REVIEW PHYSIOLOGY 36: 160–173, 2021. Published April 21, 2021; doi:10.1152/physiol.00036.

2020

Angiotensin Receptor Blockers Are Not Just Juan M. Saavedra

Department of Pharmacology and Physiology, Georgetown
for Hypertension Anymore University Medical Center, Washington, District of Columbia
[email protected]

Beyond blood pressure control, angiotensin receptor blockers reduce common

injury mechanisms, decreasing excessive inflammation and protecting endothe-
lial and mitochondrial function, insulin sensitivity, the coagulation cascade,
immune responses, cerebrovascular flow, and cognition, properties useful to
treat inflammatory, age-related, neurodegenerative, and metabolic disorders of
many organs including brain and lung.

angiotensin receptor blockers; COVID-19; estrogen; inflammation;

neuroprotection

Introduction (ACE) (1). ACE generated the active effector of the sys-
tem, circulating angiotensin II [ANG II or ANG (1–8)].
Increasing evidence demonstrates that the renin-an- The discovery and characterization of specific ANG II
giotensin system (RAS) participates in the function of receptors completed the initial understanding of the
most organs and that excessive, dysregulated RAS ac- canonical RAS (renin/angiotensinogen/ANG I/ACE/
tivity is directly associated with increased allosteric ANG II/ANG II) receptors (2, 3). This system was initially
load and the development of multiple disorders. A described as a principal regulator of blood pressure
group of compounds, the angiotensin receptor block- and fluid metabolism (1). Reduced ANG II production
ers (ARBs), normalize the RAS overactivation and with ACE inhibitors (ACEI) or blockade of ANG II recep-
exhibit multiple protective effects beyond their regula- tors effectively reduced hypertension and cardiovas-
tion of cardiovascular, renal, and metabolic disease. cular disorders (2) and became standard therapy for
These pleiotropic properties, including their strong these conditions (2, 3).
anti-inflammatory effects and their capacity to protect
the endothelium, indicate that these compounds are The Current View of the Renin-Angiotensin
excellent candidates for the treatment of many disor- System
ders. The present review will focus on some of the
most relevant and novel information and mechanisms The complexity of the RAS has more recently been
of action supporting the possible therapeutic role of increased and continues to be expanded with the dis-
ARBs on brain and age-related disorders, behavior, covery of additional enzymes and peptide fragments
estrogen deficiency, lung disease, and COVID-19. that are always proposed as important modulators of
ANG II activity and participants of protective mecha-
The Renin-Angiotensin System and nisms (3). Analysis of this expanding system is beyond
the Angiotensin Receptor Blockers the scope of the present review.

This section describes the RAS, its physiologically Development of Selective, Orally Active AT1R
active AT1 receptors (AT1Rs), and their selective block- Blockers
ers, the ARBs. It emphasizes the AT1 receptor distribu-
The use of nonpeptide inhibitors of ANG II receptors
tion throughout the body, the pathophysiological
revealed that this peptide could bind to two different
relevance of excessive AT1 receptor stimulation, and
sites, identified as AT1 and AT2 receptor types, and that
the general and molecule-specific characteristics of
inhibition of ANG II AT1 receptors abolished most, if not
the individual ARBs.
all, the effects of ANG II stimulation (2, 3). The AT1 recep-
The Canonical Renin-Angiotensin System tor belongs to the class of G protein-coupled receptors
(GPCRs), a large group of proteins located at the cell sur-
The canonical RAS was slowly established with the ini- face and activating cellular responses after detection of
tial discovery of renin as a hypertensive agent found agonists outside the cell. For the AT1 GPCR, the canoni-
in the kidney (1). Many years later, it was found that re- cal agonist is ANG II, although other mechanisms of re-
nin acted on a protein substrate present in plasma, an- ceptor activation have been described, such as reverse
giotensinogen, produced in the liver, to generate agonism, not only for AT1 receptors but also for other
angiotensin I (ANG I) (1). In turn, ANG I was established GPCRs (4) (see below). Since the AT1 receptors were
as a substrate for angiotensin-converting enzyme considered the physiological effectors of ANG II activity,

160 1548-9213/21 Copyright © 2021 Int. Union Physiol. Sci./Am. Physiol. Soc.

