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Effect of Korean red ginseng on the rabbit corpus cavernosal
smooth muscle
Y-D Choi, Z-C Xin and H-K Choi
Department of Urology, Yonsei University College of Medicine, Yong Dong Severance Hospital, Yong Dong, PO Box 1217,
Seoul, Korea
The extracts of Korean red ginseng (EKG) is a complex mixture containing ginsenosides,
polysaccharides, and several other products. Animal experiments have shown that the
intravenous administration of extract of ginseng reduces blood pressure. Recently, it has been
reported that ginseng has a relaxing effect on vascular smooth muscle and that the relaxation is
associated with nitric oxide (NO) released from the vascular endothelium. The present study was
undertaken to investigate the effects of EKG on isolated rabbit corpus cavernosal smooth muscle
for evaluation of the possibility of developing EKG as an pharmacoerecting agent.
Strips of rabbit corpus cavernosum were mounted in organ chambers to measure isometric
tension. On the precontracted muscle strip with phenylephrine (PHE; 5610
76
M), EKG began to
exert a relaxing effect at the concentration of 1 mg/ml and the maximal relaxation effect was
reached at 40 mg/ml in a dose-dependent manner. EKG was inhibited signi®cantly by endothelial
disruption and by pretreatment with methylene blue, pyrogallol, L-NNA or atropine. EKG partially
inhibited the PHE (5610
76
M) induced contraction up to 45.67% of the control in a dose-dependent
fashion. EKG decreased basal tension as well as inhibited the contraction induced by addition of
CaCl
2
(10
73
M) dose-dependently in muscle strips at basal equilibrated state in Ca
2
free, high K
depolarizing solution. EKG also inhibited the contraction induced by depolarization with 20, 40
and 60 mM of KCl. However, this inhibitory effect did not occur with high concentrations of KCl
(80 and 120 mM).
EKG has a relaxing effect on the rabbit corpus cavernosal tissue in a dose dependent manner.
The relaxation action of EKG is mediated by multiple action mechanisms that include increasing
the release of NO from the corporal sinusoids, increasing intracellular calcium sequestration, and
a hyperpolarizing action.
Keywords: Korea red ginseng; extract; corpus cavernosum; erection, rabbit
Introduction
The widespread use of intracavernous injections of
vasoactive agents has revolutionized the treatment
of erectile dysfunction. Several vasoactive agents
such as papaverine, phentolamine and prostaglan-
din E1 have proven effective in relaxing the
cavernosal smooth muscle and are useful in the
pharmacotherapy of erectile dysfunction. However,
patient dissatisfaction with these agents has been
associated with a high incidence of prolonged
erection, signi®cant pain in the penis and corporal
®brosis.
1,2
Ginseng has been used in maintaining physical
vitality as a tonic and restorative throughout the far-
eastern countries including Korea and China. Brekh-
man et al
3
described it as an adaptogenÐa substance
that does not impair physiological functions, but
helps to increase resistance against noxious or
stressful in¯uences of a physical, chemical or
biological nature, and in general has a normalizing
effect. Ginseng relieves and prevents a variety of
ailments and physiologic conditions such as dia-
betes mellitus, atherosclerosis, hypertension, stress,
aging, cancer, impotence and improves blood circu-
lation.
4±14
The molecule responsible for the effects of
ginseng is unknown, as is the cellular basis of action
of ginseng.
Various types of pharmacological studies on the
biological effect of ginseng have been conducted in
the past by a number of investigators. Studies from
animal experiments have shown that the intrave-
nous administration of extract of ginseng reduced
blood pressure.
12,15,16
Ginseng has a relaxing effect
on vascular smooth muscle and this is associated
with nitric oxide (NO) released from the vascular
endothelium.
12,14,17±19
Ginseng is also a potent
Correspondence: Dr Y-D Choi.
Received 12 March, 1996; revised 4 April 1997; accepted
30 May 1997
International Journal of Impotence Research (1998) 10, 37±43
ß1998 Stockton Press All rights reserved 0955
-
9930/98 $12.00
inhibitor of calmodulin±dependent phosphodiester-
ase.
