Chinese

Journal of
Natural
Chinese Journal of Natural Medicines 2015, 13(10): 07210729 Medicines

Reviews
Current natural products with antihype rtensive activity
BAI Ren-Ren1, 2 , WU Xiao-Ming2, 3* , XU Jin-Yi2, 3*
1
School of Medicine, Emory University, Atlanta 30322, GA, USA;
2
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;
3
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China

Available online 20 Oct., 2015

[ABSTRAC T] Natural products have been an important source of new dr ugs, which also played a dominant role in the discovery and
research of new drugs for the treatment of hypertension. This review article reviews the recent progress in the research and develop-
ment of natural lead compounds with antihypertensive activity, including alkaloids, diterpenes, coumarins, flavonoids, and peptides.
We summarized their structures, sources, as well as the antihypertensive mechanisms. T hese information provides instructive reference
for the following structural modifications and optimization.

[KEY WO RDS] Natural products; Antihypertensive activity; Lead compounds; Action mechanism

[CLC Number] R28, R965 [Document code] A [Article ID] 2095-6975(2015)10-0721-09

plant-derived products is well documented. Some plant

Introduction
Natural products have been an exemplary source of new
drugs, and many of the currently available medicines have been
directly or indirectly derived from them, which is particularly
evident in the areas of cancer and infectious diseases [1-2].
M eanwhile, the influence of natural product is also quite evi-
dent in other areas [3]. The research, development, and use of
natural products as therapeutic agents, especially those de-
rived from plants, have been increasing in recent years.
Hypertension has become one of the most important pre-
ventable causes for premature morbidity and mortality
worldwide. It is estimated to cause 7.5 million deaths, about
12.8% of all annual deaths [4-5]. M ost of the currently used
antihypertensive agents cannot be used as a single drug ther-
apy because of their limited efficacy and side effects. There-
fore, the research and development of new drugs with mul-
tiple therapeutic effects is most desirable [6].
The treatment of hypertension with plant extracts or
[Re ceived on] 07-Nov.-2014
[Research funding] This work was supported by the National
Natural Science Foundation of China (No. 81302635).
[*Corresponding author] Tel: 86-25-83242366, E-mail: xmwu@
cpu.edu.cn (WU Xiao-Ming); Tel: 86-25-83271299, E-mail: jinyixu@
china.com (XU Jin-Yi)
These authors have no conflict of interest to declare.
Copyright 2015, China Pharmaceutical University.
Published by Elsevier B.V. All rights reserved
sources of antihypertensive natural products were listed in
Fig. 1. However, references about isolation, identification and
mechanism research of the lead compounds really contribu-
tive to antihypertensive activity are still limited. In this review
article, we discuss the recent progress in the research of natu-
ral lead compounds with antihypertensive activity, emphasiz-
ing the mechanisms underlying their antihypertensive action.
Alkaloids
(+)-Dicentrine
(+)-Dicentrine (Compound 1, Fig. 2) is an alkaloid apor-
phine derivative isolated from the plant Lindera megaphylla
and Actinodaphne sesquipedalis. Several in vitro and in vivo
evaluations have proven that this alkaloid is a good cand i-
date for treatment of hypertension and other card iovas cular
diseas es. After oral administration of (+)- dicentrine (5 and
10 mgkg1, twice a day) for 4 weeks, the mean arterial
pressure (M AP) in spontaneously hypertensive rats (SHRs)
decreased from 160 mmH g to 102 mmHg, and the declining
rates was 36.3% [7]. However, a higher dos e of
(+)-dicentrine (10 mgkg1, i.v.) did not cause any signif i-
cant changes in heart rate (HR), cardiac output (CO), or
stroke volume (SV) [8] . M echanistic research has shown that
(+)- dicentrine is an 1-adrenocepter antagonist which is
more selective towards the putative 1D-adrenocepter sub-
type of the rat aorta than the 1 B-adrenocepter subtype of the
spleen [9].

