Review S131
Angiotensin II: multitasking in the brain
Juan M. Saavedra, Julius Benicky and Jin Zhou
In addition to controlling systemic blood pressure,
angiotensin II (Ang II) has several roles in the brain,
including the regulation of cerebrovascular flow and the
reaction to stress. In order to clarify the central effects of
Ang II and its type 1 (AT1) receptors, we reviewed the
literature reporting recent research on the effects of
pretreatment with the AT1-receptor blocker, candesartan, on
experimental ischemia, cerebrovascular remodeling, and
inflammation in spontaneously hypertensive rats (SHRs),
and the responses to stress induced by isolation and by
cold-restraint. Angiotensin II regulates the brain circulation
through stimulation of AT1-receptors located in the
cerebrovascular endothelium and central pathways. SHRs
express greater numbers of endothelial AT1-receptors and
a central sympathetic overdrive, resulting in pathological
cerebrovascular growth, inflammation, decreased
cerebrovascular compliance, and enhanced vulnerability to
brain ischemia. Sustained central AT1-receptor antagonism
reverses these effects. Sustained reduction of AT1-receptor
stimulation before stress prevents the hormonal and
sympathoadrenal stress responses during isolation and
prevents the gastric ulceration stress response to cold-
restraint, indicating that increased AT1-receptor stimulation
is essential to enhance the central sympathetic response
and the formation and release of corticotropin-releasing
Introduction
Angiotensin II (Ang II), initially described as a peripheral
circulating hormone regulating blood pressure and fluid
homeostasis, has been recognized as a brain neuromodu-
lator inducing fluid and salt intake and blood pressure
increase [1]. There are two closely integrated central Ang
II systems, one responding to Ang II generated in the
brain and stimulating receptors inside the blood–brain
barrier and another with Ang II receptors in circumven-
tricular organs and in cerebrovascular endothelial cells
(Fig. 1), responding to circulating Ang II of peripheral
origin or to locally generated Ang II, or both [1–3]. Ang II
type 1 (AT1) receptors located in selective forebrain and
brain stem structures mediate the classical functions of
brain Ang II, including the control of the hormonal and
central sympathetic systems [2,3]. The selective localiza-
tion of large numbers of AT1-receptors in sensory path-
ways, all limbic structures [4], and the endothelium of
cerebral microvessels (Fig. 1) [5] indicated the possibility
of several additional central roles for Ang II, including the
regulation of the reaction to stress, brain development,
neuronal migration, sensory information and motor
0263-6352 ß 2006 Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
factor (CRF) and arginine vasopressin that occur during
stress. AT1-receptor blocking agents reverse the cortical
alterations in CRF1 and benzodiazepine receptors
characteristic of isolation stress, effects probably related to
their anti-anxiety effect in rodents. Sustained reduction of
Ang II tone by AT1-receptor antagonism could be
considered as a preventive and therapeutic approach for
brain ischemia and stress-related and mood disorders.
Additional preclinical studies and controlled clinical trials
are necessary to confirm the efficacy of this novel
therapeutic approach. J Hypertens 24 (suppl 1):S131–S137
Q 2006 Lippincott Williams & Wilkins.
Journal of Hypertension 2006, 24 (suppl 1):S131–S137
Keywords: angiotensin receptor blockers, renin–angiotensin system, brain
ischemia, stroke, brain inflammation, stress, corticotropin-releasing factor,
vasopressin, anxiety
Section on Pharmacology, National Institute of Mental Health, National Institutes
of Health, Department of Health and Human Services, Bethesda, Maryland, USA
Correspondence and requests for reprints to Juan M. Saavedra, Section on
Pharmacology, DIRP, NIMH, NIH, DHHS, 10 Center Drive, MSC 1514, Building
10, Room 2D-57, Bethesda, MD 20892, USA
Tel: +1 301 496 0160; fax: +1 301 402 0337; e-mail: Saavedrj@mail.nih.gov
Sponsorship: This research was supported by the Intramural Research Program
of the National Institute of Mental Health, NIH, DHHS. The authors thank
AstraZeneca for their supply of candesartan.
activity, cognition, control of emotional responses, and
cerebral blood flow [1–3].
It is of interest that Ang II, a well established cardiovas-
cular hormone, could be proposed as a multitasking
central neuroregulator. Ang II is a phylogenetically old
regulatory system: in invertebrates, it is involved in water
and ion metabolism, immune responses, and neuronal
function [6]. As organisms evolved and increased in
complexity, Ang II was recruited as a regulator of increas-
ingly sophisticated metabolic, circulatory, and neuronal
systems. Thus the participation of Ang II in blood pres-
sure control is a relatively new regulatory role from the
phylogenetic point of view. However, because Ang II was
initially discovered on the basis of its capacity to increase
blood pressure through peripheral vasoconstriction,
research was initially focused on its cardiovascular effects,
and only recently it was realized that it has effects in the
brain beyond blood pressure control.
