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Sumac as a novel adjunctive treatment in
hypertension: a randomized, double-blind,
placebo-controlled clinical trial
Hamidreza Ardalani,
*
a
Maryam Hassanpour Moghadam,
b
Roja Rahimi,
c
Jalal Soltani,
d
Azadeh Mozayanimonfared ,
e
Mehdi Moradi
e
and Ali Azizi
f
Background: Sumac (Rhus coriaria L., Anacardiaceae) is a medicinal plant traditionally used for the
treatment of cardiovascular disorders. This study was designed to evaluate the effects of Sumac fruits in
hypertensive patients. Material and Methods: a randomized, double-blind, placebo-controlled clinical
trial was conducted on 80 hypertensive patients who were receiving captopril (25 mg day
1
). The
patients were randomly divided into 2 groups: the first group received R. coriaria fruit capsules (500 mg
twice a day) and captopril (25 mg once a day), and the second one received placebo capsules (500 mg
starch twice a day) and captopril (25 mg once a day), for 8 weeks. Blood pressure (BP) and body weight
index (BMI) in all patients were determined every week. Phytochemical analysis of R. coriaria fruits was
performed by using HPLC-DAD/QTOF-MS for analysing its phenolic compounds. Results: data indicated
that hypertension was decreased significantly in R. coriaria group compared to baseline and placebo
groups after 8 weeks, but BMI did not demonstrate a marked change in comparison with baseline and
placebo groups. Moreover, the most abundant phenolic compounds identified in R. coriaria fruits were
luteolin, apigenin, and quercetin flavonoids. Discussion: this finding suggests that R. coriaria fruits could
be used as an effective natural remedy for management of hypertension. Since flavonoids were the main
chemical constituents of this plant, its antihypertensive activity could be attributed to such compounds.
Introduction
Hypertension (HTN: blood pressure above 140/90 mmHg) is one
of the most important medical problems worldwide.
1
It is the
most common, readily identiable and reversible risk factor for
stroke, myocardial infarction, congestive heart failure (CHF),
renal failure, atrial brillation, aortic dissection, and coronary
and peripheral arterial diseases.
2,3
The global burden of HTN is
increasing due to escalating obesity, population aging and
urbanization in developed and developing countries.
4
Preven-
tion and treatment of obesity, avoidance of high sodium chlo-
ride intake, appropriate amounts of aerobic physical activity,
adequate dietary and calcium intakes, limiting alcohol
consumption and avoiding cigarette smoking are appropriate
strategies to reduce cardiovascular disease risk, morbidity and
mortality due to HTN.
5
The sympathetic nervous system over-
activity
6
and increase in norepinephrine cause hypertrophy of
cardiac and vascular cells and stimulate renin release.
7
So,
renal, hormonal and vascular mechanisms are involved and
conspire in a myriad of ways to produce HTN. Over time,
endothelial dysfunction, neuro-hormonal activation, vascular
inammation and elevated blood pressure (BP) cause re-
modelling of both small and large arteries which further
perpetuates HTN. As a result, apart from life style modication,
most patients need multiple antihypertensive drugs of different
classes to overcome multiple mechanisms suspected to have
a role in inducing their HTN. Initiation of drug therapy is rec-
ommended for individuals with systolic BP above 140 mmHg or
diastolic BP more than 90 mmHg when re-measured at least
three times over at least four weeks. However, if the level of BP is
very high (>180/110 mmHg) or symptomatic end organ damage
is manifested at rst presentation; medication should be star-
ted before the denite diagnosis is established. The degree of
benet derived from antihypertensive agents is related to the
magnitude of the BP reduction.
8
Lowering systolic BP by 10–
12 mmHg and diastolic BP by 5–6 mmHg confers relative risk
reductions of 35–40% for stroke and 12–16% for coronary heart
disease (CHD) within ve years of initiating treatment.
