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Attenuation of the Extract from Moringa Oleifera on Monocrotaline-Induced Pulmonary Hypertension in Rats


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The purpose of this study was to determine the effects of an extract from Moringa oleifera (MO) on the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in Wistar rats. An ethanol extraction was performed on dried MO leaves, and HPLC analysis identified niaziridin and niazirin in the extract. PH was induced with a single subcutaneous injection of MCT (60 mg/kg) which resulted in increases in pulmonary arterial blood pressure (Ppa) and in thickening of the pulmonary arterial medial layer in the rats. Three weeks after induction, acute administration of the MO extract to the rats decreased Ppa in a dose-dependent manner that reached statistical significance at a dose of 4.5 mg of freeze-dried extract per kg body weight. The reduction in Ppa suggested that the extract directly relaxed the pulmonary arteries. To assay the effects of chronic administration of the MO extract on PH, control, MCT and MCT+MO groups were designated. Rats in the control group received a saline injection; the MCT and MCT+MO groups received MCT to induce PH. During the third week after MCT treatment, the MCT+MO group received daily i.p. injections of the MO extract (4.5 mg of freeze-dried extract/kg of body weight). Compared to the control group, the MCT group had higher Ppa and thicker medial layers in the pulmonary arteries. Chronic treatments with the MO extract reversed the MCT-induced changes. Additionally, the MCT group had a significant elevation in superoxide dismutase activity when normalized by the MO extract treatments. In conclusion, the MO extract successfully attenuated the development of PH via direct vasodilatation and a potential increase in antioxidant activity.
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Corresponding author: Mei-Jung Chen, Ph.D., Department of Biomedical Engineering, School of Health, Ming Chuan University, No. 5,
De-Ming Road, Gui-Shan Taoyuan 333, Taiwan, ROC. Tel: +886-2-28824564 ext. 3657, Fax: +886-2-28213938, E-mail: meijungchen@
Received: November 3, 2010; Revised: January 31, 2011; Accepted: February 17, 2011.
2012 by The Chinese Physiological Society and Airiti Press Inc. ISSN : 0304-4920.
Chinese Journal of Physiology 55(1): xxx-xxx, 2012 1
DOI: 10.4077/CJP.2012.AMM104
Attenuation of the Extract from Moringa
Oleifera on Monocrotaline-Induced
Pulmonary Hypertension in Rats
Kang-Hua Chen1, 2, Yi-Jui Chen3, 4, Chao-Hsun Yang5, Kuo-Wei Liu6,
Junn-Liang Chang7, 8, Shwu-Fen Pan9, Tzer-Bin Lin10, and Mei-Jung Chen8
1Department of Surgery, Keelung Hospital, Department of Health, Executive Yuan, Keelung
2Department of Nursing, Ching Kuo Institute of Management and Health, Keelung
3Department of Pharmacy, Min-Sheng General Hospital, Taoyuan
4Department of Nursing, Cardinal Tien College of Healthcare and Management, New Taipei City
5Department of Cosmetic Science, College of Science, Providence University, Taichung
6Department of Electronic Engineering, School of Information Technology, Ming Chuan University
7Department of Pathology and Laboratory Medicine, Taoyuan Armed Forces General Hospital
8Department of Biomedical Engineering
9Department of Biotechnology, School of Health, Ming Chuan University, Taoyuan
10Department of Physiology, School of Medicine, China Medical University, Taichung
Taiwan, Republic of China
The purpose of this study was to determine the effects of an extract from Moringa oleifera (MO) on
the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in Wistar rats. An
ethanol extraction was performed on dried MO leaves, and HPLC analysis identified niaziridin and niazirin
in the extract. PH was induced with a single subcutaneous injection of MCT (60 mg/kg) which resulted in
increases in pulmonary arterial blood pressure (Ppa) and in thickening of the pulmonary arterial medial
layer in the rats. Three weeks after induction, acute administration of the MO extract to the rats decreased
Ppa in a dose-dependent manner that reached statistical significance at a dose of 4.5 mg of freeze-dried
extract per kg body weight. The reduction in Ppa suggested that the extract directly relaxed the pulmonary
arteries. To assay the effects of chronic administration of the MO extract on PH, control, MCT and
MCT+MO groups were designated. Rats in the control group received a saline injection; the MCT and
MCT+MO groups received MCT to induce PH. During the third week after MCT treatment, the MCT+MO
group received daily i.p. injections of the MO extract (4.5 mg of freeze-dried extract/kg of body weight).
Compared to the control group, the MCT group had higher Ppa and thicker medial layers in the pulmonary
arteries. Chronic treatments with the MO extract reversed the MCT-induced changes. Additionally, the
MCT group had a significant elevation in superoxide dismutase activity when normalized by the MO extract
treatments. In conclusion, the MO extract successfully attenuated the development of PH via direct
vasodilatation and a potential increase in antioxidant activity.
Key Words: pulmonary hypertension, Moringa oleifera, monocrotaline, superoxide dismutase
Moringa oleifera (MO) belongs to the species
Moringaceae. MO contains several phytochemicals
some of which are of high interest for their medicinal
value. The leaves of MO contain nitrile glycosides
2Chen, Chen, Yang, Liu, Chang, Pan, Lin and Chen
such as niazirin and niazirinin, and mustard oil glyco-
sides such as 4-[(4'-O-acetyl-alpha-L-rhamnosyloxy)
benzyl] isothiocyanate, niaziminin A, and niaziminin
B (5). These glycosides are reported to have hypoten-
sive (5) and antioxidant activities (9). Animal studies
have shown that administration of an extract from
MO for two weeks elevates the level of glutathione
(GSH) in the liver (7) and prevents acetaminophen-
induced liver injury (7). Niaziridin, a nitrile glycoside,
is a bioenhancer for drugs and nutrients, including vi-
tamins A and C (15). Clinically, co-administration of
niaziridin is useful for reducing drug toxicities. There-
fore, in this study we sought to determine the medici-
nal properties of the MO extract.
Pulmonary hypertension (PH), a severe and life-
threatening disease in humans, is characterized by a
significant increase in pulmonary arterial blood pres-
sure (Ppa). To investigate this ailment, animal models
of PH induced by chronic hypoxia exposure (23) or
monocrotaline (MCT) administration (18) have been
established. MCT is a pyrrolizidine alkaloid that is
metabolized in the liver producing a toxic metabolite.
Pulmonary endothelial injury is evident within one
week of MCT administration (11, 12). This pathologic
lesion induces proliferation of smooth muscle cells in
the pulmonary arterial tree (12). Remodeling is the
critical step in the development of PH (12) as smooth
muscle proliferation increases the resistance in the
pulmonary circulation to elevate Ppa (12). Ppa is sig-
nificantly increased two weeks after MCT treatment
and is more severe three weeks post-MCT (2). Pro-
longed elevation of Ppa leads to compensatory right
ventricular hypertrophy (16).
