrate
(l-arginine) and cofactors (e.g., tetrahydrobiopterin) contrib-
ute to “uncoupling” of eNOS and loss of NO bioavailability
(Figure 2).14 Thus, endothelial dysfunction has been causally
linked to atherosclerosis and its clinical manifestations.
Cardiovascular agents modify endothelial function through
processes that may be, in part, unrelated to their primary phar-
macologic target of action. Drugs that improve vascular NO
levels include nitrates, angiotensin-converting enzyme (ACE)
inhibitors, angiotensin-receptor blockers (ARBs), CCBs, and
HMG–CoA reductase inhibitors (statins). These agents rep-
resent two broad classes of compounds—those that release
NO or one of its redox analogs spontaneously and those that
require enzymatic metabolism to generate NO. By inhibiting
ACE activity, for example, ACE inhibitors influence the levels
of angiotensin II and bradykinin within the vascular wall while
statins upregulate eNOS expression (Figure 3).15,16
Hypertension Dyslipidemia Diabetes
Endothelial dysfunction
NO synthesis COX activity Inflammation Endothelin
Vasoconstriction Thromboxane A2 Leukocyte Vasoconstriction
adhesion
Thrombosis Prostaglandin H2 Endothelial Calicium
permeability mobilization
Superoxide Prostacyclin Foam cell
formation
T-cell activation
Figure 2 | Integrated cellular mechanisms of cardiovascular disease. COX,
cyclooxygenase; NO, nitric oxide. Adapted with permission from ref. 40.
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 STATE OF THE ART
Angiotensin II Kinins Inactive peptides
ACE I
NO
AT II BK2 ACE
L-Arginine NO + L-Citrulline
eNOS
Statins eNOS mRNA Endothelial cell
Figure 3 | Postulated effects of various agents on endothelial cell nitric
oxide (NO) production. ACE I, angiotensin-converting enzyme inhibitor;
AT II, angiotensin II receptor, type 2; BK2, bradykinin receptor type 2; eNOS,
endothelial NO synthase. Adapted from refs. 86–88.
Role Of Neurohormonal And Physiologic
Mechanisms In Vascular Disease
Renin–Angiotensin–Aldosterone system
The RAS plays a central role in the short- and long-term regu-
lation of BP, as well as in the regulation of fluid and electro-
lyte balance. In vascular disease, activation of the RAS also
promotes arterial remodeling and inflammation, further con-
tributing to progressive vascular and renal dysfunction.6 The
binding of angiotensin II to AT1 receptors on vascular smooth
muscle cells promotes vasoconstriction while simultaneously
stimulating aldosterone secretion from the adrenal cortex and
sodium reabsorption in renal proximal tubules. AT1 activa-
tion also facilitates sympathetic neurotransmission.17 Beyond
its genomic effects on volume regulation, recent studies indi-
cate that aldosterone contributes to hypertension through
enhanced restriction of renal afferent arterioles—an effect
that is augmented with inhibitors of endothelial-dependent
NO release.18 The vasoconstrictive effects of aldosterone, for
example, were reduced by inhibiting protein kinase C– or IP3-
induced calcium release, indicating that aldosterone promotes
vasoconstriction by mobilizing intracellular calcium stores.18
In addition, the interaction of angiotensin II with AT1 recep-
tors on endothelial cells, vascular smooth muscle cells, and
leukocytes activates signal transduction mechanisms that
promote oxidative stress, inflammation, cell proliferation,
and fibrosis.6,19 Angiotensin II activates NAD(P)H oxidase in
endothelial and vascular smooth muscle cells, which stimu-
lates production of reactive oxygen species.19 Angiotensin II
also increases the activity of the proinflammatory transcrip-
tion factor nuclear factor−κB, which controls expression of
inflammatory cytokines. Finally, angiotensin II stimulates
growth factors, extracellular proteins, and matrix metallopro-
teinases, thereby promoting proliferative and fibrotic mecha-
nisms involved in vascular remodeling.17
The interaction of angiotensin II with AT2 receptors appears
to counteract some of the effects mediated by the AT1 ­receptor.