We will focus on recent research proposing novel func-
tions for brain Ang II, and in particular for AT1-receptors,
 S132 Journal of Hypertension 2006, Vol 24 (suppl 1)
Fig. 1
Localization of angiotensin II type 1 (AT1) receptors in cerebrovascular
endothelial cells. AT1-receptors are localized to the endothelium of a
cerebrovascular arteriole (arrow), as revealed by immunocytochemistry
using an antimouse monoclonal antibody. Modified from Saavedra et al.
[3], with permission.
in the regulation of cerebrovascular flow, brain ischemia
and inflammation, stress, mood disorders, and cognition.
Role of angiotensin II in the regulation of the
cerebral circulation
Hypertension is characterized by alterations in the
cerebral vasculature, including vasoconstriction and
increased pathological growth with proliferation of
smooth muscle, decreased lumen, and decreased vascular
compliance [7]. These changes shift the cerebrovascular
autoregulation towards the right, in the direction of
higher blood pressures [8]. As a consequence, there is
a decreased capacity of cerebral vessels to dilate during
hypoperfusion, increasing the vulnerability to brain
ischemia and stroke. Ang II, through stimulation of
AT1-receptors located in cerebrovascular endothelium
and smooth muscle, is a major factor contributing to these
cerebrovascular alterations [5]. In addition, activation of
AT1-receptors stimulates the central and peripheral
sympathetic system, increasing cerebrovascular vasocon-
striction [9,10]. These observations are supported by
the finding of increased expression of endothelial
AT1-receptors – a signal of increased AT1-receptor
stimulation – in brain microvessels and middle cerebral
artery of spontaneously (genetic) hypertensive rats
(SHRs) when compared with normotensive controls [5].
In SHRs, inhibition of Ang II AT1-receptors with the Ang
II AT1-receptor blocker (ARB) candesartan, an inhibitor
of peripheral and brain AT1-receptors [11], shifts the
cerebrovascular autoregulatory response to the left, in
the direction of lower blood pressures, making the brain
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
more resistant to ischemia [8]. The normalization of
cerebrovascular autoregulation by sustained AT1-recep-
tor blockade obtained by continuous administration of
candesartan for 2 weeks is the consequence of a reversal
of cerebrovascular pathological growth (Fig. 2) [8,12,13].
In SHRs, chronic AT1-receptor blockade significantly
reduced the volume of ischemia and tissue swelling
resulting from middle cerebral artery occlusion with
reperfusion [8] and in the model of permanent distal
middle cerebral artery occlusion (Fig. 2) [13]. The result-
ing increased capacity of the cerebral arteries to dilate, by
increasing collateral flow, reduced the loss of cerebro-
vascular flow in the periphery of the zone of ischemia and
contributed to the neuroprotective effect of the ARBs
[8,13]. Improved cerebrovascular flow is most probably
related to dilatation of collateral vessels. Preservation of
cerebrovascular flow above a crucial threshold of 0.50 ml/g
per min as a result of AT1-receptor blockade was essential
for tissue survival, and the area where cerebrovascular
flow was less than 0.50 ml/g per min correlated well with
the total area of ischemia [13]. Inhibition of the Ang II
system, and not a reduction in blood pressure, is essential
to ensure tissue survival after middle cerebral artery occlu-
sion, because a similar degree of blood pressure reduction
obtained after adrenergic receptor blockade [8] or calcium
channel inhibition [13] did not protect from ischemia.
Normalization of brain arterial compliance requires sus-
tained AT1-receptor blockade [13], paralleling the reversal
of the decreased lumen diameter and increased medial
thickness characteristic of hypertension-induced cerebro-
vascular pathological remodeling (Fig. 2) [14].