Analysis of lung tissue homogenate has shown
that reactive oxygen species contribute to the de-
velopment of PH (2, 3). Reducing the production of
reactive oxygen species, either in the early or late pe-
riod of MCT-induced PH, successfully attenuates the
development of PH (2, 3). This effect reflects the fact
that oxygen radical scavengers are effective either in
the prevention or in the treatment of PH. The major
consideration of the clinical treatment of PH shall
be in vasodilation. Many of the vasodilators that are
useful for systemic hypertension work poorly for PH.
Inhalation of nitric oxide gas is a common clinical
therapy for PH, but tolerance by patients is poorly
(20). PH is not well understood and is not easily de-
tected or treated. Therefore, one of the purposes of
this study is to find a useful treatment for PH.
Considering the role of reactive oxygen species
in enhancing PH and both the antioxidant and va-
sodilatory properties of the MO extract (7, 9), we hy-
pothesized that the MO extract could reverse the
development of PH. In this study, we examined the
effects of an MO extract on MCT-induced PH. Our
results suggest that the MO extract attenuates PH in
rats via an elevation in antioxidant activity. As far as
we are aware of, this report is the first to demonstrate
the pharmacological benefits of the MO extract in
Materials and Methods
MO Extract
The extract was prepared by Dr. Chao-HsunYang
of Providence University in Taichung, Taiwan. In
brief, fresh leaves of MO were collected from Nan-
tou, Taiwan. Soon after collection, the leaves were
freeze-dried, ground into powder, and stored at -18°C
until further use. The bioactive components of the
herbal powder were then isolated by hexane extraction
(powder:solvent = 1:2 w/v) with constant shaking (50
rpm) at room temperature overnight. The extract was
filtered, and the residue was suspended in hexane to
repeat the extraction process. The filtered fluids were
mixed well and were concentrated under vacuum at
50°C. The concentrate was then freeze-dried as a
powder form and stored at -18°C. Before usage, the
extract was dissolved in ethanol (stock solution was
3 g freeze-dried MO extract/100 ml ethanol). The
working solution was further diluted with double-
distilled H2O.
High Performance Liquid Chromatography (HPLC)
The compounds in the extract from MO were
determined by HPLC (Agilent 1100 series, USA)
using a pre-packed RT 250-4.6 MIGHTYSIL RP-18
GP 5 mm column (4.6 × 250 nm, Kanto Chemical,
Tokyo, Japan) and a 220-nm UV detector. The mobile
phase, composed of methanol:sodium dihydrogen
phosphate-acetic acid buffer (0.1 M, pH 3.8; 20:80),
was used as the eluant at a flow rate of 1.0 ml/min.
Animal Preparation
All the animals were cared for in accordance
with the Guide for the Care and Use of Laboratory
Animals (1996, published by National Academy Press,
2101 Constitution Ave. NW, Washington, DC 20055,
U.S.A.), and experiments were approved by the
Laboratory Animal Care Committee of the School of
Health, Ming Chuan University, and by the Taiwan
Council on Animal Care. We obtained the experi-
mental animals from the animal center of National
Taiwan University.
The schedule of acute treatments and functional
assays is depicted in Fig. 1A. To understand the acute
vasodilatory effects of the MO extract on PH, 6-
week-old male Wistar rats were divided into two
groups: control (n = 26) and MCT (n = 22). Rats in
Moringa Oleifera and Pulmonary Hypertension 3
the control group received a saline injection. For the
MCT group, one bolus of MCT (60 mg/kg) was given
subcutaneously to each rat to induce PH. Neither
activity nor food was restricted in either group of rats.
Various doses of the MO extract were administered
3 weeks following MCT treatment to determine its
acute effects on Ppa.
The schedule of chronic animal treatments and
functional evaluation is depicted in Fig. 1B. To ex-
amine the chronic effects of the MO extract on the de-
velopment of PH, 6-week-old male Wistar rats were
divided into three groups: control (n = 7), MCT (n =
7) and MCT+MO (n = 8). Rats in the control group
each received a saline injection. Rats in the MCT and
MCT+MO groups each received a subcutaneous MCT
injection (60 mg/kg). Rats in the MCT+MO group
received daily i.p. administrations of the MO extract
(4.5 mg of freeze-dried MO extraction/kg) on days
14-20 following MCT injection. All rats were freely
mobile and fed ad libitum. Functional studies were
carried out when the rats were 9 weeks old.
Functional Studies
Acute Vasodilatory Effects of the MO Extract on PH
Ppa was used as the index for PH. Measurements
of Ppa and systemic hemodynamics were carried out
3 weeks after the MCT or saline treatment. Rats in the
control group were monitored for the same period of
time as the MCT group. On the day of the measure-
ments, rats were anesthetized with urethane (1.2 g/kg,
i.p.). After insertion of an endotracheal cannula and
a femoral arterial catheter, a saline-filled catheter
was introduced into the right jugular vein and then ad-
vanced to the right atrium, right ventricle, and finally
to the pulmonary artery. The catheter monitored
acute changes in Ppa. Ppa was measured with a Grass
pressure transducer (P23XL, Grass technologies,
Rhode Island, USA), with its diaphragm located at the
level of the heart, and Ppa was recorded on a Biopac
System (MP35, Biopac, Goleta, CA, USA) (Fig. 2).
Mean Ppa was further calculated according to the
following formula: diastolic pressure + 1/3 pulse
pressure. The systemic mean blood pressure and
heart rate were measured through the right femoral
arterial catheter with a Grass pressure transducer and
Biopac MP35 System recorder, as described for Ppa
measurement and recording. The measurements were
collected when values stabilized after the surgical
procedures. After recording the baseline hemody-
Fig. 1. Time schedules of treatments with the MO extract for analyzing acute and chronic effects of the extract on MCT-induced
pulmonary hypertension (PH). (A) 6-week-old rats in the control and monocrotaline (MCT) groups received saline or an MCT
injection on day 0. Functional studies to test the vasodilatory effects of an extract from moringa olifera (MO) were carried
out on day 21. (B) The control, MCT and MCT+MO groups were designed to analyze the chronic effects of the MO extract on
MCT-induced PH. The injection of saline in the control group, or MCT in the MCT and MCT+MO groups, was carried out
on day 0. The MO extract was given to the MCT+MO group from day 14 to day 20.
(A) Acute effects of the MO extraction on PH
(B) Chronic effects of the MO extract on PH
Animal preparation Functional studies
To collect Ppa data and
tissue samples for
examination and
analysis of SOD activity
MO extract
MCT treatment
MCT treatment
Saline injection
Animal preparation Functional studies
Saline injection
MCT treatment
To test the Ppa responses
to the incremental doses of
Time (days)
Time (days)
4Chen, Chen, Yang, Liu, Chang, Pan, Lin and Chen
namic parameters and the mean Ppa, the effects of
incremental doses of the MO extract (1.5, 4.5 and
15.0 mg of freeze-dried MO extract/kg, i.v.) were
then studied. Each animal received two different
doses. The second dose was always higher than the
first one and was administered at least one hour after
all parameters had recovered to their initial level.