9
The
optimal goal of antihypertensive therapy in patients with
60 years old or older, who do not have diabetes or chronic
a
Department of Horticultural Sciences, Science and Research Branch, Islamic Azad
University, Tehran, Iran. E-mail: hrardalani@srbiau.ac.ir
b
Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical
Sciences, Mashhad, Iran
c
Department of Tradition al Pharmacy, School of Traditional Medicine, Tehran
University of Medical Sciences, Tehran, Iran
d
Department of Phytopathology, Bu-Ali Sina University, Hamedan, Iran
e
Department of Cardiology, Hamedan University of Medical Science, Hamedan, Iran
f
Department of Horticultural Sciences, Faculty of Agriculture, Bu-Ali Sina University,
Hamedan, Iran
Cite this: RSC Adv.,2016,6, 11507
Received 30th Octob er 2015
Accepted 5th January 2016
DOI: 10.1039/c5ra22840a
www.rsc.org/advances
This journal is © The Royal Society of Chemistry 2016 RSC Adv.,2016,6, 11507–11512 | 11507
RSC Advances
PAPER
kidney disease, is <150/90 mmHg; and in patients with 18 to
59 years old without major comorbidities, is <140/90 mmHg.
10
Control is enhanced when access to health care is readily
available, frequent contact with the same physician is main-
tained, and physician performance is monitored.
11
The side
effects of antihypertensive drugs such as dizziness, dehydra-
tion, constipation and drowsiness have a pivotal role in
discontinuation of therapy.
12
In recent years, herbal remedies
such as saffron, celery, hawthorn and garlic are used for
management of hypertension.
13
Rhus coriaria L., commonly
called tanner's Sumac is a member of Anacardiaceae family.
Benecial effects of Sumac on cardiovascular diseases are re-
ported.
14,15
However, clinical antihypertensive activity of R. cor-
iaria has not been investigated yet. The aim of the present work
was to investigate the effi cacy of Sumac fruits in management of
hypertension, as well as analysing its chemical components.
Our results clarify the efficacy of this medicinal plant on clinical
BP. So, the results of this study introduce this plant as a prom-
ising herbal antihypertensive agent.
Results
Out of 95 patients, 80 patients [39 (48.75%) females and 41
(51.25%) male] accomplished this trial. The R. coriaria group,
included 21 (53.75%) men and 18 (46.25%) women with an
average age of 59.76 6.17 years old, and the placebo group
included 21 (51.25%) men and 20 (48.75%) women with an
average age of 57.52 7.43 years old. The baseline systolic
blood pressure/diastolic blood pressure (SBP/DBP) values in
R. coriaria and placebo groups were 145.34/90.95 mmHg and
143.64/90.51 mmHg, respectively; and the baseline BMI values
in R. coriaria and placebo groups were 30.83 kg m
2
and 31.13
kg m
2
, respectively. There were no signicant differences
between demographic characteristics of the outpatients in these
two groups (P > 0.05) (Table 1).
At the end of week 8, the SBP/DBP values in R. coriaria and
placebo groups were 115.21/78.33 mmHg and 131.39/81.66
mmHg, respectively; and BMI values were 30.29 kg m
2
in
R. coriaria and 30.54 kg m
2
in placebo group. Also, it was
obvious that, R. coriaria decreased systolic (Fig. 1) and diastolic
BP (Fig. 2). These results showed a signicant decrease in BP
level in R. coriaria group as compared to the placebo group aer
8 weeks (P < 0.05) and no signicant decrease on BMI in two
groups aer 8 weeks (Fig. 3) (P > 0.05).
There was a signicant reduction in SBP and DBP aer 8
weeks of R. coriaria administration when compared with base-
line. However, such an effect was not observed in the placebo
group (P > 0.05) (Table 2).
Clinical complications were determined as any unwanted
effects that occurred from the time of informed consent until
one month aer the last treatment dose. No serious adverse
effects were reported or observed during this trial, except for the
R. coriaria group in which a patient reported drowsiness. Among
the patients who could not accomplish this study there were no
reports of any side effects, and most of them le due to missing
the follow up. In placebo group two patients reported insomnia
Table 1 Baseline characteristics of the outpatients
a
Placebo R. coriaria P-value
Sex Female 21 21 0.46
Male 20 18
Age 57.52 7.43 59.76 6.17 0.33
Weigh 80.61 9.69 81.55 7.40 0.82
BMI 31.13 1.95 30.83 2.21 0.42
SBP 143.64 1.79 145.34 2.08 0.92
DBP 90.51 1.81 90.95 1.97 0.93
a
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic
blood pressure. Differences between groups were analysed by ANOVA
followed by Tukey's honestly signicant difference test. Values are
expressed as mean SD.
