Chinese

Journal of
Natural
Chinese Journal of Natural Medicines 2015, 13(10): 07210729 Medicines
doi: 10.3724/SP.J.1009.2015.00721

·Reviews·
Current natural products with antihypertensive 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

[ABSTRACT] Natural products have been an important source of new drugs, 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
development 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. These information provides instructive
reference for the following structural modifications and optimization.

[KEY WORDS] Natural products; Antihypertensive activity; Lead compounds; Action mechanism
[CLC Number] R28, R965 [Document code] A [Article ID] 2095-6975(2015)10-0721-09

sources of antihypertensive natural products were listed in

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].
Meanwhile, the influence of natural product is also quite
evident in other areas [3]. The research, development, and use
of natural products as therapeutic agents, especially those
derived from plants, have been increasing in recent years.
Hypertension has become one of the most important
preventable 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]. Most of the currently used
antihypertensive agents cannot be used as a single drug
therapy because of their limited efficacy and side effects.
Therefore, the research and development of new drugs with
multiple therapeutic effects is most desirable [6].
The treatment of hypertension with plant extracts or
plant-derived products is well documented. Some plant
[Received 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.
Fig. 1. However, references about isolation, identification and
mechanism research of the lead compounds really
contributive to antihypertensive activity are still limited. In
this review article, we discuss the recent progress in the
research of natural lead compounds with antihypertensive
activity, emphasizing the mechanisms underlying their
antihypertensive action.
Alkaloids
(+)-Dicentrine
(+)-Dicentrine (Compound 1, Fig. 2) is an alkaloid
aporphine 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 candidate for treatment of hypertension and other
cardiovascular diseases. After oral administration of (+)-
dicentrine (5 and 10 mg·kg−1, twice a day) for 4 weeks, the
mean arterial pressure (MAP) in spontaneously hypertensive
rats (SHRs) decreased from 160 mmHg to 102 mmHg, and
the declining rates was 36.3% [7]. However, a higher dose of
(+)-dicentrine (10 mg·kg−1, i.v.) did not cause any
significant changes in heart rate (HR), cardiac output (CO),
or stroke volume (SV) [8]. Mechanistic research has shown
that (+)- dicentrine is an α1-adrenocepter antagonist which is
more selective towards the putative α1D-adrenocepter
subtype of the rat aorta than the α1B-adrenocepter subtype of
the spleen [9].

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Fig. 1 Some 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 (Monimiaceae), an
endemic Chilean tree known as “Laurel”, are used by the
Mapuche Amerindians for treating headache and as a
diuretic. Intravenous administration of a hydroalcoholic L.
sempervirens extract to rats, elicited a hypotensive response
of (−27.0 ± 2.0)% in the MAP of normotensive animals at a
dose of 5 mg·kg−1. 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 mg·kg−1) produced a hypotensive response of
(−29.0 ± 2.1)% in the MAP of normotensive rats, with a
duration of 2 min, which was comparable to that of the
crude extract at 5 mg·kg−1 [10].

Fig. 2 Chemical structures of Compounds 1–9

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
rutaecarpa, which has been shown to produce vasorelaxant
and hypotensive effects. Biological tests have demonstrated
that DeHE induces relaxation in precontracted rat isolated
mesenteric arteries in a concentration-dependent manner. The
underlying mechanisms may be complex, involving
interaction with the endothelium through the NO-guanylyl
cyclase pathway, α-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
rhynchophylla. Studies have shown that the properties of
rhynchophylline 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 MAP by 42.0%) is much stronger than that of
Compound 4 (lowering of MAP by 32.1%) in anesthetized
rats. In anesthetized thoracotomized dogs, Compound 5
(1 mg·kg−1, 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) mL·min−1·g−1, respectively. The

