P a g e | 751 eISSN: 2231-0541
CAS CODEN: PHARN8
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PHARMANEST An International Journal of Advances in Pharmaceutical Sciences Volume 4|Issue 4|July-August 2013|Pages 751-763 Original Research Article ACUTE TOXICITY AND CARDIAC EFFECTS OF A CHROMATOGRAPHIC FRACTION FROM BIDENS PILOSA L. (ASTERACEAE) LEAVES IN MAMMALS aLÉANDRE
KOUAKOU KOUAKOU, aMATHIEU NAHOUNOU BLÉYÉRÉ, bANDRÉ BROU KONAN, bAUGUSTIN KOUAO AMONKAN, cJEAN CLAUDE KOUAKOU ABO, aPAUL ANGOUÉ YAPO, aETIENNE EHOUAN EHILÉ
aLaboratory
of Physiology, Pharmacology and African Pharmacopoeia of UFR-SN, University of Nangui Abrogoua, 02 BP 801 Abidjan 02, Côte d’Ivoire. bLaboratory
of Pharmacology and Nutrition of UFR-Biosciences, University of Felix Houphouet Boigny, Cocody, 22 BP 582 Abidjan 22, Côte d’Ivoire. cLaboratory
of Animal Physiology of UFR-Biosciences, University of Felix Houphouet Boigny, Cocody, 22 BP 582 Abidjan 22, Côte d’Ivoire.
Author for Correspondence:
[email protected] Received: 01-07-2013
Revised: 07-07-2013
Accepted: 10-07-2013
Available online: 01-09-2013
ABSTRACT Bidens pilosa L. (Asteraceae) is a plant commomly used in traditional medicine to treat several ailments. The effects of a chromatographic fraction isolated from the aqueous leaf extract (BpF2) were investigated for the acute toxicity in mice, isolated rat heart and rabbit ECG. The graphic method of Miller and Tainter (1944) permitted to determine a LD50 of 429.14 ± 28.11 mg/kg b.w. while the calculation method of Dragsted and Lang (1957) gave 452.50 ± 23.10 mg/kg b.w. as LD50. BpF2 induced negative inotropic and chronotropic effects on isolated rat heart preparations for concentrations ranging from 10-12 to 10-4 mg/ml. Those effects were significantly attenuated by the use of atropine, a muscarinic cholinoceptors antagonist. The dose-response effect (5-25 mg/kg b.w.) on anesthetized rabbit ECG revealed a decrease of P, QRS, T waves and the cardiac frequency. In contrast, PQ interval was increased and QT interval was not significantly affected. These results indicated that BpF2 was relatively toxic but could be used with caution. The cardioinhbition induced suggested the presence of cholinomimetic substances acting via muscarinic M 2 receptors and the non significant variation of QT interval was important in so far as an extension of this interval could be source of arrhythmia induction. Key words: Bidens pilosa, Acute toxicity, ECG, Isolated rat heart, cholinomimetic substances.
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P a g e | 752 INTRODUCTION Traditional medicine has been practiced for
This study was aimed to evaluate in mice
years in developing countries, especially in
the acute toxicity of a chromatographic
Africa. According to WHO, this use is
fraction from the leaves of Bidens pilosa L.
widespread and is becoming increasingly
(BpF2) and to investigate its effects on
important in terms of health and economy,
isolated
since more than 80% of the population
electrocardiogram.
resort to it for health needs.1 According to the
same
and
rabbit
MATERIAL AND METHODS
Asia
still
use
traditional
Animals: Rabbits (Oryctolagus cuniculus)
of
historical
weighing 2 ± 0.2 kg, Mice (Mus musculus)
circumstances and cultural beliefs. Bidens
weighing between 20 and 25 g and rats
pilosa L. is an herbaceous plant, set up,
(Ratus norvegicus) weighing between 180
with regularly cogged and glabrous leaflets.
and 250 g were used. They were bred in
Very widespread pantropical species from
Animal
Angola to Cameroon, it is also found in Côte
Pharmacology and Phytotherapy of the
d’Ivoire.2,3 The plant is used in traditional
University of Nangui Abrogoua (Former
medicine to treat diverse illnesses such as
University of Abobo-Adjamé, Abidjan, Côte
diarrhoea and inflammation in Côte d’Ivoire
d’Ivoire) according to the principles for the
and is prescribed as anti-poison, against flu
care and use of laboratory animals of the
and
Ethical Committee of the University (Nangui
medicine
people
because
haemorrhoids
in
and
heart
in
America,
source,
rat
Latin
Congo
and
Rwanda.2,3,4 Many works carried out on this
house
of
Animal
Physiology,
Abrogoua, Abidjan, Côte d’Ivoire).