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Hypertensive Vascular Disease
More important, angiotensin II binding to AT2 stimulates
NO release, promoting normal endothelial function and anti-
­inflammatory activity.20
Hypertension and endothelial dysfunction
Endothelial dysfunction and reduced NO bioactivity are asso-
ciated with hypertension as shown in a recent study in which
forearm blood flow was measured by strain-gauge plethys-
mography after infusion with the endothelium-dependent
and endothelium-independent vasodilators, that is, acetylcho-
line and sodium nitroprusside, respectively.21 Vasodilation in
response to acetylcholine, but not to nitroprusside, was signifi-
cantly reduced in patients with hypertension compared with
control subjects, thus indicating an endothelial-dependent
pathway. Endothelial dysfunction increased with age in both
hypertensive and normotensive patients in this study.
The cellular mechanisms that contribute to endothelial dys-
function in hypertension have been characterized in experi-
mental models of the disease. In stroke-prone spontaneously
hypertensive rats, there is a pronounced loss in NO bioavail-
ability despite increased eNOS levels.22 A similar change in
eNOS expression, as well as an increase in O2− and ONOO−
generation, was observed in normal rats that were made
hypertensive by surgical procedures such as aortic banding.23
The basis for this paradox is attributed to eNOS uncoupling
mechanisms.24,25
Endothelial dysfunction is more common in African
Americans than whites, which may reflect reduced NO pro-
duction in African Americans.26 Nebivolol, a β-blocker with
antioxidant properties, reduced superoxide and peroxynitrite
levels and restored NO bioavailability in endothelial cells from
African-American donors to levels observed in cells from
white donors.27 Thus, blocking reactive oxygen species offers
the potential to improve NO release. It should be noted that
in some of the aforementioned studies, investigators used
suprapharmacologic treatment levels; however, these stud-
ies still provide important insights into potential new areas of
clinical intervention.
Mechanism Of Action Of Antihypertensive Therapy:
Calcium Channel And Ras Blockade
CCB and RAS blockade in cardiovascular disease:
intravascular effects
Antihypertensive agents produce different effects on central
aortic pressure and hemodynamics despite similar effects on
BP measured over the brachial artery. The ­combination of cal-
cium channel and RAS blockade, in particular, may be more
effective than other antihypertensive ­combinations in reducing
central aortic pressure. In Conduit Artery Function Evaluation
(CAFE),28 a substudy of the Anglo-Scandinavian Cardiac Out­
comes Trial (ASCOT) in which patients with ­hypertension and
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 Hypertensive Vascular Disease
at least three other cardiovascular risk factors were assigned to
amlodipine plus perindopril as needed or atenolol plus bend-
roflumethiazide as needed to achieve BP targets,29 central aor-
tic pressure and hemodynamic variables were assessed by radial
artery applanation tonometry and pulse wave analysis in 2,199
patients for up to 4 years.28 Nearly all patients (95%) received
at least two antihypertensive agents, with 56 and 60% of sub-
jects in the CCB/ACE inhibitor and β-blocker/diuretic groups,
respectively, receiving their predefined combination. Both regi-
mens produced similar reductions in brachial SBP (P = 0.2)
(Figure  4). However, the CCB-based regimen produced sig-
nificantly greater reductions in central aortic SBP (4.3 mm Hg;
95% confidence interval, 3.3–5.4 mm Hg; P < 0.0001) and cen-
tral aortic pulse pressure (3.0 mm Hg; 95% confidence interval,
2.1–3.9 mm Hg; P < 0.0001) than the β-blocker-based regimen.
Notably, differences between brachial and central aortic BP val-
ues persisted throughout the follow-up period. Higher central
aortic SBP and pulse pressure with atenolol-based treatment
was primarily attributable to greater wave reflection (augmen-
tation index) than to differences in the forward wave following
ejection from the left ventricle.
Post hoc analysis of the CAFE data provided additional infor-
mation about the relationship between the effect of treatment
on central aortic pressure and patient outcomes. Central aor-
tic pulse pressure, central aortic wave augmentation, forward
pressure wave height, and brachial pulse pressure correlated
significantly with the composite end point of cardiovascular
events/procedures and development of renal impairment.28
After adjustment for age and baseline risk factors, central
­aortic pulse pressure remained significantly associated with
the composite end point.