Fig. 1 Decrease in (SBP) Systolic Blood Pressure in response to Sumac
in comparison with placebo. Statistical analyses showed a significant
difference between Sumac and placebo group and baseline (P < 0.05).
Fig. 2 Decrease in Diastolic Blood Pressure (DBP) in response to
Sumac in comparison with placebo. Statistical analyses showed
a significant difference between Sumac and placebo group and
baseline (P < 0.05).
11508
| RSC Adv.,2016,6, 11507–11512 This journal is © The Royal Society of Chemistry 2016
RSC Advances Paper
and headache. All groups were well matched, and no statisti-
cally signicant differences were observed among groups on the
frequency of side effects (Table 3).
In this study the efficacy and tolerability of R. coriaria fruit
extracts combined with captopril in improving BP and
decreasing BMI was investigated. The results showed that
R. coriaria signicantly decreased BP in hypertensive patients
compared to the baseline and group received only captopril
aer 8 weeks (Table 4). Therefore, R. coriaria may serve as an
effective complementary therapy along with conventional anti-
hypertensive agents for reducing hypertension.
According to HPLC-DAD/QTOF-MS analyses, 191
compounds in R. coriaria along with their retention times (t
R
),
mass of each phytochemical, as well as the MS/MS fragment
ions used in the characterization process were identied. The
HPLC analyses showed that apigenin, luteolin and quercetin
were the most abundant compounds in R. coriaria fruits (Fig. 4,
Table 5).
Discussion
In many hypertensive patients, keeping BP in an optimal range
is difficult and prescribing several drugs from different phar-
macological classes of antihypertensive agents with high dosage
is frequently needed. Increasing the number and dosage of
drugs in 24 hours enhances the possibility of developing
medical side effects but reduces patient's compliances. As
a result, discontinuation of treatment is not far-fetched.
Currently, introduction of some adjunctive therapies, such as
herbal drugs and exercise, seems reasonable. Furthermore,
optimizing the modiable cardiovascular risk factors (i.e. high
BMI and low physical activity) is important and should be taken
into account.
The results from phytochemical analysis demonstrated that
the most abundant constituents of R. coriaria were polyphenolic
compounds including hydrolysable tannins, avonoids and
Fig. 3 Body Mass Index (BMI) in response to Sumac in comparison
with placebo group. Statistical analyses showed no significant differ-
ence between Sumac and placebo group, as well as baseline (P < 0.05).
Table 2 BMI, SBP and DBP reduction obtained with the R. coriaria
compared with placebo in patients during 8 weeks
a
Placebo R. coriaria P-value
BMI 0.59 2.45 0.54 3.12 0.71
SBP 12.25 6.12 30.13 4.45* 0.03
DBP 8.85 3.54 12.62 3.81* 0.04
a
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic
blood pressure. Values are expressed as mean SD. *P < 0.05, when
compared between groups.
Table 3 Frequency of reported adverse effects among the three study
groups
a
R. coriaria group Placebo group P-value
Weakness 1 0 1.61
Drowsiness 0 0 1.00
Insomnia 0 1 1.83
Headache 0 1 1.00
a
The Fisher's exact test was applied for analysis of side effects in both
groups.
Table 4 Characteristics of randomized subjects before and after 8
weeks
a
Variable Placebo R. coriaria P-value
BMI (kg m
2
)
Week 0 31.13 1.95 30.83 1.84 0.31
Week 8 30.54 1.14 30.29 1.48
SBP (mmHg)
Week 0 143.64 1.79 145.34 2.08 0.03
Week 8 131.39 2.75 115.21 2.89*
DBP (mmHg)
Week 0 90.51 1.81 90.95 1.97 0.04
Week 8 81.66 1.81 78.33 1.97*
a
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic
blood pressure. Values are expressed as mean SD. *P < 0.05, when
compared with baseline data.
Fig. 4 HPLC analyses and base peak chromatograms (BPC) of UV at
280 nm, for the hydro-methanol extract of R. coriaria fruits.
