integr med res 5 ( 2 0 1 6 ) 223–229

Available online at www.sciencedirect.com

Integrative Medicine Research
journal homepage: www.imr-journal.com

Original Article

Rg3-enriched Korean Red Ginseng enhances bloodpressure stability in spontaneously hypertensive
ratsHarsha Nagar a,1 , Sujeong Choi a,1 , Saet-byel Jung b , Byeong Hwa Jeon a ,Cuk-Seong Kim a,∗a Department of Physiology, BK21Plus CNU Integrative Biomedical Education Initiative, School of Medicine,

Chungnam National University, Daejeon, Koreab Department of Endocrinology, Chungnam National University Hospital, Daejeon, Korea

a r t i c l e

i n f oa b s t r a c t

Article history:

Background: Korean Red Ginseng (Panax ginseng) has been shown to exert antihypertensive

Received 2 May 2016

effects. In particular, ginsenoside Rg3 is thought to be a potent modulator of vascular func-

Received in revised formtion. The present study was performed to examine the antihypertensive efﬁcacy of Korean

23 May 2016

Red Ginseng (KRG) extract and Rg3-enriched KRG (REKRG) extract.

Accepted 30 May 2016

Methods: Spontaneously hypertensive rats (SHRs) and Wistar–Kyoto rats (WKYs) were divided

Available online 3 June 2016

into six groups (WKY control, WKY-KRG, WKY-REKRG, SHR control, SHR-KRG, and SHR-

Keywords:

at the carotid artery, followed by injection of 3 mg/kg KRG or 3 mg/kg REKRG.

endothelial nitric oxide synthase

Results: REKRG treatment signiﬁcantly decreased SBP and DBP 3 hours post-treatment in the

REKRG), and systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured

MeSH

SHR group compared with SHR control group. However, SBP and DBP were not signiﬁcantly

nitric oxide

different in KRG-treated SHRs compared with control SHRs. REKRG treatment did not sig-

Rg3-enriched Korean Red Ginseng

niﬁcantly alter SBP or DBP 3 hours post-treatment in the WKY group compared with WKY

spontaneously hypertensive rats

control group. Similarly, there were no differences in SBP or DBP with KRG treatment in
the WKY group and WKY control group. Both KRG and REKRG increased endothelial nitricoxide synthase phosphorylation levels in the aorta, and the increases in endothelial nitricoxide synthase phosphorylation levels by REKRG treatment were higher than those with
KRG treatment. Similarly, nitric oxide production in plasma from WKYs and SHRs was also
increased by both KRG and REKRG.
Conclusion: These results suggest that REKRG has a more beneﬁcial effect on blood pressure
control than KRG in SHRs.
© 2016 Korea Institute of Oriental Medicine. Published by Elsevier. This is an open accessarticle under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗

Corresponding Author: Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-131, Korea.
E-mail address: cskim@cnu.ac.kr (C.-S. Kim).
1
These authors contributed equally to this work
http://dx.doi.org/10.1016/j.imr.2016.05.006
2213-4220/© 2016 Korea Institute of Oriental Medicine. Published by Elsevier. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

224

1.