Peripheral SBP
Diff mean (AUC) = 0.7 (−0.4, 1.7) mm Hg
140
135
130
mm Hg
125
120
Central SBP
Diff mean (AUC) = 4.3 (3.3, 5.4) mm Hg
115
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 AUC
Time (years)
Atenolol 86 243 324 356 445 372 462 270 339 128 85
Amlodipine 88 248 329 369 475 406 508 278 390 126 101
Figure 4 | Comparison of brachial systolic blood pressure (SBP) (closed
symbols) and central aortic pressure (open symbols) in patients treated with
amlodipine plus perindopril as needed (triangles) vs. atenolol plus thiazide
diuretic as needed (circles) in the Conduit Artery Function Evaluation (CAFE)
study. AUC, area under the curve. Adapted with permission from ref. 28.
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Calcium channel and RAS blockade improve vessel wall
elasticity and reduce arterial stiffness. In hypertensive patients,
treatment with CCBs or ACE inhibitors significantly reduced
the central aortic augmentation index, consistent with a reduc-
tion in arterial stiffness.30,31 In healthy volunteers, infusion of
angiotensin II significantly increased the augmentation index,
whereas infusion of the vasodilator nitroglycerin reduced
the augmentation index.32 In a crossover study of untreated
hypertensive patients, bisoprolol produced a greater reduc-
tion in brachial SBP than amlodipine, lisinopril, doxazosin, or
bendroflumethiazide, but increased the central aortic augmen-
tation index;33 each of the other drugs reduced the augmen-
tation index. Similarly, in elderly patients with elevated SBP,
β-blockers increased the augmentation index and augmented
aortic SBP, whereas CCBs, ACE inhibitors, and diuretics low-
ered these parameters.34
CCB and RAS blockade in cardiovascular disease: biochemical
and physiologic effects
Long-acting CCBs, such as the highly lipophilic amlodipine,
exert antioxidant effects that protect LDL and membrane lip-
ids. Amlodipine exists in a charged state under physiologic
conditions, which enables it to strongly interact with cell mem-
brane phospholipids.35,36 The antioxidant effects of amlodipine
appear to be independent of calcium channel modulation
(Figure 5).35 The antioxidant activity of amlodipine has been
observed in animal models.37
In coronary microvessels isolated from canine cardiac ­tissue,
amlodipine caused a dose-dependent release of nitrite, the
hydration product of NO.38 The effects of amlodipine on both
nitrite release and the NO-dependent regulation of cardiac
Amlodipine
Kinins
AT? B2-kinin
133.9
133.2
125.5
121.2
Phospholipid bilayer
NO eNOS
Bradykinin
R+ enantiomer L-Arg NO
Angiotensin II
1031
1042 Figure 5 | Newer calcium channel blockers (CCBs), such as amlodipine, not
only penetrate the plasma membrane to interact with the L-type calcium
channel, but also have additional biologic or pleiotropic actions independent
of their interaction with the calcium channel. These CCBs have effects on cell
types other than vascular smooth muscle cells, including cells in which L-type
calcium channels are nonexistent or play only minor roles. eNOS, endothelial
nitric oxide synthase. Adapted with permission from ref. 35.
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 STATE OF THE ART
oxygen consumption were inhibited with specific antagonists
of eNOS. By contrast, the addition of other dihydropyridine-
type CCBs (nifedipine) and a non-dihydropyridine analog
(diltiazem) failed to reproduce this activity. The effects of
amlodipine were similar in magnitude to those observed with
ACE inhibitors.39 Amlodipine also inhibited cytokine-induced
apoptosis of endothelial cells and protected against excessive
cell loss due to apoptosis in cultured cerebellar granule cells.40
The benefit of amlodipine therapy in patients with established
coronary artery disease has been suggested in several clinical
­trials. In the Prospective Randomized Evaluation of the Vascular
Effects of Norvasc Trial (PREVENT), a study comprised of 825
patients with angiographically documented coronary artery
disease,41 amlodipine significantly slowed carotid artery athero-
sclerosis. Amlodipine was associated with fewer cases of unsta-
ble angina pectoris and coronary revascularization procedures.
