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doi: 10.1111/j.1472-8206.2008.00627.x
ORIGINAL
ARTICLE
Solanum indicum ssp. distichum extract is
effective against
L
-NAME-induced
hypertension in rats
Ashraf Bahgat
a
, Heba Abdel-Aziz
b
, Mohamed Raafat
a
, Amina Mahdy
a
,
Aiman S. El-Khatib
a
, Ahmed Ismail
c
, Mohamed T. Khayyal
a
*
a
Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
b
Department of Pharmacology, Faculty of Pharmacy, Sinai University, El-Arish, Egypt
c
Sekem Academy, 3 Cairo-Belbeis-Desert Road, Cairo, Egypt
INTRODUCTION
Solanum indicum ssp. distichum (Schumach. and Thonn.),
also known as Solanum anguivi (Lam.) or African
nightshade or bitter berries is cultivated for culinary
purposes in many parts of Africa and the Arabian
Peninsula, where the fruits are used as nutritious
vegetables, as they contain appreciable amounts of
starch, calcium, vitamin A, ascorbic acid and phosphate.
The fruits have been shown to contain steroidal glyco-
sides [1–3] and have been claimed in folk medicine to
have an antihypertensive effect [4]. So far, however, no
pharmacological studies have been published to evaluate
this assumed antihypertensive activity. In the present
study, a standardized ethanolic extract of the fruits of
S. indicum ssp. distichum was evaluated experimentally
both for its effectiveness in preventing the development
of hypertension and for its ability to lower blood pressure
in rats with established hypertension. The model of
experimental hypertension chosen was that using N
W
-
nitro-
L
-arginine methylester (
L
-NAME) as an inducing
agent. The model has been used by many authors as a
well-established, dependable screening procedure for
antihypertensive agents [5–7]. The acute toxicity of the
Keywords
antihypertensive agents,
chlorogenic acids,
herbal medicinal product,
L
-NAME,
Solanum anguivi,
Solanum indicum ssp.
distichum
Received 14 January 2008;
revised 17 April 2008;
accepted 20 June 2008
*Correspondence and reprints:
mtkhayyal@gmail.com
ABSTRACT
Solanum indicum ssp. distichum is used as a vegetable in some parts of Africa and
claimed in folk medicine to guard against cardiovascular disorders. It was of interest
to study the potential blood pressure lowering effects of a standardized extract of the
fruit. An ethanolic extract of the fruit, standardized to contain > 0.15% chlorogenic
acids, was tested orally in both normotensive rats and in those rendered hypertensive
by twice daily intraperitoneal injection of N
W
-nitro-
L
-arginine methylester (
L
-NAME)
for 1 week. The extract was either given at the same time as
L
-NAME or after the
establishment of hypertension. The systolic blood pressure (SBP) was measured non-
invasively using a tail cuff computer-aided monitoring device. Treatment of
normotensive rats with the extract (30–300 mg/kg) for 4 weeks showed no
hypotensive effect. Giving the extract (100 and 300 mg/kg) orally once daily during
the 1 week hypertension induction period with
L
-NAME prevented the development
of hypertension. Administration of the extract orally for 1 week after the establish-
ment of hypertension tended to normalize the blood pressure. Pharmacological
evidence for the antihypertensive activity of S. distichum is hereby reported for the
first time. The extract showed good prophylactic as well as curative effect against
L
-NAME-induced hypertension, whereby its content of chlorogenic acids may play a
minor role. Other constituents may be responsible for the antihypertensive action.
The findings support further development of the extract as a potential therapeutically
useful antihypertensive agent.
ª2008 The Authors Journal compilation ª2008 Socie
´te
´Franc¸aise de Pharmacologie et de The
´rapeutique
Fundamental & Clinical Pharmacology 22 (2008) 693–699 693
extract was also determined in order to give some
indication of its safety.