Integr Med Res ( 2 0 1 6 ) 223–229

Introduction

Korean Red Ginseng (Panax ginseng) is a traditional Korean
tonic medicine known for its efﬁcacy in promoting physicalstrength and immunity, which may ameliorate certain chronic
disease states such as vascular disease and hypertension.1
Ginsenosides as a biologically effective extract of P. ginseng
are a mixture of triterpene glycosides. The major fractionsof ginsenosides consist of two groups according to chemical structure: the panaxadiol group is represented by Rb1,
Rb2, Rb3, Rc, Rd, Rg3, Rh2, and Rs1, while the panaxatriol
group consists of Re, Rf, Rg1, Rg2, and Rh1. Ginsenosides
are well known to have hypotensive effects in experimental animals and hypertensive patients.2–4 Moreover, theyenhance cardiovascular functions associated with vasorelaxation and stimulation of nitric oxide (NO) production
from endothelial NO synthase (eNOS).3,5 Recently, individual ginsenosides have been shown to have different effects
via various mechanisms in many tissues. In addition, studies of vascular disease are focusing on puriﬁed individual
ginsenoside fractions from ginseng to identify the key components instead of using mixed ginsenosides. Among theginsenosides of the panaxadiol and panaxatriol groups, ginsenoside Rg3 is a potent vasodilator that has been shown toprovide vascular protective effects, such as antivascular contraction and antihypertensive effects as well as enhancementof NO production and eNOS activity.2,6,7 Previously, we also
showed that Rg3 improved vascular function through eNOS
activation.2
NO is a major endothelium-dependent relaxing factor, andits production by vascular endothelial cells plays a criticalrole in the regulation of vascular motor tone and stabilityof blood ﬂow as well as blood pressure.8,9 NO is synthesized by the vascular endothelial cells using l-arginine as a
substrate in a process catalyzed by NOS10 and induces vascular smooth muscle relaxation by activation of guanylate
cyclase.11 Because it is an isoform of NOS that produces NO,
eNOS also plays an important role in regulating systemic bloodpressure.12 Previous studies have shown that a decrease in NO
production can lead to hypertension,13 and eNOS mutation
leads to impaired endothelium-dependent vasorelaxation andmay have hypertensive effects.14 In addition, blood pressure was enhanced in rats in which eNOS was inhibitedwith N␻-nitro-l-arginine methyl ester.15 Recent studies havesuggested that production of NO is reduced and endotheliumdependent vasorelaxation is blunted in patients with essential
hypertension.16
Previous studies have shown the effects of P. ginseng on
vascular regulation and blood pressure control, and effects
of total ginsenosides and Rg3 on eNOS activation and NO
production. However, there is no previous study for comparison between KRG and Rg3-enriched KRG (REKRG). Therefore,
in this study, the efﬁcacy of total ginsenoside (KRG) and
REKRG was compared in Wistar–Kyoto rats (WKYs) andspontaneously hypertensive rats (SHRs). We examined theenhancement of blood pressure stability, eNOS phosphorylation and NO production by REKRG in SHRs compared with
WKYs.

2.

Methods

2.1.

Preparation of REKRG

Dried KRG (P. ginseng) root was purchased from Gumsan
Nonghyup (Gumsan, Korea). Korean ginseng was extracted
twice with 10 volumes of ethanol at 50 ◦ C for 7 hours (1st50%, 2nd 85%), and then concentrated under vacuum at 50 ◦ C
as described previously.2 The crude extract was dissolved inwater, and enzyme–acid hydrolysis was performed to maximize ginsenoside Rg3 (raw ginsenoside was hydrolyzed to Rg3)
under acidic (pH 2.5–3.5) and thermophilic (65–80 ◦ C) conditions. The enzyme, which has ␤-glycosidase activity including
cellulose, hemicellulose, and glucosidase activities, was produced by Aspergillus niger. To remove the acid solution andconcentrate Rg3, the reactant was passed through a column
packed with DIAION HP20 resin (Mitsubishi Chemical Industries, Tokyo, Japan). The ginsenoside Rg3, kindly provided
by BTGin Corporation (Occheon, Korea), was concentrated topowder under vacuum.

2.2.

Animals and blood pressure measurements

Male 10–12-week-old SHRs and WKYs weighing 250–320 g
were purchased from Central Lab. Animal Inc. (Seoul, Korea).
SHRs and WKYs were randomly divided into six groups: WKY
control, WKY-KRG, WKY-REKRG, SHR control, SHR-KRG, andSHR-REKRG, and systolic blood pressure (SBP) and diastolicblood pressure (DBP) were measured at the carotid artery for
3 hours, followed by jugular vein injection of 3 mg/kg KRG or
3 mg/kg REKRG, as described previously.17 Animals were raised
under conditions of controlled lighting (06:00–18:00 hours
daily) and temperature (24 ± 1 ◦ C). Rats were anesthetized withurethane (1,200 mg/kg), and the left common carotid artery
was cannulated with a cannula preﬁlled with heparinized normal saline (0.5 IU/mL) to measure arterial blood pressure. The
arterial pressure was determined using a student physiography/data system (ADInstruments, Dunedin, New Zealand) andanalyzed using Chart Pro software (ADInstruments). The jugular vein was cannulated for administration of saline as well as
REKRG or KRG.