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Fig. 1 S ome plant sources of antihypertensive natural products

Laurotetanine was proven to be a very low toxicity crude drug at doses up

The leaves of Luureliu sempervirens (M onimiaceae), an
endemic Chilean tree known as Laurel, are used by the
M apuche Amerindians for treating headache and as a d i-
uretic. Intravenous administration of a hydroalcoholic L.
sempervirens extract to rats, elicited a hypotensive response
of (27.0 2.0)% in the M AP of normotens ive animals at a
dose of 5 mgkg1. In an acute oral toxicity study, Laurel
to 3 g crude extract. Bioassay -guided isolation led to the
alkaloid laurotetanine (Compound 2, Fig. 2) as the main
hypotensive principle of L. sempervirensleaves. Lauro-
tetanine (1 mgkg1) produced a hypotensive response of
(29.0 2.1)% in the M AP of normotens ive rats, with a
duration of 2 min, which was comparable to that of the
crude extract at 5 mgkg1 [10] .

Fig. 2 Chemical structures of Compounds 19

Dehydroevodiamine
Dehydroevodiamine (DeHE) (Compound 3, Fig. 2) is an
isoquinazolinocarboline alkaloid isolated from the Chinese
herbal drug Wu Chu Yu, the dried unripe fruit of Evodia ru-
taecarpa, which has been shown to produce vasorelaxant and
hypotensive effects. Biological tests have demonstrated that
DeHE induces relaxation in precontracted rat isolated mesen-
teric arteries in a concentration-dependent manner. The un-
derlying mechanisms may be complex, involving interaction
with the endothelium through the NO-guanylyl cyclase path-
way, -adrenoceptor blockade, K + channel activation, and
Ca2+ channel blockade [11] .
Rhynchophylline and isorhynchophylline
Uncaria rhynchophylla is one of the original plants of the
important Chinese crude drug, Gouteng, which is mainly
used for the treatment of hypertension. Rhynchophylline
(Compound 4, Fig. 2) and isorhynchophylline (Compound 5,
Fig. 2) are the main hypotensive constituents in Uncaria rhyn-
chophylla. Studies have shown that the properties of rhyn-
chophylline and isorhynchophylline are very similar and that
the latter undergoes rapid transformation into the former in
acidic medium. The hypotensive potency of Compound 5
(lowering of M AP by 42.0%) is much stronger than that of
Compound 4 (lowering of M AP by 32.1%) in anesthetized
rats. In anesthetized thoracotomized dogs, Compound 5
(1 mgkg1, i.v.) reduced the mean arterial pressure, heart rate,
and coronary blood flow by (3.58 0.19) kPa, (26 18)
beats/min, and (0.10 0.04) mLmin1g1, respectively. The