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 REVIEW
AT1 receptor inhibitors are commonly referred to as ANG these compounds. In particular, the section focuses
II receptor blockers (ARBs). on the major anti-inflammatory effects, the normaliza-
ARBs are selective, orally active, safe compounds tion of the coagulation cascade, and the regulation of
blocking excessive AT1 receptor activity, and their de- the expression of multiple genes involved in all major
velopment was a major advance in the treatment of aspects of cellular function.
high blood pressure, cardiovascular and renal dis-
ease, and diabetes (2, 5–7). Binding techniques using Anti-Inflammatory Effects
these selective blockers revealed the presence of AT1
receptors in most, if not all, tissues studied, suggesting A most relevant effect is the control of dysregulated,
that AT1 receptor activity may regulate organ function excessive inflammation associated with increased AT1
throughout the body (8–19). Of special interest is the receptor activity, both in the circulation and in the pa-
demonstration, with accepted techniques (autoradiog- renchyma of multiple organs (25, 27–29). Reduction
raphy, in situ hybridization, or qPCR) of AT1 receptors of inflammation by ARBs, at low doses not affecting
in vascular endothelial cells (20–22). This substanti- blood pressure, plays a fundamental role in the
ates the relevance of AT1 receptors in endothelial decreased endothelial and vascular senescence, an
function in multiple organs and of their major patho- early universal injury mechanism (20, 21, 23–26, 30).
physiological significance (23, 24). Additional research Inflammatory factors reduced by ARBs include, but
demonstrated that AT1 receptor stimulation played im- are not limited to, decreased cytokine and chemokine
portant physiological roles and that receptor overac- production and reduction of the NOD-like receptor
tivity is a major injury factor associated with increased family, pyrin domain containing 3 (NLRP3) inflamma-
allostatic load, the cost of exposure to chronic and some and NF-κB activation, as detailed in FIGURE 1.
repeated stressors, and the effects on multiple organs
including the brain (25, 26) (FIGURE 1). Regulation of the Coagulation Process

ARBs reduce the prothrombotic state resulting from

Pleiotropic Effects of ARBs beyond age-dependent AT1 receptor stimulation by reducing
Blood Pressure Control inflammation, endothelial dysfunction, platelet reactiv-
ity and aggregation, and plasminogen activator inhibi-
This section describes the pleiotropic effects of ARBs, tor 1 activity by direct effects on platelets, the
responsible for the expanding therapeutic range of endothelium and coagulation factors (3, 31–36), as

FIGURE 1. Mechanisms of action, principal protective effects, and influence of angiotensin receptor blocker (ARB) treatment beyond car-
diovascular, renal, and metabolic disorders
ARB effects are group specific, molecule specific, not related to ANG II, or by modulation of non-AT1 receptors. Principal mechanisms of action include reduc-
tion of inflammation, prothrombotic state, and genomic instability, regulation of innate and adaptive immunity, and protection of endothelium, mitochondrial
function, cerebral vasculature and blood-brain barrier, and cognition. ARB therapeutic effects are noted in aging, obesity, Alzheimer’s and Parkinson’s dis-
ease, brain damage, stress, lack of estrogens and osteoporosis, pneumonia and lung fibrosis, and liver steatosis and inflammation. PPARc, peroxisome prolif-
erator-activated receptor-c; TLR, Toll-like receptor.