Chronic Effects of the MO Extract on PH
To evaluate the chronic effects of the MO ex-
tract on PH, three weeks after the MCT treatment, we
measured Ppa, conducted morphologic examinations,
and determined superoxide dismutase (SOD) activity
in the control, MCT and MCT+MO groups. On the
day of the measurement, rats were anesthetized with
urethane (1.2 g/kg, i.p.). After insertion of an endo-
tracheal cannula and a right femoral arterial catheter,
artificial ventilation with a respirator at a rate of 60
breaths/min and a tidal volume of 6-8 ml/kg was ap-
plied. The chest of the rat was then opened via a
midline sternotomy. A 22-G needle filled with hep-
arinized saline was inserted through the wall of the
right ventricle and advanced into the pulmonary artery
(15). Ppa, systemic mean blood pressure and heart
rate were measured, and mean Ppa was calculated as
the sum of diastolic pressure and 1/3 pulse pressure.
After the measurements were obtained, the heart was
removed and the right ventricle (RV) was separated
from the left ventricle and septum (LV+S). Both por-
tions were weighed, and the weight ratio RV/(LV+S)
was calculated and used as the index of right ventricular
hypertrophy. Finally, the right lung tissue was dissected
and frozen at -80°C for subsequent determination of
superoxide dismutase (SOD) activity. The left lung
was dissected for morphological examinations.
Morphological Examinations
Lung samples were taken from each experi-
mental group for morphological examinations. The
left lung was excised after the functional study and
was inflated for 30 min with 4% formaldehyde to
maintain a pressure of 25 cm H2O. Then, the trachea
was tied, and the lung lobe was immersed in a 4%
formaldehyde solution. Tissue blocks were taken
from rostral, middle and caudal portions of the
formaldehyde-immersed lung. These blocks were
washed, fixed and vacuum-embedded in paraffin.
From each block, at least three nonconsecutive 2-µm
sections were cut, stained with hematoxylin and eosin,
and examined by light microscopy for the thickness
of pulmonary arteries according to the method of
Zhou and Lai (24).
SOD Activity Assay
The endogenous SOD activity in the lung tissue
was measured by an SOD assay kit (cat 7500-100K;
Trevigen Int, Gaithersburg, MD, USA). Aliquots of
supernatants from the homogenized lung tissues were
used for determining SOD activity by both the xanthine/
xanthine oxidase (X/XOD) (8) and the NitroBlue
Tetrazolium (NBT) assays. In brief, homogenized lung
tissue (0.05 g) was added to 60 µl of cold PBS for 5
min. The insoluble components were separated by
centrifugation. The supernatant was then removed into
a clean cuvette and deionized water was added to 42.5
Ppa (mmHg)
SBP (mmHg)
0.5 sec
Fig. 2. Tracing curves of pulmonary arterial blood pressure (Ppa) and systemic blood pressure (SBP) in the control rats.
Moringa Oleifera and Pulmonary Hypertension 5
µl. The 25x Reaction Buffer (60 µl), X Solution (7.5
µl) and NBT Solution (30 µl) were then mixed well
with the homogenized tissue extract. At the absor-
bance at 550 nm, each sample was measured for 330
seconds immediately after addition of 10 µl XOD.
Displacement of tissue extract by deionized water was
used as a negative control, and SOD was used as a
positive control. Superoxide anion, generated from the
conversion of X/XOD, converted NBT to NBT-
diformazan which absorbed light at 550 nm (A550).
SOD reduced superoxide anion concentrations and
thereby lowered the rate of NBT-diformazan formation.
Determinations of the rate of increase in absorbance
units (A) per minute for the negative control and samples
were calculated as (A550330 sec. – A55030 sec.)/5 min =
A550/min. Thus, the % inhibition of SOD in the lung
tissue was calculated as [(A550/min)negative control
(A550/min)sample]/(A550/min)negative control × 100 =
% inhibition. This value increased with the con-
centration of SOD in the lung tissue. All measure-
ments were performed in duplicates.
Statistical Analysis
Data are presented as means ± SEM. Using
Student’s t test, the acute Ppa responses to the MO
extract were analyzed by comparison to baseline data
before MO extract administration. To evaluate the
chronic effects of the MO extract, the systemic hemo-
dynamic parameters, Ppa, pulmonary arterial medium
thickness, RV/(LV+S) and % inhibition of SOD were
analyzed as follows: a one-way analysis of variance
was used to establish the statistical significance of
differences among groups; if there was a significant
difference among groups, statistical differences
between any two groups were analyzed with Newman-
Keuls multiple group comparisons. Differences were
considered significant if P < 0.05.
The HPLC fingerprint of the crude 3% MO
extract is shown in Fig. 3. The fingerprint was similar
to that reported by Shanker et al. (17). Two peaks
representing niaziridin and niazirin were identified
in the spectrum from the MO extract (Fig. 3).
The acute responses of Ppa to the MO extract
are summarized in Fig. 4. In the control rats, there
was no significant difference in Ppa at any dose used.
In addition, vehicle did not alter Ppa either in the con-
trol or MCT-treated rats. Ppa decreased immediately
after the administration of the MO extract to MCT-
treated rats (data not shown). The MO extract caused
a dose-dependent decrease in Ppa in the MCT groups.
Low doses of the MO extract (e.g. 1.5 mg/kg) caused
a small non-significant decrease in Ppa. Administra-
tion of 4.5 mg/kg of the MO extract reduced Ppa to
approximately 80% of that of the MCT control and
reached statistical significance. The highest dose, at
15.0 mg/kg, significantly reduced Ppa to 51.4% of
that of the MCT control.
The effects of chronic administrations of the
MO extract to MCT-treated rats are summarized in
Table 1 and Figs. 5-9. There were no significant dif-
ferences in either body weight or systemic blood
pressure among the groups (Table 1). Notably, the
MO extract increased the heart rate of the rats (Table
1). The chronic effects of treatment with the MO ex-
tract on Ppa are shown in Fig. 5. In comparison to
the control group, MCT administration increased Ppa
indicative of PH (Fig. 5). Repeated administrations
of the MO extract during the latter stages (third week)
significantly reversed the MCT-induced increase in
Fig. 3. Analysis of the 3% Moringa oleifera (MO) crude extract
by HPLC identified two components, niazirin and
0102030405060 min
Fig. 4. Pulmonary arterial pressure (Ppa) in rats. Abscissa: log
of dose (mg of freeze-dried MO extract per kg of body
weight). Open circles indicate the Ppa changes caused by
the acute Moringa oleifera (MO) extract in the control
group. Solid circles indicate the Ppa changes affected
by acute treatment with the MO extract in the monocro-
taline (MCT)-treated group. Bars indicate 1 SE. The MO
extract caused a significant decrease in Ppa at the dose
of 4.5 (#P < 0.05) and 15.0 (##P < 0.01) mg of freeze-
dried MO extract/kg.