2.3.

Western blotting

Anti-phospho-eNOS antibody was purchased from Cell
Signaling (Beverly, MA, USA). Anti-NOS3 antibody was purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).
Western blotting analysis was performed by adding 30 ␮gtissue homogenate (obtained from rat aorta) to SDS–PAGE
loading buffer followed by boiling and separation by electrophoresis and transfer onto nitrocellulose membranes.
After incubation with appropriate primary and peroxidaseconjugated secondary antibodies (Santa Cruz Biotechnology),
the chemiluminescent signal was developed using Super
Signal West Pico or Femto Substrate from Thermo Fisher
Scientiﬁc (Rockford, IL, USA). Blots were imaged and band densities quantiﬁed with a Gel Doc 2000 Chemi Doc system using

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H. Nagar et al/Effect of Korean Red Ginseng on hypertension

Nitrite and nitrate measurements

NO metabolites nitrite (NO2 − ) and nitrate (NO3 − ), the stablebreakdown products of NO, were quantiﬁed using a commercially available kit (Nitrate/nitrite Fluorometric Assay Kit;
Cayman Chemicals, Lexington, KY, USA). Plasma obtained
from rat blood was deproteinized using a 10-kDa cutoff ﬁlter(Microcon YM10; Millipore, Bedford, MA, USA). After subtraction of background ﬂuorescence, values were normalized todetermine the total protein level.

2.5.

Statistical analysis

All experiments were performed at least three times. Statistical analysis was performed using SPSS version 13.0 (SPSS Inc.,
Chicago, IL, USA). Data are presented as the mean ± standard
deviation. Statistical signiﬁcance was determined by analysis of variance followed by the multiple comparison test with
Bonferroni adjustment. In all analyses, p < 0.05 was taken to
indicate statistical signiﬁcance.

3.

Results

3.1.

REKRG reduces BP of SHRs

In our previous study, we showed that the concentration ofginsenoside Rg3 in REKRG is ∼300-fold higher than that in KRG,
and that REKRG improves impaired endothelium-dependentvasorelaxation in the aorta in SHRs.2 In this study, we examined the effects of REKRG or KRG treatment on SBP and DBP in
SHRs and WKYs. For this, REKRG and KRG were injected into
the jugular vein of SHRs and WKYs at a dose of 3 mg/kg and theblood pressure was recorded for 3 hours. Measurements weretaken at baseline and then at 30 minutes, 1 hour, 90 minutes,
2 hours, 150 minutes, and 3 hours. Many previous studies haveshown that ginsenosides reduce BP via increases in the production of endothelial NO,7 and that Rg3 is the most potent
ginsenoside that activates eNOS in the rat aorta. As shown in
Fig. 1, administration of both KRG and REKRG to WKYs caused
no changes in either SBP (Fig. 1A) or DBP (Fig. 1B) recorded from0 hours to 3 hours following treatment. By contrast, administration of REKRG caused signiﬁcant decreases in both SBP and
DBP in SHRs (Figs. 2A and 2B) starting as early as 30 minutes
post-treatment of REKRG. However, both SBP and DBP were
unaffected by administration of KRG in SHR.

3.2.

REKRG stimulates phosphorylation of eNOSeNOS serves an important basal regulatory function in thevasculature. When subjected to stimuli, such as shear stressor acetylcholine, eNOS constitutively expressed in endothelial cells oxidizes l-arginine to generate l-citrulline and NO.
Rg3 is one of the major biologically active components of ginseng and is regarded as the main compound responsible forits many pharmacological actions, including enhancement

Systolic blood pressure change
from baseline (mmHg)

2.4.

(A)
20

0

30

60

90

120

150

180 min

60

90

120

150

180 min

15
10
5
0
-5
-10

saline
KRG
REKRG

-15

(B)
Diastolic blood pressure change
from baseline (mmHg)

Quantity One software (Bio-Rad, Hercules, CA, USA). Values
were normalized relative to ␤-actin loading control.

