Comparative evaluation of antidiabetic antihypertensive activity of Cynodon dactylon L. and Phyllanthus niruri L in ratswith simultaneous type 2 diabetic and hypertension

Abstract

In recent years, the use and search for drugs and dietary supplements derived from plants have accelerated in the treatment of diabetes and hypertension because of the hazardous adverse effects of the current therapy. A comparison was made between the antidiabetic-antihypertensive activities of aqueous extracts of leaves of Cynodon dactylon and Phyllanthus niruriin rats with simultaneous type 2 diabetic and hypertension. The aq. extracts of leaves of Cynodon dactylon (200mg/kg/day)and Phyllanthus niruri (600mg/kg/day) was administered orally in Diabetic Control (DC), SHR and Diabetic-SHR (D-SHR). Body weight of animals were measured weekly throughout the study (28 days). Blood glucose level and total cholesterol level was measured at day 0 after induction of diabetes and at day 28. Arterial blood pressure of all the groups was measured at day 14 and day 28 by tail cuff method. Serum glutamic oxaloacetic transaminase (SGOT) levels in all the groups were measured at the end of experiment. No loss in the weight of animal was observed in the group treated with the aqueous herbal extracts. The study showed that herbal extracts prevented attenuation of the blood glucose and total cholesterol levels; significant decrease in mean arterial blood pressure (MABP) and decrease in SGOT level. The findings of the study support the traditional use of C. dactylon and P. niruri for the treatment of diabetes and arterial hypertension, and indicate that they may have a beneficial effect in patients with co-existing diabetic hypertension.

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Comparative evaluation of antidiabetic antihypertensive activity of Cynodon
dactylon L. and Phyllanthus niruri L in ratswith simultaneous type 2 diabetic
and hypertension
Deepak Bharati*
1
, Swati Rawat
2
, Pankaj Sharma
3
and Birendra Shrivastava
3
1
Dept. of Pharmacology, St John Institute of Pharmacy and Research, Palghar (E), Dist-Palghar, Maharashtra,
India
2
S. N. D. College of Pharmacy, Tal-Yeola, Dist- Nashik, Maharashtra, India
3
School of Pharmaceutical Sciences, Jaipur National University, Jaipur, Rajasthan, India
_____________________________________________________________________________________________
ABSTRACT
In recent years, the use and search for drugs and dietary supplements derived from plants have accelerated in the
treatment of diabetes and hypertension because of the hazardous adverse effects of the current therapy. A
comparison was made between the antidiabetic-antihypertensive activities of aqueous extracts of leaves of Cynodon
dactylon and Phyllanthus niruriin rats with simultaneous type 2 diabetic and hypertension. The aq. extracts of
leaves of Cynodon dactylon (200mg/kg/day)and Phyllanthus niruri (600mg/kg/day) was administered orally in
Diabetic Control (DC), SHR and Diabetic-SHR (D-SHR). Body weight of animals were measured weekly throughout
the study (28 days). Blood glucose level and total cholesterol level was measured at day 0 after induction of
diabetes and at day 28. Arterial blood pressure of all the groups was measured at day 14 and day 28 by tail cuff
method. Serum glutamic oxaloacetic transaminase (SGOT) levels in all the groups were measured at the end of
experiment. No loss in the weight of animal was observed in the group treated with the aqueous herbal extracts.
The study showed that herbal extracts prevented attenuation of the blood glucose and total cholesterol levels;
significant decrease in mean arterial blood pressure (MABP) and decrease in SGOT level. The findings of the study
support the traditional use of C. dactylon and P. niruri for the treatment of diabetes and arterial hypertension, and
indicate that they may have a beneficial effect in patients with co-existing diabetic hypertension.