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active mechanisms are related to the modulation of calci-
umion channel, protection of neural and neuroglial cells
against -amyloid (2535)-induced neurotoxicity and via
inducing autophagy [12-14].
Dihydrocorynantheine
Dihydrocorynantheine (Compound 6, Fig. 2) is an alka-
loid present in Uncaria macrophylla, a Uncaria genus plant.
It exhibits significant vasodilating activity against phenylep h-
rine-induced contraction in rat thoracic aorta rings (IC 5 0
6.73 gmL1), which has potential effect for the treatment of
hypertension [15].
Isoliensinine
Isoliensinine (Compound 7, Fig. 2) is the main alkaloid in
Nelumbonucifera Gaertn, which exhibits certain antihy -
pertensive activity. In pithed rats (pretreated with phenylep h-
rine), the systolic arterial pressure (SAP) and diastolic arterial
pressure (DAP) were declined by 29% and 37% in 30 min after
the administration of liensinine (2 mgkg1, i.v.). It is concluded
that isoliensinine blocks Ca2+ influx and antagonizes the func-
tion of 1-adrenoceptor [16-17].
()-Lobeline
()-Lobeline (Compound 8, Fig. 2) is a major alkaloid of
Lobelia siphilitica and als o found in Hippobr oma longiflora,
which w as demonstrated to antagoniz e the bioactive effect
of endothelin-1 (ET-1) and prevent the proliferation of vas-
cular smooth muscle cells (VSM Cs). VSM Cs proliferation
induced by various growth factors can develop a variety of
pathological processes including atherosclerosis, hypertension
and restenosis after balloon angioplasty, of which ET-1 is one
of the most important cytokines. Consequently, inhibition of
VSM Cs proliferation induced by ET-1 represents a potential-
ly important therapeutic strategy for the treatment of afore-
mentioned diseases. Lobeline antagonizes proliferation of
human umbilical arterial VSM Cs induced by ET-1 by inhibi-
Fig. 3 Chemical structures of Compounds 1012
Reserpine and deserpidine
Reserpine (Compound 13, Fig. 4) and deserpidine (Com-
pound 14, Fig. 4) were first isolated in 1952 from Indian snake
root, Rauwolfia serpentine. Reserpine was introduced for the
treatment of hypertension in late 1950s, but deserpidine has not
been widely employed in medicine due to its poor availability
from natural extracts. The antihypertensive actions of reserpine
are a result of its ability to deplete catecholamines from peri-
pheral sympathetic nerve endings. Reserpine irreversibly blocks
the vesicular monoamine transporter (VMAT), which normally
transports free norepinephrine, serotonin, and dopamine from
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tion the increase of [Ca2+ ]i in a concentration-dependent
manner. These results suggest that lobeline can be used for
the treatment of atherosclerosis and hypertension [18-19] .
(+)-Nantenine
(+)-Nantenine (Compound 9, Fig. 2) is an aporphine al-
kaloid isolated from Nandina domestica, extracts of which
have been widely used in Japan for the treatment of asthma,
uterine bleeding and diabetes. In a recent research,
(+)-nantenine (330 molL1) totally relaxed the contrac-
tions induced by NA (IC50 6.24 0.55 molL1) or by a high
extracellular KCl concentration (IC50 5.23 0.48 molL1) in
intact rat aortic rings in a concentration-dependent fashion
and with almost equal effectiveness under both assay condi-
tions. These findings indicate a therapeutic potential as an
original chemical basis for the design and subsequent devel-
opment of new antihypertensive drugs [20].
Puqienine A, puqienine B and puqienine E
It has been reported that the steroidal alkaloids in many
plants have antihypertensive effects in humans. Puqienine A
(Compound 10, Fig. 3), puqienine B (Compound 11, Fig. 3)
and puqienine E (Compound 12, Fig. 3) are steroidal alkalo-
ids isolated from Fritillaria puqiensis, and their antihyperten-
sive effects have been assessed in vitro, based on the inhibi-
tion of the purified angiotensin converting enzyme (ACE)
using a high-performance liquid chromatography assay. The
reported results have shown that puqienine A, puqienine B
and puqienine E exhibit better inhibitory activity than ACE,
with inhibition ratios of (20.4 2.8)%, (24.7 0.5)% and
(70.2 0.5)%, respectively at the concentration of 200
molL1. The IC50 of puqienine E is 68 molL1. The
screening and identification of these ACE inhibitory alkal o-
ids could, to some extent, provide evidence for the applic a-
tion of F. puqiensis or other species of Fritillaria genus in
hypertensive therapy [21].
the cytoplasm of the presynaptic nerve terminal into storage