15

0

30

10
5
0
-5
-10
-15

salineKRG
REKRG

Fig. 1 – Acute effects of Rg3-enriched Korean Red Ginseng
extract (REKRG) on changes in blood pressure in
Wistar–Kyoto rats (WKYs). Korean Red Ginseng extract(KRG) and REKRG were injected intravenously at 3 mg/kg,
and both systolic blood pressure (SBP) and diastolic bloodpressure (DBP) were measured in WKYs for 3 hours.
(A) KRG and REKRG did not signiﬁcantly alter SBP comparedwith controls. (n = 6). (B) KRG and REKRG did not
signiﬁcantly alter DBP compared with controls. (n = 7).

of eNOS phosphorylation and NO production. We examined eNOS phosphorylation by western blotting analysisof tissue homogenate from the aortas of both WKYs andSHRs after administration of KRG or REKRG. As shown in
Fig. 3A, administration of both KRG and REKRG stimulated
Ser-1177 phosphorylation of eNOS in WKYs. Similarly, Ser1177 phosphorylation of eNOS was also increased in SHRs
after administration of KRG and REKRG (Fig. 3B), but theoverall level of phosphorylation was higher in SHRs than in
WKYs. In addition, the efﬁciency of REKRG to stimulate eNOS
phosphorylation was much higher than that of KRG in bothgroups.

3.3.

REKRG stimulates production of NO

NO is an endothelium-derived relaxing factor that plays animportant role in the control of vascular tone and vascularfunctions. The synthesis of NO by the vascular endothelium
is responsible for vasodilator tone, which is essential for the
regulation of BP. High BP is characterized by deﬁciency ofeNOS and decreased NO production, especially in the endothelium. Therefore, we measured the plasma levels of NO in
WKYs and SHRs after administration of KRG or REKRG. As
expected, administration of both KRG and REKRG stimulated
NO production in WKYs and SHRs (Figs. 4A and 4B). The

Integr Med Res ( 2 0 1 6 ) 223–229(A)administration has the potential to stabilize BP and prevent
cardiovascular disease.
Several recent studies regarding cardiovascular disease
focused on puriﬁed individual ginsenoside components ofginseng to show speciﬁc mechanisms instead of using
whole ginseng extracts. Various components of whole ginseng extracts (i.e., ginsenosides Rg3, Rb1, and Re) display
antihypertensive and cardiovascular protective effects.7,24
Therefore, they are considered potential components for vascular protection. In particular, ginsenoside Rg3 has beenstudied extensively because it is the most potent vasodilator
among the ginsenosides characterized to date. For example, Rg3 induces endothelium-independent vasorelaxation
through inhibition of vascular smooth muscle tone by prevention of Ca2+ inﬂux and stimulation of K+ efﬂux.7 Moreover,it stimulates vascular-endothelium-derived NO and induces
vasodilation in the rat aorta.23,24 Another important factor isthat it can be easily extracted from red ginseng by a steamingand drying process. Processed ginseng, which contains highlevels of Rg3, has emerged as a health-supporting agent insome East Asian countries, including Korea and China. In thisstudy, we further investigated the vasoactive efﬁcacy of theselected ginsenosides on vascular function and compared theeffects of ginsenosides to two major isolated fractions (KRG
and REKRG). In our previous study, we analyzed 11 ginsenosides (Rg1, Re, Rf, Rh1, Rg2, Rb1, Rc, Rb2, Rg3, Rk1, and Rg5) byhigh-performance liquid chromatography.2 The REKRG fraction was shown to contain Rg1, Re, Rf, Rh1, Rg2, Rb1, Rc, Rb2,
Rg3, Rk1, and Rg5 at levels of 0.6 mg/g, 1.9 mg/g, 12.3 mg/g,
5.0 mg/g, 4.2 mg/g, 3.8 mg/g, 1.2 mg/g, 1.0 mg/g, 100.0 mg/g,
12.0 mg/g, and 21.0 mg/g, respectively, while the levels in
KRG were 2.9 mg/g, 4.2 mg/g, 0.3 mg/g, 0.1 mg/g, 0.2 mg/g,
5.9 mg/g, 2.2 mg/g, 2.1 mg/g, 0.3 mg/g, 0.05 mg/g, and 0.12 mg/g,
respectively. These results indicate that the concentrationof ginsenoside Rg3 in REKRG is ∼300-fold greater than thatin KRG. We showed that REKRG improved endotheliumdependent vasorelaxation in the WKYs and SHRs comparedwith controls, and that REKRG treatment for 6 weeks reduced
the mean aortic intima–media thickness compared with controls. The results of the present study also indicate that REKRG
stimulates endothelium-dependent vasorelaxation throughnot only eNOS phosphorylation but also NO production.
Although REKRG did not signiﬁcantly decrease BP in WKYs,
it markedly decreased BP in SHRs. In addition, REKRG has
a greater antihypertensive effect than KRG at the same
dose even though KRG is known to have an effect on highBP. Therefore, these data suggest that Rg3 is the principal pharmacologically active component of KRG and that it
could be an excellent candidate for use in antihypertensive
therapy.
One of the limitations of our study was that we measured the BP of rats under anesthesia. It has been shown
previously that anesthesia itself can have an inﬂuence on cardiovascular function.25 Anesthetic drug administration has
an effect on the autonomic nervous system, thus limiting
the evaluation of changes in BP. Therefore, in this study,administration of KRG or REKRG to the rats under anesthesia
may have caused changes in parameters, such as heart rate,
resulting in tachycardia or bradycardia in anesthetized rats
as a compensation against hypotension by the decrease of