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REVIEW
well as the regulation of the expression of genes pre- approved ARBs include losartan, candesartan, telmi-
disposing to thrombosis (28, 37). For these reasons sartan, valsartan, irbesartan, azilsartan, eprosartan,
ARBs may be effective on the treatment of age-related and olmesartan. Most ARBs share common chemical
prothrombotic states and those present during structures such as biphenyl-tetrazole or imidazole
COVID-19 (38–40) (FIGURE 1). groups, responsible for their AT1 receptor binding
specificity and their class-specific effects. Some of
Gene Regulation them have unique structures and physicochemical
properties that determine differences in pharmacoki-
Bioinformatic analysis of injured neuronal and micro-
netic, tissue penetration and distribution, metabolism,
glia cultures treated with ARBs and correlated with
and excretion profiles (53–56). However, all ARBs
transcriptomes from multiple independently published
share similar principal targets involved in their regula-
age and senescence-related, neurodegenerative dis-
tion of blood pressure, resulting from AT1 receptor
eases and COVID-19 databases revealed that ARBs
blockade predominantly in blood vessels and renal tu-
normalize the expression of hundreds of genes
bular cells (54).
altered in these disorders (37, 41–43). The normaliza-
Some ARBs have molecule-specific effects, not
tion of altered gene expression as a result of ARBs
shared by all members of the group. A most important
treatment is associated, in addition to inflammation
effect is the partial agonism of PPARc, a property of
and oxidative stress, to all principal cellular alterations
telmisartan, candesartan, and irbesartan (53, 55, 56).
including apoptosis, mitochondrial dysfunction, and
PPARc activation has also have been identified as in-
metabolic disorders such as reduced insulin sensitiv-
dependent of the AT1 receptor (56). PPARc is a major
ity, to genomic instability; to the increased tendency
regulator involved in multiple processes including but
for DNA mutations or changes occurring during cell di-
not limited to lipid and glucose metabolism, regulation
vision, and to all aspects of altered innate and adapt-
of excessive inflammation, and protection of the cere-
ive and immune responses and reduction of cognition
bral blood flow (57). PPARc activation by ARBs amelio-
(37, 41–43).
rates neurodegenerative processes by activating anti-
It is now increasingly recognized that ARBs use may
inflammatory mechanisms and reducing oxidative
be beneficial for the treatment of multiple disorders,
stress and neuronal injury and death in models of
and recent results set up the stage for investigation of
stroke and traumatic brain injury (57–62) and reduces
novel ARBs effects everywhere in the organism. For
inflammation in neurons and human monocytes (63,
example, telmisartan, an ARB with potent peroxisome
64). However, the role of PPARc activation by ARBs is
proliferator-activated receptor-c (PPARc)-activating
not universal and it is dependent on the model studied
properties, reduces oxidative stress, inflammation,
(54) (FIGURE 1).
and fibrogenesis, improving insulin sensitivity and pro-
tecting lipid metabolism in patients with nonalcoholic Effects in the Absence of ANG II
fatty liver disease, a disease with no effective therapy
(8, 44). It has been reported that both AT1R blockade ARB effects have been repeatedly demonstrated to
and PPARc activation are important for the beneficial occur in the absence of ANG II in neuronal and micro-
effects of telmisartan, and it was suggested that telmi- glia cultures (37, 41–43, 65) and can be explained by
sartan is the ARB of choice in this condition (8). reverse agonism (54, 66), a phenomenon not exclu-
In addition, numerous studies are reporting that sive of AT1 receptors but shared by other GPCRs (4). In
ARBs may be beneficial as adjunct treatment for can- addition, reverse antagonism may be the mechanism
cer therapies (45–52). of AT1 receptor inhibition following receptor activation
by mechanical stretch, which stabilizes b-arrestin-bi-
Individual Characteristics of ARBs ased conformations different from those activated by
and Mechanisms of Their Cellular ANG II (67) (FIGURE 1).
Effects
Effects Beyond AT1 Receptor Blockade
This section addresses class-specific effects of ARBs
There are many indications of ARB effects beyond AT1
and individual, molecule-specific effects of individual
receptor blockade, including strong evidence of anti-
members of the group and different mechanisms of
inflammatory and other protective effects in cells not
ARB effects in cells.
expressing AT1 receptors (42, 63, 68). ARB effects
Individual Characteristics of ARBs: Class- have also been identified even in cells devoid not only
Specific and Molecule-Specific Effects of AT1 receptors but also of PPARc (42) (FIGURE 1).
The microglia-like BV2 cell line, not expressing AT1
Following the development of the first orally active receptors or PPARc activation, was used to determine
ARB, losartan (7), several additional ARBs have been the effects of telmisartan. Cultured BV2 cells, in the
marketed initially as antihypertensive compounds. At absence of ANG II, were injured with endotoxin [lipo-
present, in the U.S., Food and Drug Administration- polysaccharide (LPS)] with and without telmisartan.