MATERIALS AND METHODS
Animals
Adult male albino mice each weighing 25–30 g were used
for determination of acute toxicity. Adult male albino
Wistar rats, each weighing 200–250 g were used for the
rest of the experiments. All animals were obtained from
the Modern Veterinary Office for Laboratory Animals,
Cairo, Egypt and kept to acclimatize to standard animal
house conditions (Faculty of Pharmacy, Cairo University)
for at least 1 week before assignment to an experimental
protocol. They were provided with the standard pellet diet,
given water ad libitum and kept at a temperature of
22 ± 3 C and a constant relative humidity throughout
the experimental protocol. The study was carried out
according to The European Communities Council Direc-
tive of 1986 (86/609/EEC) and approved by the Ethical
Committee for Animal Experimentation at the Faculty of
Pharmacy, Cairo University.
Drugs and chemicals
A powdered ethanolic extract of S. distichum fruits was
supplied by Sekem Academy, Cairo, Egypt. It was
standardized by high-performance liquid chromato-
graphy (HPLC) to contain not less than 0.15% chloro-
genic acid. The extract was shown to have a total
alkaloid content of 0.2%, as determined spectrophoto-
metrically by Sreevidya and Mehrotra [8] and a potas-
sium content of 1.9%. For administration to animals, a
suspension of the extract in saline was freshly prepared
immediately before use.
L
-NAME was obtained from
Sigma-Aldrich (St. Louis, MO, USA) and was freshly
prepared in normal saline before administration. The kit
for determination of nitric oxide (NO) metabolites
(nitrate and nitrite) was obtained from R&D Systems,
GmbH (Wiesbaden, Germany).
Acute toxicity
The acute toxicity of the extract was tested in mice by
both oral and intraperitoneal routes. The extract was
given in doses of 8, 16, 32, 64, 128, 256, 512, 1024
and 2048 mg/kg body weight to groups of mice, each of
10 animals. For oral toxicity testing, food was withheld
from the animals overnight before administration of the
extract. The extract was freshly prepared by suspending
it in saline to provide a concentration allowing the
injection of each dose in a volume not exceeding 0.1 mL/
10 g body weight of mouse. Mortality was assessed over
two consecutive days.
Blood pressure measurement
Systolic blood pressure (SBP) and heart rate were
measured non-invasively in conscious animals using a
tail cuff and a computer-assisted monitoring device
(model V2.1; TSE Systems, Bad Homburg, Germany).
The animals were let in a chamber kept at 30C for
15–30 min to allow reproducible blood pressure mea-
surements (four to five measurements per animal per
session). All blood pressure measurements were carried
out at the same time of day. The rats were trained for
2 weeks to let them get used to the restrainer and tail
cuff measurement before starting any experiment.
Effect of extract on normotensive animals
The SBP of normal rats was measured as described
above. The extract was then given by oral gavage daily
for 4 weeks to three groups of animals in doses of 30,
100 and 300 mg/kg, while an additional control group
received a gavage of saline. The SBP and heart rate of the
treated rats were measured after 1, 2 and 4 weeks from
initiation of treatment. The body weights of the animals
were determined at the beginning and at the end of the
experimental period.
Induction of hypertension
Animals were rendered hypertensive by the intraperito-
neal injection of
L
-NAME twice daily for 1 week in a dose
of 185 lmol/kg [9]. By the end of that period, the
animals showed a significant rise in SBP.
Prophylactic antihypertensive effect
In order to investigate the potential usefulness of the
extract in preventing the development of hypertension
induced by
L
-NAME, rats were divided blindly into the
following groups (eight animals each):
Normal control group: Animals received no L-NAME and
no extract medication, but were given an oral gavage of
physiological saline (0.2 ml) every day for 1 week.
Hypertensive control group: Animals were rendered hyper-
tensive by treatment with
L
-NAME for 1 week as
described above.
Hypertensive treated groups: Two groups of animals
were treated with
L
-NAME as described above, in
addition to the concomitant administration of the
extract in daily oral doses of either 100 or 300 mg/kg
for 1 week.