Systolic blood pressure change
From baseline (mmHg)

226

20

0

30

60

90

120

150

180 min

10
0
-10
-20

*

saline
KRG
REKRG

-30

*

*

Diastolic blood pressure change
From baseline (mmHg)

(B)
20

0

30

60

90

saline
KRG
REKRG

*

*

120

150

180 min

10
0
-10
-20
-30

*

Fig. 2 – Acute effects of Rg3-enriched Korean Red Ginseng
extract (REKRG) on changes in blood pressure in
spontaneously hypertensive rats (SHRs). Korean Red
Ginseng extract (KRG) and REKRG were injected
intravenously at 3 mg/kg, and both systolic blood pressure(SBP) and diastolic blood pressure (DBP) were measured in
SHRs for 3 hours.
(A) REKRG signiﬁcantly decreased SBP compared with
controls. However, KRG did not. (B) REKRG signiﬁcantly
decreased DBP compared with controls. However, KRG did
not.
Data are presented as mean ± standard deviation(n = 6 or n = 7).
* p < 0.05 compared with control.

efﬁciency of REKRG to stimulate NO production was higher
than that of KRG in both groups. These results suggest that
REKRG stimulates the eNOS signaling pathway, leading to its
phosphorylation, which in turn leads to an increase in NO
production in SHR.

4.

Discussion

High BP is one of the major risk factors for the developmentof vascular diseases such as atherosclerosis, coronary heartdisease, and stroke,18 and several studies have reported cardiovascular risks associated with elevated BP.19,20 High BP isrelated to morphological changes and impaired function ofvascular smooth muscle and endothelial cells. The beneﬁcial effects of ginsenosides have been widely studied andshown to have new antihypertensive effects3 and prevent orameliorate various diseases, including atherosclerosis, cancer, and thrombosis.21–23 In this study, we demonstrated that
REKRG increased eNOS phosphorylation and NO production
and decreased BP in SHRs. These results indicate that REKRG

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H. Nagar et al/Effect of Korean Red Ginseng on hypertension

Fig. 3 – Effects of Rg3-enriched Korean Red Ginseng extract (REKRG) on phosphorylation of endothelial nitric oxide synthase(eNOS). The phosphorylation of eNOS was measured in the aorta 3 hours after intravenous injection of Korean Red Ginseng
extract (KRG) and REKRG 3 mg/kg.
(A) REKRG and KRG signiﬁcantly increased eNOS phosphorylation compared with saline control in Wistar Kyoto rat (WKY).
The levels of eNOS phosphorylation were quantiﬁed by densitometrie analysis (lower panels). (B) REKRG and KRG
signiﬁcantly increased eNOS phosphorylation compared with saline control in spontaneously hypertensive rat (SHR). The
levels of eNOS phosphorylation were quantiﬁed by densitometrie analysis (lower panels) western blots shown are
representative of three independent experiments.
Data are presented as mean ± standard deviation (n = 6 or n = 7).
* p < 0.05 compared with control.