This journal is © The Royal Society of Chemistry 2016 RSC Adv.,2016,6,11507–11512 | 11509
Paper RSC Advances
anthocyanins. This analysis is almost in accordance with our
previous analysis on a sample of R. coriaria collected from
different place. However a new compound, benzoic acid, 3,4,5-
trihydroxy-2-oxo-1,3-propanediyl ester, was identied in the
present study. Other investigations have indicated that Sumac
is highly rich in cyanidin and galloyl-galactose and anthocyanin
derivatives.
16,17
A number of studies have shown that avonoids
such as quercetin can play important roles in decreasing BP.
18,19
The potential of quercetin as an effective vasodilator has been
indicated.
20
In addition, reductions in systolic, diastolic and
mean arterial pressures were observed in stage 1 hypertensive
patients aer a high dose quercetin treatment in a randomized,
double-blind, placebo-controlled, crossover study.
21
Apigenin,
another avonoid in R. coriaria, showed antihypertensive
activity in spontaneously hypertensive rats via up-regulating the
expression of angiotensin-converting enzyme 2 in kidney.
22
Renin is a crucial enzyme in the renin–angiotensin system, and
its inhibition is considered as a useful approach to the treat-
ment of hypertension. Gallic acid as another main phenolic
compound of R. coriaria has exhibited inhibitory effect on renin.
It seems that galloyl moiety and ortho-trihydroxy phenyl struc-
tures are favorable for the renin-inhibitory activity.
23
Oxidative stress, due to the accumulation of free radicals,
may play an important role in pathogenesis of cardiovascular
diseases like hypertension.
24
Oxidative stress stimulates the
proliferation and hypertrophy of vascular smooth muscle and
collagen deposition which lead to narrowing of the vascular
lumen caused by thickening of the vascular media.
25
Also,
increased oxidative stress can damage the endothelium and
increase vascular contractile activity.
26
All these effects can
explain how oxidative stress can be a cause of hypertension. So,
treatment with antioxidant components is suggested for
improving BP.
27
As mentioned the R. coriaria is highly rich in
antioxidative phenolic components, such as tannins and
avonoids.
28
Thus, adjunctive therapy with R. coriaria can
provide further protection as it contains powerful antioxidants
and plays an important role in preventing free radical-induced
damage in vessels endothelium.
29
The effect of avonoid intake on body weight and BMI is
already investigated.
30
Indeed, benecial antioxidant effects can
modulate BMI.
31
Also it is observed that a source of avonoid
(green tea) can reduce body weight and body fat in overweight
individuals.
32
Additionally, animal studies have shown an anti-
obesity effect for avonoids, through mechanisms such as fatty
acid catabolism or intervention on glucose uptake.
33
However in
our study R. coriaria as a reach source of avonoids could not
decrease BMI in patients aer 8 weeks of administration.
Adverse effects such as vertigo, ashing, insomnia and head-
ache have been reported previously in administration of anti-
hypertensive drugs.
34
Our ndings indicated that R. coriaria did
not have serious side effects in administered dose, although
more investigations are needed. Moreover, long term studies
with larger sample size is recommended for better under-
standing of the R. coriaria effects on BP and BMI is being
recommended.
Experimental
Plant material
Sumac (R. coriaria L.) fruits with voucher specimen no. 21121
were obtained from the Shahid Beheshti University of Medical
Sciences, Teharn, Iran (identied by Prof. Dr Valiollah Moza-
farian). The samples were transferred to the lab, dried at 70
C
for 24 hours and stored at 5
C until used.
