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Sumac as a novel adjunctive treatment in hypertension: A

randomized, double-blind, placebo-controlled clinical trial
a* b c d

RSC Advances Accepted Manuscript

Received 00th January 20xx, Hamidreza Ardalani , Maryam Hassanpour Moghadam , Roja Rahimi , Jalal Soltani , Azadeh
Accepted 00th January 20xx e e f
Mozayanimonfared , Mehdi Moradi , Ali Azizi
DOI: 10.1039/x0xx00000x 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
www.rsc.org/
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). 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 was not demonstrated 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.
Keywords: Rhus coriaria L., Sumac, Anacardiaceae, blood pressure, body mass index, flavonoids,
involved and conspire in a myriad of ways to produce HTN. Over
Introduction time, endothelial dysfunction, neuro-hormonal activation, vascular
Hypertension (HTN: Blood pressure above 140/90 mmHg) is one of inflammation and elevated Blood pressure (BP) cause re-modelling
1
the most important medical problems worldwide . It is the most of both small and large arteries which further perpetuates HTN. As
common, readily identifiable and reversible risk factor for stroke, a result, apart from life style modification, most patients need
myocardial infarction, congestive heart failure (CHF), renal failure, multiple antihypertensive drugs of different classes to overcome
atrial fibrillation, aortic dissection, and coronary and peripheral multiple mechanisms suspected to have a role in inducing their
2, 3
arterial diseases . The global burden of HTN is increasing due to HTN. Initiation of drug therapy is recommended for individuals with
escalating obesity, population aging and urbanization in developed systolic BP above 140 mmHg or diastolic BP more than 90 mmHg
4
and developing countries . Prevention and treatment of obesity, when re-measured at least three times over at least four weeks.
avoidance of high sodium chloride intake, appropriate amounts of However, if the level of BP is very high (> 180/110 mmHg) or
aerobic physical activity, adequate dietary and calcium intakes, symptomatic end organ damage is manifested at first presentation;
limiting alcohol consumption and avoiding cigarette smoking are medication should be started before the definite diagnosis is
appropriate strategies to reduce cardiovascular disease risk, established. The degree of benefit derived from antihypertensive
morbidity and mortality due to HTN 5. The sympathetic nervous agents is related to the magnitude of the BP reduction 8. Lowering
6
system overactivity and increase in norepinephrine cause systolic BP by 10-12 mmHg and diastolic BP by 5-6 mmHg confers
hypertrophy of cardiac and vascular cells and stimulate renin relative risk reductions of 35-40% for stroke and 12-16% for
7
release . So, renal, hormonal and vascular mechanisms are coronary heart disease (CHD) within five 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
a.
Department of Horticultural Sciences, Science and Research Branch, Islamic Azad chronic kidney disease, is <150/90 mmHg; and in patients with 18
10
University, Tehran, Iran. E-mail: hrardalani@srbiau.ac.ir to 59 years old without major comorbidities, is <140/90 mmHg .
b.
Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Control is enhanced when access to health care is readily available,
Medical Sciences, Mashhad, Iran
c. frequent contact with the same physician is maintained, and
Department of Traditional Pharmacy, School of Traditional Medicine, Tehran
University of Medical Sciences, Tehran, Iran physician performance is monitored 11. The side effects of
d.
Department of Phytopathology, Bu-Ali Sina University, Hamedan, Iran antihypertensive drugs such as dizziness, dehydration, constipation
e.
Department of Cardiology, Hamedan University of Medical Science, Hamedan, and drowsiness have a pivotal role in discontinuation of therapy 12.
Iran
f.
Department of Horticultural Sciences, Faculty of Agriculture, Bu-Ali Sina In recent years, herbal remedies such as saffron, celery, hawthorn
University, Hamedan, Iran and garlic are used for management of hypertension 13. Rhus
coriaria L., commonly called tanner's sumac is a member of

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Anacardiaceae family. Beneficial effects of sumac on cardiovascular

14, 15
diseases are reported . However, clinical antihypertensive
activity of R. coriaria has not been investigated yet. The aim of the
present work was to investigate the efficacy 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
promising herbal antihypertensive agent.
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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