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Genome-wide expression profiling and pathway analysis small ANG II concentrations detected in brain tissue
demonstrated that telmisartan normalized the expres- represent circulating peptide bound to AT1 receptors
sion of hundreds of genes altered by LPS and involved in endothelial and smooth muscle cells of the cerebro-
in apoptosis, inflammation, oncological, and viral and vascular microcirculation and not formed in the brain
neurodegenerative disorders, including the proinflam- parenchyma (79–83). ANG II may also be produced
matory Toll-like receptor 2 (TLR2). Furthermore, Gene from circulating ANG I in cerebrovascular endothelial
Set Enrichment Analysis (GSEA) and Gene Ontology cells expressing ACE (80, 84). ANG II levels may
analysis (GO) revealed significant negative correlations increase when the blood-brain barrier is disrupted dur-
of telmisartan modulated genes with multiple genes in ing hypertension or systemic inflammation (25, 80).
independently published databases involved in Increased ANG II levels may also be found at sites out-
neurodegenerative, metabolic, and toxic disorders side the blood-brain barrier such as the circumventric-
and positive correlations with gene sets participat- ular organs (25, 80). In these cases, information may
ing in neuroprotective mechanisms. Ingenuity be transmitted to areas rich in AT1 receptors, with their
Pathway Analysis (IPA) revealed a negative correla- activity dependent on the regulation of the receptor
tion with proinflammatory upstream regulators and a number (25). This explains how circulating ANG II con-
positive association with neuroprotective upstream reg- trols pituitary and central sympathetic functions during
ulators (42). In addition, the effects of the ARB telmisar- stress, cerebral blood flow, and flow to other brain
tan were positively correlated with upregulated genes areas involved in sensory information, motor activity,
in rodent models of caloric restriction, associated with emotional responses, and cognition, both in the
prolongation of life (42) (FIGURE 1). rodent and the human brain (85, 86) (FIGURE 1).
We conclude that major protective effects of telmisar- Uncontrolled brain inflammation associated with AT1
tan were the result of activation or blockade of alterna- receptor overactivation is the common mechanism
tive receptors or pathways (42). A candidate group is explaining the comorbidity between alterations in
the TLRs, pattern recognition receptors localized in cerebrovascular flow and mood disorders such as
cells participating in innate and adaptive immunity as major depression, dysfunctional responses to stress,
well as in epithelial and endothelial cells and fibroblasts and neurodegenerative disorders (87–92). Substantial
(69). There is an inverse relationship between AT1 evidence supports ARBs neuroprotective effects on
receptors and TLR activity. TLR receptor activity and age-related disorders including stroke, Alzheimer’s
gene expression of their downstream pathways are and Parkinson’s disease, and their associated risk fac-
enhanced by AT1 receptor stimulation and reduced by tors including traumatic brain injury, brain ischemia,
ARBs administration in many in vitro and in vivo models and diabetes, all conditions leading to alterations in
by both AT1-dependent (43, 70–75) and -independent cerebral blood flow and hypoxia, increased inflamma-
mechanisms (42, 76, 77) (FIGURE 1). tion, endothelial dysfunction, and neuronal injury and
Additional evidence for non-AT1 receptor effects of comorbid with depression and chronic emotional
ARBs was reported in cultured human circulating stress (25, 26, 93–97). Preclinical studies and mecha-
monocytes not expressing AT1Rs. In these cells, the nisms of action of the protection of the cerebrovascu-
ARB candesartan reduced inflammation produced by lar circulation by ARBs have been extensively
LPS at concentrations like those found in obesity, insu- reviewed elsewhere (26, 61), and ARBs have been
lin resistance, and diabetes, including reduction of re- proposed as a first-line treatment for stroke preven-
active oxygen species (ROS) formation and NF-κB tion (98–100). Similarly, ARBs are effective in traumatic
activation (25, 63, 68). Furthermore, the ARB valsartan brain injury; reducing lesion volume, neuronal injury
suppressed, when given orally to normal subjects, astrogliosis, microglial activation, and inflammation,
ROS generation and NF-κB in their polymorphonu- inducing microglia M2 polarization, and protecting cer-
clear and mononuclear cells (78). ebral blood flow, neurological performance, and cog-
nition (60, 62, 101, 102) (FIGURE 1).
Effects of ARBs in Brain and Brain-
Related Disorders Effects of ARBs on Stress, Quality of Life,
Anxiety, Depression, and Other
This section addresses the current understanding of Neuropsychiatric Conditions
the role of ABSs in brain, their beneficial effects on
Increased brain AT1 receptor stimulation is associated
brain-related disorders, the therapeutic effects on
with dysregulated and enhanced hormonal and sym-
neurodegenerative disorders, and the antiaging prop-
pathetic responses during stress and frequently asso-
erties of these compounds.
ciated with inflammation, anxiety, and depression (26,
Brain ANG II and AT1 Receptors 103, 104). There is a good correlation between the
antistress, antianxiety, antidepressant, anti-inflamma-
There is strong evidence that there is no parenchymal tory, and cerebrovascular-protective effects of ARBs.
production of ANG II in the brain. The exceedingly AT1 receptor blockade normalized the hypothalamic-

