Hypertension Research

https://doi.org/10.1038/s41440-025-02229-5

REVIEW ARTICLE

Renin-angiotensin-aldosterone system and its relation to

hypertension
Shin-ichiro Miura1 Yoshino Matsuo1 Yasunori Seumatsu1
● ●

Received: 11 February 2025 / Revised: 2 April 2025 / Accepted: 18 April 2025

© The Author(s), under exclusive licence to The Japanese Society of Hypertension 2025

Abstract
Regulation of the renin-angiotensin-aldosterone system plays an important role in the onset and progression of hypertension.
In this system, there are two types of angiotensin II (Ang II) receptors: type 1 (AT1) and type 2. Pathological effects such as
high blood pressure and cardiac hypertrophy are generally mediated by AT1 receptor. Therefore, direct renin inhibitors,
angiotensin-converting enzyme inhibitors, AT1 receptor blockers, angiotensin receptor-neprilysin inhibitors, and
mineralocorticoid receptor antagonists have been developed to suppress these adverse effects. We have been studying
this field since the 1990s. When the AT1 receptor is activated, its structure changes and various signals are transmitted into
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the cell. AT1 receptor blockers suppress this change in the structure of the receptor and inhibit intracellular signals. Recent
studies have focused on the development of biased ligands that do not inhibit all intracellular signals, and instead inhibit only
some adverse signals and activate necessary signals. New therapeutic drugs that are not AT1 receptor blockers but are
mediated by AT1 receptor may be developed. Therefore, we mainly review the structure and function of the AT1 receptor, as
well as the roles of its blockers or inhibitors and biased ligands, including their role in the prevention of cardiometabolic
syndrome including hypertension.
Keywords Angiotensin II G protein-coupled receptor AT1 receptor blockers Biased ligand Morning hypertension
● ● ● ●

Introduction cardiovascular disease. Cardiometabolic syndrome includes

a combination of metabolic, renal, and cardiovascular risk
I am extremely honored to receive the Japanese Society of factors. These include central or visceral obesity, insulin
Hypertension 2024 Award. I would like to express my resistance, dyslipidemia, microalbuminuria, oxidative
deepest gratitude to everyone who contributed to this stress, increased inflammation, hypercoagulability and
research. This review focuses on our research results hypertension in particular. Regulation of the RAAS plays an
regarding the “renin-angiotensin-aldosterone system important role in the onset and progression of hypertension.
(RAAS) and its relation to hypertension”, which is the basis In addition, activation of the RAAS system also plays a role
for the above award. in morning hypertension, an important factor in the devel-
Cardiometabolic syndrome is a multifaceted condition opment of cardiovascular disease.
that encompasses metabolic and vascular abnormalities [1]. Figure 1 illustrates the RAAS [2]. The octapeptide hor-
It is closely associated with activation of the RAAS and mone angiotensin II (Ang II) binds to both Ang II type 1
significantly increases the risk of chronic kidney disease and (AT1) and type 2 (AT2) receptors are both G protein-
coupled receptors. The AT1 receptor mediates most of the
actions of Ang II, such as vasoconstriction, cell growth, and
aldosterone production. In contrast, the AT2 receptor med-
iates opposing effects, including vasodilation and anti-
I received the Japanese Society of Hypertension 2024 Award for this
paper. inflammatory actions. There are five classes of anti-
hypertensive drugs that target components of the RAAS:
* Shin-ichiro Miura direct renin inhibitors (DRI), angiotensin-converting
[email protected]
enzyme inhibitors (ACEI), AT1 receptor blockers (ARB),
1
Department of Cardiology, Fukuoka University School of angiotensin receptor-neprilysin inhibitors (ARNI), and
Medicine, Fukuoka, Japan mineralocorticoid receptor antagonists (MRA). This review
 S. Miura et al.