plant revealed different properties among which
anti-microbial,
Plant material: The plant material was
anti-inflammatory,
described.14,15
anti bacterial, anti-malarial and anti-gastric
leaves
ulcer effects.5,6,7,8,9
of
Authentication
Bidens
pilosa
L.
of
fresh
(Asteracea)
collected from Abidjan, Côte d’Ivoire was The cardiovascular aspect was also subject
implemented by Prof. Aké-Assi Laurent, an
to many studies.10,11,12,13,14, 15. Investigations
expert in Botany (Department of Botany,
showed that a chromatographic fraction
University
from Bidens pilosa L. leaves (BpF2) elicited a
d’Ivoire). In Côte d’Ivoire, Bidens pilosa L.
decrease of the blood pressure of rabbit via
was first found on November 12, 1966 in
cholinomimetic
Bondoukou
and
β-adrenomimetic
of
Cocody,
and
Abidjan,
herbarium
Côte
specimen
agonist substances.14,15 The phytochemical
(voucher n° 9266) was made and deposited
study of the fraction revealed flavonoids,
at the National Botanic Centre (University
polyphenols and catechic tannins.
of Cocody, Abidjan, Côte d’Ivoire) and then
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P a g e | 753 in Kakpin (Côte d’Ivoire) on June 20, 1968.
differences
Herbarium specimen (voucher n° 10286)
concentrations were precised by an analysis
was
the
of variances (ANOVA) of the multiple test of
of
comparison of Turkey-Kramer and were
also
National
made Botanic
and deposited at Centre
(University
Cocody, Abidjan, Côte d’Ivoire).
between
considered statistically
the
significant when
p < 0.05.
Plant extraction: The extraction and the separation of extracts were as previously
Acute toxicity assessment
described.14,15 Hundred grams (100g) of
Mice were divided into 9 groups of 10 mice
powder from Bidens pilosa L. leaves dried at
(5 males and 5 females). Each mouse in the
room temperature were macerated under
first group (control group) was treated with
magnetic shaker during 48h in 2 L of
0.5 ml isotonic solution of NaCl 9 ‰ . The
distilled water. The supernatant was filtered
other 8 groups were treated with a single
on cotton and filter paper Whatman. Two
administration
litres of distilled water were added to the
normal
base and then mixed during two hours and
of
saline
BpF2 diluted
isotonic
in
solution.
the The
different doses of BpF2 ranging from 215
also filtered. The filtrates were freeze-dried
mg/kg b.w to 740 mg/kg b.w. and the
using a lyophilisator TELSTAR (Terrassa,
normal saline solution of the control group
Spain). 0.8 g of the powder obtained were
were administered intraperitoneally (i.p.).
dissolved in 10 ml of distilled water and
Behavioural
chromatographed on a fine Sephadex G25
changes
of
the
8
treated
groups were observed every 30 min for a
column (3 by 20 cm) packed in distilled
period of 2 hours after administration of the
water. Elution was carried out with the
extract (Mandal et al., 2001) and mortality
same solvent. Fractions (5) of 20 ml each
rate were recorded for 24 hours post
were collected then freeze-dried. They were
treatment.16
tested on the blood pressure of the rabbit.
calculation
The fraction 2 (BpF2) was found to be the
The
graphic
methods
were
and
the
used
to
determine the LD50.17,18
most active.
Recording
Chemicals: Atropine was purchased from
of
the
isolated
rat
heart
activity
Sigma Chemical Company (St Louis, MO, USA).
The experimental process used to record and assess the isolated rat inotropic and
Data analysis: Statistical analysis and
chronotropic activities was as previously
graphics were performed with the software
described.13,
GraphPad Instat and GraphPad Prism 4
the
mean
(m
±
sem).
Rat was anesthetized with injection
of
20%
placed under artificial respiration to avoid
The
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ethyl
urethane at 1 g/kg body weight. It was then
values are expressed as mean ± standard on
19
intraperitoneal
(San Diego California, USA) respectively. All error
observed
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P a g e | 754 anoxia of the heart during operation. To do
BpF2 was dissolved in Mac Ewen solution.
this, a tracheotomy was performed and a
Registration
cannula connected to an air pump was
of
the
global
electrical
activity (ECG) of the rabbit
placed in the trachea. Then, a thoracotomy was practiced. A hemisection of the aorta
Methods
was carried out. A cannula fixed to a
described.19,20,21.