20
Earlier animal studies indicated that ginseng
has anti±in¯ammatory properties and cause analge-
sia.
9,21,22
Ginseng is used to protect tissues from
damage when an organism is in stress.
4,9
Ginseno-
sides protect vascular endothelium against free
radical±induced injury.
23
There are many species of ginseng growing in the
world including Korea, China, and Japan. However,
species differ in composition and their concentra-
tion. Extract of Korean red ginseng (EKG), harvested
from Korean ginseng root, have compounds unique
to ginseng such as ginsenosides, polysaccharides,
polyacetylenes, antioxidative aromatic compounds,
alkaloids, lignanes and other nitrogen compounds
(adenosine, acidic peptide, radiation protective
protein, immunocyte generative protein etc.). Gin-
seng saponins, known as the major effective com-
pounds in Korean red ginseng, is composed of
several ginsenosides. It is known that ginsenoside
induces vascular relaxation. But the combined
activity of several action principles of the extract is
responsible for its bene®cial effects.
From these we speculated that ginseng has an
effect specially on the corpus cavernosal smooth
muscle system with no side effects.
9
The present study was undertaken to investigate
the effects of EKG on the isolated rabbit corpus
cavernosal smooth muscle for determining its
potential as a diagnostic and therapeutic agent for
erectile dysfunction.
Materials and methods
Animal preparation
Sixty male New Zealand White rabbits (2.5±3.5 kg)
were anesthetized with pentobarbital sodium
(50 mg/kg). Rabbit penises were surgically removed
en bloc. with care being taken to keep the tunica
albuginea intact. The corpus cavernosum tissue was
then carefully dissected free from the surrounding
tunica albuginea. Each rabbit provided two strips of
corpus cavernosum tissue that were studied in
separate chambers.
Preparation of tissue in organ chambers
The strips of rabbit corpus cavernosum measuring
approximately 26266 mm. were mounted long-
itudinally in 10 ml organ±bath chambers containing
Tyrode buffer solution. The strips were suspended
with silk ties to a force±displacement transducer
(TSD 105, Biopac systems, Santa barbara, CA,
U.S.A) on one end and ®xed to a metallic support
on the opposite end. The chambers contained
Tyrode solution (pH 7.4) at 37C equilibrated with
95% oxygen and 5% CO
2
. Changes in isometric
tension were measured and recorded by MP100WS
(Biopac systems, Santa barbara, CA, U.S.A.) on
computer. The corpus cavernosum tissue was
stretched incrementally for a period of two hours
and the optimal resting isometric tension for con-
traction was determined. The tissue was contracted
with phenylephrine 5610
76
M (PHE) after every
stretch (0.5 gm, tension/stretch). When the ampli-
tude of the contraction was within 10% of the
previous contraction, that tension was considered
optimal for isometric contraction.
Each strip was used up to four separate rounds of
testing, washed three times with Tyrode solution,
and was allowed to equilibrate for 30 min between
rounds.
Organ bath experiments
To evaluate the effect of EKG in basal state, tension
changes were recorded after treating the muscle
strips in basal equilibrium with EKG solution from
1 mg/ml in cumulative increments.
Relaxations were studied in muscle strips pre-
contracted with PHE (5610
76
M). After muscle
strips precontracted with PHE (5610
76
M) were
stabilized, solutions of EKG were treated in increas-
ing concentrations from 1 mg/ml.
The mechanism of muscle relaxation by EKG was
studied in deendothelialized muscle and muscles
pretreated N
W
-nitro-L-arginine (L-NNA; 3610
74
M), methylene blue (10
74
M, guanylate cyclase
antagonist), pyrogallol (10
74
M), atropine (5610
76
M, muscarinic receptor antagonist), or indometha-
cin (10
74
M). Disruption of the endothelium was
achieved by rubbing the cavernosal tissue strips
between the thumb and index ®nger for about 20 s.
After rinsing in chilled Tyrode solution, tissue strips
were gently rolled across a dry paper towel to
generate shear forces across the endothelial surfaces
of the lacunar spaces. Removal of the endothelium
was con®rmed by the absence of the relaxation
response of the strip to acetylcholine (10
75
M) or
when relaxed within 10% range of the control state.