Key words: Diabetic hypertension, Cynodon dactylon, Phyllanthus niruri, Spontaneously hypertensive rats,
Streptozotocin,
_____________________________________________________________________________________________
INTRODUCTION
Diabetes mellitus (DM) and hypertension (HTN) have emerged as major medical and public health issues
worldwide, and both are important risk factors for coronary artery disease (CAD), heart failure, and cerebrovascular
disease. DM is increasing in epidemic proportions globally [1]. DM exerts a significant burden resulting in increased
morbidity and mortality, decreased life expectancy, and reduced quality of life, as well as individual and national
income losses. Additionally, HTN affects about one billion people worldwide [2] and it is estimated that by 2025, up
to 1.56 billion adults worldwide will be hypertensive [3]. Raised blood pressure (BP) is estimated to cause 7.5
million deaths.

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DM and HTN are also known to coexist in patients [4]. Indeed, there is a strong correlation between changing
lifestyle factors and increase in both DM and HTN. The presence of hypertension in diabetic patients substantially
increases the risks of coronary heart disease, stroke, nephropathy and retinopathy. For all these considerations,
therapeutic interventions should target all the risk factors, including blood glucose levels and arterial hypertension.
In this context, many studies have demonstrated the ability of phytotherapy to significantly decrease plasma glucose
level and blood pressure, in addition to the conventional hypoglycemic agents and hypotensive drugs used in the
treatment of T2DM and arterial hypertension.
Since from ages, plants have been the main source of medicines for human beings. Plants contain various
phytochemicals which can play an important role in reducing occurrence of several diseases by boosting up various
organ functions. Numerous traditional healing herbs and their parts have been shown to have medicinal value and
can be used to prevent, alleviate or cure several human diseases [5]. It is estimated that 70–80 % of people
worldwide rely chiefly on traditional, largely herbal medicine to meet their primary healthcare needs [6,7 ].
Cynodon dactylon (L.) (Family: Poaceae) is a perennial grass, possess various medicinal properties such as
antimicrobial and antiviral activity [8]. Furthermore, the aqueous extract of this plant has anti- inflammatory [9],
diuretic [10], and anti-emetic [11] activity. It has been reported to possess anti-arrhythmic [12], cardioprotective
[13], antioxidant [9], immunomodulatory [14], anti-anaphylactic and mast cell stabilizing [15] activity. Cynodon
dactylon has been used as an Indian traditional medicine for asthma [16]. Leaf, root and rhizome of the plant have
been used in folk medicine in various countries as anticystitis [17], antihysteria, antipsychotic [18] antigonorrheal
infection [19]. The phytochemical studies on Cynodon dactylon revealed the presence of flavonoids, glycosides,
saponins, tannins, carbohydrates and essential oil [20.21]
Phyllanthus niruri L., (Family: Phyllanthaceae) is a little shrub found both in tropical and subtropical countries.
Several species from this genus are used worldwide in folk medicine for diverse therapeutic purposes [22].Various
active constituents to which the biological activity of P. niruri has been attributed include lignans, tannins,
coumarins, terpenes, flavonoids, alkaloids, saponins and phenylpropanoids. These active constituents along with
common lipids, sterols and flavonols are mainly found in the leaves, stem and roots of the plant [23].These all
phytochemicals present in P. niruri exert different pharmacological actions, for example, a) hepatoprotective [23,
24] and anti-viral properties by lignans [25] b) anti-microbial activity by terpenes [26] c) anti-oxidant[27],
antileishmanial [28], andanti-inflammatory activities by flavonoids [29], d)antispasmodic activity,[30] smooth
muscle relaxation effect by alkaloid[ 31]e) aldosereductase inhibitory (ARI) activity [32] by glycosides
(quercitrinand geraniin).
It is desirable to explore the action of herbal medicines for safe and effective management of diabetes
hypertension, a) As the diabetes and hypertension has become a global burden and long term management with
available pharmacological therapy is gradually getting costlier, sometime ineffective as well as associated with
number of side effects, b) As patients have to consume separate medicine for these two diseases though both
diseases are existed in same individual i.e. diabetes hypertensive patients.
Here we report antidiabetic antihypertensive activity of the water extract from leaves of Cynodon dactylon and
Phyllanthus niruri with a view to provide scientific evidence of modern lines in Streptozotocin induced diabetes in
SHR to evaluate and compare their antidiabetic and antihypertensive activity. The effects produced by these extracts
on arterial blood pressure, blood glucose level, and total cholesterol and SGOT level were evaluated.