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active mechanisms are related to the modulation of
calciumion channel, protection of neural and neuroglial cells
against β-amyloid (25–35)-induced neurotoxicity and via
inducing autophagy [12-14].
Dihydrocorynantheine
Dihydrocorynantheine (Compound 6, Fig. 2) is an
alkaloid present in Uncaria macrophylla, a Uncaria genus
plant. It exhibits significant vasodilating activity against
phenylephrine-induced contraction in rat thoracic aorta rings
(IC50 6.73 μg·mL−1), 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
phenylephrine), 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 mg·kg−1,
i.v.). It is concluded that isoliensinine blocks Ca2+ influx and
antagonizes the function of α1-adrenoceptor [16-17].
(−)-Lobeline
(−)-Lobeline (Compound 8, Fig. 2) is a major alkaloid of
Lobelia siphilitica and also found in Hippobroma longiflora,
which was demonstrated to antagonize the bioactive effect
of endothelin-1 (ET-1) and prevent the proliferation of
vascular smooth muscle cells (VSMCs). VSMCs 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
VSMCs proliferation induced by ET-1 represents a
potentially important therapeutic strategy for the treatment of
aforementioned diseases. Lobeline antagonizes proliferation
of human umbilical arterial VSMCs induced by ET-1 by
Fig. 3 Chemical structures of Compounds 10–12
Reserpine and deserpidine
Reserpine (Compound 13, Fig. 4) and deserpidine
(Compound 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 peripheral sympathetic nerve endings. Reserpine irrever-
sibly blocks the vesicular monoamine transporter (VMAT),
which normally transports free norepinephrine, serotonin, and
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inhibition 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
alkaloid 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 (3−30 μmol·L−1) totally relaxed the contrac-
tions induced by NA (IC50 6.24 ± 0.55 μmol·L−1) or by a high
extracellular KCl concentration (IC50 5.23 ± 0.48 μmol·L−1) in
intact rat aortic rings in a concentration-dependent fashion
and with almost equal effectiveness under both assay
conditions. These findings indicate a therapeutic potential as
an original chemical basis for the design and subsequent
development 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
alkaloids isolated from Fritillaria puqiensis, and their
antihypertensive effects have been assessed in vitro, based on
the inhibition 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 μmol·L−1. The IC50 of puqienine E is 68 μmol·L−1. The
screening and identification of these ACE inhibitory
alkaloids could, to some extent, provide evidence for the
application of F. puqiensis or other species of Fritillaria
genus in hypertensive therapy [21].
dopamine from the cytoplasm of the presynaptic nerve terminal
into storage vesicles for subsequent release into the synaptic
cleft. Unprotected 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 because of its numerous side-effects and the
development of better 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): 721729
Fig. 4 Chemical structures of Compounds 13–24
isoquinoline of Han Fang Ji (Stephania tetrandra, Meni-
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
selective blockade of calcium channels and its interaction
with α1-adrenergic receptors [23].
Diterpenes
Forskolin
Forskolin (Compound 16, Fig. 4) is the main active
compound in the Indian plant Coleus forskohlii. Several
studies demonstrated that forskolin lowers blood pressure via
relaxation of vascularsmooth muscle. On the one hand,
forskolin activates adenylate cyclase, producing an increase in
cAMP, which in turn will activate cAMP-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 μg·kg−1·min−1, i.v.)
decreases vascular resistance, improves left ventricular
contractility and decreases the arterial pressure [1, 24-26].
Stevioside
Stevioside (Compound 17, Fig. 4), a diterpenoid
glycoside comprising of an aglycone (steviol) and three
molecules 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
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effects on both SAP and DAP were dose-dependent for
intravenous doses of 50, 100 and 200 mg·kg−1 in conscious
SHRs. The maximum reductions in SAP and DAP were (31.4 ±
4.2) % and (40.8 ± 5.6)%, respectively [27]. However, crude
stevioside at does up to 15.0 mg·kg−1·d−1 did not show an
antihypertensive effect on previously untreated mild hyperten-
sive 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 Malaysia as a
potent medicine in the treatment of diabetes and hypertension.
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 MAP 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
actions in a non-competitive and dose-dependent manner.
These results further support the bradycardia-inducing and
β-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
aethiopica, which is an evergreen and aromatic tree in
Africa. Intravenous administration of these two compounds
at 10 mg·kg−1 in normotensive rats produced an immediate
decrease of SAP by 17% and 18%, respectively, no change
of DAP, and a significant decrease of heart rate by 20% and
55%, respectively. Other similar results also show that ent-
kaur-16-en-19-oic acid (15 mg·kg−1, i.v.) decreases MAP of
conscious normotensive 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
neuronal NO synthase and NO-cGMP pathway [33].
8-(17), 12 E, 14-Labdatrien-18-oic acid
The diterpene 8-(17), 12E, 14-labdatrien-18-oic acid