RSC Advances Accepted Manuscript

(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 Fig. 1 Decrease in (SBP) Systolic Blood Pressure in response to
2 2
30.83 kg/m and 31.13 kg/m , respectively. There were no Sumac in comparison with placebo. Statistical analyses showed a
significant differences between demographic characteristics of the significant difference between sumac and placebo group and
outpatients in these two groups (P > 0.05) (Tab 1). baseline. (P < 0.05)

Tab. 1 Baseline characteristics of the outpatients

Placebo R. coriaria P-value

Sex: 0.46
Male 21 21
Female 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
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic
blood pressure.
Differences between groups were analysed by ANOVA followed by
Tukey’s honestly significant difference test.
Values are expressed as mean ± SD.

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, Fig. 2 Decrease in Diastolic Blood Pressure (DBP) in response to
2 Sumac in comparison with placebo. Statistical analyses showed a
respectively; and BMI values were 30.29 kg/m in R. coriaria and
2 significant difference between sumac and placebo group and
30.54 kg/m in placebo group. Also, it was obvious that, R. coriaria
decreased systolic (Fig 1) and diastolic BP (Fig 2). These results baseline. (P < 0.05)
showed a significant decrease in BP level in R. coriaria group as
compared to the placebo group after 8 weeks (P < 0.05) and no
significant decrease on BMI in two groups after 8 weeks (Fig 3) (P >
0.05).

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The Fisher’s exact test was applied for analysis of side effects in
both groups
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 significantly
decreased BP in hypertensive patients compared to the baseline
and group received only captopril after 8 weeks (Tab 4). Therefore,
R. coriaria may serve as an effective complementary therapy along
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with conventional antihypertensive agents for reducing

hypertension.

Tab. 4 Characteristics of randomized subjects before and after 8

weeks.

RSC Advances Accepted Manuscript

Variable Placebo R. coriaria P-value
2
BMI (kg/m ) 0.31
Week 0 31.13 ± 1.95 30.83 ± 1.84
Fig. 3 Body Mass Index (BMI) in response to Sumac in comparison
Week 8 30.54 ± 1.14 30.29 ± 1.48
with placebo group. Statistical analyses showed no significant
difference between Sumac and placebo group, as well as baseline (P SBP (mmHg) 0.03
< 0.05) Week 0 143.64 ± 1.79 145.34 ± 2.08
There was a significant reduction in SBP and DBP after 8 weeks of R. Week 8 131.39 ± 2.75 115.21 ± 2.89*
coriaria administration when compared with baseline. However, DBP (mmHg) 0.04
such an effect was not observed in the placebo group (P > 0.05) Week 0 90.51 1.81 90.95 ± 1.97
(Tab 2). *
Week 8 81.66 1.81 78.33 ± 1.97
Tab. 2 BMI, SBP and DBP reduction obtained with the R. coriaria BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic
compared with placebo in patients during 8 weeks blood pressure.
Values are expressed as mean ± SD
Placebo R. coriaria P-value *
P < 0.05, when compared with baseline data
BMI 0.59 ± 2.45 0.54 ± 3.12 0.71
SBP 12.25 ± 6.12 30.13 ± 4.45* 0.03 According to HPLC–DAD/QTOF-MS analyses, 191 compounds in R.
DBP 8.85 ± 3.54 12.62 ± 3.81
*
0.04 coriaria along with their retention times (tR), mass of each
phytochemical, as well as the MS/MS fragment ions used in the
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic characterization process were identified. The HPLC analyses showed
blood pressure. that apigenin, luteolin and quercetin were the most abundant
Values are expressed as mean ± SD compounds in R. coriaria fruits (Fig 4, Tab 5).
*
P < 0.05, when compared between groups.