Graphical Abstract

will primarily focus on the structure and function of the AT1 are observed when the effects of ARBs are directly com-
receptor and ARBs. Additionally, we will discuss ARNI pared in clinical studies. For instance, valsartan is more
and biased ligands of the AT1 receptor. effective than losartan at reducing left ventricular mass [8],
while Exp3174 most strongly prevents coronary artery
contraction [9].
Structure and function of the AT1 receptor Oparil et al. studied the antihypertensive effects of four
and ARBs different ARBs (olmesartan, losartan, valsartan and irbe-
sartan) in patients with essential hypertension [10]. Their
Figure 2 illustrates the binding sites of Ang II to the results showed that olmesartan has the most potent anti-
secondary-structure model of AT1 receptor. The AT1 hypertensive effect among these ARBs. Olmesartan-based
receptor is a 7-transmembrane protein that belongs to the G treatment was also effective in lowering both morning home
protein-coupled receptor superfamily. It is composed of 359 BP and clinic BP [11]. We have conducted eight studies to
amino acids. Four key interactions between Ang II and the compare the antihypertensive effects of ARBs in hyper-
AT1 receptor have been identified. Previous studies have tensive patients [12–18]. For example, Sugihara et al.
demonstrated that tyrosine 4 and phenylalanine 8 of Ang II compared the antihypertensive effects of olmesartan and
may mainly interact with asparagine 111 and histidine 256 valsartan, and found that olmesartan significantly reduced
of the AT1 receptor, respectively [3–6]. systolic blood pressure (SBP) by about 3 mmHg more than
The specific characteristics of ARBs are summarized in valsartan [12]. In clinical studies, the differences between
Table 1. Not all ARBs have the same effects [7]. There are the SBP-reducing effects of ARBs are small. Even see-
variations in their binding modes, selectivity for the AT1 mingly small BP reductions can have very large beneficial
receptor, half-live in the blood, and other properties effects at a population level. For example, it is estimated
(Table 1). Exp3174, the active metabolite of losartan, shows that a 3 mmHg reduction in SBP reduces the mortality rate
the highest selectivity for the AT1 receptor. Telmisartan has from stroke by 8% and the mortality rate from coronary
the longest half-life in the blood. Furthermore, differences heart disease by 5% [19].
Renin-angiotensin-aldosterone system and its relation to hypertension

Fig. 1 Renin-angiotensin-
aldosterone system (RAAS).
Ang II binds to AT1 and AT2
receptors which belong to the G
protein-coupled receptor
(GPCR) family. MAS receptor is
also a GPCR which binds Ang
(1-7). Ang II angiotensin II, AT1
Ang II type 1, AT2 Ang II type
2, DRI direct renin inhibitor,
ACEI angiotensin converting
enzyme inhibitor, ARB
angiotensin II receptor type 1
receptor blocker, ARNI
angiotensin receptor neprilysin
inhibitor (SAC/VAL: Sacubitril/
Valsartan), MRA
mineralocorticoid receptor
antagonist, EP endopeptidase,
Ang (1–7) angiotensin (1–7)

Fig. 2 Binding sites of Ang II to the secondary-structure model of AT1 256 of the AT1 receptor, respectively. Arginine 2 and the carboxyl-
receptor. Four key interactions between Ang II and the AT1 receptor terminal of Ang II may interact with aspartic acid (D) 281 and lysine
have been identified. Tyrosine (Tyr) 4 and phenylalanine (Phe) 8 of (K) 199 of the AT1 receptor, respectively. Ang II angiotensin II, AT1
Ang II may mainly interact with asparagine (N) 111 and histidine (H) Ang II type 1

To understand why olmesartan exhibits stronger anti- structures of these ARBs [7]. Most ARBs share a common
hypertensive effects, it is important to consider the chemical chemical structure, which includes a biphenyltetrazole
 S. Miura et al.

hydroxyl group (-) / hydroxyl group (-) / hydroxyl group (-) / hydroxyl group (+) / hydroxyl group (-) / α- hydroxyl group (-) / α-
carboxyl group (+),

insurmountable
cyclopentane ring (+) oxadiazole (+)
Azilsartan

40,000

13 h
(+)
(–)

(–)
carboxyl group (-),

insurmountable
Irbesartan

10–15 h
> 8500

(+)
(–)

(–)
Fig. 3 Data on inositol phosphate (IP) production in mock-transfected
or AT1-WT receptor transfected COS1 cells. When AT1-WT receptor
α-carboxyl group (-) α-carboxyl group

has constitutive activity, the receptor is in a partially active state

insurmountable

[R’WT]. When Ang II binds to the AT1-WT receptor. the receptor is in

Olmesartan
medoxomil

olmesartan

a fully active state [R*WT]. On the other hand, the receptor is in an

>12,000

12–18 h

inactive state [RWT] when an inverse agonist binds to the AT1-WT

receptor. Thus, upon ligand binding, the receptor alternates between
(+)

(+)

