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

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

Fig. 2 Chemical structures of Compounds 19

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

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active mechanisms are related to the modulation of calci- tion the increase of [Ca2+ ]i in a concentration-dependent
umion channel, protection of neural and neuroglial cells manner. These results suggest that lobeline can be used for
against -amyloid (2535)-induced neurotoxicity and via the treatment of atherosclerosis and hypertension [18-19] .
inducing autophagy [12-14]. (+)-Nantenine
Dihydrocorynantheine (+)-Nantenine (Compound 9, Fig. 2) is an aporphine al-
Dihydrocorynantheine (Compound 6, Fig. 2) is an alka- kaloid isolated from Nandina domestica, extracts of which
loid present in Uncaria macrophylla, a Uncaria genus plant. have been widely used in Japan for the treatment of asthma,
It exhibits significant vasodilating activity against phenylep h- uterine bleeding and diabetes. In a recent research,
rine-induced contraction in rat thoracic aorta rings (IC 5 0 (+)-nantenine (330 molL1) totally relaxed the contrac-
6.73 gmL1), which has potential effect for the treatment of tions induced by NA (IC50 6.24 0.55 molL1) or by a high
hypertension [15]. extracellular KCl concentration (IC50 5.23 0.48 molL1) in
Isoliensinine intact rat aortic rings in a concentration-dependent fashion
Isoliensinine (Compound 7, Fig. 2) is the main alkaloid in and with almost equal effectiveness under both assay condi-
Nelumbonucifera Gaertn, which exhibits certain antihy - tions. These findings indicate a therapeutic potential as an
pertensive activity. In pithed rats (pretreated with phenylep h- original chemical basis for the design and subsequent devel-
rine), the systolic arterial pressure (SAP) and diastolic arterial opment of new antihypertensive drugs [20].
pressure (DAP) were declined by 29% and 37% in 30 min after Puqienine A, puqienine B and puqienine E
the administration of liensinine (2 mgkg1, i.v.). It is concluded It has been reported that the steroidal alkaloids in many
that isoliensinine blocks Ca2+ influx and antagonizes the func- plants have antihypertensive effects in humans. Puqienine A
tion of 1-adrenoceptor [16-17]. (Compound 10, Fig. 3), puqienine B (Compound 11, Fig. 3)
()-Lobeline and puqienine E (Compound 12, Fig. 3) are steroidal alkalo-
()-Lobeline (Compound 8, Fig. 2) is a major alkaloid of ids isolated from Fritillaria puqiensis, and their antihyperten-
Lobelia siphilitica and als o found in Hippobr oma longiflora, sive effects have been assessed in vitro, based on the inhibi-
which w as demonstrated to antagoniz e the bioactive effect tion of the purified angiotensin converting enzyme (ACE)
of endothelin-1 (ET-1) and prevent the proliferation of vas- using a high-performance liquid chromatography assay. The
cular smooth muscle cells (VSM Cs). VSM Cs proliferation reported results have shown that puqienine A, puqienine B
induced by various growth factors can develop a variety of and puqienine E exhibit better inhibitory activity than ACE,
pathological processes including atherosclerosis, hypertension with inhibition ratios of (20.4 2.8)%, (24.7 0.5)% and
and restenosis after balloon angioplasty, of which ET-1 is one (70.2 0.5)%, respectively at the concentration of 200
of the most important cytokines. Consequently, inhibition of molL1. The IC50 of puqienine E is 68 molL1. The
VSM Cs proliferation induced by ET-1 represents a potential- screening and identification of these ACE inhibitory alkal o-
ly important therapeutic strategy for the treatment of afore- ids could, to some extent, provide evidence for the applic a-
mentioned diseases. Lobeline antagonizes proliferation of tion of F. puqiensis or other species of Fritillaria genus in
human umbilical arterial VSM Cs induced by ET-1 by inhibi- hypertensive therapy [21].

Fig. 3 Chemical structures of Compounds 1012

Reserpine and deserpidine the cytoplasm of the presynaptic nerve terminal into storage
Reserpine (Compound 13, Fig. 4) and deserpidine (Com- vesicles for subsequent release into the synaptic cleft. Unpro-
pound 14, Fig. 4) were first isolated in 1952 from Indian snake tected neurotransmitters are metabolized by MAO (as well as
root, Rauwolfia serpentine. Reserpine was introduced for the by COMT) in the cytoplasm and consequently never reach the
treatment of hypertension in late 1950s, but deserpidine has not synapse. It may take the body days to weeks to replenish the
been widely employed in medicine due to its poor availability depleted VMAT, so that the effects of reserpine are long-lasting.
from natural extracts. The antihypertensive actions of reserpine As a second-line drug for patients, it is rarely used today be-
are a result of its ability to deplete catecholamines from peri- cause of its numerous side-effects and the development of bet-
pheral sympathetic nerve endings. Reserpine irreversibly blocks ter drugs for these purposes [22].
the vesicular monoamine transporter (VMAT), which normally Tetrandrine
transports free norepinephrine, serotonin, and dopamine from Tetrandrine (Compound 15, Fig. 4) is the major bisbenzyl