Log dose (mg/kg)
Ppa (mmHg)
0.176 0.653 1.176
6Chen, Chen, Yang, Liu, Chang, Pan, Lin and Chen
Ppa to a level similar to that of the control group (Fig.
5). This finding reflected treatment, but not pre-
vention, of progression of MCT-induced PH by the
MO extract.
Photomicrographs of histological sections also
supported the results from measurements of Ppa (Fig.
6). Compared to the control group, MCT administra-
tion induced thickening of vessel walls with luminal
narrowing (Figs. 6A and 6B). Administration of the
MO extract for one week reduced the MCT-induced
thickening of vessel walls (Figs. 6B and 6C). The
statistical results of pulmonary arterial medium thick-
ness are summary in Fig. 7. Consistent to the Ppa re-
sults (Fig. 5), the MCT-induced morphologic change
was attenuated by administration of the MO extract
(Fig. 7).
The effects of the MO extract on right ventricular
hypertrophy are summarized in Fig. 8. MCT adminis-
tration significantly elevated the weight ratio of RV/
(LV+S) indicating right ventricular hypertrophy. The
MCT and MCT+MO groups had a similar degree of
right ventricular hypertrophy (Fig. 8).
The results from the SOD activity assay on the
tissue samples from the three groups are summarized
in Fig. 9. There was no significant difference in the
SOD activity between the control and the MCT groups.
The MO extract treatments caused a significant in-
crease in SOD activity (Fig. 9).
We sought to determine the acute and chronic
effects of an extract from MO on MCT-induced PH.
Acute administration of the extract reduced Ppa in
a dose-dependent manner (Fig. 4). To determine
whether the MO extract is able to treat MCT-induced
PH, we administered the extract in the third week
after MCT treatment. Chronic administrations of the
MO extract significantly attenuated the MCT-induced
increase in Ppa (Fig. 5) and thickening of pulmonary
arterial walls (Figs. 6 and 7). The extract also in-
creased SOD activities (Fig. 9). These effects are
further discussed below.
Two important components, niaziridin and
niazirin, were identified by HPLC analysis of the MO
extract in ethanol (Fig. 3). The HPLC pattern analysis,
so-called the “fingerprint” method, provides a useful
means of identifying crude drugs and of preparatory
batches of pharmacologically active standardized
extract. Our results were consistent with those of
Shanker et al. (17): two peaks representing niaziridin
and niazirin were identified in the spectrum from the
MO extract (Fig. 3). Niaziridin has been demonstrated
to be a bioenhancer for antioxidative nutrients such as
vitamin A and vitamin C (15), and hypotensive effects
of niazirin on spontaneous hypertension in rats have
also been documented (6). The hypotensive activity
of the MO extract on the systemic circulation has
been demonstrated in several studies (5, 6). Bioactive
Table 1. Body weight (BW) and systemic hemodynamic parameters in three groups of rats
Group Control MCT MCT+MO
(n = 7) (n = 7) (n = 8)
BW (g) 259.3 ±3.5 247.9 ±3.5 245.6 ±7.7
SBP (mmHg) 89.0 ±5.1 79.1 ±4.1 84.3 ±4.9
DBP (mmHg) 55.7 ±5.2 60.9 ±6.0 65.9 ±3.8
MBP (mmHg) 66.8 ±4.8 67.0 ±5.3 72.0 ±3.8
HR (beats/min) 313.5 ±14.0 315.1 ±12.8 387.6 ±12.8*, #
Values are means ± SE. n, number of rats; SBP, systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood
pressure; HR, heart rate; MCT, monocrotaline; MO, Moringa oleifera (MO) extract was injected once daily during the
third week post MCT. MO extract caused an increase in HR when compared to control group (*P < 0.05) or MCT group
(#P < 0.05).
Fig. 5. Pulmonary arterial pressure (Ppa) in three groups of rats.
MCT, monocrotaline. MO, Moringa oleifera extract
administered at 4.5 mg/kg once daily during the third
week post MCT. Bars indicate 1 SE. MCT administra-
tion caused a significant increase in Ppa (**P < 0.01)
that was attenuated by the MO extract (#P < 0.05).
Ppa (mmHg)
Control MCT MCT+MO
Moringa Oleifera and Pulmonary Hypertension 7
components extracted from the leaves of plants such
as thiocarbamates (5) and niazirin (6) have shown hy-
potensive activity. However, there are many differences
between the systemic and pulmonary circulations. The
hypotensive agents used in the clinic to control systemic
hypertension often do not induce similar reductions
in PH thereby limiting the treatment and worsening
the severity of PH. In this study, the hypotensive ac-
tivity of the extract from MO was evaluated by measure-
ments of Ppa (Fig. 4). The extract we used for this
study was from the leaves of MO, similar to that used
by Faizi et al. (6). We also identified the active com-
Fig. 6. Photomicrograph of histologic sections from the three
groups of rats. MCT, monocrotaline; MCT+MO,
monocrotaline treatment followed by MO extraction
injections within the third week post MCT. Arrows
indicate the smooth muscular layers in pulmonary
arterioles. Arrow head in (B) indicates red blood
cells. All the imaged fields are amplified 100-fold.
(A) Control
Fig. 7. Differences in pulmonary arterial medium thickness
among different experimental groups. MCT, mono-
crotaline; MCT+MO, monocrotaline treatment followed
by the MO extract injections within the third week post
MCT. Bars indicate 1 SE. MCT administration caused
a significant increase in the muscularization (*P < 0.05)
that was attenuated by the MO extract (#P < 0.05).
Pulmonary arterial
medial thickness (%)
Control MCT MCT+MO
Fig. 8. Weight ratio of the right ventricle (RV) to the sum of the
left ventricle and septum (LV+S) in three groups of rats.
MCT, monocrotaline; MO, Moringa oleifera extract
(MO) administered at 4.5 mg/kg once daily during the
third week post MCT. Bars indicate 1 SE. MCT adminis-
tration caused a significant increase in this ratio (**P <
Control MCT MCT+MO
8Chen, Chen, Yang, Liu, Chang, Pan, Lin and Chen
ponent, niazin (Fig. 3). Pulmonary hypotensive activity
was observed only in MCT-treated rats immediately
after injection of the MO extract, and this activity was
dose-dependent (Fig. 4). According to our results,
the acute hypotensive effect is attributable to the bio-
active component, niazin. Moreover, the MO extract
caused a slight, but not statistically significant, increase
in Ppa in control rats (Fig. 4), consistent with previous
findings (4, 19) that tonic pressure plays an important
role in vasodilation and contraction in pulmonary
circulation. The only difference between our results
and those of Faizi et al. (6) was the lack of systemic
hypotensive effects. We used the low-dose MO treat-
ment (4.5 mg/kg) in contrast with the high dose (30
mg/kg) used in Faizi’s study (6). This most likely ex-
plains the absence of systemic hypotension in our study
(Table 1). Many reagents have acted as systemic vasodi-
lators, but few have affected pulmonary circulation.