(–)

three states: [R*WT], [R’WT], and [RWT]. Ang II angiotensin II, AT1
Ang II type 1, WT wild type
insurmountable

group and an imidazole group (Table 1). Additionally,

Telmisartan

Exp3174, candesartan, valsartan, and olmesartan, but not

>2,7000

20–24 h

losartan, contain an alpha(α)-carboxyl group. Notably,

(+)
(–)

olmesartan also includes a hydroxyl group in addition to

(-)

the α-carboxyl group. This structural difference may

contribute to its enhanced antihypertensive effect.
α-carboxyl group

insurmountable

If a G-protein-coupled receptor exhibits spontaneous

or constitutive activity, it exists in a partially active state.
Candesartan cilexetil Valsartan

Agonists induce a transition from this partially active

30,000

4–6 h
(+)

(+)

(+)

state to a fully active state. In contrast, inverse agonists

(–)

shift the receptor from a partially active state to an

inactive state. Over 60 wild-type G-protein-coupled
α-carboxyl group (-) (losartan), α-carboxyl group

insurmountable

receptors have been shown to exhibit constitutive activ-

candesartan

ity [7]. We have also demonstrated that the AT1 receptor

>17,000

possesses constitutive activity. To confirm this, we nee-

ded to identify an AT1 receptor blocker as an inverse
(+)

(+)
9h

(–)

agonist. Figure 3 presents data on inositol phosphate (IP)

α-carboxyl group (+) (Exp3174)

production [7, 20]. In mock-transfected COS1 cells, the

(-) (losartan), (+) (Exp3174)
surmountable (losartan), and
insurmountable (Exp3174)
>1000 fold (losartan), and

sample shows 2000 cpm, whereas the AT1 receptor-

and hydroxyl group (-) /

2 h (losartan), and 6–9 h

>44,000 fold (Exp3174)

transfected sample shows 2800 cpm. This 800 cpm dif-

Table 1 Specific characteristics of ARBs

hydroxyl group (-) /

ference likely reflects constitutive activity, suggesting

that the AT1 receptor is in a partially active state in
recombinant cell systems. Olmesartan suppresses this
(Exp3174)
Active metabolite Exp 3174
Losartan

activity, indicating that the AT1 receptor transitions to an

AT1 angiotensin II type 1

inactive state. Therefore, olmesartan acts as an inverse

(–)

agonist. It is clear that treatment with an antagonist could

Half-life in blood

be useful, but not as effective as treatment with an

Influence of diet
Inverse agonism
⋘structure⋙

Binding mode

AT1 receptor

inverse agonist. The constitutive activity of AT1 receptor

Feature of

selectivity

is relatively slight. Since hypertension induces congestive

chemical

heart failure, and since this process takes a couple of

decades [21], it may be important to block constitutive
Renin-angiotensin-aldosterone system and its relation to hypertension

Ang II-dependent AT1 receptor-induced signaling is

shown in Fig. 6A. When Ang II binds to AT1 receptor, Ang
II-dependent signaling occurs, and the receptor enters a
fully active state. Ang II-independent AT1 receptor-induced
signaling (constitutive activity of AT1 receptor), is also
shown in Fig. 6B. When Ang II binds to the AT1 receptor,
Ang II-dependent signaling occurs, leading to full activation
of the receptor. Olmesartan effectively blocks both Ang II-
dependent and Ang II-independent signaling pathways
(Fig. 6C), potentially providing a stronger inhibition of
signaling than other ARBs. It has also been suggested that
slight differences in the chemical structures of ARBs may
Fig. 4 Progression from hypertension to congestive heart failure.
result in unique binding modes with the AT1 receptor,
Hypertension progresses left ventricular hypertrophy, and subse- strengthening the binding of ARBs to the AT1 receptor and,
quently induces heart failure through left ventricular diastolic and as a result, leading to differences in antihypertensive effects.
systolic dysfunction. Hypertension is also a critical risk factor for the
onset of myocardial infarction which induces heart failure through left
ventricular systolic dysfunction
Effectiveness of ARNI (SAC/VAL: Sacubitril/
Valsartan)