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pituitary-adrenal axis and brain and peripheral sympa- receptor blockade at low doses not affecting blood
thetic responses and reduced anxiety in all rodent pressure (132–136). Long-term ARB administration or
models of stress including isolation, restraint, cold life-long depletion of AT1 receptors prolongs life (106,
temperature, LPS-induced inflammation, shock, and 137–139) and ARBs are of superior benefit when com-
open field with no escape available in normal rodents pared with other antihypertensive therapies for the
and in those with enhanced vulnerability to stress, preservation of cognition (99, 120, 140–142). There is
anxiety, and depression and reduced anxiety and cog- substantial evidence in favor of a beneficial role of
nitive loss in prematurely ovariectomized rodents (71, ARBs on Alzheimer’s disease (141, 143–145) and
105–113). ARBs also attenuated acute gastric ulcera- Parkinson’s disease (95, 146–148), and these studies
tions as a consequence of the combination of cold have been extensively reviewed (26, 97) (FIGURE 2).
and restraint stress (114, 115) (FIGURE 1). To determine molecular mechanisms of ARBs neu-
Enhanced AT1 receptor activity is associated with roprotection in age-related disorders, a culture of pri-
depression and anxiety (110, 116), and ARBs improve mary rat neurons was incubated in the absence of
quality of life, decrease stress, anxiety, and depression ANG II with excitotoxic concentrations of glutamate, a
by partially restoring diminished sexual activity (117). primary early injury factor in age-related disorders of
ARBs also improve the efficacy of antidepressants, the brain, with and without addition of candesartan
not only in hypertensive subjects, but also in normo- (41). Genome-wide expression profiling and pathway
tensive patients (117–123). Beneficial effects were also analysis demonstrated that candesartan normalized
described for mood disorders (124, 125), schizophrenia the expression of hundreds of genes upregulated by
(126, 127), and posttraumatic stress disorder in rodent glutamate injury and involved in aging and senes-
models (128–130) and in humans (131). Lack of con- cence hallmarks such as upregulated inflammation,
trolled clinical studies prevents the determination of oxidative stress, alterations in cell cycle, genomic
the role of ARBs on these disorders. instability, cardiovascular disease, diabetes, mitochon-
drial dysfunction, amyloid b-metabolism signal trans-
Effects of ARBs on Age-Related Disorders duction pathways, and the senescent-associated
secretory phenotype (41) (FIGURE 2).
Allostatic load is strongly dependent on time, corre- GSEA demonstrated a positive correlation of gluta-
lates with AT1 receptor overactivity and microvascular mate-induced changes with similar alterations in gene
senescence, and this process is ameliorated by AT1 expression found in independently published gene

FIGURE 2. Angiotensin receptor blocker (ARB) treatment normalized the expression of multiple genes
enriched in all aging and senescence databases studied
These genes participate in all hallmarks of aging and senescence; associated disorders; Gene Ontology categories such as
inflammation, apoptosis, integrin signaling and extracellular matrix, and immune, cardiovascular, and pharmacogenomic asso-
ciated disorders; and pathways including signal transduction, T-cell differentiation and immune response, proliferation, cell mo-
tility, and secretion and exocytosis.