Clinical complications were determined as any unwanted effects

that occurred from the time of informed consent until one month
after 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 left due to missing the follow up. In
placebo group two patients reported insomnia and headache. All
groups were well matched, and no statistically significant
differences were observed among groups on the frequency of side
effects (Tab 3).
Fig. 4 HPLC analyses and base peak chromatograms (BPC) of UV at
Tab. 3 Frequency of reported adverse effects among the three 280 nm, for the hydro-methanol extract of R. coriaria fruits
study groups.
R. coriaria Placebo group P-value
group
Weakness 1 0 1.61
Drowsiness 0 0 1.00
Insomnia 0 1 1.83
Headache 0 1 1.00

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Tab. 5 Chemical compositions detected and characterised in R. coriaria fruits by HPLC–DAD/QTOF-MS

Error Molecular
Peak Tentative assignment tR(min.) [M+H]+(m/z) [M−H]−(m/z) mSigma
(ppm) formula
1 Galloylhexose II 9.10 – 331.0669 0.6 14. 9 C13H16O10
2 Digalloyl-hexoside II 11.91 – 483.0773 1.3 1.8 C20H20O14
3 Tri-galloyl-hexoside III 19.07 637.1100 635.0882 1.2 2.1 C27H24O18
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Benzoic acid, 3,4,5– trihydroxy-2-oxo-1,3-

4 25.15 – 393.0449 3.7 46.8 C17H14O11
propanediyl ester
5 Dihydroxybenzoic acetate-digallate I 28.14 – 544.9894 5.2 43.9 C24H18O15
6 Dihydroxybenzoic acetate-digallate III 29.60 – 546.0121 3 37.5 C24H18O15

RSC Advances Accepted Manuscript

7 Apigenin glucuronide 29.89 445.0245 446.0312 −1.2 143.2 C21H20O11
8 Galloyl-valoneic acid bilactone 31.10 623.1457 621.0412 −2.2 26.7 C22H22O21
9 Quercetin-rhamnose malic acid I 31.18 564.8637 563.1127 3.7 4.1 C25H24O15
10 Quercetin I 32.14 – 302.0119 2.8 13.0 C15H10O7
11 Quercetin-hexose malic acid IV 32.18 581.1312 – 1.0 46.1 C25H24O16
12 Isorhamentin hexosemalic acid 33.57 594.9197 – −12.6 49.2 C26H26O16
13 Kaempferol rhamnosemalic acid 33.81 – 548.1168 6.0 31.5 C25H24O14
14 Quercitrin O-gallate 34.75 – 599.1019 5.1 26.1 C28H24O15
15 Isorhamnetin hexoside IV 34.80 – 477.1021 5.4 14.5 C22H22O12
16 Di-benzopyranofuranacetic acid deriv. 35.30 515.0526 – 7.0 50.9 C23H16O14
17 Luteolin 36.32 286.8776 285.0348 −5.4 6.9 C15H10O6
18 Quercetin II 36.58 303.0486 301.2481 0.5 2.4 C15H10O7