vesicles for subsequent release into the synaptic cleft. Unpro-
tected neurotransmitters are metabolized by MAO (as well as
by COMT) in the cytoplasm and consequently never reach the
synapse. It may take the body days to weeks to replenish the
depleted VMAT, so that the effects of reserpine are long-lasting.
As a second-line drug for patients, it is rarely used today be-
cause of its numerous side-effects and the development of bet-
ter drugs for these purposes [22].
Tetrandrine
Tetrandrine (Compound 15, Fig. 4) is the major bisbenzyl
 BAI Ren-Ren, et al. / Chin J Nat Med, 2015, 13(6): 721729
Fig. 4 Chemical structures of Compounds 1324
isoquinoline of Han Fang Ji (Stephania tetrandra, M eni-
spermaceae) and the most characteristic active constituent of
this Chinese herbal remedy, which has been used for centuries
in the treatment of hypertension. The smooth muscle relaxant
and hypotensive action of tetrandrine is attributed to its selec-
tive blockade of calcium channels and its interaction with
1-adrenergic receptors [23].
Diterpenes
Forskolin
Forskolin (Compound 16, Fig. 4) is the main active
compound in the Indian plant Coleus forskohlii. Several stu-
dies demonstrated that forskolin lowers blood pressure via
relaxation of vascular smooth muscle. On the one hand, fors-
kolin activates adenylate cyclase, producing an increase in
cAMP, which in turn will activate cAM P-dependent protein
kinase (PKA) and produce relaxation. On the other hand, the
relaxation induced by forskolin also involves hyperpo-
larization of smoothmuscle and Ca2+ extrusion across the
plasma membrane. In humans, forskolin (4 gkg1min1, i.v.)
decreases vascular resistance, improves left ventricular con-
tractility and decreases the arterial pressure [1, 24-26].
Stevioside
Stevios ide (Compound 17, F ig. 4), a diterpenoid gly-
coside comprising of an aglycone (steviol) and three mol e-
cules of glucose, is extracted from Stevia rebaudiana Bertoni,
which is a small shrub originally grown in South America. It
has previously been shown to reduce blood pressure in studies
in animals and humans. The hypotensive effects on both SAP
and DAP were dose-dependent for intravenous doses of 50, 100
and 200 mgkg1 in conscious SHRs. The maximum reductions
in SAP and DAP were (31.4 4.2) % and (40.8 5.6)%, re-
spectively [27] . However, crude stevioside at does up to 15.0
mgkg1d1 did not show an antihypertensive effect on pre-
viously untreated mild hypertensive patients [28]. The possible
antihypertensive mechanism of stevioside is to affect vascular
resistance via inhibition of extracellular Ca2+ influx and the
release of a vasodilator prostaglandin. Stevioside also produces
diuresis and natriuresis resulting in reduction of extracellular
fluid volume [29].
14-Deoxy-11, 12-didehydroandrographolide
Andrographis paniculata (Burm. f.) Nees (Acanthaceae)
has a considerable medicinal reputation in M alaysia as a p o-
tent medicine in the treatment of diabetes and hyp ertension.
14-Deoxy-11, 12-didehydroandrographolide (DDA) (Compound
18, Fig. 4) is a diterpenoid isolated from A. peniculata. In an
aesthetised rats, DDA produced significant falls in M AP and
heart rate in a dose-dependent manner with the maximum
decrease of (37.6 2.6)% and (18.1 4.8)%, respectively. It
seems to work via adrenoceptors, autonomic ganglia receptor
or angiotensin- converting enzyme, since the hypotensive
effect of DDA is negated or attenuated in the presence of
propranolol, hexamethonium and captopril. In the isolated
right atria, DDA caused negative chronotropic action and
antagonised isoproterenol-induced positive chronotropic ac-
tions in a non-competitive and dose-dependent manner. Thes e
results further support the bradycardia-inducing and
-adrenoceptor antagonistic properties of DDA in vivo [30] .
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ent-Kaur-16-en-19-oic acid and ent-kaur-16-en-15-one-19-
oic acid
ent-Kaur-16-en-19-oic acid (Compound 19, Fig. 4) and
ent-kaur-16-en-15-one-19-oic acid (Compound 20, Fig. 4)
are two kaurane-type diterpenes isolated from Xylopia ae-
thiopica, which is an evergreen and aromatic tree in Africa.
Intravenous administration of thes e two compounds at 10
mgkg1 in normotensive rats produced an immediate d e-
crease of SAP by 17% and 18%, respectively, no change of
DAP, and a significant decreas e of heart rate by 20% and
55%, respectively. Other similar results also show that ent-
kaur-16-en-19-oic acid (15 mgkg1, i.v.) decreas es M AP of
conscious normotens ive rats [1, 31-32]. Further study on the