syringe
solution
the rabbit was recorded by the technique of
(2500 UI, 0.2 ml/100 g body weight) was
external electrodes used in the human
inserted in the aorta. The heart was rapidly
practices and adapted to the rabbit.20
removed
Briefly,
containing
and
the
heparinized
heparinized
solution
were
the
as
previously
The electrocardiogram of
saphenous
vein
of
the
injected to dissolve and expel any blood
anesthetized rabbit by an intraperitoneal
clots that were probably formed in the heart
injection of 40% ethyl urethane (1 g/kg
to prevent thrombosis in the coronary
body weight) was intubated in order to
circulation. The isolated heart was perfused
administer plant extract.20 The armpits of
with Mac Ewen solution of the following
the anterior limbs and the groin of the
composition (mM): NaCl 147; KCl 5.6; CaCl2
posterior limbs were shaved and cleaned
2.6; NaH2PO4 0.66; CO3NaH 11.9; MgCl2
with
0.24; C6H12O6 11 with a pH adjusted to 7.4.
electrolytic dough, four electrodes were put
The apex of the heart was fixed by a fine
and bound to the four sockets of the
clip and linked to the needle of the
registration
cardiograph
electrocardiograph
treatment,
for the
recording. heart
was
After
each
washed
90%
ethanol.
cable
After
connected
applying
to
(CARDIOFAX
the ECG-
by
6851K, Nihon Kohden, Japan). The studied
perfusion fluid for 10 min, time within
parameters (P, QRS, T waves, PQ, QT
which the baseline recording was achieved,
intervals
and the second dose was then given. The
recorded from the DIII derivation of the
recording before the direct perfusion of
standards or bipolar Einthoven derivations
extract was considered as baseline reading
on thermo sensitive paper, at constant
for each dose (control).
speed (25 mm/s).
and
cardiac
frequency)
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were
P a g e | 755
Decrease of amplitude of cardiac contractions (%)
A
*
100 90 80 70 60 50 40 30 20 10 0
*
* * -14
-12
-10
-8
-6
-4
-2
Log(Concentration of BpF 2 in mg/ml)
Log(EC50 ) = -9,702
B
* Decrease of frequency of cardiac contractions (%)
100 90 80 70 60 50 40 30 20 10 0 -14
-12
-10
-8
-6
-4
-2
Log(Conce ntration of BpF 2 in mg/ml) Log(EC50 ) = -7,709
Fig.1.Dose-response effect of BpF2 on isolated rat heart Increasing concentrations of BpF2 induced a significant (*p < 0.05, n = 4) drop of the amplitude (A) and the frequency (B) of the cardiac activity in a dose-dependent manner. The EC50 determined graphically were 1.98 x 10-10 mg/ml and 1.95 x 10-8 mg/ml respectively for the amplitude and the frequency.
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Reduction of cardiac amplitude and frequency (%) induced by BpF 2 at 10 -4 mg/ml
P a g e | 756
50 40 Amplitude Frequency
30
* 20
*
*
*
*
10
*
0 0
10-9
10-10
10-8
Concentrations of atropine (mg/ml)
Fig.2.Effect of different concentrations of atropine on the negative inotropic and chronotropic effects induced by BpF2 at 10-4 mg/ml
The negative inotropic and chronotropic effects induced by BpF 2 at 10-4 mg/ml were significantly (*p < 0.05, n = 4) inhibited by atropine at 10-10, 10-9 and 10-8 mg/ml.
Table.1.Acute toxicity of BpF2 in mice
Groups of 10 mice
Doseof BpF2 (mg/kg b.w.)
Number of mice dead
Mortality %
1 2 3 4 5 6 7 8 9
NS 215 290 365 440 515 590 665 740
0 0 2 4 5 6 8 10 10
0 0 20 40 50 60 80 100 100
Group 1 (Control group) was administered normal saline (NS) intraperitoneally. The 8 other groups received BpF2 (215-740 mg/kg b.w.) intraperitoneally and the mortality rate was evaluated after treatment.
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P a g e | 757
Table.2.Dose-response effect of BpF2 on rabbit ECG BpF2 (mg/kg b.w.) 0(Control)
P wave (µv)
QRS complex (µv)
T wave (µv)
PQ interval (ms)
168.75 ±11.96
612.5±65.74
118.75±6.25
85±5
QT interval (ms) 150±5.77
5
125 ±28.86
562.5±65.74
112.5±7.21
90±5.77
150±5.77
269±4.6
15
100 ±14.43
418.75±86.22
81.25±6.25*
100±8.16
155±9.57
264±3.48*
20
75 ±17.67*
312.5±21.65*
68.75±6.25*
120±8.16*
160±8.16
258±3.31*
25
62.5 ±12.5*
193.75±27.71*
0*
125±9.57*
--------
242±2.16*
Frequency (cycles/min) 280±4.4
BpF2 elicited a decrease of P, QRS, T waves and the heart rate. PQ interval increased. These changes were significant (*p < 0.05, n = 4). QT interval was not significantly affected.