The Comparison of Amlodipine versus Enalapril to Limit
Occurrences of Thrombosis (CAMELOT) study evaluated the
effects of amlodipine and enalapril on cardiovascular events
in 1991 normotensive patients with ­angiographically docu-
mented coronary artery disease.42 Amlodipine reduced the
risk of cardiovascular events which was attributable to reduc-
tions in coronary revascularization procedures and hospi-
talizations for angina pectoris. In a substudy of CAMELOT,
conducted to assess the progression of coronary atheroscle-
rosis by intravascular ultrasound, amlodipine reduced the
change in atheroma volume, with significantly less progres-
sion observed in the subgroup with SBP values above the
mean (0.2% vs. 2.3%; P = 0.02).
The effect of amlodipine in patients aged ≥55 years with
hypertension and at least one other coronary heart ­disease
risk factor was evaluated in the Antihypertensive and Lipid-
Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).43
Amlodipine was compared to lisinopril and a thiazide diuretic
in 33,357 patients. A review of outcomes showed the rate of
combined fatal coronary heart disease or nonfatal myocardial
infarction in the amlodipine and lisinopril groups was not sig-
nificantly different from that in the thiazide group. This trial
led to the recommendation that diuretics be used as first-line
therapy for uncomplicated hypertension despite the observed
higher rates of hypokalemia and new onset diabetes.
RAS blockade with ACE inhibitors or ARBs exerts numer-
ous antiatherogenic effects that interrupt the vascular disease
process. In a randomized, active-controlled trial of patients
with essential hypertension, treatment with an ARB signifi-
cantly improved the vasoconstrictive response to l-NMMA,
indicating an increase in basal NO production, whereas diu-
retic treatment had no effect despite similar BP reductions.44
RAS blockade also significantly decreased markers of mono-
cyte and endothelial cell activation in hypertensive patients
with type 2 diabetes.45 In a study of patients with coronary
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Hypertensive Vascular Disease
artery disease, treatment with an ACE inhibitor or ARB sig-
nificantly increased flow-mediated vasodilation, primarily due
to increased NO bioavailability.46
In addition to RAS blockade, AT1 receptor antagonists con-
fer distinct atheroprotective benefits by allowing stimulation
of unblocked AT2 receptors. Several reports have shown that
AT1 receptor antagonism reduces endothelial dysfunction by
improving basal NO synthesis. Valsartan reduced intimal thick-
ening in hypercholesteremic rabbits,47 and both valsartan and
losartan stimulated NO release from platelets and endothelial
cells, resulting in inhibition of platelet adhesion and aggrega-
tion.48 Other studies showed that candesartan-induced eNOS
augmentation was abolished by a specific AT2 receptor antag-
onist, consistent with AT2 receptor-mediated NO release.49 In
coronary arteries, activation of AT1 receptors by a low concen-
tration of angiotensin II caused vasoconstriction by increasing
NAD(P)H oxidase superoxide production. By contrast, higher
concentrations of angiotensin II caused vasodilatation by acti-
vating AT2 receptors through enhanced NO bioavailability
(Figure 3).50
RAS blockade also produces antiatherogenic and anti-
inflammatory effects. In animal models of hypercholeste-
rolemia, treatment with valsartan or benazepril decreased the
intimal lesion area, increased the lumen area, and decreased
macrophage proliferation.47,51 In a recent study, RAS block-
ade decreased the release of proinflammatory cytokines, IL-6
and TNF-α, from leukocytes.52 In a large randomized trial of
patients with stage 2 hypertension, treatment with an ARB
significantly reduced levels of high-sensitivity C-reactive pro-
tein as compared with an ARB/diuretic combination, despite
greater BP reductions with the combination.53
Effects of CCB and RAS blockade in cerebrovascular disease
Hypertension is the overwhelming risk factor for cerebrov-
ascular disease and its clinical manifestations such as stroke,
cognitive decline, and dementia. Any of the commonly used
antihypertensive drugs lower the incidence of stroke, with
larger reductions in BP resulting in larger reductions in risks.
Some clinical data have suggested advantages for ACE inhibi-
tors, ARBs, and CCBs.