vascular relaxation effects has proven that ent-kaur-16-en-
19-oic acid blocks extracellular Ca2+ influx stimulated neu-
ronal NO synthase and NO-cGM P pathway [33].
8-(17), 12 E, 14-Labdatrien-18-oic acid
The diterpene 8-(17), 12E, 14-labdatrien-18-oic acid (Com-
pound 21, Fig. 4) is isolated from Xylopia langsdorffiana stem
ethanolic extracts. In normotensive, conscious animals, this
diterpene produces dose-dependent hypotension and tachy-
cardia. In isolated mesenteric artery rings, the diterpene
(101 010 4 molL1) elicits concentrat ion-dependent relax-
ation of phenylephrine-induced contractions (IC50 5.4 1.4
molL 1). It also causes concentration-dep endent relaxa-
tion in arterial rings pre-contracted with high extracellular
KCl (80 mmolL1). In Ca2+ -free depolarized preparations,
it inhibits contractions produced by cumulative increases in
extracellular Ca2+ concentration. These res ults demonstrate
that Compound 21 caus es hypotension through peripheral
vasodilation, which is mediated in part by NO and PGI 2 as
well as by blockade of Ca2+ entry through L-type Ca2+
channels [ 34].
Labd-8(17)-en-15-oic acid
Labd-8(17)-en-15-oic acid (Labd-8, Compound 22, Fig. 4)
is a labdenicditerpene isolated from methanolic extract of
Moldenhawera nutans. Biological evaluation has shown that
i.v. treat ment with Compound 22 induces dos e-dependent
hypotensive and tachycardiac effects in both conscious and
anesthetized rats. Compound 22 (11 000 gmL1) in-
duces a concentration-dependent reduction of potassium
(60 mmolL1 )-induced contraction (IC50 = 313.6 gmL1),
an effect that remains unaffected (IC50 = 440.8 gmL1) by
removal of vascular endothelium. The hypotension is mainly
due to withdrawal of sympathetic tone to the vasculature and
also partly to an active vascularrelaxation [35].
Triptolide
Tripterygium wilfordii Hook F. (TWHF ) is an herb
used in traditional Chinese medicine. Triptolide (Com-
pound 23, Fig. 4) is a highly oxy genated diterpene lactone
epoxide compound extract ed from TWHF. In pneumonec-
tomized rats that receive monocrotaline, triptolide attenuates
the development of pulmonary hypertension and right ventri-
cularhypertrophy, and promotes regression of pulmonary
arterial neointimal formation [36].
Coumarins
(+)-Praeruptorin A
(+)-Praeruptorin A (Compound 24, Fig. 4) is a coumarin
isolated from Peucedanumpra eruptorum Dunn, which is a
well-known traditional Chinese medicine used for the treat-
ment of respiratory diseases and pulmonary hypertension.
(+)-Praeruptorin A produces significant relaxant effects in
rabbit tracheal preparations constricted with KCl or acetyl-
choline, and completely relaxes tracheas constricted with 40
nmolL1 KCl at a concentration of 30 molL1. The relaxant
activity is due to its calcium antagonistic action [37].
Imperatorin
Imperatorin (Imp, Compound 25, Fig. 5), a dietary fura-
nocoumarin, is wide spread and found not only in the med i-
cinal plant such as Cnidium monnieri cuss and Angelica da-
hurica, but also in popular culinary herbs such as parsnip,
pars ley, and fennel. Aft er 13 w eeks of treat ment w ith
Compound 25 (25 mgkg 1 d1 , i.g.), the SAP DAP in
SHRs were reduced significantly. A series of experiments
have demonstrated that Compound 25 targets the L-type cal-
cium channel. The aortic ring is relaxed with Compound 25,
and L-type calcium channel currents and intracellular calcium
free ion rise are nearly dis appeared when adding Com-
pound 25. Imperatorin is a novel structure of furanocouma-
rins calcium antagonist, which has a potential application for
the hypertension treatment in clinic [38] .
Ostruthol
Ostruthol (Compound 26, Fig. 5) is a furanocoumarin
isolated from Peucedanum ostruthium, which is used in tradi-
tional medicine in the treatment of cardiovascular diseases. It
exhibits a much higher activity against K + -spasms than
against norepinephrine-contractions; the inhibition ratio is
about 35% at the concentrations of 0.01 gmL1, suggesting a
blockade of voltage-operated calcium channel [39] .
Flavonoids
Quercetin and isorhamnetin
Total flavones of Hippophae Rhamnoides (TFH) are ex-
tracts of Hippophae Rhamnoides, mainly composed
of quercetin (Compound 27, Fig. 5) and isorhamnetin (Com-
pound 28, Fig. 5), which display antihypertensive and target
organ protecting activity. After 12 weeks of treatment w ith
TFH (30 mgkg 1d1 ), the SAP of SHRs was decreased by
14%, comparable w ith enalapril group (30 mgkg1d1,
decreased by 16%) and hydrochlorothiazide group (25
mgkg1 d1, decreased by 14%). M oreover, TFH may inhibit
the expression of M CP-1 in aorta and intimal medial thick-