To our knowledge, our study is the first to demon-
strate hypotensive activity of the MO extract on the
pulmonary circulation.
We suggest that the effects of the prolonged MO
extract treatment in attenuating MCT-induced PH
occur via its anti-oxidant properties. Pharmaco-
logically-induced PH in rats is due to inflammatory
damage of the pulmonary endothelium (11, 12) fol-
lowed by remodeling of the pulmonary arterial tree
and subsequent elevation of Ppa (12, 14). This pro-
gression has been associated with the appearance
of reactive oxygen species (2). Administrations of
antioxidants, dimethylthiourea and hexa(sulfobutyl)
fullerenes during the late phase of vascular injury
reduced the MCT-induced increases in Ppa and reac-
tive oxygen species, indicative of the ability of ROS
scavengers to treat MCT-induced PH (2). Further-
more, inducing SOD expression via gene transfer
increased oxygen radical scavenging in MCT-treated
rats and successfully prevented the development of
MCT-related PH (13). Notably, the MO extract has
previously been reported to have antioxidant properties
(13). Our data, which show that treatment with the
MO extract during the third week following MCT
successfully attenuated both the MCT-induced in-
crease in Ppa (Fig. 5) and the thickening of pulmonary
arterial walls (Fig. 6), support this claim. Additionally,
the MO extract increased SOD activity (Fig. 9). Ac-
cordingly, we hypothesize that modulation of PH by
the MO extract is due to its antioxidant effects.
The MCT-induced right ventricular hypertrophy
was not improved by treatment with the MO extract
(Fig. 8). Two possibilities might explain its ineffec-
tiveness. First, the length of administration of the
extract was long enough to reduce Ppa but not long
enough to decrease right ventricular hypertrophy, which
is a compensatory mechanism occurring subsequent
to high Ppa. Second, the MO extract might affect car-
diac tissue directly. The bioactive components of the
MO extract are purported cardiac stimulants (1). Time-
course studies in MCT-induced PH suggest the oc-
currence of right ventricular hypertrophy as soon as 10
days post-MCT treatment (10), with severity increasing
until 3 weeks (21, 22). We administered the MO extract
only in the third week by which point the right ven-
tricular hypertrophy might have already manifested.
Although both the MCT-induced increase in Ppa and
the thickening of the pulmonary arterial walls were
reduced by treatment with the MO extract (Figs. 5, 6
and 7), evidence revealed that MCT-induced right
ventricular hypertrophy was not affected by this ex-
tract (Fig. 8). Additionally, the heart rate was also
significantly accelerated by the MO extract in com-
parison to the MCT group (Table 1). Given these results,
we attributed the appearance of right ventricular
hypertrophy following treatment with the MO extract
to our second hypothesis, a direct stimulatory effect of
the MO extract.
There are limited clinical agents to treat PH;
thus, it is necessary to develop a new source of phar-
macological agents. We demonstrated that the MCT-
induced increase in Ppa was reduced by treatment
with an extract from MO acting through the antioxidant
properties and vasodilatory effect of the extract. The
MO extract is readily available and might be a novel
drug candidate. More studies are needed, however,
to examine therapeutic applications of the MO extract
in the future.
This study was supported by grants from the
Fig. 9. The SOD activity in three groups of rats. MCT, mono-
crotaline; MO, Moringa oleifera extract (MO) adminis-
tered at 4.5 mg/kg once daily during the third week post
MCT. Bars indicate 1 SE. The MO extract caused
a significant increase in SOD activity when compared
with the control group (**P < 0.01) and the MCT group
(#P < 0.05).
Inhibition rate (%)
Control MCT MCT+MO
Moringa Oleifera and Pulmonary Hypertension 9
National Science Council (NSC93-2320-B254-001)
and from Keelung Hospital.
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... When given for 20 weeks, the same research group showed that MO seed powder was found to reduce free 8-isoprostane and SOD2, vascular p22phox and p47phox, iNOS, and NF-KB and enhance endothelium-dependent carbachol-induced relaxation (Randriamboavonjy et al., 2017). Chen et al. (2012) demonstrate that MO leaves hexane extracts lower pulmonary arterial pressure and the thickening of vessel walls in monocrotaline-induced pulmonary hypertension in rats. ...
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Cardiometabolic disorders (CMD) have become a global emergency and increasing burden on health and economic problems. Due to the increasing need for new drugs for cardiometabolic diseases, many alternative medicines from plants have been considered and studied. Moringa oleifera Lam. (MO), one of the native plants from several Asian countries, has been used empirically by people for various kinds of illnesses. In the present systematic review, we aimed to investigate the recent studies of MO in CMD and its possible mechanism of action. We systematically searched from three databases and summarized the data. This review includes a total of 108 papers in nonclinical studies and clinical trials of MO in cardiometabolic-related disorders. Moringa oleifera , extracts or isolated compound, exerts its effect on CMD through its antioxidative, anti-inflammatory actions resulting in the modulation in glucose and lipid metabolism and the preservation of target organ damage. Several studies supported the beneficial effect of MO in regulating the gut microbiome, which generates the diversity of gut microbiota and reduces the number of harmful bacteria in the caecum. Molecular actions that have been studied include the suppression of NF-kB translocation, upregulation of the Nrf2/Keap1 pathway, stimulation of total antioxidant capacity by reducing PKCζ activation, and inhibiting the Nox4 protein expression and several other proposed mechanisms. The present review found substantial evidence supporting the potential benefits of Moringa oleifera in cardiovascular or metabolic disorders.
... Its young fruits and leaves can be eaten, and recently, its medicinal properties have also attracted attention of researchers. It has been reported to have a wide range of therapeutic effects (Bhattacharya et al., 2018), including lowering cholesterol (Almatrafi et al., 2017), regulating blood pressure (Chen et al., 2012), improving immunity, reducing inflammation (Omodanisi et al., 2017), suppressing appetite (Ahmad et al., 2018), and controlling blood sugar (Mbikay, 2012). ...