Study design
A randomized, parallel-group, double-blind, and placebo-
controlled clinical trial was conducted on 80 hypertensive
patients in the Arad Hospital, Tehran, Iran, from September to
Table 5 Chemical compositions detected and characterised in R. coriaria fruits by HPLC-DAD/QTOF-MS
Peak Tentative assignment t
R
(min) [M + H] + (m/z)[M H] (m/z) Error (ppm) mSigma Molecular formula
1 Galloylhexose II 9.10 — 331.0669 0.6 14.9 C
13
H
16
O
10
2 Digalloyl-hexoside II 11.91 — 483.0773 1.3 1.8 C
20
H
20
O
14
3 Tri-galloyl-hexoside III 19.07 637.1100 635.0882 1.2 2.1 C
27
H
24
O
18
4 Benzoic acid, 3,4,5-trihydroxy-2-oxo-1,3-
propanediyl-ester
25.15 — 393.0449 3.7 46.8 C
17
H
14
O
11
5 Dihydroxybenzoic acetate-digallate I 28.14 — 544.9894 5.2 43.9 C
24
H
18
O
15
6 Dihydroxybenzoic acetate-digallate III 29.60 — 546.0121 3 37.5 C
24
H
18
O
15
7 Apigenin glucuronide 29.89 445.0245 446.0312 1.2 143.2 C
21
H
20
O
11
8 Galloyl-valoneic acid bilactone 31.10 623.1457 621.0412 2.2 26.7 C
22
H
22
O
21
9 Quercetin-rhamnose malic acid I 31.18 564.8637 563.1127 3.7 4.1 C
25
H
24
O
15
10 Quercetin I 32.14 — 302.0119 2.8 13.0 C
15
H
10
O
7
11 Quercetin-hexose malic acid IV 32.18 581.1312 — 1.0 46.1 C
25
H
24
O
16
12 Isorhamnetin hexose malic acid 33.57 594.9197 — 12.6 49.2 C
26
H
26
O
16
13 Kaempferol rhamnosemalic acid 33.81 — 548.1168 6.0 31.5 C
25
H
24
O
14
14 Quercitrin-O-gallate 34.75 — 599.1019 5.1 26.1 C
28
H
24
O
15
15 Isorhamnetin hexoside IV 34.80 — 477.1021 5.4 14.5 C
22
H
22
O
12
16 Di-benzopyranofuranacetic acid deriv. 35.30 515.0526 — 7.0 50.9 C
23
H
16
O
14
17 Luteolin 36.32 286.8776 285.0348 5.4 6.9 C
15
H
10
O
6
18 Quercetin II 36.58 303.0486 301.2481 0.5 2.4 C
15
H
10
O
7
11510 | RSC Adv.,2016,6,11507–11512 This journal is © The Royal Society of Chemistry 2016
RSC Advances Paper
January 2014 with code of ethics no. 93776 (approval date: 2014
August). During 8 weeks aer, 80 patients (aged from 30 to
65 years old) with uncontrolled HTN stages [stage 1 (SBP: 140–
159 and DBP: 90–99 mmHg), stage 2 (SBP: 160–179 and DBP:
100–109 mmHg) or stage 3 (SBP: 180 and DBP: 110) that in their
medical history during the last 6 months, were receiving just
captopril as an antihypertensive therapy were enrolled in our
study. This study was done in accordance with the Declaration
of Helsinki. Patients who had SBP more than 180 mmHg at the
time of selection, documented secondary HTN, congestive heart
failure, moderate to severe valvular heart disease, recent history
of myocardial infarction (MI # 6 months), chronic renal failure,
as well as alcohol consumers and pregnant patients were
excluded. Informed consent was obtained from all participants
before the study began. All patients were assessed weekly for
8 weeks, and data were recorded at baseline and aer every
week. Parameters collected at baseline were BP, age, sex, weight,
height and marital status.
Interventions
All participants were divided randomly in two groups. Each
group contained 40 patients. In the Sumac group, patients
received captopril (25 mg day
1
once a day, before breakfast)
plus R. coriaria powder capsules [1000 mg day
1
: 500 mg BID
(twice a day), one capsule before lunch and one before dinner]
and patients in the placebo group received captopril (25
mg day
1
once a day, before breakfast) plus placebo capsules
(1000 mg day
1
starch: 500 mg BID, one capsule before lunch
and one before dinner) as an adjunctive therapy for 8 weeks.
R. coriaria and placebo capsules were prepared in the same way.
They were similar in shape, color, size and order. All capsules
were prepared by a pharmacist and packed in the same
container with a code number. Thus, participants and investi-
gators were all blind to the treatment group assignments.
Participants were not permitted to receive any other antihy-
pertensive drugs during the study time. All patients were
checked regularly and their compliance and medication
adherence were estimated through checking with the patient
and his/her care taker along with a pill count at each visit.