(Compound 21, Fig. 4) is isolated from Xylopia langsdorffiana
stem ethanolic extracts. In normotensive, conscious animals,
this diterpene produces dose-dependent hypotension and
tachycardia. In isolated mesenteric artery rings, the diterpene
(10 10−10 4 mol·L−1) elicits concentration-dependent
relaxation of phenylephrine-induced contractions (IC50 5.4 ±
1.4 μmol·L −1 ). It also causes concentration-dependent
relaxation in arterial rings pre-contracted with high
extracellular KCl (80 mmol·L−1). In Ca2+-free depolarized
preparations, it inhibits contractions produced by cumulative
increases in extracellular Ca2+ concentration. These results
demonstrate that Compound 21 causes hypotension
through peripheral vasodilation, which is mediated in part
by NO and PGI2 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. treatment with Compound 22 induces dose-dependent
hypotensive and tachycardiac effects in both conscious and
anesthetized rats. Compound 22 (1–1 000 μg·mL−1)
induces a concentration-dependent reduction of potassium
(60 mmol·L−1)-induced contraction (IC50 = 313.6 μg·mL−1),
an effect that remains unaffected (IC50 = 440.8 μg·mL−1) 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
(Compound 23, Fig. 4) is a highly oxygenated diterpene
lactone epoxide compound extracted from TWHF. In
pneumonectomized rats that receive monocrotaline, triptolide
attenuates the development of pulmonary hypertension and
right ventricularhypertrophy, and promotes regression of
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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
treatment of respiratory diseases and pulmonary hypertension.
(+)-Praeruptorin A produces significant relaxant effects in
rabbit tracheal preparations constricted with KCl or
acetylcholine, and completely relaxes tracheas constricted
with 40 nmol·L−1 KCl at a concentration of 30 μmol·L−1. The
relaxant activity is due to its calcium antagonistic action [37].
Imperatorin
Imperatorin (Imp, Compound 25, Fig. 5), a dietary
furanocoumarin, is wide spread and found not only in the
medicinal plant such as Cnidium monnieri cuss and Angelica
dahurica, but also in popular culinary herbs such as
parsnip, parsley, and fennel. After 13 weeks of treatment
with Compound 25 (25 mg·kg −1 ·d −1 , i.g.), the SAP DAP
in SHRs were reduced significantly. A series of experiments
have demonstrated that Compound 25 targets the L-type
calcium channel. The aortic ring is relaxed with Compound
25, and L-type calcium channel currents and intracellular
calcium free ion rise are nearly disappeared when adding
Compound 25. Imperatorin is a novel structure of
furanocoumarins 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
traditional 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 g·mL−1, suggesting
a blockade of voltage-operated calcium channel [39].
Flavonoids
Quercetin and isorhamnetin
Total flavones of Hippophae Rhamnoides (TFH) are
extracts of Hippophae Rhamnoides, mainly composed
of quercetin (Compound 27, Fig. 5) and isorhamnetin
(Compound 28, Fig. 5), which display antihypertensive and
target organ protecting activity. After 12 weeks of
treatment with TFH (30 mg·kg−1·d−1), the SAP of SHRs
was decreased by 14%, comparable with enalapril group
(30 mg·kg−1·d−1, decreased by 16%) and hydrochlorothiazide
group (25 mg·kg−1·d−1 , decreased by 14%). Moreover, TFH
may inhibit the expression of MCP-1 in aorta and intimal
medial thickness 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 25–33
moderate angiotensin-converting enzyme inhibitory activity.
Among them, astragalin (Compound 29, Fig. 5) produces
inhibition by 67% at a concentration of 300 μg·mL−1, The
IC50 of astragalin is 180 μg·mL−1 [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 μmol·L−1 in the endothelium-intact and
with an IC50 value being around 7.27 μmol·L−1 in the
endothelium 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), tetraethylammonium, chloride
(K+channels inhibitor) or propranolol (β-receptor inhibitor).
Furthermore, Orientin inhibits norepinephrine (NE), CaCl2 and
KCl-induced vasoconstriction concentration-dependently in a
non-competitive manner, and also reduces both the initial fast
release and the sustained phases of phenylephrine-induced
contractions. Orientin can stimulate NO production from
endothelial cells. These results indicate that Orientin relaxes
thoracic aortic rings by the nitric oxide-cGMP 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) μmol·L−1.
They inhibit 60 mmol·L 1 K+-induced contraction with
respective IC50 of (11.5 ± 0.3) and (37.9 ± 3.6) μmol·L−1. In
addition, both agents inhibit the transient contraction induced
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by 3 μmol·L−1 of phenylephrine or by 10 mmol·L−1 of caffeine
in Ca2+-free Krebs solution. These results indicat that purified
cardamonin and alpinetin relax mesenteric arteries of rats
through multiple mechanisms. They induce both
endothelium-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
patients 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
enzyme (ACE) inhibitors raise the possibility that hypertension
could be modulated through dietary intake. ACE-inhibitory
peptides 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
pterocarpinoid extracted from the roots of Dalea filiciformis
Snader (Fabaceae). Biological assays have shown that
daleformis is a novel inhibitor of endothelin converting
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Table 1 Examples of ACE inhibitory peptides derived from marine sources