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Fig. 4 Chemical structures of Compounds 1324

isoquinoline of Han Fang Ji (Stephania tetrandra, M eni- and DAP were dose-dependent for intravenous doses of 50, 100
spermaceae) and the most characteristic active constituent of and 200 mgkg1 in conscious SHRs. The maximum reductions
this Chinese herbal remedy, which has been used for centuries in SAP and DAP were (31.4 4.2) % and (40.8 5.6)%, re-
in the treatment of hypertension. The smooth muscle relaxant spectively [27] . However, crude stevioside at does up to 15.0
and hypotensive action of tetrandrine is attributed to its selec- mgkg1d1 did not show an antihypertensive effect on pre-
tive blockade of calcium channels and its interaction with viously untreated mild hypertensive patients [28]. The possible
1-adrenergic receptors [23]. antihypertensive mechanism of stevioside is to affect vascular
resistance via inhibition of extracellular Ca2+ influx and the
Diterpenes
release of a vasodilator prostaglandin. Stevioside also produces
Forskolin diuresis and natriuresis resulting in reduction of extracellular
Forskolin (Compound 16, Fig. 4) is the main active fluid volume [29].
compound in the Indian plant Coleus forskohlii. Several stu- 14-Deoxy-11, 12-didehydroandrographolide
dies demonstrated that forskolin lowers blood pressure via Andrographis paniculata (Burm. f.) Nees (Acanthaceae)
relaxation of vascular smooth muscle. On the one hand, fors- has a considerable medicinal reputation in M alaysia as a p o-
kolin activates adenylate cyclase, producing an increase in tent medicine in the treatment of diabetes and hyp ertension.
cAMP, which in turn will activate cAM P-dependent protein 14-Deoxy-11, 12-didehydroandrographolide (DDA) (Compound
kinase (PKA) and produce relaxation. On the other hand, the 18, Fig. 4) is a diterpenoid isolated from A. peniculata. In an
relaxation induced by forskolin also involves hyperpo- aesthetised rats, DDA produced significant falls in M AP and
larization of smoothmuscle and Ca2+ extrusion across the heart rate in a dose-dependent manner with the maximum
plasma membrane. In humans, forskolin (4 gkg1min1, i.v.) decrease of (37.6 2.6)% and (18.1 4.8)%, respectively. It
decreases vascular resistance, improves left ventricular con- seems to work via adrenoceptors, autonomic ganglia receptor
tractility and decreases the arterial pressure [1, 24-26]. or angiotensin- converting enzyme, since the hypotensive
Stevioside effect of DDA is negated or attenuated in the presence of
Stevios ide (Compound 17, F ig. 4), a diterpenoid gly- propranolol, hexamethonium and captopril. In the isolated
coside comprising of an aglycone (steviol) and three mol e- right atria, DDA caused negative chronotropic action and
cules of glucose, is extracted from Stevia rebaudiana Bertoni, antagonised isoproterenol-induced positive chronotropic ac-
which is a small shrub originally grown in South America. It tions in a non-competitive and dose-dependent manner. Thes e
has previously been shown to reduce blood pressure in studies results further support the bradycardia-inducing and
in animals and humans. The hypotensive effects on both SAP -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- arterial neointimal formation [36].