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The zebrafish obesogenic test (ZOT) is a powerful tool for identifying anti‐adipogenic compounds for in vivo screening. In our previous study, we found that Moringa oleifera (MO) leaf powder suppressed the accumulation of visceral adipose tissue (VAT) in ZOT. MO demonstrates a wide range of pharmacological effects; however, little is known about its functional constituents. To identify the anti‐adipogenic components of MO leaves, we prepared extracts using different extraction methods and tested the obtained extracts and fractions using ZOT. We found that the dichloromethane extract and its hexane:EtOAc = 8:2 fraction reduced VAT accumulation in young zebrafish fed a high‐fat diet. We also performed gene expression analysis in the zebrafish VAT and found that CCAAT/enhancer‐binding protein beta and CCAAT/enhancer‐binding protein delta (associated with early stages of adipogenesis) gene expression was downregulated after fraction 2 administration. We identified a new MO fraction that suppressed VAT accumulation by inhibiting early adipogenesis using the ZOT. Phenotype‐driven zebrafish screening is a reasonable strategy for identifying bioactive components in natural products. We performed zebrafish obesogenic test to identify anti‐adipogenic fraction in Moringa oleifera leaf. Phenotype‐driven zebrafish screening can be a reasonable strategy for identifying bioactive components in natural products. Using zebrafish obesogenic test, we identified that the dichloromethane extract of Moringa oleifera leaf and its subfraction (Fr. 2) reduced VAT accumulation in young zebrafish. In the zebrafish VAT, expression of early adipogenesis markers, cebpb and cebpd, was significantly (p < .05) decreased by Fr. 2, as was the expression of the late differentiation marker cebpa. We also confirmed that the subfractions of Fr. 2 also suppressed adipogenesis in ZOT and mouse 3T3‐L1 preadipocytes.
... Statistically 'Paired-t test' was done to analyze the efficacy and it was found signi cantly effective with P >0.001 for systolic BP. was able to bring down the blood-pressure in anesthetized rats at a 5 dose of 3mg/kg by 35-40%. In a rat model of monocrotalineinduced pulmonary hypertension, injections of the leaf extract at 4.5mg/kg appear to cause a reduction in blood-pressure associated 6,7 with vasodilatation and increased antioxidant potential. In another study Moringa oleifera leaves extract produced dose 8 dependant diuretic action . ...
Experiment Findings
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Introduction Moringa belonging to the Moringaceae family, popularly known as the 'miracle tree' in Africa has been in use in India for thousands of years ago. It is a small or medium sized tree, native of the sub-Himalayan parts of India, cultivated along the tropical and the subtropical areas of the world. Traditional herbal medicines use almost all parts of the plant. The leaves and pods are widely consumed in India. Moringa leaves are rich source of minerals and vitamins. A cup of chopped Morringa leaves contains 2 grams Vitamin B6: 19% of the Recommended Dietary Allowance (RDA), Vitamin C: 12% of the RDA, Ribo avin (B2): 11%, Iron: 11%, Vitamin A (from beta-carotene): 9% and Magnesium: 8% of the RDA. Several in-vitro and in-vivo studies were conducted to establish the anti-hypertensive effect of Moringa leaves. Various studies done in wistar rat strains, mice, guinea pigs etc have proved that repeated oral administration of Moringa leaves in the form of aqueous extract has reduced the 1 hypertension signi cantly. Method The study was carried out as an open label single armed pilot trial. Ten patients were diagnosed as spontaneous hypertension was selected after three assessments of blood pressure done on three different dates and times for the study. Patients within the age group of 40-80 yrs diagnosed with spontaneous hypertension with systolic BP-ranging from 130-220mmhg and diastolic ranging from 80-120mmhg were included for the study, provided their Mean Arterial Pressure (MAP) was within the range of 70 to 110mmhg. Patients with other systemic pathology were excluded. Routine blood examination, LFT, RFT, and ECG were done to rule out other systemic illnesses. No other antihypertensive drug was given to the patients during the study. Even no dietary modi cations, exercise or other concomitant medication were advised. The patients were asked to follow their same lifestyle as before. The drug was administered in decoction form. 20 g of Moringa leaves were boiled in 1 liter of water till it is reduced to 750 ml. It was then ltered and given to drink sip by sip in a day. BP was checked daily but assessment was done once a weak. The drug administration continued till the end of 5 weeks. Result
... Globally, hypertension, heart failure, and their associated risk factors have been a major cause of death without restriction to age (113) while almost half the losses in dialysis patients are ascribed to heart disease (114). High blood pressure is a typical symptom of hypertension with severe complications and increases the risk of heart disease, stroke, and death (115,116). Findings of different health interventions by the University College Hospital (UCH), Ibadan, Nigeria, indicated that hypertension is the commonest disease after the age of 40 (117). Management and cure for cardiac arrest and hypertension are cumbersome using synthetic drugs and usually with side effects. ...
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In the last few decades, Moringa oleifera , a multipurpose medicinal plant (MMP) has received increased research attention and commercial interest for its nutritional, therapeutic and pharmacological properties. Rigorous approaches including biological assays, animal and clinical trials are required towards safe usage as herbal therapy. We conducted a systematic review of the known pharmacological activities, toxicity, and safety of M. oleifera , usually used locally in the treatment and prevention of myriads of illnesses. Five major bibliographic databases (SCOPUS, Web of Science, Science Direct, PubMed, and Mendeley) were searched for studies reported on pharmacological activities, toxicity, and safety assessment of M. oleifera in the last 29 years (1990 – 2019). Studies on animals and humans involving aqueous leaf extracts and different preparations from M. oleifera seed and bark were also considered. All articles retained, and data collected were evaluated based on the period of the article, country where such studies were conducted and the document type. Our search results identified and analyzed 165 articles while 63 studies were eventually retained. Diverse pharmacological activities including neuroprotective, antimicrobial, antiasthmatic, anti-malaria, cardioprotective, antidiabetic, antiobesity, hepatoprotective and cytotoxic effects, amongst others, were recorded. Toxicity studies in animal models and few human studies showed that M. oleifera is safe with no adverse effect reported. The importance of the plant is highlighted in the search for new bioactive compounds to explore its therapeutic potentials towards drug discovery and development in the pharmaceutical and allied industries.
... Other studies show that M. oleifera can increase the GSH levels in liver tissue (Fakurazi et al., 2008). Chen et al. (2012) found an increase in SOD levels and a decrease in pulmonary pressure and in pulmonary arterial wall thickness due to treatment with M. oleifera in MCT induced PH in rats. It has been demonstrated that niazirin and thiocarbamates (two of the active compounds of M. oleifera) have antihypertensive effects on spontaneous hypertension in rats (Faizi et al., 1998). ...
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Background Pulmonary hypertension (PH) is a progressive disease that is associated with pulmonary arteries remodeling, right ventricle hypertrophy, right ventricular failure and finally death. The present study aims to review the medicinal plants and phytochemicals used for PH treatment in the period of 1994 – 2019.Methods PubMed, Cochrane and Scopus were searched based on pulmonary hypertension, plant and phytochemical keywords from August 23, 2019. All articles that matched the study based on title and abstract were collected, non-English, repetitive and review studies were excluded.ResultsFinally 41 studies remained from a total of 1290. The results show that many chemical treatments considered to this disease are ineffective in the long period because they have a controlling role, not a therapeutic one. On the other hand, plants and phytochemicals could be more effective due to their action on many mechanisms that cause the progression of PH.Conclusion Studies have shown that herbs and phytochemicals used to treat PH do their effects from six mechanisms. These mechanisms include antiproliferative, antioxidant, antivascular remodeling, anti-inflammatory, vasodilatory and apoptosis inducing actions. According to the present study, many of these medicinal plants and phytochemicals can have effects that are more therapeutic than chemical drugs if used appropriately.