Origin Hydrolysis Peptide sequence IC50/(μmol·L−1)
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 fermented fish sauce Unknown Lys-Pro 22.00
Val-Glu-Cys-Tyr-Gly-Pro-Asn-Arg-
Algae protein waste Pepsin 29.60
Pro-Gln-Phe
Ile-Tyr, 6.10
Wakame (Undariapinnatifida) Protease S "Amano" Val-Trp, 3.30
Ile-Trp 1.50

enzyme (ECE), with an IC50 being 9 μmol·L−1 ECE is a
membrane bound neutral metalloprotease that catalyzes the
conversion 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
widely employed in China to improve blood flow and dilate
blood vessels. SAP is significantly descended in SHRs given
magnesium lithospermate B at 10 mg·kg−1 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
significantly 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. Additionally, a study on the acute toxicity of oral magne-
sium lithospermate B in terms of LD50 determined by the up and
down method has shown a high safety of this substance (> 3 000
mg·kg−1 in 6-week-old male ddY mice weighing 31−35 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 activities. One of the sponge extracts isolated
from sponge Pachastrella 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
active constituent, which is a novel inhibitor of ECE, with an
IC50 being 2.1 μmol·L−1 [49].

Fig. 6 Chemical structures of Compounds 34–37

Ursolic and moronic acids Phoradendron reichenbachianum and show a significant

Phoradendron reichenbachianum is a medicinal plant
which is used in Mexican 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
relaxant effect in a concentration and endothelium-dependent
manners on rat aorta rings after contraction with NA (ursolic
acid EC50 11.7 μmol·L−1; moronic acid EC50 16.1 μmol·L−1).
Moreover, the relaxant effects induced by these two triterpenic
acids seem to be involved NO release in functional experiments.