694 A. Bahgat et al.
ª2008 The Authors Journal compilation ª2008 Socie
´te
´Franc¸aise de Pharmacologie et de The
´rapeutique
Fundamental & Clinical Pharmacology 22 (2008) 693–699
The SBP and heart rate of all animals, as well as their
body weight, were recorded as described previously at
the beginning and at the end of the experimental period.
Effect in hypertensive rats
In order to study whether or not the extract is capable of
reducing the blood pressure of rats with established
hypertension, rats were first rendered hypertensive as
described above before being treated with the extract.
The hypertensive animals were allocated to the following
groups of eight rats each:
Hypertensive control group: The hypertensive rats were
maintained on
L
-NAME for a further week, and were given
an oral gavage of physiological saline (0.2 ml) every day.
Hypertensive treated groups: Treatment of the hyperten-
sive rats with S. distichum extract in oral doses of 1, 10,
30 or 100 mg/kg body weight was started and contin-
ued daily for 1 week, while still maintaining them on
L
-NAME intraperitoneally during that time.
A separate group of eight animals served as normal
controls and received only saline for the entire experi-
mental period (2 weeks). The SBP and heart rate of all
animals were recorded after 1 and 2 weeks from the start
of the experiment. The ‘normalization’ of the high blood
pressure was calculated as follows:
At the end of the experimental period, the rats were
killed and samples of blood were withdrawn to obtain
serum for the estimation of nitric oxide using a color-
imetric assay kit.
Data analysis and statistics
Data in graphs and tables are presented as mean values
of nanimals ± SEM, where nindicates the number of
animals studied. Comparison between the mean values
of different groups was carried out by one-way analysis
of variance (
ANOVA
), followed by Tukey–Kramer post hoc
test for multiple comparisons.
RESULTS
Acute toxicity
Oral and intraperitoneal administration of the extract in
doses up to 2.048 g/kg body weight produced no
mortality and no signs of morbidity or behavioural
changes in any of the animals of the treated groups
during the 2 days of observation following extract
administration.
Effect of extract on normotensive animals
The extract did not seem to have any appreciable
hypotensive effect on normotensive animals in the doses
tested. There was no significant difference in blood
pressure between the rats taking the extract and those
taking the vehicle. A small transient drop in blood
pressure of about 10% was observed with a dose of
100 mg/kg after 2 weeks of treatment, but the effect was
not sustained (Table I). No effects were observed on heart
rate or body weight of treated animals when compared
with control animals (data not shown).
Effect of extract in preventing the development
of
L
-NAME-induced hypertension
The administration of
L
-NAME intraperitoneally for
1 week elevated significantly the SBP of rats from a mean
of 124 mmHg in control animals to 169 mmHg, indicat-
ing a rise of blood pressure by 36.3% (Table II). Treatment
with either of the two doses of S. distichum extract, given
simultaneously with
L
-NAME, prevented the significant
rise in blood pressure induced by the latter. There was no
significant difference in the effectiveness of the two doses
used in lowering the blood pressure. The hypertension
induced by
L
-NAME was associated with a 12% lowering
of the heart rate, which dropped from about 320 to about
280 beats/min after induction of hypertension. Although
treatment with the extract at any of the two dose levels
prevented the rise in blood pressure of the treated rats,
such treatment did not appreciably affect the slowing of
the heart rate (Table II). The rate of growth of the rats was
Table I Effect of S. distichum extract on the systolic blood pressure
of normotensive rats.
Pre-treatment Week 1 Week 2 Week 4
Control 120.7 ± 4.1 115.5 ± 3.0 113.5 ± 3.4 116.2 ± 4.8
30 mg/kg 120.0 ± 3.7 112.1 ± 3.5 115.0 ± 2.3 116.6 ± 5.0
100 mg/kg 120.3 ± 3.8 116.6 ± 3.6 101.2 ± 3.4* 108.0 ± 5.4
300 mg/kg 120.5 ± 3.0 116.0 ± 3.9 112.3 ± 3.2 114.6 ± 5.0
The extract was given orally daily for 4 weeks at different dose levels.