The chemical structure of the sacubitril valsartan hydrate

complex consists of SAC and VAL in a 1:1 molar ratio
[24–26]. VAL, an ARB, blocks cell signals including those
associated with sodium retention, vasoconstriction, cardiac
hypertrophy and endothelial dysfunction through the AT1
receptor. SAC is a prodrug that is metabolized to sacubitrilat,
which inhibits neprilysin. Neprilysin is responsible for the
degradation of several vasoactive peptides including atrial
Fig. 5 Features of olmesartan. Olmesartan has a unique chemical and brain natriuretic peptides (ANP and BNP). The increased
structure in which the hydroxyl and carboxyl groups within these levels of natriuretic peptides in blood by SAC enhance
structures play critical roles in inverse agonism and a high binding
natriuretic and vasodilatory effects and inhibit cardiac
affinity
hypertrophy and fibrosis. The elevation of peptides blocks the
negative cardiovascular effects of Ang II and aldosterone by
activity by using an inverse agonist (Fig. 4). Therefore, we reducing the release of renin and aldosterone secretion in the
should use ARBs that are stronger inverse agonists. blood. Thus, these natriuretic peptides exert antagonistic
We hypothesize that although olmesartan shares a com- effects against Ang II-induced AT1 receptor signals. In a
mon structure with other ARBs, including a biphenyltetrazole clinical study [27], hypertensive patients receiving amlodi-
group and an imidazole group, the hydroxyl and carboxyl pine 5 mg/day were randomly divided into two groups: one
groups within these structures play critical roles in its inverse group continued to receive amlodipine 5 mg/day, and the
agonism and high binding affinity (Table 1 and Fig. 5). These other group received SAC/VAL 200 mg/day + amlodipine
groups likely facilitate strong binding to the receptor, con- 5 mg/day. Changes in 24-h mean ambulatory SBP, mean
tributing to its enhanced antihypertensive effect compared to ambulatory diastolic BP (DBP), and pulse pressure were
other ARBs. Previous studies have suggested that the evaluated. The group that received a combination of SAC/
biphenyl-tetrazole group in olmesartan binds to Lys199 and VAL 200 mg/day + amlodipine 5 mg/day showed significant
His256 [3, 4, 20, 22, 23]. We then analyzed the binding sites reductions in 24-h mean ambulatory SBP, mean ambulatory
on the AT1 receptor for the hydroxyl and alpha-carboxyl DBP, and pulse pressure compared to the amlodipine 5 mg/
groups of olmesartan. Based on prior work and computa- day group. In another clinical study [28], hypertensive
tional modeling [3, 4, 20, 22, 23], we identified 13 potential patients were randomly assigned to two groups: one group
binding sites. Using binding affinity data, we conducted received olmesartan 20 mg/day, and the other received SAC/
computational modeling. The tetrazole group in olmesartan VAL 200 or 400 mg/day. That study assessed changes in
binds to Lys199 and Glu257. The alpha-carboxyl group may mean sitting SBP and DBP. The SAC/VAL 200 or 400 mg/
interact with Lys199 and His256, while the hydroxyl group day group showed significant reductions in both mean sitting
likely binds to Tyr113 and His256. SBP and DBP compared to the olmesartan 20 mg/day group.
 S. Miura et al.

Fig. 6 Ang II-dependent (A) or -independent (B) AT1 receptor- Olmesartan blocks both Ang II-dependent and Ang II-independent
induced cell signaling pathways. Blocking of both Ang II-dependent signaling pathways (C) because it is an inverse agonist. Ang II angio-
and Ang II-independent signaling by olmesartan (C). When Ang II tensin II, AT1 Ang II type 1, PLC phospholipase C, DAG diacylgly-
binds to AT1 receptor (A) and Ang II-dependent signaling occurs, the cerol, PKC protein kinase C, MAPKK mitogen-activated Protein
receptor is in a fully active state to induce high blood pressure (BP). Kinase-kinase, ERK extracellular signal-regulated kinase, CaMK
Constitutive activity of AT1 receptor is a form of Ang II-independent calmodulin-dependent protein kinase, STATs signal transducers and
AT1 receptor-induced signaling which induces a small BP elevation (B). activator of transcriptions