ness of aorta [40].
Astragalin
The leaves of the persimmon Diospyros kaki have been
traditionally used for treatment of hypertensive diseases in
Japan. Several flavonoids isolated from the leaves showed
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Fig. 5 Chemical structures of Compounds 2533
moderate angiotensin-converting enzyme inhibitory activity.
Among them, astragalin (Compound 29, Fig. 5) produces
inhibition by 67% at a concentration of 300 gmL1, The
IC50 of astragalin is 180 gmL1 [41].
Orientin
Orientin (Compound 30, Fig. 5) is an active compound
isolated from Bamboo leaves, Phyllostachys nigra, which have
been used as a Chinese medicament for thousands of years.
Orientin relaxes phenylephrine-induced contractions with an
IC50 value being 2.28 molL1 in the endothelium-intact and
with an IC50 value being around 7.27 molL1 in the endothe-
lium removed aortic rings. The vasorelaxant effect of Orientin
on endothelium- intact thoracic aortic rings is attenuated by the
nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl
ester, but not by indomethacin (a cyclooxygenase inhibitor), te-
traethylammonium, chloride (K + channels inhibitor) or propra-
nolol (-receptor inhibitor). Furthermore, Orientin inhibits no-
repinephrine (NE), CaCl2 and KCl-induced vasoconstriction
concentration-dependently in a non-competitive manner, and
also reduces both the initial fast release and the sustained phas-
es of phenylephrine-induced contractions. Orientin can stimu-
late NO production from endothelial cells. These results indi-
cate that Orientin relaxes thoracic aortic rings by the nitric
oxide-cGM P pathway, and inhibits the contraction induced by
the activation of receptor- operating and voltage-dependent
Ca2+ channels in the vascular smooth muscle. The inhibition of
both intracellular Ca2+ release and extracellular Ca2+ influx may
be one of the main vasorelaxant mechanisms of Orientin [42].
Cardamonin and Alpinetin
The natural vascular products cardamonin (Compound 31,
Fig. 5) and alpinetin (Compound 32, Fig. 5) are isolated from
Alpinia henryi K. Schum. Both cardamonin and alpinetin
induce relaxation of phenylephrine-preconstricted arteries
with respective IC50 of (9.3 0.6) and (27.5 2.8) molL1.
They inhibit 60 mmolL1 K + -induced contraction with re-
spective IC50 of (11.5 0.3) and (37.9 3.6) molL1. In (Fabaceae). Biological assays have shown that daleformis is a
addition, both agents inhibit the transient contraction induced
by 3 molL1 of phenylephrine or by 10 mmolL1 of caffeine
726
in Ca2+ -free Krebs solution. These results indicat that purified
cardamonin and alpinetin relax mesenteric arteries of rats
through multiple mechanisms. They induce both endothe-
lium-dependent and -independent relaxation; the former is
likely mediated by nitric oxide, whereas the latter is probably
mediated through non-selective inhibition of Ca2+ influx and
intracellular Ca2+ release and inhibition of the protein kinase
C-dependent contractile mechanism [43].
ACE inhibitory Peptides
ACE inhibitors have been prescribed for hypertensive p a-
tients throughout the world. Synthesized chemical drugs such
as Captopril, Enalapril, Alacepriland Lisinopril are extensively
used medications in treatment and prevention of hypertension.
However, these drugs often cause side-effects in the patients,
such as a persistent dry cough, taste disturbance, increased
potassium levels, reduced renal function, and skin rashes [44].
In recent years, peptides from partial enzymatic hydrolysates
of food proteins have received a greater attention than before.
Many biological peptides promoting health benefits have been
classified and identified from food protein hydrolysates. These
peptides are inactive within the sequence of the parent protein,
but can be released during enzymatic digestion or food
processing [45]. Naturally sourced angiotensin converting en-
zyme (ACE) inhibitors raise the possibility that hypertension
could be modulated through dietary intake. ACE-inhibitory pep-
tides have been isolated from various marine proteins such as
Heshiko, a fermented mackerel product, skipjack tuna muscle,
sardine muscle, shark meat, Alaskan Pollack skin, marine
shrimps, pacific hake, and salmon chum (Table 1) [46].
Other natural products with antihypertensive activity
Daleformis
Daleformis (Compound 33, Fig. 5) is a novel pterocarpi-
noid extracted from the roots of Dalea filiciformis Snader
nov e l i nh ib it o r of e nd ot h e li n c onv e rt i n g
 BAI Ren-Ren, et al. / Chin J Nat Med, 2015, 13(10): 721729