L-NNA, methylene blue, atropine and indomethacin
were added to the muscle strips precontracted with
PHE (5610
76
M) and incubated for 20 min prior to
the addition of EKG. Pyrogallol was added to the
muscle strips precontracted with PHE (5610
76
M)
for 5 min before the addition of EKG.
For evaluating the effect of EKG on PHE
(5610
76
M) induced contraction, PHE (5610
76
M) induced contraction were studied following
pretreatment with EKG from 5 mg/ml.
After the muscle strip was incubated in a Ca
2
free high K
depolarizing solution, Ca
2
induced
Effect of Ginseng on rabbit corporal smooth muscle
Y-D Choi
et al
38
contraction by addition of CaCl
2
(10
73
M) was
recorded in EKG pretreated muscle strips to evaluate
the relationship of EKG to Ca
2
in the cavernosal
smooth muscle.
Untreated and EKG treated muscle strips were
depolarized with 20, 40, 60, 80 and 120 mM of KCl
to investigate the relationship of EKG relaxation to
K
.
Drugs and solutions
Phenylephrine hydrochloride, acetylcholine chlor-
ide, atropine, pyrogallol, L-NNA, methylene blue
and indomethacin were obtained from Sigma Che-
mical Co. (St. Louis, MO, U.S.A.). EKG was
provided from the Korean Ginseng and Tabacco
Research Institute (Taejon, Korea).
Composition of Tyrode solution (mEq/L) was Na
153.6, K
5.3, Ca
2
3.0, Mg
2
1.2, Cl
7
157.2, H
2
PO
47
0.6, SO
4
27
1.2, HCO
37
7.1 and glucose 5.0. And the
composition of Ca
free solution (mEq/L) was Na
17.0, K
126.0, Mg
1.2, Cl
7
128.8, H
2
PO
4
7
1.2,
HCO
3
7
15.4, glucose 11.4.
Data and statistical analysis
Data were analyzed with computer (Acqknowledge
3.2 program, Biopac systems, U.S.A) and all relaxant
responses were expressed as percentage of maximal
relaxation which was calculated from the perpendi-
cular vertical distance between PHE-induced max-
imal contraction point and the largest downward
de¯ection in the tracing at any given experiment.
Inhibitory actions on contractile responses were also
expressed as a percentage of the contraction in the
control state. The statistical analysis was performed
using one-way ANOVA test or Student's t-test.
P<0.05 was taken as being of statistical signi®-
cance. N denotes the number of cavernosal strips
tested and results are expressed as mean standard
error of the mean.
Results
Effect of EKG under the basal condition
EKG did not induce any contraction of muscle strips
in their basal state, but EKG slightly decreased the
resting tone and reduced the spontaneous contrac-
tile activity of the corpus cavernosal smooth muscle
from 5 mg/ml EKG.
Effect of EKG on the submaximally precontracted
muscle strips with PHE
On the precontracted muscle strip with PHE
(5610
76
M), EKG began to exert a relaxing effect at
the concentration of 1 mg/ml and the muscle strips
reached 95.63 4.85% relaxation at the concentra-
tion of 40 mg/ml in a dose-dependent manner
(Figure 1 and Figure 2).
This relaxation effect by EKG was signi®cantly
reduced by removing the endothelium (Figure 3).
The relaxation effect of EKG was also signi®cantly
inhibited by pretreatment with a guanylate cyclase
inhibitor, methylene blue (10
74
M) or a NO scaven-
ger, pyrogallol (10
74
M) or a NO synthesis inhibitor,
L-NNA or a muscarinic receptor antagonist, atropine
(5610
76
M) (Figure 3). However, the relaxation
effect of EKG was not in¯uenced by indomethacin
(10
74
M) (P>0.05) (Figure 3).
Effect of EKG on PHE induced contraction
The contraction of the isolated corpus cavernosal
muscle was submaximally induced with PHE
(5610
76
M). The contractile response of the isolated
Figure 1 Representative tracing of ginseng effects on the isolated rabbit corpus cavernosal smooth muscle strip precontracted by
phenylephrine (5610
76
M). Ginseng relaxed submaximally precontracted muscle strip in a rapid fashion. It reached 95.63% relaxation
effect at the concentration of 40 mg/ml; causing a dose-dependent relaxation.