Discussion effect on renin. It seems that galloyl moiety and ortho-trihydroxy

23
In many hypertensive patients, keeping BP in an optimal range is phenyl structures are favorable for the renin-inhibitory activity .
difficult and prescribing several drugs from different Oxidative stress, due to the accumulation of free radicals, may play
pharmacological classes of antihypertensive agents with high an important role in pathogenesis of cardiovascular diseases like
dosage is frequently needed. Increasing the number and dosage of hypertension 24. Oxidative stress stimulates the proliferation and
drugs in 24 hours enhances the possibility of developing medical hypertrophy of vascular smooth muscle and collagen deposition
side effects but reduces patient's compliances. As a result, which lead to narrowing of the vascular lumen caused by thickening
25
discontinuation of treatment is not far-fetched. Currently, of the vascular media . Also, increased oxidative stress can
introduction of some adjunctive therapies, such as herbal drugs and damage the endothelium and increase vascular contractile activity
26
exercise, seems reasonable. Furthermore, optimizing the modifiable . All these effects can explain how oxidative stress can be a cause
cardiovascular risk factors (i.e. high BMI and low physical activity) is of hypertension. So, treatment with antioxidant components is
27
important and should be taken into account. suggested for improving BP . As mentioned the R. coriaria is highly
The results from phytochemical analysis demonstrated that the rich in antioxidative phenolic components, such as tannins and
28
most abundant constituents of R. coriaria were polyphenolic flavonoids . Thus, adjunctive therapy with R. coriaria can provide
compounds including hydrolysable tannins, flavonoids and further protection as it contains powerful antioxidants and plays an
anthocyanins. This analysis is almost in accordance with our important role in preventing free radical-induced damage in vessels
previous analysis on a sample of R. coriaria collected from different endothelium 29.
place. However a new compound, Benzoic acid, 3,4,5– trihydroxy-2- The effect of flavonoid intake on body weight and BMI is already
oxo-1,3- propanediyl ester, was identified in the present study. investigated 30. Indeed, beneficial antioxidant effects can modulate
31
Other investigations have indicated that sumac is highly rich in BMI . Also it is observed that a source of flavonoid (green tea) can
cyanidin and galloyl-galactose and anthocyanin derivatives
16, 17
.A reduce body weight and body fat in overweight individuals 32.
number of studies have shown that flavonoids such as quercetin Additionally, animal studies have shown an anti-obesity effect for
18, 19
can play important roles in decreasing BP . The potential of flavonoids, through mechanisms such as fatty acid catabolism or
33
quercetin as an effective vasodilator has been indicated 20. In intervention on glucose uptake . However in our study R. coriaria
addition, reductions in systolic, diastolic and mean arterial as a reach source of flavonoids could not decrease BMI in patients
pressures were observed in stage 1 hypertensive patients after a after 8 weeks of administration. Adverse effects such as vertigo,
high dose quercetin treatment in a randomized, double-blind, flashing, insomnia and headache have been reported previously in
34
placebo-controlled, crossover study 21. Apigenin, another flavonoid administration of antihypertensive drugs . Our findings indicated
in R. coriaria, showed antihypertensive activity in spontaneously that R. coriaria did not have serious side effects in administered
hypertensive rats via up-regulating the expression of angiotensin- dose, although more investigations are needed. Moreover,
22
converting enzyme 2 in kidney . Renin is a crucial enzyme in the Long term studies with larger sample size is recommended for
renin-angiotensin system, and its inhibition is considered as a useful better understanding of the R. coriaria effects on BP and BMI is
approach to the treatment of hypertension. Gallic acid as another being recommended.
main phenolic compound of R. coriaria has exhibited inhibitory

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Experimental adults) was encircled the left arm which lowered edge of its
Plant Material position in 2.5 cm above the antecubital space. Inflated the bladder
Sumac (R. coriaria L.) fruits with voucher specimen No.21121 were quickly to a pressure 20 mmHg above SBP, was recognized by the
obtained from the Shahid Beheshti University of Medical Sciences, disappearance of radial pulse and then deflated it 3mmHg/s. BP
Teharn, Iran (Identified by Prof. Dr. Valiollah Mozafarian). The was recorded the korotkoff phase 1 (appearance) and phase 5
samples were transferred to the lab, dried at 70 °C for 24 hours and (disappearance) as SBP and DBP, respectively. On each occasion, at
stored at 5 °C until used. least three measurements were applied, separated by 10 minute
Study design intervals. If data showed variations of more than 5 mmHg, an
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A randomized, parallel-group, double-blind, and placebo-controlled additional measurement was applied until two of them were close
clinical trial was conducted on 80 hypertensive patients in the Arad and the highest BP was recorded.
Hospital, Tehran, Iran, from September to January 2014 with code Ascertainment of BMI
of ethics No.93776 (approval date: 2014 August). During 8 weeks BMI (body mass index) is a person's weight in kilograms divided by
after, 80 patients (aged from 30 to 65 years old) with uncontrolled the square of height in meters. BMI was calculated in the baseline