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 BAI Ren-Ren, et al. / Chin J Nat Med, 2015, 13(6): 721729
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
development 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
displays potent antihypertensive activity in both acute and
therapeutic antihypertensive tests in renal hypertensive rats
(RHRs); the maximum antihypertensive effect of (±)-XJP at
the dose of 100 mg·kg−1 is comparable to that of captopril at
the dose of 25 mg·kg−1. The mechanistic studies have
revealed 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 38–40
Conclusion
In summary, the prevalence of hypertension has been
increasing dramatically in the world during the past decades.
Although many antihypertensive drugs with various
mechanisms 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 explored 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.
References
[1] Tirapelli CR, Ambrosio SR, de Oliveira AM, et al.
Hypotensive action of naturally occurring diterpenes: A
therapeutic promise for the treatment of hypertension [J].
Fitoterapia, 2010, 81(7): 690-702.
– 728 –
[2] Cragg GM, Newman DJ. Natural products: A continuing
source of novel drug leads [J]. Biochim Biophysi Acta, 2013,
1830(6): 3670-3695.
[3] Newman DJ, Cragg GM. Natural products as sources of new
drugs over the 30 years from1981 to 2010 [J]. J Nat Prod,
2012, 75(3): 311−335.
[4] Jing P, Qian BJ, He YW, et al. Screening milk-derived
antihypertensive peptides using quantitative structure activity
relationship (QSAR) modelling and in vitro/in vivo studies on
their bioactivity [J]. Int Dairy J, 2014, 35(1): 95-101.
[5] Nakamura K, Naramoto K, Koyama M. Blood-pressure-
lowering effect of fermented buckwheat sprouts in
spontaneously hypertensive rats [J]. J Funct Foods, 2013, 5(1):
406-415.
[6] Bai RR, Wei Z, Liu J, et al. Synthesis and biological
evaluation of 4’-[(benzimidazole-1-yl) methyl] biphenyl-2-
sulfonamide derivatives as dual angiotensin II/endothelin A
receptor antagonists [J]. Bioorg Med Chem Lett, 2012, 20(15):
4661-4667.
[7] Yu SM, Kang YF, Chen CC, et al. Effects of dicentrine on
haemodynamic, plasma lipid, lipoprotein level and vascular
reactivity in hyperlipidaemic rats [J]. Brit J Pharmacol, 1993,
108(4): 1055-1061.
[8] Yu SM, Hsu SY, Ko FN, et al. Haemodynamic effects of
dicentrine, a novel α1-adrenoceptor antagonist: comparison
with prazosin in spontaneously hypertensive and normotensive
Wistar-Kyoto rats [J]. Brit J Pharmacol, 1992, 106(4): 797-801.
[9] Mustafa MR, Achike FI. Dicentrine is preferentially
antagonistic to rat aortic than splenic α1-adrenoceptor stimu-
lation [J]. Acta Phamacol Sin, 2000, 21(12): 1165-1168.
[10] Schmeda Hirschmann G, Loyola JI, Rodriguez, J. Hypotensive
effect of laurelia sempervirens (Monimiaceae) on normo-
tensive Rats [J]. Phytother Res, 1994, 8(1): 49-51.
[11] Chiou WF, Liao JF, Shum, YC, et al. Mechanisms of
vasorelaxant effect of dehydroevodiamine: A bioactive
isoquinazolinocarboline alkaloid of plant origin [J]. J
Cardiovasc Pharm, 1996, 27(6): 845-853.
[12] Ndagijimana A, Wang XM, Pan GX, et al. A review on indole
alkaloids isolated from Uncaria rhynchophylla and their
pharmacological studies [J]. Fitoterapia, 2013, 86: 35-47.
[13] Song CQ, Fan Y, Huang WH, et al. Different hypotentive
effects of various active constituents isolated from Uncaria
rhynchophylla [J]. Chin Tradit Herb Drugs, 2000, 31(10):
762-764.
[14] Zhou JY, Zhou SW. Isorhynchophylline: A plant alkaloid with
therapeutic potential for cardiovascular and central nervous
system diseases [J]. Fitoterapia, 2012, 83(4): 617-626.
[15] Wang K, Zhou XY, Wang YY, et al. Macrophyllionium and
macrophyllines A and B, oxindole alkaloids from Uncaria