To reveal why SAC/VAL is so effective at lowering BP, we improved primary outcomes compared to the valsartan
conducted basic research using human adrenocortical cell group. Why is SAC/VAL so effective at preventing car-
lines [29]. We hypothesized that SAC in SAC/VAL sup- diovascular events in heart failure patients? To investigate
presses aldosterone production, thereby lowering BP. In Ang this point, we used three mouse models of heart failure. In
II-sensitized human adrenocortical cells, LBQ657, the active the first experiment, we used a streptozotocin-induced
form of sacubitril, significantly suppressed aldosterone pro- diabetic mouse model [32]. This model showed increased
duction. There are several possible mechanisms by which heart weight/body weight and cardiac fibrosis, and
NPs can block aldosterone synthesis. We also found that Ang decreased left ventricular ejection fraction. Compared to
II-sensitized Gq-dependent aldosterone synthesis was the control group, the SAC/VAL group showed a sig-
blocked by ANP-induced activation of a cGMP-dependent-G nificantly suppressed increase in the heart weight/body
protein signaling 4 pathway. Another possible mechanism for weight ratio and cardiac fibrosis, and a significanty sup-
the attenuation of aldosterone synthesis by ANP is that ANP pressed decrease in the left ventricular ejection fraction.
may block aldosterone synthesis in the biosynthetic pathway The second experiment used an Ang II-induced hyper-
from cholesterol to pregnenolone and in that from corticos- tensive heart failure mouse model [33]. In this model, Ang
terone to aldosterone. II infusion induces hypertension and cardiac hypertrophy,
SAC/VAL is indicated not only as an antihypertensive which eventually lead to heart failure. SAC/VAL, val-
agent but also as a treatment for heart failure. In the sartan and enalapril all attenuated cardiomyocyte hyper-
PARADIGM-HF trial, heart failure patients with reduced trophy in a mouse model of Ang II-induced cardiac
ejection fraction were randomly assigned to either the hypertrophy. Of note, SAC/VAL most strongly sup-
SAC/VAL group or the enalapril group [30]. The primary pressed hypertrophy despite having BP-lowering effects
outcome was a composite endpoint of cardiovascular similar to those of valsartan and enalapril. The third
mortality or heart failure requiring hospitalization. The experiment used an apolipoprotein E knockout mouse
SAC/VAL group showed a significantly improved pri- model fed a high-fat diet, inducing a reduction in the left
mary outcome compared to the enalapril group. In the ventricular ejection fraction and fractional shortening
PARAGON-HF trial, heart failure patients with preserved [34]. The SAC/VAL group showed a significantly sup-
ejection fraction were randomly assigned to either the pressed reduction in both the left ventricular ejection
SAC/VAL group or the valsartan-only group [31]. The fraction and fractional shortening compared to the control
primary outcome was a composite of cardiovascular death group. Furthermore, the SAC/VAL group showed a sig-
and total (first and recurrent) hospitalizations for heart nificant increase in the mRNA levels of CD34 and vas-
failure. The SAC/VAL group showed a trend toward cular endothelial growth factor A in the left ventricle
Renin-angiotensin-aldosterone system and its relation to hypertension

Fig. 7 Potential pharmacological mechanisms of biased G protein- signals, whereas compound B activated both cell signals. Compound B
coupled receptor signaling. When Ang II binds to AT1 receptor, two suppressed IP production while inducing ERK1/2 activation. Com-
main cell signals, G protein-dependent (IP production through a Gqα pound B may be considered a potential biased ligand. ERK, extra-
pathway) and G protein-independent (ERK1/2 activation through β- cellular signal regulated kinase
arrestin), occur. Compound A did not induce either of these cell