... 20.6 ---20.89 20.89 -20.79, 20.67, 20.64 -21.05 20.87 immediately after administration of monocrotaline to rats (Chen et al. 2012). O-Ethyl-4-(α-L-rhamnosyloxy) benzyl carbamate (6) showed promising hypotensive effect . ...
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Moringa Adans. (Moringaceae) is a multipurpose plant showing uncountable uses due to nutritional, folklore, and pharmacological worldwide applications. Moringa is rich in nitrogenous compounds, viz., glucosinolates, thiocarbamates, cyanogens, isothiocyanates, and alkaloids. Plants of this genus are a good source of vitamins, β-carotene, proteins, and various phenolics. This review focuses on spectrophotometrical characteristics of nitrogenous compounds along with their pharmacological properties. Aligning traditional usage with scientific assessment, Moringa have compounds with a great commercial potential especially nitrogenous compounds. We hope to support a new research on Moringa, especially on those species whose biological properties have not been studied to date moreover explore the mechanisms at the molecular level.
The effectiveness of chemical drugs has been reduced by the resistance of cancer cells to chemical drugs, such as breast cancer as one of the most common cancers in women. Hence, it is important to study the development of more effective drugs with fewer side effects, such as herbs. Thus, the present study aimed to assess the effects of Moringa oleifera (MO) grown in Iran with anti-cancer properties in the inhibition of apoptosis and proliferation in breast cancer cells. MO extract was prepared in this study while confirming phenolic compounds, namely quercetin, gallic acid, and folic acid, through HPLC methods. Afterward, the apoptotic and anti-proliferative impacts of phenolic compounds were evaluated on 4T1 breast cancer cells via MTT, BrdU, Annexin V-FITC/PI staining, and caspases-9 and -3 activity assays. Furthermore, ELISA was applied to evaluate BAX/Bcl2 ratio. MO extract (0.02, 0.04, and 0.08 g daily for four weeks) was used to treat the BALB/c mice. The size of tumors was measured. MO reduced the proliferation significantly and induced apoptosis (P < 0.01). Furthermore, tumor volume in MO-treated mice was decreased. The reduction in tumor volume at 0.02 g dose was higher than the other two doses (P < 0.001). According to in vitro results, the apoptotic pathway was possibly induced by activating caspases-9 and -3 and an increase in the Bax/Bcl-2 ratio. Through the in vivo results, and significant reduction in tumor size, new evidence was added to the possible treatment of breast tumor provoking intrinsic apoptotic paths.
Pulmonary diseases such as asthma, chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, pulmonary hypertension, pneumonia, pleurisy, sarcoidosis, and pulmonary embolism cause severe respiratory difficulties and can even be fatal without proper treatment. Although several chemical drugs are available for the treatment of pulmonary diseases, these drugs cause severe side effects and are not completely efficient. Herbal medicine is a suitable alternative with lesser side effects and can be used for the treatment of pulmonary diseases. Several herbal plants such as Allium sativum, Crataegus rhipidophylla, Moringa oleifera, Salvia miltiorrhiza, Terminalia arjuna, Withania somnifera can be used for the treatment of pulmonary diseases. Apple polyphenol, ligustrazine, salidroside, Resveratrol, quercetin are some examples of phytochemicals which exhibit characteristics with the potential to modulate the symptoms of pulmonary diseases. These herbal plants and phytochemicals undergo various mechanisms such as decreasing proliferation of epithelial cells, reducing oxidative stress, anti-inflammation, inhibiting proliferation of tumor cells, vasodilation, reducing bronchial constrictions, etc., to reduce the progression of pulmonary diseases. The different types of medicinal plants and phytochemicals which can be used to treat pulmonary diseases along with their mechanisms will be discussed in detail in this chapter.
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Pulmonary hypertension is a chronic and advanced disease associated with increased resistance to the pulmonary vasculature, which causes changes in the morphology of the pulmonary arteries and is a major reason for death worldwide. It is associated more in women than in men. It remains asymptomatic until the harmful effects of hypertension such as stroke, myocardial infarction, etc. are observed. Synthetic drugs are used to overcome this disease, but they produce serious side effects, so alternative medicines from medicinal plants need to be developed. Traditionally, medicinal plants have been used since ancient time and are shown to be effective. Examples of plants include Moringa Oleifera Lam, Allium sativum L., Terminalia Arjuna, Withania Somnifera, and many more. They act by decreasing SOD, increasing nitric oxide levels, and also lowering the BCL2/BAX ratio. This chapter focuses on the recent discovery of medicinal plants and its phytoconstituents used in the treatment of pulmonary hypertension and the pathways involved.
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Pulmonary hypertension is a serious complication of a number of lung and heart diseases that is characterized by peripheral vascular structural remodeling and loss of vascular tone. Nitric oxide can modulate vascular injury and interrupt elevation of pulmonary vascular resistance selectively; however, it can also produce cytotoxic oxygen radicals and exert cytotoxic and antiplatelet effects. The balance between the protective and adverse effects of nitric oxide is determined by the relative amount of nitric oxide and reactive radicals. Nitric oxide has been shown to be clinically effective in the treatment of congenital heart disease, mitrial valvular disease combined with pulmonary hypertension and in orthotropic cardiac transplantation patients. Additionally, new therapeutic modalities for the treatment of pulmonary hypertension, phosphodiesterase inhibitors, natriuretic peptides and aqueous nitric oxide are also effective for treatment of elevated pulmonary vascular resistance.
The pulmonary arterial blood pressure was recorded in anaesthetized cats by means of a special cannula, according to MELLIN's technique. In most experiments the thorax was closed and the animal was breathing spontaneously.The pulmonary arterial pressure in 9 experiments averaged 23 cm water, or approximately 17 mm Hg, at an average systemic pressure of 132 mm Hg. The average ratio thus was about 1: 8, with the limits 1: 5 and 1: 14.Pressure variations of 1–2 cm blood synchronous with the breathing were regularly recorded. In one case, slow large waves of 1–2 minutes duration and about 5 cm amplitude were observed.Even great variations in the systemic blood pressure, elicited from the pressoregulating reflex mechanisms, were hardly accompanied by variations in the pulmonary arterial pressure.During muscular work a moderate rise in pulmonary blood pressure generally occurred, greater when air was breathed than when oxygen alone was administered.Clamping the pulmonary artery to one lung did not cause any change in systemic pressure (confirming LICHTHEIM and TIGERSTEDT) but caused a moderate rise in pulmonary arterial pressure.Breathing of pure oxygen lowered the pulmonary arterial pressure and oxygen-lack raised it. Carbon dioxide 6.5–20.5 per cent in oxygen raised the pressure sligthly, but constantly. These effects were not influenced by vagotomy.The effect of injections of adrenaline, nor-adrenaline, acetylcholine and histamine and of stimulation of pulmonary nerves were studied in some cases.The experiments seem to warrant the conclusion, that the regulation of the pulmonary blood flow is mainly mediated by a local action of the blood and alveolar gases leading to an adequate distribution of the blood through the various parts of the lungs according to the effeciency of aeration.