macrophylla [J]. J Nat Prod, 2011, 74(1): 12-15.
[16] Feng XL, Yu X, Xiao JH, et al. Effect of isoliensinine on
cardiovascular function and experimental left ventricular
hypertrophy [J]. J Huazhong U SCI-MED, 2002, 31(6): 608-610.
[17] Shang J, Pan Y. Advances in chemical and pharmacological
research of isoliensinine [J]. J Nanjing U Tradit Chi Med, 2010,
26(3): 238-240.
[18] Kesting JR, Tolderlund IL, Pedersen AF, et al. Piperidine and
tetrahydropyridinealkaloids from lobelia siphilitica and
hippobroma longiflora [J]. J Nat Prod, 2009, 72(2): 312-315.
[19] Wang JJ, Liu SM, Chen R, et al. A novel effect of lobeline on
vascular smooth muscle cell: inhibition of proliferation
induced by endothelin-1 [J]. Pharmazie, 2007, 62(8): 620-624.
 BAI Ren-Ren, et al. / Chin J Nat Med, 2015, 13(10): 721729
[20] Orallo F, Alzuta A. Preliminary study of the vasorelaxant
effects of (+) –nantenine, an alkaloid isolated from platycapnos
spicata, in rat aorta [J]. Planta Med, 2001, 67(9): 800-805.
[21] An JJ, Zhou JL, Li HJ, et al. Puqienine E: An angiotensin
converting enzyme inhibitory steroidal alkaloid from
Fritillaria puqiensis [J]. Fitoterapia, 2010, 81(3):149-152.
[22] Varchi G, Battaglia A, Samori C. Synthesis of deserpidine
from reserpine [J]. J Nat Prod, 2005, 68(11): 1629-1631.
[23] Iturriaga-Va´squez P, Miquel R, Ivorra MD, et al. Simplified
tetrandrine congeners as possible antihypertensive agents with
a dual mechanism of action [J]. J Nat Prod, 2003, 66(7):
954-957.
[24] Lincoln TM, Fisher-Simpson V. A comparison of the effects of
forskolin and nitroprusside on cyclic nucleotides and relaxation
in the rat aorta [J]. Eur J Pharmacol, 1984, 101(1-2): 17-27.
[25] Den Hertog A, Pielkenrood J, Van den Akker JT. The effect of
forskolin on smooth muscle cells of guinea-pig taenia caeci [J].
Eur J Pharmacol, 1984, 106(1): 181–184.
[26] Schlepper M, Thormann J, Mitrovic V. Cardiovascular effects
of forskolin and phosphodiesterase-Ⅲ inhibitors [J]. Basic Res
Cardiol, 1989, 84(1): 197-212.
[27] Chan P, Xu DY, Liu JC, et al. The effect of stevioside on
blood pressure and plasma catecholamines in spontaneously
hypertensive rats [J]. Life Sci, 1998, 63(19): 1679-1684.
[28] Ferri LA, Alves-Do-Prado W, Yamada SS, et al. Investigation
of the antihypertensive effect of oral crude stevioside in
patients with mild essential hypertension [J]. Phytother Res,
2006, 20(9): 732-736.
[29] Liu JC, Kao PK, Chan P, et al. Mechanism of the
antihypertensive effect of stevioside in anesthetized dog [J].
Pharmacology, 2003, 67(1): 14-20.
[30] Zhang CY, Kuroyangi M, Kh Tan B. Cardiovascular activity of
14-deoxy-11, 12-didehydroandrographolide in the anaesthetized
rat and isolated right atria [J]. Pharmacol Res, 1998, 38(6):
413-417.
[31] Tirapelli CR, Ambrosio SR, Da Costa FB, et al. Diterpenes: a
therapeutic promise for cardiovascular diseases [J]. Recent Pat
Cardio Drug Discov, 2008, 3(1): 1-8.
[32] Somova LI, Shode FO, moodley K, et al. Cardiovascular and
diuretic activity of kaurene derivatives of Xylopia aethiopica
and Alepidea ama tymbica [J]. J Ethnopharmacol, 2001,
77(2-3): 165-174.
[33] Tirapelli CR, Ambrosio SR, da Costa FB, et al. Analysis of the
mechanisms underlying the vasorelaxant action of kaurenoic
acid in the isolated rat aorta [J]. Eur J Pharmacol, 2004,
492(2-3): 233-241.
[34] de Oliveira AP, Furtado FF, da Silva MS, et al. Calcium
channel blockade as a target for the cardiovascular effects
induced by the 8 (17), 12E, 14-labdatrien-18-oic acid
(labdane-302) [J]. Vasc Pharmacol, 2006, 44(5): 338-344.
[35] Lahlou S, de Barros Correia Jr CA, dos Santos MV, et al.
Mechanisms underlying the cardiovascular effects of a
labdenic diterpene isolated from moldenhawera nutans in
normotensive rats [J]. Vasc Pharmacol, 2007, 46(1): 60-66.