Measurement of BP
Standard BP was assessed by trained research nurses with
a random-zero sphygmomanometer in accordance with Amer-
ican Heart Association protocols.
35
Due to measurement bias at
each visit, controlling of BP was performed with the same nurse
and sphygmomanometer and from. Before assessing BP, the
patients were asked to seat comfortably with the le arm sup-
ported and positioned at the level of the heart and the back
resting against a chair. The measurement time was under the
morning fasting condition (12 2haer the last drug inges-
tion). The patients rested at least ve minutes and avoided
caffeine or smoke within 30 minutes preceding the measure-
ment. The cuff size (12 22 for small-size adults, 16 30 for
medium-size adults and 16 42 for large-size adults) was
encircled the le arm which lowered edge of its position in
2.5 cm above the antecubital space. Inated the bladder quickly
to a pressure 20 mmHg above SBP, was recognized by the
disappearance of radial pulse and then deated it 3 mmHg s
1
.
BP was recorded the Korotkoff phase 1 (appearance) and phase
5 (disappearance) as SBP and DBP, respectively. On each occa-
sion, at least three measurements were applied, separated by
10 minute intervals. If data showed variations of more than
5 mmHg, an additional measurement was applied until two of
them were close and the highest BP was recorded.
Ascertainment of BMI
BMI (body mass index) is a person's weight in kilograms divided
by the square of height in meters. BMI was calculated in the
baseline and in the last follow up session by the same trained
nurses.
Statistical analyses
All data were expressed as mean SD. The characteristics of
groups at baseline were compared by one-way analyses of vari-
ance (ANOVA). The changes in BP and BMI were analysed using
one-way repeated measures ANOVA and Tukey's post hoc and
their comparison with the baseline data. A P-value <0.05 was
considered to be statistically signicant. Statistical analyses
were performed using SPSS soware version 17.0 (SPSS Inc.,
Chicago, IL, USA).
Plant extraction and HPLC analyses
Extraction of phenolic compounds were done according to Abu-
Reidah et al.
36
Briey, one gram of R. coriaria dried fruit was
mixed with 16 mL of methanol/H
2
O (80 : 20, v/v) and sonicated
for 60 min. Then, the solvent was evaporated under vacuum at
40
C and the dry remnant was resolved in 0.5 mL of methanol/
H
2
O (80 : 20, v/v). The extract was centrifuged and the super-
natant was ltered through a in syringe lter (d ¼ 0.2 mm) and
stored at 15
C. Chromatographic analysis of extracts was
carried out by an Agilent 1200 series Rapid Resolution Machine
through an Agilent Zorbax C18 column (4.6–150 mm, 5 mm).
Acetic acid 0.5% v/v and acetonitrile were used as mobile phases
A and B, respectively. The gradient program was set as follow:
0 min, 0% B; 20 min, 20% B; 30 min, 30% B; 40 min, 50% B;
50 min, 75% B; 60 min, 100% B; 62 min 0% B. Ultimately, the
initial conditions were held for 10 min for re-equilibration. The
injection volume and column temperature were 10 mL and
25
C, respectively. The HPLC system was coupled to a quadru-
pole time of ight (Bruker Daltonik GmbH, Bremen, Germany)
orthogonal accelerated Q-TOF mass spectrometer, tted out
with an electrospray ionization source (ESI). Analyses of
parameters were set by negative and positive ion modes, with
spectra obtained over a mass range from m/z 50 to 1100.
Conclusions
In this study, administration of R. coriaria fruit capsules [1000
(2 500) mg day
1
] augmented the effects of antihypertensive
drugs in hypertensive's patients. Without causing any consid-
erable side effect, R. coriaria was shown to be an effective
therapeutic adjuvant. Moreover, the effects of Sumac could be
This journal is © The Royal Society of Chemistry 2016 RSC Adv.,2016,6, 11507–11512 | 11511
Paper RSC Advances
attributed to avonoids as the dominant constituents in this
plant. However, further research is required to clarify the
mechanisms behind these observations.
Acknowledgements
The authors gratefully acknowledge the Vice Chancellor of
Research, Tehran University of Medical Sciences for nancial
supports (grant number no. 93776).
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