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sets of autopsy samples from hippocampus of cardiovascular, metabolic, cerebrovascular and
Alzheimer’s disease patients (41) and with multiple kidney diseases, and obesity (2, 176), and amelio-
brain and peripheral aging and senescence datasets rate pneumonia in COVID-19 patients (176–178).
obtained from different tissues, different array plat- Associated findings include reduced IL-6 in periph-
forms, and different species including several areas of eral blood, increased CD3 and CD8 T cell counts,
the aging human brain (43), and there was a very sig- lower concentrations of high-sensitivity C-reactive
nificant negative correlation between the genes protein and procalcitonin, and reduced peak viral
altered by glutamate and responding to candesartan load (177, 179).
with those genes affected in all databases studied (41, The direct efficacy of ARBs treatment in coronavirus
43). In both studies, IPA and GO analysis identified infections has been demonstrated in a clinically rele-
hundreds of genes involved in inflammation, oxidative vant mouse model of acid aspiration (180). In this
stress, neurodegeneration, microvascular alterations, model, in vivo injection of recombinant SARS-CoV
apoptosis, the immune response, and all principal Spike protein [Spike(S-1190-Fc)] worsened lung injury
mechanisms of cellular and organism injury (41, 43) and pulmonary edema (180), and these effects were
(FIGURE 2). These results may be interpreted as evi- reduced by in vivo administration of the ARB losartan
dence of ARB amelioration of pathological processes (180). There are accumulating data warranting consid-
in age-related disorders, based on two sequential eration of the use of ARBs in the therapeutic arsenal
and/or concomitant processes: enhanced inflamma- to treat COVID-19 (177, 181–183). Furthermore, a recent
tion and oxidative stress in microvascular endothelial GSEA compared the effects of candesartan on gene
cells and neuronal injury (30, 149–151) (FIGURE 2). expression in injured neurons with alterations in gene
expression of SARS-CoV-2 and COVID-19 human tran-
Effects of ARBs on Lung Function scriptomes (37). There were highly significant positive
and COVID-19 correlations between the upregulation of hundreds of
genes associated with SARS-CoV-2 infection and
This section describes the beneficial effects of ARBs those upregulated by neuronal injury that were nega-
on lung function and their anti-inflammatory, protec- tively correlated with genes normalized by candesar-
tive effects on COVID-19. tan in neuronal cultures. Gene Ontology analysis
revealed common gene signatures corresponding to
ARBs Effects on Lung Function candesartan’s beneficial effects: cytokine and chemo-
kine activity, chemokine receptor binding, cytokine-
AT1 receptors are highly expressed in lung (14, 152,
mediated signaling pathways, NF-κB complex, cellular
153), and AT1 receptor overactivity impairs lung func-
response to type I interferon, type I interferon signal-
tion, increases production of proinflammatory cyto-
ing pathway, response to interferon-c, and response
kines, injures the microvascular endothelium,
to virus, including pattern recognition receptors such
enhances epithelial cell apoptosis and neutrophil
as TLR4 and their associated genes (37). Using IPA
recruitment, impairs the lung’s capacity to clear
upstream regulator analysis, we generated a potential
edema, and is associated with the development of fi-
list of drugs and transcription factors that may be con-
brosis (153–162). Conversely, ARB administration
sidered to normalize the altered gene expression in
ameliorates the AT1 receptor-induced alveolar epithe-
COVID-19, including dexamethasone, immunoglobu-
lial cell apoptosis, the LPS-induced acute lung injury,
lin, anti-inflammatory, and immune-suppressing drugs
and lung edema and the increased production of
and also b-estradiol, supporting the association
inflammatory mediators (154–157, 159). In animal mod-
between beneficial effects of estrogens and ARBs (37)
els, ARBs delay the onset of acute respiratory distress
(FIGURE 3).
syndrome, inhibit neutrophil recruitment, reduce sep-
The results demonstrate that candesartan nor-
sis and ventilation-induced lung injury and hypoxia-
malized the expression of many genes that are
induced inflammation, and decrease the development
characteristic of the COVID-19 cytokine storm and
of fibrosis (160, 163–166).
of the development of pulmonary fibrosis (37), sug-
In humans, AT1 receptor expression is enhanced in
gesting that ARBs treatment may not only amelio-
patients with chronic obstructive pulmonary disease
rate the initial major inflammatory component of
and in fibrotic lesions, correlated with decreased lung
SARS-CoV-2 infection but could also be of benefit
function and respiratory compliance (152, 161). ARBs
during the process of recovery from this illness. At
protect lung function against viral pneumonia, diabe-
present (09/14/2020), there are 50 ongoing clinical
tes, and chronic obstructive pulmonary disorder and
trials to definitely determine whether ARBs treat-
ameliorate lung fibrosis, improving survival (167–175).
ment is of benefit for the prevention of SARS-CoV-
ARBs and COVID-19 2 infection, the degree of COVID-19 symptom pre-
sentation, its treatment, and the recovery success
ARBs are effective for the treatment of COVID-19 of these patients (www.clinicaltrials.gov, accessed
comorbidities in addition to hypertension, such as 9/14/2020) (184).