Table 1 Examples of ACE inhibitory peptides derived from marine sources

Origin Hydrolysis Peptide sequence IC50 /(molL1)
Sardine muscle Alkaline protease Lys-Trp 1.63
Driedskipjack tuna muscle Thermolysin Leu-Lys -Pro-Met-Asn, 2.4
Skipjack tuna muscle Acid extract Pro-Thr-His-Ile-Lys -Trp-Gly-Asp 2.0
Phe-Leu, 13.6
Salmon chum muscle Thermolysin
Leu-Phe 383.2
Cys-Phe, 1.96
Shark meat Protease SM98011 Glu-Try, 2.68
Phe-Glu 1.45
Asp-Pro, 2.15
Shrimp Aceteschinensis L. fermentum SM 605 Gly-Thr-Gly, 5.54
Ser-Thr 4.03
Oyster protein Pepsin Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe 66.00
Alcalase, Gly-Pro-Met, 17.13
Alaska Pollack skin
PronaseE & collagenase Gly-Pro-Leu 2.60
Anchovy ferm ented fish sauce Unknown Lys-Pro 22.00
Algae protein waste Pepsin Val-Glu-Cys-Tyr-Gly-Pro-Asn-Arg- 29.60
Pro-Gln-Phe
Ile-Tyr, 6.10
Wakame (Undariapinnati fida) Protease S "Amano" Val-Trp, 3.30
Ile-Trp 1.50