An additional mechanism contributing to the regulation
of cerebrovascular compliance is the production of nitric
oxide at specific cellular sites. Ang II increases reactive
oxygen species, enhancing scavenging of nitric oxide
[14]. In the common carotid artery, principal arteries
forming the Willis polygon, and cerebral microvessels
of SHRs, there were lower concentrations of endothelial
nitric oxide synthase (eNOS) mRNA and protein, and
higher concentrations of adventitial inducible NOS
(iNOS) mRNA and protein than in normotensive con-
trols, Wistar–Kyoto (WKY) rats [15]. Decreased cerebro-
vascular expression of eNOS during genetic hypertension
might be responsible for the decreased capacity to vaso-
dilate in response to ischemia, and might influence the
development of pathological remodeling by non-hemo-
dynamic actions [16]. Conversely, increased expression
of iNOS may result in upregulation of nitric oxide
production, leading to induced generation of reactive
oxygen species and inflammation. AT1-receptor blockade
decreased iNOS mRNA and protein and increased eNOS
mRNA and protein in all brain vessels from SHRs,
eliminating the difference in expression of eNOS and
iNOS proteins between SHRs and WKY rats and restor-
ing the eNOS : iNOS ratio [15]. Restoration of eNOS
expression may stimulate production of nitric oxide by
 AT1-receptors in ischemia and stress Saavedra et al. S133

Fig. 2

Angiotensin II type 1 (AT1) receptor antagonism prevents pathological growth of cerebral arteries and protects against brain ischemia. (a) Cross
sections of the middle cerebral artery from a Wistar–Kyoto (WKY) rat and a spontaneously hypertensive rat (SHR) treated with vehicle or the
AT1-receptor blocker, candesartan, 1 mg/kg per day subcutaneously for 2 weeks. Note the enhanced growth in the SHR treated with vehicle, and
the reversal of remodeling after treatment with candesartan. (b) Brain sections from SHRs, treated with vehicle or candesartan as above, before
permanent occlusion of the middle cerebral artery. Note the decreased tissue swelling and infarct area when the rats were pretreated with the
AT1-receptor blocker. Modified from Ando et al. [5], with permission.

Fig. 3

Anti-inflammatory effects of angiotensin II type 1 (AT1) receptor blockade in brain microvessels from a Wistar–Kyoto (WKY) rat treated with vehicle,
a spontaneously hypertensive rat (SHR) treated with vehicle, and an SHR treated with candesartan as in Fig. 2. Note the presence of infiltrating
macrophages attached to the microvessel wall in the SHR treated with vehicle, and the absence of infiltrating macrophages in the WKY rat and the
SHR treated with candesartan. Modified from Ando et al. [5], with permission.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 S134 Journal of Hypertension 2006, Vol 24 (suppl 1)
the endothelium, improving vasodilatation and reversing
the pathological arterial remodeling, an important mech-
anism for neuroprotection during ischemia [17]. Inhi-
bition of iNOS may reduce Ang II-induced generation
of reactive oxygen species, decreasing nitric oxide scav-
enging, cellular damage, and inflammation [18]. The
reversal of the eNOS : iNOS ratio, a restoration of the
balance lost during hypertension that occurs throughout
the entire cerebrovascular system, is associated with the
normalization of brain arterial morphology and with pro-
tection against ischemia.
Chronic inflammation of blood vessels is also important
for vulnerability to stroke in patients suffering from
hypertension and arteriosclerosis. Endothelial dysfunc-
tion with endothelial macrophage adhesion is followed by
their infiltration into the blood vessel wall (Fig. 3) [19].
Alterations in eNOS expression in SHRs correlate with
increased expression of endothelial Ang II AT1-receptor
and intracellular adhesion molecule-1 (ICAM-1), greater
numbers of endothelium-adhering macrophages in
cerebral microvessels and carotid artery, and increased
numbers of perivascular infiltrating macrophages in
microvessels of SHRs – evidence of cerebrovascular
inflammation [5]. In addition, microvessels from SHRs
express enhanced tumor necrosis factor a (TNFa), inter-
leukin-1b, and nuclear factor-kB, and upregulation of
heat shock protein (HSP) genes such as HSP60, HSP70
and HSP90 and heat shock factor-1 [20]. Sustained block-
ade of the AT1-receptor with peripherally administered
candesartan decreases the expression of ICAM-1 to a
level similar to that in WKY rats [5], reduces the number
of perivascular infiltrating macrophages (Fig. 3) [5], and
fully reverses the upregulation of the HSP genes that is
characteristic of SHRs [20].
The reversal of the cerebrovascular inflammation in
SHRs by AT1-receptor blockade demonstrates that
AT1-receptor overstimulation is a molecular mechanism
leading to brain inflammation. The suppression of inflam-
mation in brain vessels suggests important therapeutic
advantages of ARBs, not only in the prevention of brain
ischemia, but also in the treatment of inflammatory
diseases of the brain [2,3].