Effect of Ginseng on rabbit corporal smooth muscle
Y-D Choi
et al
39
cavernosal muscle strips to PHE (5610
76
M) were
signi®cantly inhibited by ginseng pretreatment at
10 mg/ml. Pretreatment with EKG partially inhibited
PHE (5610
76
M) induced contraction up to
45.67 4.16% of the control in a dose-dependent
fashion (Figure 4).
Effect of EKG on Ca
2
induced contraction
When a muscle strip was incubated in a Ca
2
free
solution, the muscle tone was reduced almost to the
level of zero. Cumulative addition of Ca
2
recovered
the muscle tone to a level even higher than the
normal equilibrated condition. At the basal equili-
brated state of muscle strips in Ca
2
free high
potassium depolarizing solution, adding EKG de-
pressed the basal tone of the muscle strip to some
degree. The contraction induced by addition of
CaCl
2
(10
73
M) was diminished dose-dependently
up to 6.92 3.69% of the control when pretreated
with 40 mg/ml EKG (Figure 5).
Effect of EKG on the K
induced contraction
Pretreatment with EKG signi®cantly inhibited the
contraction induced by depolarization with 20, 40
and 60 mM of KCl (P<0.001) (Figure 6). However,
this inhibitory effect did not occur with high
concentrations of KCl of 80 and 120 mM (Figure 6).
Discussion
Penile erection follows the relaxation of penile
smooth muscle. Dilatation of the cavernosal and
helicine arteries increases blood ¯ow to the lacunar
spaces. Relaxation of the trabecular smooth muscle
Figure 2 Relaxation effects of ginseng on the submaximally
precontracted muscle strips by phenylephrine (5610
76
M). Note
the contraction dependent relaxation up to 95.634.85% at
40 mg/ml of ginseng. Values represent mean standard error of
mean and were expressed as percentage of the relaxation (n8).
Figure 3 Effects of various treatments on the ginseng induced relaxation in the phenylephrine (5610
76
M) induced precontracted
muscle strip. The relaxation effects of ginseng were signi®cantly inhibited by deendothelialization (De-endo), by pretreatment with
methylene blue (MB; 10
74
M) or pyrogallol (10
74
M) or a nitric oxide synthesis inhibitor, N
W
-nitro-L-arginine (L-NNA; 3610
74
M) or
atropine (5610
76
M). But relaxation effects of ginseng were not in¯uenced by indomethacin (10
74
M). Values represent mean standard
error of mean and were expressed as percentage of the relaxation. *P<0.05, P<0.001, P>0.05 compared to control.
Figure 4 Effects of ginseng pretreatment on phenylephrine
(5610
76
M) induced contraction in the rabbit corpus cavernosal
muscle strip. The contractile response of the isolated cavernosal
muscle strips to phenylephrine (5610
76
M) were signi®cantly
inhibited by ginseng pretreatment at 10 mg/ml. Pretreatment with
ginseng inhibited partially the phenylephrine (5610
76
M) in-
duced contraction up to 45.67 4.16% of the control in a dose-
dependent fashion. Values represent mean standard error of
mean and were expressed as percentage of the initial contraction
by phenylephrine (5610
76
M) (n7). P>0.05, *P<0.01,
P<0.001 compared to control.
Effect of Ginseng on rabbit corporal smooth muscle
Y-D Choi
et al
40
dilates the lacunar spaces, causing engorgement of
penis. The relaxed trabecular walls by trapping the
blood against tunica albuginea compresses the
plexus of subtunical venules, reduces venous out-
¯ow in the lacunar space, and elevates lacunar
space pressure, making the penis rigid. Therefore,
corporal smooth muscle relaxation plays a critical
role in erection, which is largely nerve mediated by
a nonadrenergic noncholinergic (NANC) mechan-
ism. However, endothelium-dependent cholinergic
neurotransmission may also mediate penile erection
and recent studies have shown that NO is the major
neuronal mediator of erection.