The prospective randomized Losartan Intervention For
Endpoint Reduction (LIFE) trial showed a significant differ-
ence in stroke rate in favor of the ARB (losartan) compared
with atenolol despite similar reductions in BP.54 Even the role
of hypertension and its treatment remain controversial as
the Acute Candesartan Cilexetil Therapy in Stroke Survivors
(ACCESS) trial suggested that candesartan is safe in hyper-
tensive acute stroke patients and offers advantages independ-
ent from BP control.55 In the Heart Outcomes Prevention
Evaluation (HOPE) trial, the ACE inhibitor ramipril reduced
the occurrence number of primary stroke by 32% compared
october 2008 | VOLUME 21 NUMBER 10 | AMERICAN JOURNAL OF HYPERTENSION
 Hypertensive Vascular Disease
with placebo.56 In the Perindopril Protection Against Recurrent
Stroke Study (PROGRESS) trial, combination therapy with
ACE inhibitor (perindopril) and indapamide reduced the risk
of stroke among both hypertensive and normotensive patients
with a history of stroke or transient ischemic attack.57 Larger
BP reductions were associated with the risk reductions in the
active regimen group. A substudy analysis also showed a lower
frequency of cognitive decline among patients undergoing
active therapy with perindopril and indapamide.58
The brain possesses the same RAS as the systemic cir­
culation.59–61 Angiotensin II plays a pathophysiologic role in
the development of ischemic stroke, and inhibition of the RAS
reduces the risk of stroke in a manner independent from altera-
tions of systemic BP. Activation of AT1 receptors by angiotensin
II contributes to vasoconstriction, vascular proliferation, and
inflammation leading to cerebrovascular insufficiency as well as
disruption of the blood–brain barrier. ARBs which selectively
block AT1 receptors, decrease local vasoconstriction, and allow
free angiotensin II to stimulate unoccupied AT2 receptors, which
alleviates local brain ischemia and reduces the extent of tissue
loss.62,63 The protective effects of ARBs may be superior to that
of ACE inhibitors due to the differential activation of AT2 recep-
tors. Many neuronal processes are regulated by calcium influx
through voltage-sensitive calcium channels, including protein
phosphorylation, gene expression, neurotransmitter release,
and modulation of action potential firing pattern.64 Consistent
with these experimental data, CCBs have been shown to have
cerebrovascular protective effects in clinical trials. In the Systolic
Hypertension in Europe (Syst-Eur) trial, a nitrendipine-based
regimen significantly lowered the frequency of fatal and nonfa-
tal stroke compared with placebo and contributed to a reduc-
tion in both vascular and Alzheimer’s-type dementia.65,66 The
Nordic Diltiazem (NORDIL) trial, which compared the effects
of diltiazem with diuretics or β-blockers, or combination of diu-
retic and β-blockers, the diltiazem regimen was more effective
than the combined diuretic and β-blocker regimen in lower-
ing the rate of all strokes beyond BP lowering, even though the
mean reductions in diastolic pressure were identical in the two
groups and the reduction of SBP was greater in the diuretic/β-
blocker group (20.3/18.7 mm Hg in the diltiazem group vs.
23.3/18.7 mm Hg in the diuretic/β-blocker group).67 However,
in the Intervention as a Goal in Hypertension Treatment
(INSIGHT) trial, nifedipine and coamilodzide (a thiazide diu-
retic) were equally effective in preventing overall cardiovascular
or cerebrovascular complications.68
The cerebrovascular-protective effects of both RAS and
CCBs are attributed to their pleiotropic properties. In the
recent Anglo-Scandinavian Cardiac Outcomes Trial–Blood
Pressure Lowering Arm (ASCOT–BPLA), older antihyper-
tensive agents (β-blockers and diuretics) were compared with
newer antihypertensive drugs (the CCB, amlodipine, and the
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STATE OF THE ART
ACE inhibitor, perindopril). The results showed significant
advantage for the CCB/ACE inhibitor combination in lowering
stroke frequency.69 In the ASCOT lipid-lowering arm, there
was evidence of a further advantage for patients on a lipophilic
statin (atorvastatin) when used in combination with the CCB/
ACE inhibitor combination, as compared to the β-blocker/
diuretic regimen.70 The basis for this benefit may be due to
synergistic effects with atorvastatin on endothelial-dependent
NO release and reactive oxygen species mechanisms.71
Rationale For Calcium Channel/Ras Blockade
Combination Therapy
Certain lipophilic CCBs and RAS antagonists have ancillary and
synergistic effects that enhance NO bioavailability, reduce oxi-
dative stress, and suppress inflammatory responses. Evidence
from preclinical and clinical studies suggests that the comple-
mentary mechanisms of these drug classes provide greater effi-
cacy when used in combination. The pleiotropic effects of RAS
and CCBs on the mechanisms underlying hypertensive vascu-
lar disease, coupled with the efficacy of combination therapy on
reducing central aortic pressure, indicate the beneficial effects
that this combination has on patient outcomes.