Role of angiotensin II in stress
Angiotensin II is an important stress hormone. AT1-
receptors are highly concentrated in all parts of the
hypothalamic–pituitary–adrenal axis, including the par-
vocellular paraventricular nucleus, the site of formation of
corticotropin-releasing factor (CRF) [4]. Stress enhances
the production of peripheral and brain Ang II and the
expression of brain and peripheral AT1-receptors, includ-
ing those in the paraventricular nucleus [21–24]. Stimu-
lation of AT1-receptors during stress increases thirst, fluid
retention, and central [25] and peripheral sympathetic
system responses [23], activates the hypothalamic–
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
pituitary–adrenal axis causing increased secretion of
CRF, adrenocorticotropic hormone (ACTH) and corti-
coids, and increases the formation and release of arginine
vasopressin (AVP) [1,23].
The regulation of AT1-receptor expression and stimula-
tion is most important as it determines the level of
activation of the brain Ang II system, and inhibition of
brain AT1-receptors could prevent the response to stress.
Candesartan was used to maintain a sustained decrease in
peripheral and central AT1-receptor stimulation before
the presentation of stress challenge. Pretreatment with
candesartan prevented the following responses to the
stress induced by isolation: enhanced AT1-receptor
expression in the paraventricular nucleus, the increase
in ACTH and decrease in AVP content in the pituitary
gland, the increase in adrenal corticosterone, aldosterone
and catecholamine concentrations, the increase in brain
and adrenal transcription of tyrosine hydroxylase (the
rate-limiting enzyme in catecholamine synthesis), and
decreased urinary AVP and corticosterone concentrations
[23,25]. Thus, prior inhibition of brain AT1-receptors
prevented stress-induced hormonal and sympathoadrenal
stimulation.
The regulation of the stress response by AT1-receptors
includes regulatory effects at higher central levels. Iso-
lation stress in the rat decreases the expression of CRF
type 1 receptor (CRF1) and benzodiazepine binding in
the frontal, parietal, and cingulate cortices – effects
prevented by AT1-receptor inhibition before the stress
challenge [25].
Pretreatment with candesartan was therapeutically
beneficial in a stress-induced disorder, the formation of
gastric ulcers induced by cold-restraint in the rat, dramatic-
ally decreasing the number of gastric ulcerations (Fig. 4)
[26]. The mechanisms involved in the protective effect of
the ARB include reduction of the formation and release of
the stress-induced adrenomedullary catecholamines, pre-
vention of inflammation, and protection of the blood flow
by inhibition of receptors in the endothelium and smooth
muscle cells of arteries located in the gastric mucosa [26].
The anti-inflammatory effects include inhibition of the
enhanced expression of the proinflammatory cytokine
TNFa, ICAM-1, and the number of infiltrating neutro-
phils in the gastric mucosa [26], which have crucial roles in
the progression of gastric injury. Protection of gastric blood
flow and anti-inflammatory effects by ARBs is similar to
the protective effect exerted on cerebral blood flow and
brain inflammation during brain ischemia [5,8,13,15,20].
Role of angiotensin II in mood disorders
and cognition
It appears that overstimulation of AT1-receptors is
linked to anxiety. Mice expressing increased hypothala-
mic–pituitary–adrenal AT1-receptor numbers as a
 AT1-receptors in ischemia and stress Saavedra et al. S135

Fig. 4

Prevention of gastric mucosal lesions induced by cold-restraint stress by pretreatment with angiotensin II type 1 (AT1) receptor blockers. Gastric
mucosa from rats treated with (a) vehicle or (b) the AT1-receptor blocker candesartan, for 2 weeks before being submitted to cold-restraint. Sections
of the glandular portion of the stomach in animals treated with (c) vehicle or (d) candesartan, for 2 weeks before being submitted to cold-restraint
stress. Note that pretreatment with candesartan prevented the development of stress-induced gastric ulcers. Bar represents 100 mm. (e) Number of
lesions in animals treated with vehicle (&) or pretreated with candesartan (&). P < 0.05 compared with stress vehicle. Modified from Bregonzio
et al. [26], with permission.

consequence of a gene deficiency in AT2-receptors [27]
exhibit anxiety behavior [28]. The benzodiazepine bind-
ing site is part of the g-aminobutyric acid type A (GABAA)
receptor complex, regulating, in higher centers, the
response to anxiety [29]. As ARBs prevent the stress-
related decrease in benzodiazepine binding, protecting
GABAA function, AT1-receptors may be involved in
higher regulatory mechanisms controlling the behavioral
and cognitive responses to stress and anxiety. In the
elevated plus maze, a model representative of anxiety-
related behavior, candesartan pretreatment significantly
enhanced the number of entries into the open arm and
the time spent in the open arm, indicating a clear anxio-
lytic effect of the ARB. This effect is similar to that found
after peripheral administration of other ARBs such as
losartan [30].