peripheral resistance.3 Similarly, KRG or REKRG administration may also cause a decrease in heart contractility directlyin anesthetized rats because rats under anesthesia may have
reduced nervous reﬂex control and synaptic transmission in
the autonomic nervous system.
NO is a radical generated from l-arginine by NOS, whichplays a critical role as a second messenger in cell signaling.10
Low levels of NO produced and released by the endothelial
cells play critical roles in the maintenance of basal vascu-

(B)

WKY

20

*

15
10
5
0
SalineKRG

REKRG

Nitrite + Nitrate (μM)

Nitrite + Nitrate (μM)

(A)

SHR

20
15

*

10
5
0
SalineKRG

REKRG

Fig. 4 – Effects of Rg3-enriched Korean Red Ginseng extract(REKRG) on nitric oxide (NO) production. Metabolites of NO(nitrite and nitrate) were measured in the plasma of rats
3 hours after intravenous injection of Korean Red Ginseng
extract (KRG) and REKRG 3 mg/kg.
(A) REKRG signiﬁcantly increased NO production comparedwith saline control in Wistar Kyoto rat (RAT). (B) REKRG
signiﬁcantly increased NO production compared withsaline control in spontaneously hypertensive rats (SHR).
Data are representative of three independent experiments
and are presented as mean ± standard deviation.
* p < 0.05 compared with control.

lar tone. Some biochemical stimuli, such as thrombin, ADP,
serotonin, acetylcholine, and bradykinin, as well as mechanical stimuli including shear stress and cyclic strain, resultin increased synthesis of endothelial NO. Previous studies
have shown a relationship between NO and hypertension.
Inhibition of NO synthesis in the vasculature may lead to
hypertension or ischemic stroke, likely through its effects on
vascular tone. NO produced by vascular endothelial cells has
been implicated in many of the effects of ginsenosides, including those on vessel relaxation, protection of the cardiovascularsystem, and antithrombotic and antiplatelet effects.23,26
Various factors can inhibit NO synthesis; one of whichis excessive production of reactive oxygen species (ROS)
by endothelial cells. ROS refers to oxygen radicals such as
superoxide anion, hydroxyl radical, hydrogen peroxide, andperoxynitrite.27 Studies over the past decade have indicatedthat ROS generated by endothelial cells play key roles inthe signaling mechanisms and affect vascular homeostasis.
Endothelial cells are not only major sources but also targets of
ROS. Among the various ROS species, the superoxide anion
destroys most of the NO28 and further increases oxidative
stress.29 The superoxide anion level has also been shown to be
increased in endothelial cells in SHRs,30 which scavenges NO
as soon as it is produced. Similarly, concentrations of superoxide anions produced by the aortic rings from SHRs were greaterthan those produced by these structures from WKYs.31 Our
results were consistent with this observation and showed thatthe level of NO production under basal conditions in WKYs
was higher than that in SHRs because increased ROS in SHRs
immediately destroyed endothelium-derived NO. Some previous reports have demonstrated the antihypertensive effectof REKRG in human randomized control trials.32,33 Our results
demonstrate the antihypertensive effect of REKRG in compar-

228

ison to KRG in a rat model and we provide the mechanistic
pathway for its antihypertensive effect. We show that thevasodilatory effect of REKRG is endothelium dependent, andeNOS phosphorylation followed by NO production is the major
contributory factor to the observed vascular dilatation shownin human trials.
In conclusion, the present results indicate that REKRG has
a signiﬁcant antihypertensive effect in SHRs, which may be
due to activation of eNOS and stimulation of NO production,and that REKRG intake may be beneﬁcial for individuals withhigh risks of hypertension and cardiovascular diseases.

Conﬂicts of interest
No competing ﬁnancial interests exist.