Values represent the mean ± SEM of eight animals in each group.
*Significant difference from corresponding control values at P< 0.05.
% normalization ¼ðSBP of hypertensive control SBP of treated groupÞ
ðSBP of hypertensive control SBP of normal controlÞ100:
Solanum indicum in
L
-NAME-induced hypertension 695
ª2008 The Authors Journal compilation ª2008 Socie
´te
´Franc¸aise de Pharmacologie et de The
´rapeutique
Fundamental & Clinical Pharmacology 22 (2008) 693–699
not affected by the administration of
L
-NAME or the
extract within the experimental period (data not shown).
Effect of the extract in reducing SBP in
hypertensive rats
Treatment of rats with
L
-NAME twice daily intraperito-
neally induced a significant rise in SBP within 1 week of
administration, which continued to rise when treatment
was continued for a further week (Figure 1). Oral daily
administration of the extract at different dose levels was
commenced after 1 week of
L
-NAME treatment and was
continued for a further week, while maintaining the
animals on
L
-NAME during that period. There was a
dose-dependent drop in SBP after treatment with the
extract, reaching 45% normalization of the elevated
blood pressure with the 1 mg/kg dose and 73% normal-
ization with the 30 mg/kg dose. A further increase in the
dose of the extract up to 100 mg/kg did not further
enhance its antihypertensive effect (Figure 2).
Samples of blood from treated animals showed that the
administration of
L
-NAME for 2 weeks led to a dramatic
lowering of serum total nitrite concentration. After
1 week of treatment with the higher doses of the extract,
there was a tendency, albeit statistically non-significant,
to offset this effect. Thus, normalization of serum nitrite
concentration reached only 12% with the 30 mg/kg
dose of the extract but rose to nearly 22% with the
100 mg/kg dose (Figure 3).
DISCUSSION
Hypertension is a primary risk factor for stroke, heart
disease and renal failure, and remains one of the most
critical issues for human health. Both lifestyle and
hereditary factors are known to be related to the
development of hypertension, including food habits.
Many foods as well as herbal remedies are claimed by
those practising folk medicine to be effective in the
prevention and/or treatment of this serious disease.
The aim of the present study was to evaluate the
antihypertensive effects of S. indicum ssp. distichum fruits,
used in several African countries as vegetables and
claimed by those practising folk medicine to have
Table II Effect of 1-week concomitant treatment with S. distichum
extract and
L
-NAME on the heart rate and systolic blood
pressure (SBP) of Wistar rats.
Group Heart rate (bpm) SBP (mmHg)
Normotensive control 321.0 ± 7.3 124.0 ± 2.0
Hypertensive control 281.0 ± 7.3* 169.0 ± 7.3*
S. distichum (100 mg/kg) 298.0 ± 8.6 139.0 ± 6.5
S. distichum (300 mg/kg) 278.0 ± 13.8* 142.0 ± 4.2*
The extract was given simultaneously with
L
-NAME in oral daily doses of 100
and 300 mg/kg.
Values represent the mean ± SEM of eight animals.
*Significant difference from corresponding normotensive control values at
P< 0.05.
Significant difference from corresponding hypertensive control values at
P< 0.05.
*
*#
*#
##
100
110
120
130
140
150
160
170
180
Normal
control
0 1 10 30 100
Dose of S. distichum extract (mg/kg)
SBP (mmHg)
Figure 1 Effect of 1 week of treatment with S. distichum extract on
the SBP of
L
-NAME-induced hypertensive rats. Rats were treated
with
L
-NAME for 1 week (grey columns) then given the extract
orally for a further week together with
L
-NAME (black columns).