RSC Advances Accepted Manuscript

HTN stages [stage 1 (SBP: 140-159 and DBP: 90-99 mmHg), stage 2 and in the last follow up session by the same trained nurses.
(SBP: 160 – 179 and DBP: 100-109 mmHg) or stage 3 (SBP: 180 and Statistical Analyses
DBP: 110) that in their medical history during the last 6 months, All data were expressed as mean ± SD. The characteristics of groups
were receiving just captopril as an antihypertensive therapy were at baseline were compared by one-way analyses of variance
enrolled in our study. This study was done in accordance with the (ANOVA). The changes in BP and BMI were analysed using one-way
Declaration of Helsinki. Patients who had SBP more than 180 mmHg repeated measures ANOVA and Tukey’s post hoc and their
at the time of selection, documented secondary HTN, congestive comparison with the baseline data. A P-value < 0.05 was considered
heart failure, moderate to severe valvular heart disease, recent to be statistically significant. Statistical analyses were performed
history of myocardial infarction (MI ≤ 6 months), chronic renal using SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA).
failure, as well as alcohol consumers and pregnant patients were Plant Extraction and HPLC analyses
excluded. Informed consent was obtained from all participants Extraction of phenolic compounds were done according to Abu-
36
before the study began. All patients were assessed weekly for 8 Reidah et al . . Briefly, one gram of R. coriaria dried fruit was
weeks, and data were recorded at baseline and after every week. mixed with 16 mL of methanol/H2O (80:20, v/v) and sonicated for
Parameters collected at baseline were BP, age, sex, weight, height 60 min. Then, the solvent was evaporated under vacuum at 40 °C
and marital status. and the dry remnant was resolved in 0.5 mL of methanol/H2O
Interventions (80:20, v/v). The extract was centrifuged and the supernatant was
All participants were divided randomly in two groups. Each group filtered through a in syringe filter (d = 0.2 μm) and stored at 15 °C.
contained 40 patients. In the sumac group, patients received Chromatographic analysis of extracts was carried out by an Agilent
captopril (25 mg/day once a day, before breakfast) plus R. coriaria 1200 series Rapid Resolution Machine through an Agilent Zorbax
powder capsules [1000 mg/day: 500 mg BID (twice a day), one C18 column (4.6 _ 150 mm, 5 μm). Acetic acid 0.5% v/v and
capsule before lunch and one before dinner] and patients in the acetonitrile were used as mobile phases A and B, respectively. The
placebo group received captopril (25 mg/day once a day, before gradient program was set as follow: 0 min, 0% B; 20 min, 20% B; 30
breakfast) plus placebo capsules (1000 mg/day starch: 500 mg BID, min, 30% B; 40 min, 50% B; 50 min, 75% B; 60 min, 100% B; 62 min
one capsule before lunch and one before dinner) as an adjunctive 0% B. Ultimately, the initial conditions were held for 10 min for re-
therapy for 8 weeks. R. coriaria and placebo capsules were equilibration. The injection volume and column temperature were
prepared in the same way. They were similar in shape, color, size 10 μL and 25 °C, respectively. The HPLC system was coupled to a
and order. All capsules were prepared by a pharmacist and packed quadrupole time of flight (Bruker Daltonik GmbH, Bremen,
in the same container with a code number. Thus, participants and Germany) orthogonal accelerated Q-TOF mass spectrometer, fitted
investigators were all blind to the treatment group assignments. out with an electrospray ionization source (ESI). Analyses of
Participants were not permitted to receive any other parameters were set by negative and positive ion modes, with
antihypertensive drugs during the study time. All patients were spectra obtained over a mass range from m/z 50 to 1100.
checked regularly and their compliance and medication adherence
were estimated through checking with the patient and his/her care Conclusions
taker along with a pill count at each visit. In this study, administration of R. coriaria fruit capsules [1000
Measurement of BP (2×500) mg/day] augmented the effects of antihypertensive drugs
Standard BP was assessed by trained research nurses with a in hypertensive's patients. Without causing any considerable side
random-zero sphygmomanometer in accordance with American effect, R. coriaria was shown to be an effective therapeutic
35
Heart Association protocols . Due to measurement bias at each adjuvant. Moreover, the effects of sumac could be attributed to
visit, controlling of BP was performed with the same nurse and flavonoids as the dominant constituents in this plant. However,
sphygmomanometer and from. Before assessing BP, the patients further research is required to clarify the mechanisms behind these
were asked to seat comfortably with the left arm supported and observations.
positioned at the level of the heart and the back resting against a
chair. The measurement time was under the morning fasting Acknowledgements
condition (12±2 h after the last drug ingestion). The patients rested The authors gratefully acknowledge the Vice Chancellor of
at least five minutes and avoided caffeine or smoke within 30 Research, Tehran University of Medical Sciences for financial
minutes preceding the measurement. The cuff size (12×22 for small- supports (grant number No.93776).
size adults, 16×30 for medium-size adults and 16×42 for large-size

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