oic acid
Coumarins
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) (+)-Praeruptorin A
are two kaurane-type diterpenes isolated from Xylopia ae- (+)-Praeruptorin A (Compound 24, Fig. 4) is a coumarin
thiopica, which is an evergreen and aromatic tree in Africa. isolated from Peucedanumpra eruptorum Dunn, which is a
Intravenous administration of thes e two compounds at 10 well-known traditional Chinese medicine used for the treat-
mgkg1 in normotensive rats produced an immediate d e- ment of respiratory diseases and pulmonary hypertension.
crease of SAP by 17% and 18%, respectively, no change of (+)-Praeruptorin A produces significant relaxant effects in
DAP, and a significant decreas e of heart rate by 20% and rabbit tracheal preparations constricted with KCl or acetyl-
55%, respectively. Other similar results also show that ent- choline, and completely relaxes tracheas constricted with 40
kaur-16-en-19-oic acid (15 mgkg1, i.v.) decreas es M AP of nmolL1 KCl at a concentration of 30 molL1. The relaxant
conscious normotens ive rats [1, 31-32]. Further study on the activity is due to its calcium antagonistic action [37].
vascular relaxation effects has proven that ent-kaur-16-en- Imperatorin
19-oic acid blocks extracellular Ca2+ influx stimulated neu- Imperatorin (Imp, Compound 25, Fig. 5), a dietary fura-
ronal NO synthase and NO-cGM P pathway [33]. nocoumarin, is wide spread and found not only in the med i-
8-(17), 12 E, 14-Labdatrien-18-oic acid cinal plant such as Cnidium monnieri cuss and Angelica da-
The diterpene 8-(17), 12E, 14-labdatrien-18-oic acid (Com- hurica, but also in popular culinary herbs such as parsnip,
pound 21, Fig. 4) is isolated from Xylopia langsdorffiana stem pars ley, and fennel. Aft er 13 w eeks of treat ment w ith
ethanolic extracts. In normotensive, conscious animals, this Compound 25 (25 mgkg 1 d1 , i.g.), the SAP DAP in
diterpene produces dose-dependent hypotension and tachy- SHRs were reduced significantly. A series of experiments
cardia. In isolated mesenteric artery rings, the diterpene have demonstrated that Compound 25 targets the L-type cal-
(101 010 4 molL1) elicits concentrat ion-dependent relax- cium channel. The aortic ring is relaxed with Compound 25,
ation of phenylephrine-induced contractions (IC50 5.4 1.4 and L-type calcium channel currents and intracellular calcium
free ion rise are nearly dis appeared when adding Com-
molL 1). It also causes concentration-dep endent relaxa-
pound 25. Imperatorin is a novel structure of furanocouma-
tion in arterial rings pre-contracted with high extracellular
rins calcium antagonist, which has a potential application for
KCl (80 mmolL1). In Ca2+ -free depolarized preparations,
the hypertension treatment in clinic [38] .
it inhibits contractions produced by cumulative increases in
Ostruthol
extracellular Ca2+ concentration. These res ults demonstrate
Ostruthol (Compound 26, Fig. 5) is a furanocoumarin
that Compound 21 caus es hypotension through peripheral
isolated from Peucedanum ostruthium, which is used in tradi-
vasodilation, which is mediated in part by NO and PGI 2 as
tional medicine in the treatment of cardiovascular diseases. It
well as by blockade of Ca2+ entry through L-type Ca2+
exhibits a much higher activity against K + -spasms than
channels [ 34].
against norepinephrine-contractions; the inhibition ratio is
Labd-8(17)-en-15-oic acid
about 35% at the concentrations of 0.01 gmL1, suggesting a
Labd-8(17)-en-15-oic acid (Labd-8, Compound 22, Fig. 4)
blockade of voltage-operated calcium channel [39] .
is a labdenicditerpene isolated from methanolic extract of
Moldenhawera nutans. Biological evaluation has shown that Flavonoids
i.v. treat ment with Compound 22 induces dos e-dependent
hypotensive and tachycardiac effects in both conscious and Quercetin and isorhamnetin
anesthetized rats. Compound 22 (11 000 gmL1) in- Total flavones of Hippophae Rhamnoides (TFH) are ex-
duces a concentration-dependent reduction of potassium tracts of Hippophae Rhamnoides, mainly composed
(60 mmolL1 )-induced contraction (IC50 = 313.6 gmL1), of quercetin (Compound 27, Fig. 5) and isorhamnetin (Com-
an effect that remains unaffected (IC50 = 440.8 gmL1) by pound 28, Fig. 5), which display antihypertensive and target
removal of vascular endothelium. The hypotension is mainly organ protecting activity. After 12 weeks of treatment w ith
due to withdrawal of sympathetic tone to the vasculature and TFH (30 mgkg 1d1 ), the SAP of SHRs was decreased by
also partly to an active vascularrelaxation [35]. 14%, comparable w ith enalapril group (30 mgkg1d1,
Triptolide decreased by 16%) and hydrochlorothiazide group (25
Tripterygium wilfordii Hook F. (TWHF ) is an herb mgkg1 d1, decreased by 14%). M oreover, TFH may inhibit
used in traditional Chinese medicine. Triptolide (Com- the expression of M CP-1 in aorta and intimal medial thick-
pound 23, Fig. 4) is a highly oxy genated diterpene lactone ness of aorta [40].
epoxide compound extract ed from TWHF. In pneumonec- Astragalin