Angiotensin II is a major mediator of oxidative stress, reduc-
ing NO activity by NAD(P)H oxidase activation, resulting in
the production of the superoxide anion. This molecule also
contributes to inward calcium current modulation in the fail-
ing heart.72 In atrial fibrillation, calcium influx via L-voltage-
sensitive calcium channels plays a crucial role in atrial
excitation–contraction coupling.73 Angiotensin II increases
transcription of the α1C subunit of L-voltage-sensitive cal-
cium channels in atrial myocyte, while losartan and simvas-
tatin, which inhibit NAD(P)H oxidase activity and reactive
oxygen species generation, attenuate L-voltage-sensitive cal-
cium channel current.74–76 These data suggest that combin-
ing calcium channel and RAS blockade may be more effective
than monotherapy. In a cuff-induced vascular injury model,
coadministration of azelnidipine and olmesartan at nonhypo-
tensive doses significantly inhibited VSMC proliferation and
neointimal formation in wild-type mice, while azelnidipine or
olmesartan alone at these lower doses did not affect neointimal
formation.77
In Dahl salt-sensitive rats, the animals developed hyperten-
sion, aortic hypertrophy, proteinuria, and endothelial dys-
function.78 Amlodipine (10 mg/kg/day) significantly reduced
SBP, aortic hypertrophy, and proteinuria, whereas benazepril
(40 mg/kg/day) significantly reduced proteinuria without
significantly lowering SBP. The CCB/ACE inhibitor combi-
nation was more effective than monotherapy, normalizing
SBP and proteinuria. Moreover, both the CCB and the ACE
inhibitor alone significantly improved endothelial-dependent
relaxation.
1081
 STATE OF THE ART
Comparable results were seen in a myocardial infarction model
in rats.79 Five weeks after occlusion of the left anterior descend-
ing artery, cardiac interstitial fluid levels of NO metabolites and
inflammatory mediators were measured. Cardiac ischemia sub-
stantially reduced NO levels, but treatment with amlodipine
restored NO levels (Figure  6). Treatment with benazepril also
increased NO levels, although to a lesser extent. When the CCB
and ACE inhibitor were administered in combination, NO levels
were further increased. In contrast, treatment with hydrochloro-
thiazide did not affect NO or inflammatory mediator levels.
Clinical studies show that the combination of amlodipine
and an RAS blocker produces significantly greater reductions
in BP than either agent alone.80–83 In a randomized, crossover
trial of hypertensive patients with type 2 diabetes, amlodipine
treatment significantly increased tissue plasminogen activator
(t-PA) activity with no effect on plasma plasminogen activator
inhibitor-1 (PAI-1) activity while the ACE inhibitor benazepril
significantly decreased PAI-1 activity with no effect on t-PA
activity; however, combination therapy resulted in both a signifi-
cant increase in t-PA activity and a significant decrease in PAI-1
activity.84 In hypertensive patients with at least one additional
risk factor for endothelial dysfunction, amlodipine/benazepril
combination treatment vs. amlodipine significantly increased
flow-­mediated vasodilation.85 These findings suggest that com-
bining a CCB with an ACE inhibitor may improve endothelial
function and slow the atherogenic process. In addition, prelimi-
nary results released from the recent Avoiding Cardiovascular
Events  through Combination Therapy in Patients Living With
Systolic Hypertension (ACCOMPLISH) study demonstrated
­superiority for the combination of amlodipine with an ACE
3.0
†
2.5
*
2.0
NOX (µmol/l)
1.5
*
1.0
‡ FGF and ERK 1/2 activation
0.5
0.0
Sham 30-Min 30-Min 30-Min 30-Min 30-Min
Ischemia Ischemia Ischemia Ischemia Ischemia
+ + + +
Amlodipine Benazepril HCTZ Amplodipine
+
Benazepril
Figure 6 | Change in cardiac interstitial fluid levels of nitric oxide metabolites
(NOX) at 5 weeks after occlusion of the left anterior descending artery. Rats
were treated with amlodipine 10 mg/kg/day, benazepril 40 mg/kg/day, a
combination of amlodipine and benazepril, hydrochlorothiazide 3 mg/kg/day,
or placebo (5% dextrose in water) starting 3 days after occlusion. *P < 0.05 vs.