Acknowledgments
This research was supported by the Basic Science Research
Program through the National Research Foundation of
Korea (NRF) funded by the Ministry of Education (NRF2014R1A6A1029617 and NRF-2015R1D1A1A01061516). This
study was supported by research fund of Chungnam National
University, Daejeon, Korea in 2015. This study was supported
by research fund of Chungnam National University Hospital. The English in this document has been checked by atleast two professional editors, both native speakers of English.
For a certiﬁcate, please see: http://www.textcheck.com/
certiﬁcate/C4x3Dm.

references

1. Kim JH. Cardiovascular diseases and Panax ginseng: a review
on molecular mechanisms and medical applications. J
Ginseng Res 2012;36:16–26.
2. Park JB, Kwon SK, Nagar H, Jung SB, Jeon BH, Kim CS, et al.
Rg3-enriched Korean Red Ginseng improves vascularfunction in spontaneously hypertensive rats. J Ginseng Res
2014;38:244–50.
3. Jeon BH, Kim CS, Park KS, Lee JW, Park JB, Kim KJ, et al. Effectof Korea red ginseng on the blood pressure in conscious
hypertensive rats. Gen Pharmacol 2000;35:135–41.
4. Sung J, Han KH, Zo JH, Park HJ, Kim CH, Oh BH, et al. Effects
of red ginseng upon vascular endothelial function inpatients with essential hypertension. Am J Chin Med
2000;28:205–16.
5. Jeon BH, Kim CS, Kim HS, Park JB, Nam KY, Chang SJ, et al.
Effect of Korean red ginseng on blood pressure and nitricoxide production. Acta Pharmacol Sin 2000;21:1095–100.
6. Vuksan V, Sievenpipper J, Jovanovski E, Jenkins AL. Current
clinical evidence for Korean Red Ginseng in management ofdiabetes and vascular disease: a Toronto’s Ginseng Clinical
Testing Program. J Ginseng Res 2010;34:264–73.
7. Kim ND, Kang SY, Kim MJ, Park JH, Schini-Kerth VB. The
ginsenoside Rg3 evokes endothelium-independent
relaxation in rat aortic rings: role of K+ channels. Eur J
Pharmacol 1999;367:51–7.
8. Rees DD, Palmer RM, Moncada S. Role ofendothelium-derived nitric oxide in the regulation of bloodpressure. Proc Natl Acad Sci U S A 1989;86:3375–8.