MATERIALS AND METHODS
Plant material
The fresh aerial parts of leaves of Cynodon dactylon and Phyllanthus niruri were collected from outskirt of Palghar,
Maharashtra, India and authenticated by Agharkar Research Institute, Pune, India. The animal usage protocol was
approved by the IAEC of National Toxicology Centre through Protocol No.38/1415.
Preparation of the aqueous extract
Aerial parts of leaves of C. dactylon and P. niruri were dried under shade and coarsely powdered. Powdered
material was subjected to continuous hot percolation (soxhlation) with distilled water. After the exhaustive

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extraction, the solvent was removed under reduced pressure (Buchi RV-100) using rotary flash evaporator then
finally dried in desiccator.
Animals used
The Male Wistar rats weighing 200-250 grams were procured from in-house animal facility of National Toxicology
Centre, Pune. They were housed under standard conditions of temperature and relative humidity with 12 hr
light/dark cycle. Animals were fed on standard commercial pellet diet and water ad libitum.
Induction of diabetes
Male Wistar rats were kept on fasting overnight and Streptozotocin (Sigma-Aldrich Ltd, Mumbai), 55 mg/kg, in
0.1M citrate buffer, pH 4.5 was administered intraperitoneally (i.p.) for the induction of diabetes [22]. The animals
were bled through the retro orbital plexus and blood was collected in heparinised tube. The plasma glucose was
measured in a biochemical analyzer by GOD/POD method. The rats that developed more than 250 mg/dl of plasma
glucose [23] on the 3
rd
day of induction were selected for the study.
Animal experimentation
In the present study the animals were distributed into 12groups containing six animals each (n=6) in the following
manner:
Group I (NC): Normal Control (0.1 M citrate buffer (pH 4.5)).
Group II (NC-AECD): Normal Control + aq. extract of C. dactylon (200mg/kg/day, p.o.,)
Group III (NC-AEPN): Normal Control + aq. extract of P. niruri (600mg/kg/day, p.o.,)
Group IV (DC): Diabetic Control (STZ injected rats)
Group V: D+AECD (Diabetic rats + aq. extract of C. dactylon 200mg/kg/day, p.o.,).
Group VI: D+AEPN (Diabetic rats + aq. extract of P. niruri 600mg/kg/day, p.o.,).
Group VII: SHR
Group VIII: SHR+AECD (Hypertensive rats + aq. extract of C. dactylon 200mg/kg/day, p.o.)
Group IX: SHR+AEPN (Hypertensive rats + aq. extract of P. niruri 600mg/kg/day, p.o.,).
Group X: D+SHR (Diabetic Hypertensive rats)
Group XI: D+SHR+ AECD (Diabetic Hypertensive + aq. extract of C. dactylon 200mg/kg/day, p.o.)
Group XII: D+SHR+ AEPN (Diabetic Hypertensive rats + aq. extract of P. niruri 600mg/kg/day, p.o.)
The treatment with plant extract (1 ml) was given daily for 28 days using gastric cannula. No detectable irritation or
restlessness and noticeable adverse effect (i.e., respiratory distress, abnormal locomotion or catalepsy) was observed
after extract administration. Throughout the experimental period, the body weight was monitored.The study was
conducted for 28 days to evaluate the potential of the extracts to lower blood glucose level and mean arterial blood
pressure.
Biochemical examination
During 28 days study, blood was withdrawn at an interval of 7 days from the retro orbital plexus under anaesthesia
of the fasted animals. Blood glucose levels were then estimated by GOD/POD method in an auto analyzer using the
commercial enzyme estimation kit (Coral Biosystems, India) besides this, parameters like total cholesterol, SGOT
were monitored by using commercial kit (Coral Biosystems, India).
Blood pressure measurement
Animals were anesthetized with Ketamine/Xylazine (1:1). Mean arterial blood pressure (MABP) was recorded by
tail-cuff method (ADInstruments ML125 NIBP PowerLab), at 14
th
day and 28
th
day upto end of the study and
expressed as mm Hg.