Some preclinical and clinical evidence suggests that an
overactive brain Ang II system could be implicated in the
mechanisms leading to depression. Antidepressants
reduce drinking and the vasoconstriction elicited by
Ang II [31]. In hypertensive, depressed individuals,
the angiotensin-converting enzyme (ACE) inhibitor,
captopril, improved mood – an effect not detected with
other antihypertensive medications [32–34].
The role of Ang II in cognition has been studied by
administration of ACE inhibitors or ARBs. It appears that

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 S136 Journal of Hypertension 2006, Vol 24 (suppl 1)
both ACE inhibitors and ARBs are able partially to
reverse cognitive deficits in animal models [35]. There
is some anecdotal evidence, mostly from quality-of-life
measures in hypertensive patients treated with a number
of different antihypertensive medications, that blockade
of the Ang II system with the ARB, losartan, can improve
cognition in humans [36–38]. It is possible that cognitive
improvement in hypertensive individuals and elderly
patients is partially related to improvement in the
cerebral circulation, as inhibition of AT1-receptors
improves cerebrovascular compliance, reduces pathologi-
cal cerebrovascular growth, reduces cerebrovascular
inflammation, and protects the brain from ischemia
[5,8,12,13,15]. In support of this hypothesis, increased
AT1-receptor immunocytochemistry has been reported
in association with microvessels in Alzheimer’s dementia
[39].
Evidence from the literature indicates that mood dis-
orders are associated with abnormal responses to stress
[40]. Inhibition of CRF1-receptors or AVP V1 type and V3
type receptors reduces anxiety in animal models, and a
number of CRF1, V1, and V3 receptor antagonists are
under development for the treatment of mood disorders
and stress-related conditions [40]. Conversely, adminis-
tration of atrial natriuretic peptide (ANP) reduces anxiety
in animal models and in humans [40]. All these com-
pounds share the common properties of reducing the
CRF and AVP overdrive, decreasing hormonal and sym-
pathetic response to a number of stressors, and reducing
stress-induced anxiety, depression, and other behavioral
alterations.
Angiotensin II regulates the formation and release of
CRF and AVP, and the central and peripheral sympath-
etic systems, and is a physiological antagonist of ANP
[1,40]. This explains why a reduction in Ang II tone by
long-term inhibition of its physiologically active AT1-
receptors decreases CRF and AVP overdrive and pro-
motes the effects of ANP [40], explaining the anti-stress
and anti-anxiety effects of ARBs.
Conclusions
Peripheral and brain Ang II, through stimulation of
cerebrovascular and brain AT1-receptors, contributes to
regulation of the circulation to the brain. Genetic hyper-
tension in rodents is characterized by an AT1-receptor
and central sympathetic overdrive, producing pathologi-
cal cerebrovascular growth, inflammation, and decreased
cerebrovascular compliance. This leads to increased
vulnerability to brain ischemia in hypertension. Sus-
tained central AT1-receptor antagonism with a peripher-
ally administered ARB that crosses the blood–brain
barrier reverses the pathological cerebrovascular growth
and inflammation, normalizes brain vascular compliance,
and reduces brain edema and ischemia resulting from
experimental stroke. The degree of stimulation of brain
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
and cerebrovascular AT1-receptors is a major factor deter-
mining the cerebrovascular compliance and inflammation
during hypertension and the response to brain ischemia.
Angiotensin II is an important stress hormone, regulating
CRF, AVP, and the sympathetic system response to
stress. Increased stimulation of the AT1-receptor during
stress is essential to enhance the central sympathetic
response and the formation and release of CRF and
AVP. Sustained reduction of AT1-receptor stimulation
before stress prevents the hormonal and sympathoadrenal
responses during the stress of isolation, and prevents
gastric ulcerations as a consequence of cold-restraint
stress. ARBs are also able to reverse the cortical altera-
tions in CRF1 and benzodiazepine receptors character-
istic of isolation stress – effects probably related to their
clear anti-anxiety effect in rodents.
On the basis of suggestive preclinical evidence, prelimi-
nary clinical observations, and evidence from the litera-
ture, it is tempting to speculate that sustained reduction
of Ang II tone by AT1-receptor antagonism should be
considered as a preventive and therapeutic approach to
brain ischemia and stress-related and mood disorders.
Additional preclinical studies and controlled clinical
trials are necessary to confirm the efficacy of this novel
therapeutic approach.
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