Our data demonstrate EKG relaxed the isolated
rabbit corporal smooth muscle strip. EKG is a
complex product prepared from the root of ginseng
and has a vascular relaxant effect via several
mechanisms. Our study revealed that removal of
the endothelium of muscle strips signi®cantly
inhibited relaxation by EKG. These results indicated
that ginseng caused endothelium-dependent relaxa-
tion and the muscle relaxant effect of EKG is
mediated by the release or augmentation of the
spontaneous release of endothelium derived relax-
ing factor (EDRF) in the rabbit corpus cavernosum.
Studies from vascular muscle have shown that the
relaxation by ginseng was due to the release of
EDRF.
12,14,18,19
NO was ®rst described in 1979 as a potent
relaxant of peripheral vascular smooth muscle with
an action mediated by cyclic GMP.
24
Acetylcholine
was postulated to stimulate the formation of an
EDRF,
25
which was subsequently identi®ed as being
either NO or a chemically unstable nitroso precur-
sor.
26,27
NO is synthesized from endogenous L-
arginine by the nitric oxide synthase system, located
in the endothelium.
27
The present study shows that
atropine, guanylate cyclase inhibitor (methylene
blue), nitric oxide scavenger (pyrogallol) and nitric
oxide synthesis inhibitor (L-NNA) inhibited the
relaxation effect of EKG on the rabbit corpus
cavernous muscle strip. This indicates that the
relaxing action of EKG is mediated by NO and/or
cyclic GMP. Many vascular muscle studies has
shown that ginseng has a relaxing effect on vascular
muscle and that this relaxation is related to an L-
arginine-NO-cyclic GMP pathway from the endothe-
lium
12,14,18
and mediated by NO released from NANC
nerves.
19,28,29
However, the inhibited relaxant response of
muscle strips to EKG by removal of the endothelium
or pretreatment of methylene blue, pyrogallol,
atropine and L-NNA occurred partially and not
completely. Furthermore, at a higher dose of EKG,
there was no more signi®cant inhibitory action of
relaxation than at lower dose. This suggests that the
relaxing action of EKG is mediated not only by an
endothelium mediated mechanism but also other
mechanism as well. Norepinephrine or PHE induces
concentration-dependent contraction of isolated
strip preparations of corpus cavernosum and this
contraction is attenuated or blocked by a-adrenor-
eceptor blockers.
30,31
In our studies with isolated
corpus cavernosal strips, PHE induced contraction
was inhibited by EKG. The mechanism of this
response is not understood at present. Nevertheless,
it seems clear that the inhibition of PHE response of
corpus cavernosal smooth muscle is in part due to
the ginseng induced relaxation and suggests that
EKG might have an a-adrenergic blocking effect. A
similar conclusion has been drawn by many differ-
ent muscle experiments.
32,33
When a muscle strip was incubated in a Ca
2
free
solution, the basal tone was reduced almost to the
level of zero. Addition of Ca
2
restored the basal
Figure 5 Effects of ginseng on Ca
2
induced contraction of
muscle strip in a Ca
2
free solution. The contraction induced by
addition of CaCl
2
(10
73
M) in Ca
2
free solution was diminished
dose-dependently up to 6.92 3.69% of the control with the
pretreatment with 40 mg/ml ginseng. Values represent mean
standard error of mean and were expressed as percentage of the
initial contraction by CaCl
2
(10
73
M) (n8).
Figure 6 Effects of ginseng on K
induced contraction of isolated
rabbit corpus cavernosal muscle strip. Pretreatment with ginseng
signi®cantly inhibited the contraction induced by depolarization
with 20, 40 and 60 mM of KCl. However, with high concentra-
tions of KCl of 80 and 120 mM, this inhibitory effect did not
occur. Values represent mean standard error of mean and were
expressed as percentage of the initial contraction by KCl.
*P<0.0001, P<0.001, P>0.05 compared to control.
Effect of Ginseng on rabbit corporal smooth muscle
Y-D Choi
et al
41
tone, but EKG suppressed the Ca
2
induced recov-
ery. It was evident that EKG exerted an inhibitory
action on the Ca
2
mobilization mechanism, at least
blocking the inward current of extracellular Ca
2
ion. The vasorelaxation induced by EDRF could
involve sequestration of intracellular Ca
2
.