Control animals received only normal saline instead of
L
-NAME for
the same periods of time. Each column represents the mean of six to
eight experiments with vertical bars indicating SEM. *Significant
difference from corresponding normotensive control values at
P< 0.05;
#
significant difference from corresponding hypertensive
control values at P< 0.05.
Dose of S. distichum extract (m
g
/k
g
)
0 1 10 30 100
Percentage normalization
0
20
40
60
80
100
Figure 2 Dose-normalization response curve of S. distichum extract
on the SBP of
L
-NAME hypertensive animals. The percent normal-
ization was calculated as mentioned in the text (Materials and
methods).
696 A. Bahgat et al.
ª2008 The Authors Journal compilation ª2008 Socie
´te
´Franc¸aise de Pharmacologie et de The
´rapeutique
Fundamental & Clinical Pharmacology 22 (2008) 693–699
antihypertensive effects. This claim, however, was not
based on any pharmacological evidence to date. As these
fruits, like other Solanum species, contain glycoalkaloids,
a class of compounds known to cause some adverse
effects [10,11], and as the extract was shown to have a
total alkaloid content of 0.2%, it was considered neces-
sary to determine the acute toxicity of the tested extract
as a preliminary measure of its safety and to ensure its
lack of overt adverse effects. The extract demonstrated a
good safety profile as indicated by the lack of mortality
and morbidity at doses up to 2 g/kg given acutely by the
oral and intraperitoneal routes, as well as the absence of
any behavioural changes during the 48 h following
administration. However, as hypertension is a chronic
disease, requiring long-term treatment, further investi-
gations of the extract’s sub-chronic and chronic toxicities
would be needed.
For testing the antihypertensive activity of the extract,
the experimental model of hypertension using intraperi-
toneal administration of
L
-NAME was used [9]. The
present findings showed that the S. distichum extract had
no effect on the blood pressure or heart rate of
normotensive animals in daily doses up to 300 mg/kg
during the 4 weeks of administration. However, it
showed definite prophylactic activity in effectively pre-
venting the rise in SBP induced by
L
-NAME, when both
agents were given concomitantly in doses of 100 and
300 mg/kg body weight. Both these doses of the extract
exerted about the same degree of prophylactic activity.
The fact that the 100 mg/kg dose almost completely
prevented the rise in blood pressure induced by
L
-NAME
may suggest that the extract even exerts prophylactic
activity at lower dose levels. This could explain the
traditional use of S. distichum in some African countries
as a vegetable to ensure good health [4].
L
-NAME is known to influence nitric oxide synthesis in
the endothelium and to induce changes in endothelial
responsiveness to vasoactive mediators. Its continued
administration was found to induce development of
marked hypertension by a set of different mechanisms,
including lack of tonic vasodilatation, activation of the
renin–angiotensin system, activation of the sympathetic
nervous system, as well as interference with calcium
channels and arachidonic acid derivatives [12–17].
L
-NAME-induced hypertension may also be associated
with the generation of free oxygen species [18]. Evidence
shows that oxidative stress induced by glutathione
depletion can cause severe hypertension in normal rats
associated with disturbance in the NO system [19], and
that this can be overcome by the administration of free-
radical scavengers. It is thus clear that agents that can
decrease blood pressure in
L
-NAME-induced hyperten-
sion, like the investigated extract, could do so in more
ways than one.
The constituents of S. distichum that could have
antihypertensive properties have not all been identified
yet. One constituent which has been previously reported
to possess antihypertensive properties is chlorogenic acid
[20–24]. However, the lowest concentration of chloro-
genic acids reported in the literature to have an
antihypertensive effect in spontaneously hypertensive
rats was 50 mg/kg, which is much higher than the
concentration in the doses of the extract tested here. In
the present findings, doses as low as 1 mg/kg of the
extract (corresponding to 1.5lg/kg chlorogenic acid)
showed a statistically significant antihypertensive effect.
This discrepancy in dose effect cannot be merely attrib-
uted to the difference in the models of hypertension used.