compared to the control group, suggesting that angiogenic trial, BLAST-AHF, was conducted using a biased ligand of
factors may explain its cardioprotective effects. the AT1 receptor [36]. Patients with acute heart failure were
randomly assigned to four groups: a placebo group, a
TRV027 (which is similar to TRV067) 1 mg/h group, a
Biased ligand of the AT1 receptor TRV027 5 mg/h group, and a TRV027 25 mg/h group. The
treatment was administered via infusion for 48–96 h. The
The final topic of this review is the biased ligand of the AT1 primary composite endpoint included time from baseline to
receptor. Figure 7 illustrates potential pharmacological death through day 30, time from baseline to heart failure
mechanisms of biased G protein-coupled receptor signaling. rehospitalization through day 30, and other measures.
When Ang II binds to AT1 receptor, two main cell signals, G TRV027 did not appear to significantly affect these primary
protein-dependent (IP production through a Gqα pathway) and endpoint components. TRV027, as a peptide-based biased
G protein-independent [extracellular signal-regulated kinase ligand, may be readily degradable, unstable, and incon-
(ERK)1/2 activation through β-arrestin], occur. The ligands sistent in efficacy. Although TRV027 activates the β-
exhibit bias or functional selectivity toward specific G proteins arrestin pathway, which is beneficial for treating heart
or other signal transducers, such as β-arrestin. For instance, failure, it is unclear whether it might also activate other
when a ligand binds to a receptor, the receptor undergoes a full unknown pathways that could exacerbate heart failure due
change in its conformation, fully activating the receptor and to the diversity of intracellular signals. If a non-peptide type
transmitting signals into the cell non-selectively. However, of biased ligand could be developed, these points could be
with some ligands, binding induces only a partial change in further explored. To this end, we have developed a non-
conformation, leading to partial activation and selective signal peptide form of an AT1 receptor compound as a biased
transduction. A ligand that selectively activates intracellular ligand [37]. We synthesized three non-peptide AT1 receptor
signals in this manner is called a biased ligand. Therefore, in ligands (Compounds A, B, and C) as candidates for biased
the case of the AT1 receptor, a ligand that selectively activates ligands. In vitro studies were conducted to assess whether
either IP production or ERK1/2 activation would be con- these compounds could induce IP production and ERK1/2
sidered a biased ligand. activation using an AT1 receptor-overexpressing cell sys-
Several biased agonists have been developed or identi- tem. The goal was to identify a biased ligand that sup-
fied for cardiovascular indications. One example is presses IP production and induces ERK1/2 activation.
TRV067, a peptide-based biased ligand that is currently Figure 7 summarizes the effects of olmesartan-related
being studied to determine its efficacy and safety in basic compounds on IP production and ERK activation at the
and clinical trials [35, 36]. TRV067 selectively activates β- AT1 receptor. Compound B suppressed IP production while
arrestin-mediated signaling without activating G protein- inducing ERK1/2 activation. TRV067 activated β-arrestin-
mediated signaling, and has been shown to improve cardiac mediated signaling including ERK1/2 activation without
function and morphology in an acute heart failure mouse activating G protein-mediated signaling, and improved
model of dilated cardiomyopathy [35]. A phase IIB clinical cardiac function in an acute heart failure mouse model [35].
 S. Miura et al.