placebo, †P < 0.001 vs. placebo, and ‡P < 0.01 vs. sham control. Adapted with
permission from ref. 79.
1082
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Hypertensive Vascular Disease
inhibitor vs. a diuretic in reducing cardiovascular events, despite
similar ­reductions in BP. This new trial, pending official publica-
tion, suggests a ­benefit for the CCB/ACE inhibitor combination.
Conclusions
Central arterial pressure, determined by cardiac output and
peripheral vascular resistance, as well as by arterial stiffness and
the timing and magnitude of pressure wave reflections, may be
a stronger predictor of cardiovascular events and response to
antihypertensive therapy than brachial BP. Calcium channel and
RAS blockers have ancillary and synergistic properties that may
contribute to their clinical benefit (Figure 7). These drugs lower
brachial BP to a similar extent as other antihypertensive agents,
including diuretics and β-blockers. However, as shown in the
CAFE study, a CCB/ACE inhibitor regimen produced signifi-
cantly greater reductions in central aortic SBP and pulse pressure
than a β-blocker/diuretic regimen, despite comparable reduc-
tions in brachial SBP.28 Moreover, CCBs, ACE inhibitors, and
ARBs have been shown to reduce the central aortic augmentation
index, consistent with a reduction in arterial stiffness.30,31,33,34
From a mechanistic perspective, CCBs and RAS blockers
improve endothelial function and reduce oxidative stress and
inflammation in the arterial vasculature. More important,
these drug classes enhance the bioavailability of NO, which
has vasodilatory properties and protects the endothelium from
atherogenic and thrombotic stimuli. Because hypertensive
patients have defects in endothelial function and NO produc-
tion, these drugs offer the potential to further reduce vascular
damage beyond that associated with BP lowering. A number of
clinical trials have demonstrated the efficacy of these agents, in
combination therapy, for lowering BP and improving clinical
Ca2+ Influx Angiotensin II
CCBs RAAS Blockade
SMC proliferation and migration Oxidative stress (SMC, EC)
Cell-cycle initiation/progression Decreased NO bioavailability
Inflammation (NF-κB, TNF-α, CRP)
Platelet aggregation (coagulation)
Fibrinolysis
Arterial remodeling
Vasoconstriction (SMC)
Insulin resistance (via PTP-1B)
ENDOTHELIAL DYSFUNCTION
ATHEROSCLEROSIS
Figure 7 | Rationale for the combined use of calcium channel blocker (CCB)
and renin–angiotensin system (RAS) inhibitors based on pathophysiologic
processes associated with abnormal calcium influx and angiotensin II. RAAS,
renin–angiotensin aldosterone system.
october 2008 | VOLUME 21 NUMBER 10 | AMERICAN JOURNAL OF HYPERTENSION
 Hypertensive Vascular Disease
outcomes. Future study is needed to elucidate fully the poten-
tial of combination therapy for vascular protection.
Disclosure: Dr Mason has received honoraria for speaking and/or serving on
advisory boards for Pfizer, Sanofi Aventis, Forest Laboratories, Novartis, and
Cardax Pharmaceuticals. He has also received independent investigator-
initiated grant/research support from Pfizer, Sanofi Aventis, Forest
Laboratories, Arca Discovery, and Bristol-Myers Squibb. Drs Mizuno and Jacob
have no conflicts of interest to report.
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