A high-performance liquid chromatographic method for the determination of novel bioactive nitrile glycosides niaziridin and niazirin in the leaves, pods and bark of Moringa oleifera is reported. Niaziridin is a bioenhancer for drugs and nutrients. The analytical conditions for reversed-phase HPLC with UV detection were as follows: column, Chromolith RP-18 e, 4.6 × 100 mm 0.5 μm (Merck); column temperature, 25 °C; mobile phase, a 20:80 (% v/v) mixture of acetonitrile: Phosphate buffer – pH 3.8; flow rate, 0.7 ml/min; detection at 220 nm. Method precision (relative standard deviation) was 1.81% for niaziridin and 1.94% for niazirin. Niaziridin (0.015% and 0.039%) and niazirin (0.038% and 0.033%) are present in leaves and pods, respectively. Niaziridin and niazirin were not detected in the bark of M. oleifera. Relatively higher amount of niazirin was present in leaves in comparisons to the pods while niaziridin content was about three times higher in the pods than the leaves of the M. oleifera. The method is robust to evaluate niaziridin and niazirin in samples from M. oleifera as well as for quality assurance of pharmacologically active standardized extract.
Study of cleared, histological and electron-microscope specimens shows that increased vascular permeability plays a major role in the formation of the pulmonary oedema and pleural effusions that occur in rats following the intravenous injection of a large dose of dehydromonocrotaline. There is a latent interval of 6-8 hr between injection of the dehydroalkaloid and the start of increased permeability which appears to be due to a direct damaging effect of the toxin on the endothelium of pulmonary capillaries and small venules. The endothelial injury does not cause permanent disruption of small blood vessels, and 2 days after injury all vessels are patent and lined by a complete layer of endothelium. Large numbers of mononuclear cells are present in the interstitial tissues of the lung 44 hr after injury. These cells appear to be emigrated blood monocytes but the cause of their emigration and their role in the subsequent progression of this type of injury to the lung are not clear.
Four neurokinins, substance P (SP), neurokinin A (NKA) neurokinin B (NKB) and kassinin (Kass) were used in the present study together with other peptides and nonpeptide agents to demonstrate the existence of two different neurokinin receptor types in the rabbit isolated pulmonary artery. Similar to other arterial vessels, the endothelium-dependent relaxation of the pulmonary artery in response to neurokinins is due to the activation of a SP-P receptor more sensitive to SP than to the other neurokinins. The endothelium-dependent relaxation is an indirect phenomenon, mediated by an unknown endothelial agent, similar to that released by acetylcholine. The contraction of the pulmonary artery in response to neurokinins is due to receptors of the NK-A type, particularly sensitive to NKA and NKB, and much less sensitive to SP. The contraction is a direct phenomenon, apparently not involving any of the known endogenous autacoids and neurotransmitters or metabolites of arachidonic acid. Contraction appears to be due to stimulation by the neurokinins of receptors located in the arterial smooth muscle. The results presented in this paper indicate that NK-A receptors for neurokinins (which are present in the tracheo-bronchial tree) are also to be found in pulmonary vessels and mediate contraction of arterial vascular smooth muscle, an interesting property of neurokinins.
We tested the hypothesis that monocrotaline would activate arachidonic acid metabolism in rats. If activation occurred before the pulmonary hypertension developed, arachidonate metabolites could play a role in the hypertensive monocrotaline injury. We found that 1 wk after monocrotaline administration 6-ketoprostaglandin F1 alpha and leukotriene C4 were increased in lung lavages. At 3 wk when pulmonary hypertension was well developed, lung lavage contained increased 6-ketoprostaglandin F1 alpha and thromboxane B2. In addition, the number and activity of white blood cells in the lavages was increased, and abnormal alveolar macrophages were present. The lung extract contained slow-reacting substances including leukotriene D4. Indomethacin administration inhibited the formation of cyclooxygenase metabolites but did not prevent pulmonary hypertension. Diethylcarbamazine administration reduced the numbers and activity of inflammatory cells, increased pulmonary hypertension, prevented right ventricular hypertrophy, and inhibited the formation of slow-reacting substances. We concluded that arachidonate metabolism was activated before pulmonary hypertension developed, that the inflammatory cells in the alveolus accompanied the hypertensive process, and that diethylcarbamazine attenuated both the monocrotaline-induced inflammatory response and the pulmonary hypertension.
The lungs of 11 rats fed on Crotalaria spectabilis seeds for periods ranging from 12 to 61 days were examined by both light and electron microscopy. The findings were compared with those obtained from nine control rats given a normal diet. Eight of the 11 test rats showed morphological evidence of pulmonary arterial hypertension in the form of right ventricular hypertrophy; the exceptions were rats killed after receiving the Crotalaria diet for 12, 22, and 29 days respectively. On light microscopy, all the test rats showed exudative lesions in the lungs consisting of eosinophilic alveolar coagulum, intra-alveolar haemorrhage, interstitial fibrosis, and a proliferation of mast cells. Enlarged and proliferated cells were seen to line the alveolar walls or lie free within the alveolar spaces. Electron microscopy showed these cells to be enlarged granular pneumocytes containing enlarged, electron-dense, lamellar secretory inclusions. Scanty macrophages were also seen in the alveolar spaces, in which excessive numbers of myelin figures and lattices were seen: these structures resembled phospholipid membranes and were probably related to pulmonary surfactant. We think that proliferation of granular pneumocytes is a non-specific reaction of the alveolar walls to injury. The alveolar-capillary wall showed interstitial oedema with the formation of intraluminal endothelial vesicles, probably representing the early ultrastructural phase of pulmonary oedema, and more likely to be an effect of the pulmonary hypertension than its cause.
Monocrotaline induces microvascular leak and pulmonary hypertension in rats. We have hypothesized that the leak is related in some way to the pulmonary hypertension and precedes it. In rats given 40 mg monocrotaline/kg body wt subcutaneously, lung wet weight-to-dry weight ratios and lung albumin content began to increase within the first 3 days and became maximal at 1 wk. Alveolar lavage fluid showed little or no increase in protein. Right ventricular hypertrophy increased progressively from 2 through 3 wk. An increase in lung dry weight paralleled the right ventricular hypertrophy. The amount of blood retained in the lung did not account for the increased lung water, albumin, or weight. We considered that microvascular leak without leak into the alveolar space preceded pulmonary hypertension, right ventricular hypertrophy, and increased lung dry weight. In rats not given monocrotaline but exposed for 3 wk to hypobaric hypoxia, lung albumin, lung dry weight, and right ventricular weight increased. Increased lung dry weight probably reflects hyperplasia of lung cells. If so, an association of microvascular leak, lung cell hyperplasia, and right ventricular hypertrophy may occur in both monocrotaline- and hypoxia-induced pulmonary hypertension.