Based on that study, compound B may also be considered a 8. Picca M, Agozzino F, Pelosi G. Effects of losartan and valsartan
potential biased ligand for the treatment of acute heart on left ventricular hypertrophy and function in essential hyper-
tension. Adv Ther. 2004;21:76–86.
failure. Further studies in a mouse model of heart failure are
9. Pantev E, Stenman E, Wackenfors A, Edvinsson L, Malmsjo M.
planned to evaluate its therapeutic potential. Comparison of the antagonistic effects of different angiotensin II
receptor blockers in human coronary arteries. Eur J Heart Fail.
2002;4:699–705.
10. Oparil S, Williams D, Chrysant SG, Marbury TC, Neutel J.
Conclusion Comparative efficacy of olmesartan, losartan, valsartan, and
irbesartan in the control of essential hypertension. J Clin Hyper-
We have reviewed four topics: the structure and function of tens. 2001;3:283–91.
the AT1 receptor, ARBs, sacubitril/valsartan, and biased 11. Kushiro T, Kario K, Saito I, Teramukai S, Mori Y, Okuda Y, et al.
Effectiveness of olmesartan-based treatment on home and clinic
ligands of the AT1 receptor. While more than 100 years
blood pressure in elderly patients with masked and white coat
have passed since the discovery of renin, the renin- hypertension. Hypertens Res. 2015;38:178–85.
angiotensin-aldosterone system remains a key target for 12. Sugihara M, Miura S, Takamiya Y, Kiya Y, Arimura T, Iwata A,
drug discovery. We look forward to continuing this research et al. Safety and efficacy of antihypertensive therapy with add-on
angiotensin II type 1 receptor blocker after successful coronary
in the future.
stent implantation. Hypertens Res. 2009;32:625–30.
13. Morii J, Miura S, Shiga Y, Sugihara M, Arimura T, Sako H, et al.
Acknowledgements We thank all members of the Department of Comparison of the efficacy and safety of irbesartan and olme-
Cardiology, Fukuoka University, Japan. sartan in patients with hypertension (EARTH study). Clin Exp
Hypertens. 2012;34:342–9.
Funding This work was supported by Grants-in-Aid to S.M. for Sci- 14. Morii J, Miura S, Ike A, Shiga Y, Sugihara M, Iwata A, et al.
entific Research (Nos. 19K08593 and 23K07590) from the Ministry of Comparison of the efficacies of irbesartan and olmesartan after
Education, Culture, Sports, Science and Technology of Japan. successful coronary stent implantation. Intern Med.
2013;52:713–9.
15. Motozato K, Miura SI, Shiga Y, Kusumoto T, Saku K. Efficacy
Compliance with ethical standards and safety of a single-pill fixed-dose combination of azilsartan and
amlodipine. J Clin Med Res. 2016;8:888–92.
Conflict of interest S.M. has ties to companies with COI relationships 16. Motozato K, Miura S, Shiga Y, Kusumoto T, Adachi S, Inoue T,
that should be disclosed in relation to the topic presented include; et al. Efficacy and safety of two single-pill fixed-dose combina-
Lecture fees (Otsuka Pharmaceutical, Novartis Pharma, Daiichi San- tions of angiotensin II receptor blockers/calcium channel blockers
kyo Co., Ltd.), commissioned research and joint research funds in hypertensive patients (EXAMINER study). Clin Exp Hyper-
(AMGEN, Bayer Yakuhin, Novo Nordisk Pharma, MSD), and scho- tens. 2016;38:45–50.
larship donations (Abbott, Sumitomo Pharma). 17. Adachi S, Miura S, Shiga Y, Arimura T, Kuwano T, Kitajima K,
et al. Depressor and anti-inflammatory effects of angiotensin ii
receptor blockers in metabolic and/or hypertensive patients with
coronary artery disease: a randomized, prospective study (DIA-
References MOND Study). J Clin Med Res. 2016;8:743–8.
18. Ishida T, Miura S, Fujimi K, Ueda T, Ueda Y, Matsuda T, et al.
1. Whaley-Connell A, Pavey BS, Chaudhary K, Saab G, Sowers JR. Visit-to-visit variability and reduction in blood pressure After a
Renin-angiotensin-aldosterone system intervention in the cardio- 3-month cardiac rehabilitation program in patients with cardio-
metabolic syndrome and cardio-renal protection. Ther Adv Car- vascular disease. Int Heart J. 2016;57:607–14.
diovasc Dis. 2007;1:27–35. 19. Appel LJ, Brands MW, Daniels SR, Karanja N, Elmer PJ, Sacks
2. Ksiazek SH, Hu L, Andò S, Pirklbauer M, Säemann MD, Ruotolo FM, et al. Dietary approaches to prevent and treat hypertension: a
C, et al. Renin-angiotensin-aldosterone system: from history to scientific statement from the American Heart Association.
practice of a secular topic. Int J Mol Sci. 2024;25:4035 https://doi. Hypertension. 2006;47:296–308.
org/10.3390/ijms25074035. 20. Miura S, Feng YH, Husain A, Karnik SS. Role of aromaticity of
3. Noda K, Saad Y, Karnik SS. Interaction of Phe8 of angiotensin II agonist switches of angiotensin II in the activation of the AT1
with Lys199 and His256 of AT1 receptor in agonist activation. J receptor. J Biol Chem. 1999;274:7103–10.
Biol Chem. 1995;270:28511–4. 21. Vasan RS, Levy D. The role of hypertension in the pathogenesis
4. Noda K, Feng YH, Liu XP, Saad Y, Husain A, Karnik SS. The of heart failure. A clinical mechanistic overview. Arch Intern
active state of the AT1 angiotensin receptor is generated by Med. 1996;156:1789–96.
angiotensin II induction. Biochemistry. 1996;35:16435–42. 22. Feng YH, Noda K, Saad Y, Liu XP, Husain A, Karnik SS. The
5. Feng YH, Miura S, Husain A, Karnik SS. Mechanism of con- docking of Arg2 of angiotensin II with Asp281 of AT1 receptor is
stitutive activation of the AT1 receptor: influence of the size of the essential for full agonism. J Biol Chem. 1995;270:12846–50.
agonist switch binding residue Asn(111). Biochemistry. 23. Miura S, Fujino M, Hanzawa H, Kiya Y, Imaizumi S, Matsuo Y,
1998;37:15791–8. et al. Molecular mechanism underlying inverse agonist of angio-
6. Baleanu-Gogonea C, Karnik S. Model of the whole rat AT1 tensin II type 1 receptor. J Biol Chem. 2006;281:19288–95.
receptor and the ligand-binding site. J Mol Model. 24. Langenickel TH, Dole WP. Angiotensin receptor-neprilysin
2006;12:325–37. inhibition with LCZ696: a novel approach for the treatment of
7. Miura S, Fujino M, Saku K. Angiotensin II receptor blocker as an heart failure. Drug Discov Today. 2012;9:e131–e9.
inverse agonist: a current perspective. Curr Hypertens Rev. 25. Shi J, Wang X, Nguyen J, Wu AH, Bleske BE, Zhu HJ. Sacubitril
2005;1:115–21. is selectively activated by carboxylesterase 1 (CES1) in the liver
Renin-angiotensin-aldosterone system and its relation to hypertension