Accordingly, it is very unlikely that the observed effects
of the extract to guard against the development of
hypertension, or to normalize an already established
condition, could solely be attributed to chlorogenic acids.
In fact, the antihypertensive effect of the latter was
shown to be associated with improved NO bioavailability
and reduced oxidative stress [21]. Suzuki et al. [21]
showed that the non-selective nitric oxide synthase (NOS)
inhibitor,
L
-NAME, was able to block the antihypertensive
*
*
*
0
10
20
30
40
50
60
70
Normal control 0 30 100
Dose of S. distichum extract (mg/kg)
Serum total nitrite (µmol/L)
Figure 3 Effect of 1 week of treatment with S. distichum extract on
serum total nitrite concentration of
L
-NAME-induced hypertensive
rats. Rats were treated with
L
-NAME for 1 week then given the
extract orally for a further week together with
L
-NAME. Control
animals received only normal saline for 2 weeks. Each column
represents the mean of six to eight experiments with vertical bars
indicating SEM. *Significant difference from corresponding normo-
tensive control values at P< 0.05. There was no statistical
difference between the values of the hypertensive untreated and
treated groups.
Solanum indicum in
L
-NAME-induced hypertension 697
ª2008 The Authors Journal compilation ª2008 Socie
´te
´Franc¸aise de Pharmacologie et de The
´rapeutique
Fundamental & Clinical Pharmacology 22 (2008) 693–699
response to chlorogenic acids in spontaneously hyperten-
sive rats (SHR), suggesting that their antihypertensive
effect was associated with an effect on NOS. In the present
study, the total nitrite concentration in the plasma of
treated and hypertensive animals was determined as a
measure of NO concentration. Hypertensive animals
showed a marked reduction in serum nitrite concentra-
tion, but although the extract tended to offset this
lowering to some extent, the effect was statistically non-
significant and too weak to account for the observed
antihypertensive response. Thus, even if chlorogenic acids
are known to improve NO bioavailability [21], this finding
would support the argument that chlorogenic acids are
unlikely to be solely responsible for the observed anti-
hypertensive activity of the extract. The fact that
chlorogenic acids have been used as a means of standard-
ization of the extract does not imply that they are
responsible for the pharmacological activity of the extract.
Treatment of rats with established
L
-NAME hyper-
tension for 1 week with the extract showed a marked
tendency towards normalization, with a nearly maximal
effect in doses of 30 mg/kg, showing that under these
experimental conditions, a ceiling effect was reached with
that dose. Longer treatment periods may have produced
better normalisation of the blood pressure. Interestingly,
this anti-hypertensive effect was not accompanied by a
reversal in
L
-NAME-induced bradycardia.
In view of the above, the role of chlorogenic acids in
the investigated extract (0.15%) is too small to account
for the antihypertensive effect of the extract. Other
constituents in the extract may enhance its activity, or
may have other antihypertensive properties in their own
right. As is often the case with herbal extracts, it is
sometimes difficult to attribute an overall activity to a
single component, but rather to the extract as a whole.
High-potassium diets have been shown to lower the
blood pressure of spontaneously hypertensive [25,26]
and desoxycorticosterone acetate (DOCA) salt-loaded
rats [27]. However, the potassium concentration in the
doses used is too low to account for the observed
antihypertensive effect. Further studies are being carried
out to determine the possible involvement of the renin–
angiotensin aldosterone system, and to test the effect of
the extract on vascular reactivity, in an attempt to gain
more insight into its mechanism of action.
CONCLUSION
It may be concluded that the standardized S. distichum
extract tested in the present study shows promising
antihypertensive properties against the
L
-NAME model of
hypertension associated with low toxicity. Further work
is being carried out to establish its antihypertensive
activity in other models of experimental hypertension
and to try to elucidate its mechanism of action, which
does not seem to involve changes in serum nitrite.
ACKNOWLEDGEMENTS
This work was supported by the Sekem Group, Cairo,
Egypt.
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