tomized rats that receive monocrotaline, triptolide attenuates The leaves of the persimmon Diospyros kaki have been
the development of pulmonary hypertension and right ventri- traditionally used for treatment of hypertensive diseases in
cularhypertrophy, and promotes regression of pulmonary 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. in Ca2+ -free Krebs solution. These results indicat that purified
Among them, astragalin (Compound 29, Fig. 5) produces cardamonin and alpinetin relax mesenteric arteries of rats
inhibition by 67% at a concentration of 300 gmL1, The through multiple mechanisms. They induce both endothe-
IC50 of astragalin is 180 gmL1 [41]. lium-dependent and -independent relaxation; the former is
Orientin likely mediated by nitric oxide, whereas the latter is probably
Orientin (Compound 30, Fig. 5) is an active compound mediated through non-selective inhibition of Ca2+ influx and
isolated from Bamboo leaves, Phyllostachys nigra, which have intracellular Ca2+ release and inhibition of the protein kinase
been used as a Chinese medicament for thousands of years. C-dependent contractile mechanism [43].
Orientin relaxes phenylephrine-induced contractions with an
IC50 value being 2.28 molL1 in the endothelium-intact and
ACE inhibitory Peptides
with an IC50 value being around 7.27 molL1 in the endothe- ACE inhibitors have been prescribed for hypertensive p a-
lium removed aortic rings. The vasorelaxant effect of Orientin tients throughout the world. Synthesized chemical drugs such
on endothelium- intact thoracic aortic rings is attenuated by the as Captopril, Enalapril, Alacepriland Lisinopril are extensively
nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl used medications in treatment and prevention of hypertension.
ester, but not by indomethacin (a cyclooxygenase inhibitor), te- However, these drugs often cause side-effects in the patients,
traethylammonium, chloride (K + channels inhibitor) or propra- such as a persistent dry cough, taste disturbance, increased
nolol (-receptor inhibitor). Furthermore, Orientin inhibits no- potassium levels, reduced renal function, and skin rashes [44].
repinephrine (NE), CaCl2 and KCl-induced vasoconstriction In recent years, peptides from partial enzymatic hydrolysates
concentration-dependently in a non-competitive manner, and of food proteins have received a greater attention than before.
also reduces both the initial fast release and the sustained phas- Many biological peptides promoting health benefits have been
es of phenylephrine-induced contractions. Orientin can stimu- classified and identified from food protein hydrolysates. These
late NO production from endothelial cells. These results indi- peptides are inactive within the sequence of the parent protein,
cate that Orientin relaxes thoracic aortic rings by the nitric but can be released during enzymatic digestion or food
oxide-cGM P pathway, and inhibits the contraction induced by processing [45]. Naturally sourced angiotensin converting en-
the activation of receptor- operating and voltage-dependent zyme (ACE) inhibitors raise the possibility that hypertension
Ca2+ channels in the vascular smooth muscle. The inhibition of could be modulated through dietary intake. ACE-inhibitory pep-
both intracellular Ca2+ release and extracellular Ca2+ influx may tides have been isolated from various marine proteins such as
be one of the main vasorelaxant mechanisms of Orientin [42]. Heshiko, a fermented mackerel product, skipjack tuna muscle,
Cardamonin and Alpinetin sardine muscle, shark meat, Alaskan Pollack skin, marine
The natural vascular products cardamonin (Compound 31, shrimps, pacific hake, and salmon chum (Table 1) [46].
Fig. 5) and alpinetin (Compound 32, Fig. 5) are isolated from
Alpinia henryi K. Schum. Both cardamonin and alpinetin Other natural products with antihypertensive activity
induce relaxation of phenylephrine-preconstricted arteries Daleformis
with respective IC50 of (9.3 0.6) and (27.5 2.8) molL1. Daleformis (Compound 33, Fig. 5) is a novel pterocarpi-
They inhibit 60 mmolL1 K + -induced contraction with re- noid extracted from the roots of Dalea filiciformis Snader
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 nov e l i nh ib it o r of e nd ot h e li n c onv e rt i n g
by 3 molL1 of phenylephrine or by 10 mmolL1 of caffeine

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

Fig. 6 Chemical structures of Compounds 3437

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

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Also, the docking results indicate that they could interact with [2] Cragg GM, Newman DJ. Natural products: A continuing
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Cite this article as: BAI Ren-Ren, WU Xiao-Ming, XU Jin-Yi. Current natural products with antihypertensive activity [J]. Chinese Journal of
Natural Medicines, 2015, 13(10): 721-729.

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