and the activation is affected by CES1 genetic variation. Drug angiotensin ii-induced hypertensive mice independent of a blood
Metab Dispos. 2016;44:554–9. pressure-lowering effect. Cardiol Res. 2020;11:376–85.
26. Vardeny O, Tacheny T, Solomon SD. First-in-class angiotensin 34. Suematsu Y, Tashiro K, Morita H, Ideishi A, Kuwano T, Miura S.
receptor neprilysin inhibitor in heart failure. Clin Pharm Ther. Angiotensin receptor blocker and neprilysin inhibitor suppresses
2013;94:445–8. cardiac dysfunction by accelerating myocardial angiogenesis in
27. Wang JG, Yukisada K, Sibulo A Jr, Hafeez K, Jia Y, Zhang J. apolipoprotein E-knockout mice fed a high-fat diet. J Renin
Efficacy and safety of sacubitril/valsartan (LCZ696) add-on to Angiotensin Aldosterone Syst 2021:9916789. https://doi.org/10.
amlodipine in Asian patients with systolic hypertension uncontrolled 1155/2021/9916789.
with amlodipine monotherapy. J Hypertens. 2017;35:877–85. 35. Ryba DM, Li J, Cowan CL, Russell B, Wolska BM, Solaro RJ.
28. Rakugi H, Kario K, Yamaguchi M, Sasajima T, Gotou H, Zhang Long-term biased β-arrestin signaling improves cardiac structure
J. Efficacy of sacubitril/valsartan versus olmesartan in Japanese and function in dilated cardiomyopathy. Circulation.
patients with essential hypertension: a randomized, double-blind, 2017;135:1056–70.
multicenter study. Hypertens Res. 2022;45:824–33. 36. Pang PS, Butler J, Collins SP, Cotter G, Davison BA, Ezekowitz
29. Miura S, Suematsu Y, Matsuo Y, Tomita S, Nakayama A, Goto JA, et al. Biased ligand of the angiotensin II type 1 receptor in
M, et al. The angiotensin II type 1 receptor-neprilysin inhibitor patients with acute heart failure: a randomized, double-blind,
LCZ696 blocked aldosterone synthesis in a human adrenocortical placebo-controlled, phase IIB, dose ranging trial (BLAST-AHF).
cell line. Hypertens Res. 2016;39:758–63. Eur Heart J. 2017;38:2364–73.
30. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, 37. Matsuo Y, Suematsu Y, Morita H, Miura S. Development of a
Rizkala AR, et al. Angiotensin-neprilysin inhibition versus ena- non-peptide angiotensin II Type 1 receptor ligand by structural
lapril in heart failure. N Engl J Med. 2014;371:993–1004. modification of olmesartan as a biased agonist. Biomedicines.
31. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Mag- 2023;11:1486 https://doi.org/10.3390/biomedicines11051486.
gioni AP, et al. Angiotensin-neprilysin inhibition in heart failure
with preserved ejection fraction. N Engl J Med. Publisher’s note Springer Nature remains neutral with regard to
2019;381:1609–20. jurisdictional claims in published maps and institutional affiliations.
32. Suematsu Y, Miura S, Goto M, Matsuo Y, Arimura T, Kuwano T,
et al. LCZ696, an angiotensin receptor-neprilysin inhibitor, Springer Nature or its licensor (e.g. a society or other partner) holds
improves cardiac function with the attenuation of fibrosis in heart exclusive rights to this article under a publishing agreement with the
failure with reduced ejection fraction in streptozotocin-induced author(s) or other rightsholder(s); author self-archiving of the accepted
diabetic mice. Eur J Heart Fail. 2016;18:386–93. manuscript version of this article is solely governed by the terms of
33. Tashiro K, Kuwano T, Ideishi A, Morita H, Idemoto Y, Goto M, such publishing agreement and applicable law.
et al. Sacubitril/valsartan inhibits cardiomyocyte hypertrophy in