Statistical analysis
Data were expressed as mean ± SEM of six observations. Statistical analysis was done using one-way analysis of
variance followed by post-hoc test, Bonferrani’s test by using Graph pad Prism 5 version. Statistical significance
was considered at p< 0.05.

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RESULTS
Effect on body weight
The control animals showed a linear proportion of growth in terms of weight whereas the untreated diabetic, SHR
and Diabetic SHR rats were found to have significant weight loss. However, Administration of two extracts for 28
days were able to correct this aberration significantly (p<0.05). The results of all the extracts tested are presented in
Fig1.
Fig.1- Effect of aqueous extract of C. dactylon and P. niruri on body weight of rats
Data were analysed by one way ANOVA followed by Bonferrani’s test. Values are represented as mean ± S.E.M. (n=6);
Fig. 2- Effect of aqueous extract of C. dactylon and P. niruri on blood glucose
Data were analysed by one way ANOVA followed by Bonferrani’s test. Values are represented as mean ± S.E.M. (n=6);
a
Value significantly
different from NC,(p< 0.05);
b
Value significantly different from DC, (p< 0.05);
c
Value significantly different from D-SHR, (p< 0.05);
Effects on blood glucose
Streptozotocin induced diabetic rats showed a 73.60% rise in the plasma glucose levels as compared to normal
control group. Treating those hyperglycemic rats with aqueous extract of C. dactylon (200 mg/kg) and P. niruri (600
mg/kg) resulted in significant reduction in the plasma glucose level (p< 0.05) which came at par with the normal
control animals at the end of 28 days study. On the other hand the diabetic control animals which received no

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treatment continued to show high plasma glucose throughout the study (Fig.2).Plasma glucose levels observed at 0
and 28 days after treatment with aq. extract of C. dactylon and P. niruri in hypertensive rats was almost similar to
that of pretreatment levels.
Effects on total cholesterol
Total cholesterol level were found to be significantly (p<0.05) increased in the vehicle treated diabetic group in
comparison with the control group. Treatment with two extracts for a 28 days significantly attenuated (p<0.05) the
elevated total cholesterol level in comparison with the vehicle treated diabetic rats given in Fig.3. Total cholesterol
levels observed at 0 and 28 days after treatment with aq. extract of C. dactylon and P. niruri in hypertensive rats was
almost similar to that of pretreatment levels.
Fig.3- Effect of aqueous extract of C. dactylon and P. niruri on total cholesterol
Data were analysed by one way ANOVA followed by Bonferrani’s test. Values are represented as mean ± S.E.M. (n=6);
a
Value significantly
different from NC,(p< 0.05);
b
Value significantly different from DC, (p< 0.05);
c
Value significantly different from D-SHR, (p< 0.05);
Fig.4- Effect of aqueous extract of C. dactylon and P. niruri on mean arterial blood pressure
Data were analysed by one way ANOVA followed by Bonferrani’s test. Values are represented as mean ± S.E.M. (n=6);
a
Value significantly
different from NC, (p< 0.05);
b
Value significantly different from DC, (p< 0.05);
c
Value significantly different from SHR, (p< 0.05);
d
Value
significantly different from D-SHR, (p< 0.05); after 14 days and 28 days treatment.

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Effects on blood pressure
In present study, mean arterial blood pressure of SHR reaches upto 161.2 ± 2.120mmHg. Concomitant
administration of aq. extract of C. dactylon (200 mg/kg) and aq. extract of P. niruri (600mg/kg) for 28 days
decreases blood pressure as depicted in Fig.4. Mean arterial blood pressure reaches upto 166.5 ± 1.875 mmHg in
SHR treated with Streptozotocin. Administration of aq. extract of herbal drugs for 28 days prevented the increase in
mean arterial blood pressure in diabetic hypertensive group (D+SHR) as shown in Fig. 4.