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Effects of ARBs on Estrogen gastric ulceration (114, 197) increased by ovariectomy
Deficiency (198, 199). Mechanisms associated with these oppos-
ing effects include inhibition of the NLRP3 inflamma-
This section describes the beneficial effects of some and reduction of TLR2 and TLR4 expression by
ARBs on estrogen deficiency and menopause, and ARBs (42, 71) that are enhanced by ovariectomy (199)
the similar spectrum of action of ARBs and estro- and PPARc activation by ARBs (200) that are reduced
gen treatment. by ovariectomy (201) (FIGURE 4).
Clinical studies indicate that ARBs therapy may be
Effects of ARBs in Premature Ovariectomy beneficial for menopausal women. These studies
and Menopause revealed that ARBs reduce low grade systemic
inflammation in premature ovariectomy and meno-
There is a recognized crosstalk between estrogen pause (202), improve sexual function in sexually
and AT1 receptors (185). The protective effects of active postmenopausal women (117), reduce meno-
ARBs inversely correlate with alterations induced by pause-like symptoms (203), decrease bleeding in
estrogen deficiency. Lack of estrogen upregulates the postmenopausal women during estrogen-progestin
RAS, increasing AT1 receptor expression and blood therapy (204), reduce osteoporosis (205), inhibit ox-
pressure (186, 187), and estrogen replacement in ovar- idation of low-density lipoprotein (LDL) (206), and
iectomized rats decreases AT1 receptor number (188). protect the endothelium preventing vascular dys-
ARBs have been shown to counteract multiple function in postmenopausal women (187) (FIGURE
adverse effects of premature ovariectomy. ARBs pro- 4). It is likely that ARBs will prevent many adverse
tect cerebral blood flow, blood-brain barrier function, effects of menopause, including the cognitive
and cognition (26, 59, 107, 188–191) impaired by ovari- decline and higher incidence of neurodegenerative
ectomy (192–194), reduce brain and microvessel disorders that is observed during estrogen loss
inflammation and neuronal loss (60, 71, 83, 195) (207, 208), and control studies should be con-
increased by ovariectomy (196), and decrease anxiety ducted to determine whether ARBs treatment may
and depressive-like behavior and stress-induced be considered to replace estrogen therapy.

FIGURE 3. Mechanisms of protective effects of angiotensin receptor blockers (ARBs) in lung and brain during COVID-19
ARBs reduce COVID-19 comorbidities such as hypertension and diabetes, exert anti-aging effects, reduce viral load and the cytokine storm, and reduce plate-
let activation, endothelial lesions, vasoconstriction, and thrombosis, thereby protecting the lung and the brain.

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Current Controversies in the Field, overactivation (3, 216–220). This axis includes an-
the Reasons for Disagreement and giotensin-converting enzyme 2, a monocarboxy-
the Studies That Might Resolve peptidase hydrolyzing ANG I into Ang-(1–9),
Conflicts further converted into Ang-(1–7), and ANG II [Ang-
(1–8)] producing Ang-(1–7) an agonist of the GPCR
This section enumerates some of the major controver- MasR (3), While multiple preclinical studies
sies in the field and proposes future studies to clarify reported beneficial, protective effects of Ang-(1–7)
and resolve these discrepancies. through MasR activation, their translational value
needs to be validated in controlled clinical trials
The Methodology to Study the Renin (3, 218). On the other hand, ACE2 has a broad sub-
Angiotensin System Must Be Critically strate specificity, and while identified as a recep-
Revised tor for SARS-CoV-2, enhancing the viral entry into
the cells, it also was recognized as a major protec-
The commonly used commercially available AT1 re- tive factor for lung function (182). Multiple studies
ceptor antibodies are not specific, identifying several
are attempting to clarify ACE2 functions in health
uncharacterized proteins even when using cells or tis- and disease, but the role of this enzyme remains
sues devoid of AT1 receptors (209, 210). Strict require- controversial.
ments for antibody characterization are necessary
AT2 receptor stimulation is also considered in many
(211–214). There are also published National Institutes
studies as a counter-regulatory, protective mechanism
of Health requirements for antibody validation (215).
balancing excessive AT1 receptor activity (3, 218).
For these reasons, the entire literature based on the
Proposed AT2 receptor agonists, such as CGP42112
use of AT1 receptor antibodies must be carefully
and Compound 21, are not selective (221–224) and
reexamined.
their therapeutic efficacy is not established in clinical
Alternative Proposals to Improve or Replace trials. Although never definitely identified in the same
ARBs Treatment brain cells, AT1 and AT2 receptor reciprocally influence
each other’s expression (115, 225). More studies are
The ACE2/Ang-(1–7)/Mas receptor axis has been necessary to clarify the molecular mechanisms for this
proposed and intensively studied as a counterre- interaction, and the clinical benefit of selective AT2
gulatory mechanism protecting from AT1 receptor agonists.