Integr Med Res ( 2 0 1 6 ) 223–229

9. Vallance P, Collier J, Moncada S. Effects ofendothelium-derived nitric oxide on peripheral arteriolar
tone in man. Lancet 1989;2:997–1000.
10. Palmer RM, Ashton DS, Moncada S. Vascular endothelial
cells synthesize nitric oxide from L-arginine. Nature
1988;333:664–6.
11. Palmer RM, Ferrige AG, Moncada S. Nitric oxide releaseaccounts for the biological activity of endothelium-derived
relaxing factor. Nature 1987;327:524–6.
12. Shesely EG, Maeda N, Kim HS, Desai KM, Krege JH, Laubach
VE, et al. Elevated blood pressures in mice lacking
endothelial nitric oxide synthase. Proc Natl Acad Sci U S A
1996;93:13176–81.
13. Watson T, Goon PK, Lip GY. Endothelial progenitor cells,
endothelial dysfunction, inﬂammation, and oxidative stressin hypertension. Antioxid Redox Signal 2008;10:1079–88.
14. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA,
Bevan JA, et al. Hypertension in mice lacking the gene forendothelial nitric oxide synthase. Nature 1995;377:239–42.
15. Bobadilla NA, Gamba G, Tapia E, García-Torres R, Bolio A,
López-Zetina P, et al. Role of NO in cyclosporin
nephrotoxicity: effects of chronic NO inhibition and NO
synthases gene expression. Am J Physiol 1998;274:F791–8.
16. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role ofendothelium-derived nitric oxide in the abnormal
endothelium-dependent vascular relaxation of patientswith essential hypertension. Circulation 1993;87:1468–74.
17. Parasuraman S, Raveendran R. Measurement of invasive
blood pressure in rats. J Pharmacol Pharmacother 2012;3:172–7.
18. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J,
et al. Blood pressure, stroke, and coronary heart disease Part
1, Prolonged differences in blood pressure: prospective
observational studies corrected for the regression dilution
bias. Lancet 1990;335:765–74.
19. Stamler J, Stamler R, Neaton JD. Blood pressure, systolic anddiastolic, and cardiovascular risks. US population data. Arch
Intern Med 1993;153:598–615.
20. Kannel WB. Blood pressure as a cardiovascular risk factor:
prevention and treatment. JAMA 1996;275:1571–6.
21. Zhang C, Liu L, Yu Y, Chen B, Tang C, Li X, et al. Antitumor
effects of ginsenoside Rg3 on human hepatocellular
carcinoma cells. Mol Med Rep 2012;5:1295–8.
22. Zhang YG, Zhang HG, Zhang GY, Fan JS, Li XH, Liu YH, et al.
Panax notoginseng saponins attenuate atherosclerosis in rats
by regulating the blood lipid proﬁle and ananti-inﬂammatory action. Clin Exp Pharmacol Physiol
2008;35:1238–44.
23. Jin YR, Yu JY, Lee JJ, You SH, Chung JH, Noh JY, et al.
Antithrombotic and antiplatelet activities of Korean red
ginseng extract. Basic Clin Pharmacol Toxicol 2007;100:170–5.
24. Scott GI, Colligan PB, Ren BH, Ren J. Ginsenosides Rb1 and Re
decrease cardiac contraction in adult rat ventricular
myocytes: role of nitric oxide. Br J Pharmacol
2001;134:1159–65.
25. Carruba MO, Bondiolotti G, Picotti GB, Catteruccia N, Da
Prada M. Effects of diethyl ether, halothane, ketamine andurethane on sympathetic activity in the rat. Eur J Pharmacol
1987;134:15–24.
26. Yu Z, Gao X, Yuan H, Liu T, Ma M, Chen X, et al. Simultaneous
determination of safﬂor yellow A, puerarin, daidzein,
ginsenosides (Rg(1), Rb(1), Rd), and notoginsenoside R(1) in
rat plasma by liquid chromatography-mass spectrometry. J
Pharm Biomed Anal 2007;45:327–36.
27. McIntyre M, Bohr DF, Dominiczak AF. Endothelial function in
hypertension: the role of superoxide anion. Hypertension
1999;34:539–45.
28. Stuehr DJ. Mammalian nitric oxide synthases. Biochim
Biophys Acta 1999;1411:217–30.

H. Nagar et al/Effect of Korean Red Ginseng on hypertension

29. Suzuki H, DeLano FA, Parks DA, Jamshidi N, Granger DN,
Ishii H, et al. Xanthine oxidase activity associated witharterial blood pressure in spontaneously hypertensive rats.
Proc Natl Acad Sci U S A 1998;95:4754–9.
30. Grunfeld S, Hamilton CA, Mesaros S, McClain SW,
Dominiczak AF, Bohr DF, et al. Role of superoxide in the
depressed nitric oxide production by the endothelium ofgenetically hypertensive rats. Hypertension 1995;26:854–7.
31. Auch-Schwelk W, Katusic ZS, Vanhoutte PM. Contractions tooxygen-derived free radicals are augmented in aorta of the
spontaneously hypertensive rat. Hypertension 1989;13:859–64.

229

32. Jovanovski E, Bateman EA, Bhardwaj J, Fairgrieve C, Mucalo I,
Jenkins AL, et al. Effect of Rg3-enriched Korean red ginseng(Panax ginseng) on arterial stiffness and blood pressure in
healthy individuals: a randomized controlled trial. J Am Soc
Hypertens 2014;8:537–41.
33. Jovanovski E, Peeva V, Sievenpiper JL, Jenkins AL, Desouza L,
Rahelic D, et al. Modulation of endothelial function by
Korean red ginseng (Panax ginseng C.A Meyer) and its
components in healthy individuals: a randomized controlled
trial. Cardiovasc Ther 2014;32:163–9.