Effects on SGOT
The effect of repeated oral administration of aq. extract of C. dactylon (200 mg/kg) and P. niruri (600mg/kg) for 28
days on SGOT in severe diabetic, SHR and D - SHR is presented in Fig.5. Serum glutamic oxaloacetic (SGOT)
level decreased dynamically in D-SHR-AECD and D-SHR-AEPN, (p< 0.05) after challenge with herbal extracts for
28 days. SGOT level reached peak during the study in SHR and D-SHR groups.
Fig.5- Effect of aqueous extract of C. dactylon and P. nirurion SGOT at day 28
Data were analysed by one way ANOVA followed by Bonferrani’s test. Values are represented as mean ± S.E.M. (n=6);
a
Value significantly
different from NC, (p< 0.05);
b
Value significantly different from DC, (p< 0.05);
c
Value significantly different from SHR, (p< 0.05);
d
Value
significantly different from D-SHR, (p< 0.05);
DISCUSSION
It is desirable to explore the action of herbal medicines for safe and effective management of Diabetes Hypertension
as a cost effective complementary therapies.
In the present study, the aqueous extracts of Cynodon dactylon and Phyllanthus niruri were investigated for its
antidiabetic-antihypertensive activity in diabetic hypertensive rats. The STZ-treated spontaneously hypertensive rat
(SHR) has been extensively used an example of animal model where hypertension and diabetes occur
simultaneously [33,34]. STZ-treated SHR (D-SHR) develop a hyperglycaemic syndrome, associated with other
biochemical and morphological changes that to some extent approach insulin-dependent diabetes mellitus combined
with hypertension [34]. Advantages of animal studies in the examination of alternative medicines and their efficacy
include the ability to define experimental conditions more tightly and to undertake more detailed studies of the
biologic effects of the agents being used. The mechanisms by which Streptozotocin brings about its diabetic state
include selective destruction of pancreatic insulin secreting β- cells, which make cells less active and lead to poor
glucose utilization by tissues [35].
In the present study, the administration of STZ to normal and spontaneously hypertensive rats effectively induced
diabetes as reflected by glucoseurea, hyperglycemia and loss in body weight. The two plants extracts treatment
showed as significant antihyperglycemic effects. But none of these extracts could produce any hypoglycemic effect
in normal rats. The experimental results indicated that the aq. extracts of Cynodon dactylon and Phyllanthus
niruriexhibited a potent blood glucose lowering property in diabetic rats and diabetic hypertensive rats (D-SHR).
The capacity of plant extracts to decrease the elevated blood glucose level near to normal glycogenic level is an

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essential trigger for the liver to revert to its normal homeostasis during experimental diabetes. These results
suggested that one of the possible mechanisms by which C. dactylon and P. niruri extracts bring about their
antihyperglycemic action is due to inhibition of hepatic glycogen degradation.
Induction of diabetes with STZ is associated with the characteristic loss of body weight, which is due to increased
muscle wasting and due to loss of tissue proteins [36]. Diabetic rats and diabetic hypertensive rats (D-SHR) treated
with the plant extracts showed significant gain in body weight as compared to the diabetic control, which may be
due to its protective effect in controlling muscle wasting (i.e. reversal of gluconeogenesis and glycogenolysis) and
may also be due to the improvement in insulin secretion and glycogenic control. Insulin deficiency leads to various
metabolic aberrations, namely increase blood glucose, decreased protein content and increased levels of cholesterol
and triglyceride [37].
Results from present study have shown that MABP was significantly elevated in DC by about 30 % compared to
non-diabetic control group whereas it was very slightly increased in D-SHR by about 3 % compared to non-diabetic
SHR. The increase in MABP following induction of diabetes in rats was in good agreement with a previous study
[38]. Common observations in the clinic are diabetes patients generally have higher MABP than non-diabetic
patients [39], but it is not clear why not in diabetic SHR. It may reflect the presence of a compensatory response that
opposes elevation of MABP in the underlying state of hypertension following induction of diabetes but clearly needs
further study.