FIGURE 4. Reciprocal effects of estrogen reduction and angiotensin receptor blocker (ARB) treatment
ARBs counteract the effects of premature ovariectomy and menopause; protect cerebral blood flow and the blood-brain bar-
rier; reduce brain and microvessel inflammation and neuronal loss; inhibit the NOD-like receptor family, pyrin domain contain-
ing 3 (NLRP3) inflammasome and the activity of Toll-like receptors (TLRs); activate peroxisome proliferator-activated receptor-c
(PPARc); and protect cognition. After menopause, ARBs reduce low-grade inflammation, menopause-like symptoms, vascular
dysfunction, and osteoporosis, decrease bleeding during estrogen-progestin therapy, and improve sexual function.

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REVIEW
Species Differences in AT1R Genes Conclusions
Humans express only one angiotensin II AT1 recep- In addition to their beneficial effects on cardiovascular,
tor type (226), but rodents express two AT1 recep- metabolic and renal disorders, ARBs have pleiotropic
tor subtypes, AT1A and AT1B (116, 227). Since the beneficial, protective properties influencing common
expression of AT1 receptors and their regulation mechanisms of injury affecting many different dis-
are different between rodents and humans (85), eases, including but not limited to multiple inflamma-
results obtained with rodent preclinical models tory conditions, alterations in immune responses, age-
should be interpreted with caution. related diseases and alterations in behavior.
Accumulating evidence continues to expand the pos-
The Controversy Regarding the Existence of a
sible ARBs therapeutic spectrum. To date (09/26/
Brain RAS
2020), there are 1,743 listed clinical studies to deter-
Since there is strong evidence that there is no mine the scope of ARBs therapeutic effects. Although
parenchymal production of ANG II in the brain, (79– most studies are related to cardiovascular disorders,
81, 84) ANG II effects are related to AT1 stimulation kidney disease, and diabetes, a significant number are
by circulating ANG II, indirectly affecting the control focused on inflammation including its relationship with
of multiple brain functions, predominantly through aging and fibrosis, neoplasm, cerebral small vessel
effects in the cerebrovascular system and in circumven- disease, vascular remodeling, pulmonary and liver dis-
tricular organs outside the blood-brain barrier (86) or ease, sleep disorders, and aortic aneurism, including
the result of AT1 receptor blockade in the periphery 50 studies on the effects of ARBs on COVID-19 (184).
(26). The analysis of the effects of ANG II in the brain While the potential indications for ARBs treatment
needs to be reexamined considering these recent continue to expand, many questions remain unan-
discoveries. swered and future studies are necessary to establish
the scope of ARBs therapy in medical conditions. n
Molecule-Specific Effects of ARBs
No conflicts of interest, financial or otherwise, are
Differences in chemical structure may influence declared by the authors.
their therapeutic efficacy. However, ARB(s) have J.M.S. conceived and designed research; J.M.S. prepared
never been compared head to head in preclinical figures; J.M.S. drafted manuscript; J.M.S. edited and revised
manuscript; J.M.S. approved final version of manuscript.
experiments using the same methodology in a sin-
gle study. Comparison of selected ARBs in clinical
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