[36] Faul J, nishimura T, Berry GJ, et al. Triptolide attenuates
pulmonary arterial hypertension and neointimal formation in
rats [J]. Am J Resp Crit Care, 2000, 162(6): 2252-2258.
[37] Zhao NC, Jin WB, Zhang XH, et al. Relaxant effects of
pyranocoumarin compounds isolated from a Chinese medical
plant, Bai-Hua Qian-Hu, on isolated rabbit tracheas and
pulmonary arteries [J]. Biol Pharm Bull, 1999, 22(9): 984-987.
[38] Zhang Y, Cao YJ, Wang QL, et al. A potential calcium
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.
– 729 –
antagonist and its antihypertensive effects [J]. Fitoterapia,
2011, 82(7): 988-996.
[39] Rauwald HW, Brehm O, Odenthal KP. Screening of nine
vasoactive medicinal plants for their possible calcium
antagonistic activity. Strategy of selection and isolation for the
active principles of olea europaea and peucedanum ostruthium
[J]. Phytother Res, 1994, 8(3): 135-140.
[40] Xiao J, Chen Y, Xiao HY, et al. Effect of total flavonoids of
hippophae rhamnoides L. on the expression of MCP21 in aorta
of spontaneously hypertensive rats [J]. J Sichuan U SCI-MED,
2009, 40(3): 481-485.
[41] Kame da K, Takaku T, Okuda H, et al. Inhibitory effects of
various flavonoids isolated from enzyme activity leaves of
persimmon on angiotensin-converting [J]. J Nat Prod, 1987,
50(4): 680-683.
[42] Fu XC, Wang MW, Li SP, et al. Vasodilatation produced by
orientin and its mechanism study [J]. Biol Pharm Bull, 2005,
28(1): 37-41.
[43] Wang ZT, Lau CW, Chan FL, et al. Vasorelaxant effects of
cardamonin and alpinetin from alpinia henryi K. Schum [J]. J
Cardiovasc Pharm, 2001, 37(5): 596-606.
[44] Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-
induced cough, ACCP evidence-based clinical practice
guidelines [J]. Chest, 2006, 129(1 suppl): 169S-173S.
[45] Herrera ChaléFG, Ruiz Ruiz JC, Acevedo Fernández JJ, et al.
ACE inhibitory, hypotensive and antioxidant peptide fractions
from Mucuna pruriens proteins [J]. Process Biochem, 2014,
49(10): 1691-1698.
[46] Wilson J, Hayes M, Carney M. Angiotensin-I-converting
enzyme and prolyl endopeptidase inhibitory peptides from
natural sources with a focus on marine processing by-products
[J]. Food Chem, 2011, 129(2): 235-244.
[47] Patil AD, Freyer AJ, Eggleston DS, et al. Daleformis, a new
phytoalexin from the roots of dalea filiciformis: An inhibitor of
endothelin converting enzyme [J]. J Nat Prod, 1997, 60(3):
306-308.
[48] Yokozawa T, Lee TW, Chung HY, et al. Depressor effect of
magnesium lithospermate B, a component of salviae
miltiorrhizae radix, in spontaneously hypertensive rats [J].
Phytother Res, 1994, 8(5): 271-275.
[49] Patil AD, Freyer, AJ, Breen A, et al. Halistanol disulfate B, a
novel sulfated sterol from the sponge pachastrellasp: inhibitor
of endothelin converting enzyme [J]. J Nat Prod, 1996, 59(6):
606-608.
[50] Rios MY, López-Martínez S, López-Vallejo F, et al.
Vasorelaxant activity of some structurally related triterpenic
acids from Phoradendron reichenbachianum (Viscaceae)
mainly by NO production: Ex vivo and in silico studies [J].
Fitoterapia, 2012, 83(6): 1023-1029.
[51] Liu J, Ren H, Xu JY, et al. Total synthesis and antihypertensive
activity of (±) 7, 8-dihydroxy-3-methyl- isochromanone-4 [J].
Bioorg Med Chem Lett, 2009, 19(6): 1822-1824.
[52] Bai RR, Liu J, Zhu Y, et al. Chiral separation, configurational
identification and antihypertensive evaluation of (±) -7, 8-
dihydroxy-3-methyl-isochromanone-4 [J]. Bioorg Med Chem
Lett, 2012, 22(20): 6490-6493.
[53] Wang CL, Wei GX, Yang X, et al. First total synthesis of
antihypertensive natural product S-(+)- and R-( )-XJP [J].Org
Biomol Chem, 2014, 12(37): 7338–7344.
[54] Rates SM. Plants as source of drugs [J]. Toxicon, 2001, 39(5):
603-613.