enzyme (ECE), with an IC50 being 9 molL1 ECE is a mem-
brane bound neutral metalloprotease that catalyzes the con-
version of a 38-residue inactive intermediate big endothelin to
a 21-residue potent vasoconstrictive peptide, endothelin-1
(ET-1), which is a strong promoter for vascular contraction.
As an ECE inhibitor, daleformis could reduce production of
endothelin by interfering with the ET-1 biosynthesis pathway,
which may have therapeutic utility for hypertension or renal
failure [47].
Magnesium lithospermate B
Magnesium lithospermate B (Compound 34, Fig. 6) is an
active component of Salviae Miltiorrhizae Radix, which is wide-
ly employed in China to improve blood flow and dilate blood
vessels. SAP is significantly descended in SHRs given magne-
sium lithospermate B at 10 mgkg1 for both 12 and 24 days.
Administration of magnesium lithospermate B caused an 8%
reduction in SAP from 223.7 to 206.7 mmHg on Day 12 and a
10% reduction from 230.1 to 206.3 mmHg on Day 24. Oral
administration of magnesium lithospermate B also decreased
the MAP of rats with renal failure. On Day 12, MAP was signif-
icantly lowered from 173.0 to 158.6 mmHg for a 10 mg dose of
the compound. It also significantly increased the low urinary
kallikrein level in SHRs, with a parallel increase in excretion of
prostaglandin E, sodium and potassium ions. These data suggest
that magnesium lithospermate B may ameliorate the development
of hypertension by improving the renal circulatory state. Addi-
tionally, a study on the acute toxicity of oral magnesium lithos-
permate B in terms of LD 50 determined by the up and down me-
thod has shown a high safety of this substance (> 3 000 mgkg1
in 6-week-old male ddY mice weighing 3135 g) [48].
Halistanoldisulfate B
Sulfated sterols have been described from a wide variety
of marine organisms, particularly sponges and echinoderms,
and several of these steroidal sulfates have exhibited a broad
range of act ivit ies. One of the sponge extracts isolated
from sponge Pachastr ella sp, collected in South Africa,
has been found to be active in the ECE inhibition screen.
Halistanoldisulfate B (Compound 35, Fig. 6) is the main ac-
tive constituent, which is a novel inhibitor of ECE, with an
IC50 being 2.1 molL1 [49].

Fig. 6 Chemical structures of Compounds 3437

Ursolic and moronic acids
Phoradendron reichenbachianum is a medicinal plant
which is used in M exican traditional medicine for the treatment
of renal diseases, as well as antidiabetic and antihypertensive
agent. Ursolic (Compound 36, Fig. 6) and moronic acids
(Compound 37, Fig. 6) are triterpenic acids extracted from
Phoradendron reichenbachianum and show a significant re-
laxant effect in a concentration and endothelium-dependent
manners on rat aorta rings after contraction with NA (ursolic
acid EC50 11.7 molL1; moronic acid EC50 16.1 molL1).
Moreover, the relaxant effects induced by these two triterpenic
acids seem to be involved NO release in functional experiments.

727
 BAI Ren-Ren, et al. / Chin J Nat Med, 2015, 13(6): 721729
Also, the docking results indicate that they could interact with
the binding pockets C1 and C2 that access the catalytic site and
this interaction may activate eNOS. The results could make
pentacyclic triterpenic acids as leads for the design and devel-
opment of new antihypertensive drugs [50] .
Isochroman-4-one XJP
The banana peel is a great resource in China, which has
been widely used as a folk medicine for antihypertension,
antiulceration and antibacterial treatments. A novel and
structurally unique isochroman-4-one ()-XJP (Compound 38,
Fig. 7), a natural polyphenolic compound, has been isolated
from banana (Musa sapientum L.) peel extract. ()-XJP dis-
plays potent antihypertensive activity in both acute and the-
rapeutic antihypertensive tests in renal hypertensive rats
(RHRs); the maximum antihypertensive effect of ()-XJP at
the dose of 100 mgkg1 is comparable to that of captopril at
the dose of 25 mgkg1. The mechanistic studies have re-
vealed that ()-XJP has moderate ACE inhibitory activity,
suggesting that ACE may be one of its possible targets [51].
Antihypertensive evaluation has proven that ()-XJP isomers
possess similar pharmacodynamic effects, but with different
potency, and that the R-()-XJP (Compound 39, Fig. 7) is
more potent than S-(+)-XJP (Compound 40, Fig. 7) [52-53].
Fig. 7 Chemical structures of Compounds 3840
Conclusion
In summary, the prevalence of hypertension has been in-
creasing dramatically in the world during the past decades.
Although many antihypertensive drugs with various mechan-
isms of action are used, they still cannot meet the needs in the
clinic. In recent years, the potential value of herbal medicines
for hypertension treatment has been rediscovered [54] . Natural
products as sources of new drugs have played and will continue
to play a dominant role in the discovery of lead compounds for
the treatment of hypertension. Plenty of herbal medicines and
plants extracts with antihypertensive activity remain to be ex-
plored and identified as potential leads for further structural
modifications and optimization, in hopes that they would be
developed as more potent and safer antihypertensive drugs in
the future.
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