Diabetic hypertensive rats treated with aqueous extract of C. dactylon and P. niruri exhibited significant decrease in
MABP compared with diabetic control, SHR and D-SHR.Significant(p< 0.05) decrease in mean arterial blood
pressure by about 10.7% in diabetic rats, 12% in SHR, 22% in diabetic SHR respectively after 28 days treatment
with aqueous extract of C. dactylon (200mg/kg of body weight) was observed. MABP was significantly decreased
(p< 0.05) by about 13.47 % in aqueous extract of P. niruri (600 mg/kg body weight) treated group compared with
SHR group, 20.85 % in aqueous extract of P. niruri treated group compared with D-SHR group [40]. Decline in
mean arterial blood pressure in diabetic rats treated with aqueous extract of P. niruri was not significant.
SGOT is an enzyme found mainly in heart muscle, liver cells, skeletal muscle and kidneys. Injury to these tissues
results in the release of the enzyme in blood stream. Elevated levels are found in myocardial infarction, cardiac
operations, hepatitis, cirrhosis, acute pancreatitis, acute renal diseases, and primary muscle diseases. In present
study, administrations of aqueous extracts of C. dactylon and P. niruri shows significant (p< 0.05) decrease in
SGOT level in diabetic and hypertensive animals. This result signifies that aqueous extracts of C. dactylon and P.
niruri protects theorgans from injury or damage due to high blood pressure or myocardial infarction, cardiac
operations, primary muscle diseases.
Altogether the results obtained in vivo indicated that oral treatment with aqueous extracts of C. dactylon and P.
niruri decrease blood pressure of diabetic and hypertensive rats. The hypotension can be correlated to as indicated
by prevention of abnormal vascular reactivity to constrictor and dilator stimuli in the vasculature,reduced MABP.
One important observation was the aqueous extracts of plants did not interfere with the animal growth throughout
the study. This is a positive sign of biosafety of the extract to treat diabetic hypertension without affecting the
normal body functions.
The presences of glycoside, flavonoid, saponins, tannin, sterol and carbohydrate in aqueous extracts ofC. dactylon
and P. niruri, which are known to be bioactive for the management of hypertension and diabetes, may be
responsible for its action. It is well known that certain flavonoids exhibit hypoglycaemic activity and is also known
for their ability of beta cell regeneration of pancreas. Sterols have also shown to decrease blood sugar in
experimental animal models. The cardiac glycosides have also been proved for its cardio-protective and cardio tonic
activity thus, the significant antihypertensive effect of aqueous extracts of C. dactylon and P. niruri may be due to
the presence of more than one antihypertensive principle and their synergistic properties.
To evaluate fast and short-lasting effect of the isolated compounds, new pharmacodynamic and pharmacokinetic
studies of the plant chemical constituents should be developed in contrast with the delayed onset of the hypotension
and the slow washout after oral administration.

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CONCLUSION
The present study was conducted to evaluate the antidiabetic antihypertensive activity of two herbal extracts in
ratswith simultaneous type 2 diabetic and hypertension. After completion of the study protocol, it was found that
with test, the serum level of glucose and total cholesterol improved significantly (p<0.05) as compared to diabetic
control, and in comparative evaluation the two plants found to be safe as they did not shown any sign of acute
toxicity. Meant arterial blood pressure was significantly reduced (p<0.05) in groups treated with herbal plant
extracts compared with control. The aqueous extract of Cynodon dactylon was found to be more efficacious as
compare to aqueous extract of Phyllanthus niruri. Hence, the data of present study provide impetus for further
molecular and mechanistic studies on the therapeutic action of Cynodon dactylon and Phyllanthus niruri extracts,
before they can be considerable as a possible replacement or adjuvant in the management of diabetes hypertension.
Further investigations on identification of the active principles and their mode of action are needed to explore the
molecular mechanisms involved in the observed effects.
Acknowledgements
Authors are thankful to National Toxicological Centre, Pune, India for animal studies, Mr. Albert W. D’souza,
Chairman, Aldel Education Trust and Mr. Thomas Lobo, Campus Director, St. John Educational Campus for their
motivation and support. Dr. Savita J. Tauro, Principal, St John Institute of Pharmacy and Research acknowledged
for proof reading the manuscript.
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