34
Thus, it
is possible that endothelium relaxation by EKG is
associated with the inhibition of intracellular Ca
2
release. The present data, however, do not distin-
guish which components of extra- and intracellular
Ca
2
is primarily affected by EKG. Other studies
indicate that the Ca
2
uptake by sarcoplasmic
reticulum and mitochondria and Ca
2
activated
ATPase activities are strongly inhibited by EKG.
35
It has been reported that the vasorelaxing effect of
ginseng is due to the inhibition of intracellular Ca
2
release and inhibition of Ca
2
uptake via receptor-
operated Ca
2
channel.
36
Nah et al
37
reported that a
crude extract from ginseng inhibited high-threshold,
voltage-dependent Ca
2
channels through an un-
known receptor linked to a pertussis toxin-sensitive
G protein in the neuron. Ginseng is also known as a
potent inhibitor of some calmodulin-dependent
phosphodiesterase.
20
Whether EKG has a similar
effect in corpus cavernosal components of Ca
2
pool
has yet to be determined. However, our study
provides strong evidence for the inhibition of Ca
2
mobilization into the cytosol from the intracellular
sarcoplasmic reticulum or extracellular ¯uid by
ginseng.
EKG pretreatment of muscle strips also inhibited
K
-induced contraction at the K
concentration
range of 20±60 mM. Hamilton et al
38
reported that
aK
channel opener prevented activation of the
voltage operated calcium channel by
K
induced
depolarization at the same range of K
concentration
of 20±60 mM. Therefore, Our studies indicate that
EKG also may hyperpolarize the isolated corpus
cavernosal muscle by activation of K
channels and
thus inhibit the in¯ux of Ca
2
via voltage-operated
Ca
2
channels. Recently, it has been shown that
ginsenosides-induced endothelium relaxation re-
sponse was inhibited by tetraethylammonium, a
Ca
2
-activated K
-channel blocker, but not by glib-
enaclamide, apamine and charybdotoxin in the
isolated rat aortic vascular smooth muscle.
39
Thus
it seems likely that activation of tetraethylammo-
nium-sensitive Ca
2
-activated K
-channel in the
endothelium plays an important role in ginseno-
sides-induced relaxation.
39
EKG did not induce contraction of muscle strips
in the basal state. This shows that EKG itself does
not have a contractile effect on the rabbit corpus
cavernosum. When mounted on organ baths, some
strip preparations of cavernosum exhibited sponta-
neous contractile activity. EKG decreased the resting
tone and inhibited the spontaneous contractile
activity of the corpus cavernosal smooth muscle.
The spontaneous activity is generally myogenic and
is abolished by addition of Ca
2
antagonist, K
channel opener, inhibitors of prostaglandin synth-
esis or removal of extracellular calcium.
40±43
Based
on these ®ndings, EKG has no contractile effect but
possibly some effect of Ca
2
antagonist, K
channel
opener or inhibition of prostaglandin synthesis. In
the present study, relaxation by EKG was not
in¯uenced by indomethacin (10
74
M) indicating
that vasoactive prostanoids are unlikely to contri-
bute to relaxation.
Conclusions
Our data demonstrates that EKG has a dose-related
relaxing effect on the isolated rabbit corporal smooth
muscle strip and this relaxant effect is associated
with several different mechanisms due to the
complex compound nature of ginseng. Collectively,
at least part of the relaxing effect of EKG on the
corporal smooth muscle is mediated by the release
(or augmentation of the spontaneous release) of
EDRF or nitric oxide as well as inhibition of calcium
mobilization into the cytosol from the intracellular
sarcoplasmic reticulum or extracellular ¯uid. Ad-
ditionally, a hyperpolarizing effect via potassium
channel opening might also be related to this
relaxing effect. These results indicate that there are
many potentially active constituents in EKG that
could in¯uence its ®nal action. Therefore, further
studies are required in this area to clarify the
individual mechanism of each component of EKG
and purify and select the proper components for
achieving better relaxation of the corporal smooth
muscle.
Acknowledgement
This research was supported by grants from the
Society for Korean Ginseng.
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