RESULTS Acute toxicity of BpF2
For doses of BpF2 above 215 mg/kg b.w., the mortality rate of mice increased in a
BpF2, injected at doses below 215 mg/kg of
dose-dependent manner. The first deaths
body weight (b.w.), had no significant
were noticed between 5 and 6 hours post
effects on the behaviour of mice. However,
treatment.
the injection of BpF2 at doses ranging from
convulsions
215 to 740 mg/kg b.w. caused a decrease
At the
gather. These effects were observed 25-35 after
injection.
Two
hours
groups
which
displaced
difficulties
in
painfully feeding
and and
rate
was
100%.
That
one experiment. The same experiment was
were
repeated three times and permitted to determine the LD50 by the graphic and the
exhibited
calculation
drinking.
methods.
According
to
the
graphic method the LD50 determined was
Mortality was function to the administered
429.14 ± 28.11 mg/kg b.w. The calculated
dose. Indeed, no death was observed for
LD50 was 452.50 ± 23.10 mg/kg b.w. There
doses of BPF2 less than 215 mg/kg b.w. in
is no statistical difference between the two
the treated mice.
values of LD50 (p > 0.05).
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dose
the evolution of the mortality of mice for
administered doses less than 590 mg/kg b.w.
and
mortality of all mice (LD100). Table I shows
completely immobile, refused to feed and to The
breathing
corresponded to the lethal dose that caused
between 590 and 740 mg/kg b.w. became water.
jerky
after
dose of 740 mg/kg b.w., the
mortality
after
injection, the mice that received doses
drink
and
occurred
animals remained lying down on their back.
in locomotion and the animals tended to min
Death
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P a g e | 758 Effects of BpF2 on the activity of isolated rat heart
contractile
negative inotropic and chronotropic effects induced by BpF2 at10-4 mg/ml. Thus, the
Dose-response effect of BpF2 on isolated
amplitude dropped to 14.20 ± 1.53%, 10.73
rat heart contractions
± 0.72% and 6.02 ± 0.65% respectively for atropine at 10-10, 10-9 and 10-8 mg/ml. The
The dose-response effect of BpF2 on isolated
same
rat heart contractions was achieved. This cardiac
compared
amplitude
to
control
and
noticed
with
the
0.96%, 17.83 ± 0.94% and 15.79 ± 1.51%
frequency
recordings,
was
frequency which values fell to 25.23 ±
resulted in a dose-dependent decrease of the
tendency
respectively for atropine at 10-10, 10-9 and
for
10-8 mg/ml (Fig. 2).
concentrations ranging from 10-12 to 10-4 mg/ml. In this range of concentrations, the
Effects of BpF2 on the electrocardiogram
decrease of amplitude varied from 11.18 ±
of rabbit
0.93% to 35.30 ± 1.01% and the decrease of
As shown in table 2, the dose-response
the frequency attained 8.98 ± 0.59% to
effect of BpF2 was carried out on rabbit
42.29 ± 2.77%. These effects were reversible
ECG. The
after returning to Mac Ewen reference
results indicated that BpF2
triggered some changes in the parameters
solution.
of the global electrical activity of the rabbit
The dose-response curves (Fig. 1A and B)
heart. The normal ECG values recorded
for four (n= 4) experiments permitted to
(control) significantly (p < 0.05) decreased
determine the values of EC50 which were
for P, T, and QRS waves. Indeed, P wave
1.98 x
10-10
mg/ml and 1.95 x
10-8
mg/ml
varied from 125 ± 28.86 to 62.5 ± 12.5 µv
respectively for the amplitude and the
for doses ranging from 5 to 25 mg/kg b.w.
frequency.
T wave was reduced by increasing doses of BpF2 from 5 to 25 mg/kg b.w. and dropped
Interaction atropine- BpF2 on isolated
from 112. 5 ± 7.21 to 0 µv. QRS complex
rat heart contractions
also diminished and reached 562.5 ± 65.74
In this experimentation, a control effect of
to 193.75 ± 27.71 µv in the same range of
BpF2 was implemented at the concentration
doses. The cardiac frequency was also
of 10-4 mg/ml. At this concentration, BpF2
affected by the same doses of BpF2 and
elicited negative inotropic and chronotropic
deceased from 269 ± 4.6 to 242 ± 2.16
effects. Indeed, the amplitude and the
cycles/min.
frequency diminished and reached 28 ±
found to augment significantly (p < 0.05)
2.15% and 43.55 ± 3.79% respectively. The
from 90 ± 5.77 to 125 ± 9.57 ms for doses
treatment of the heart with atropine at 10-
ranging from 5 to 25 mg/kg b.w. whereas
10,
QT interval increased slightly but not
10-9 and 10-8 mg/ml strongly and
However,
PQ
interval
was
significantly from 150 ± 5.77 to 160 ± 8.16
significantly (p < 0.05) inhibited the
ms for doses ranging from 5-20 mg/kg b.w. PHARMANEST - An International Journal of Advances in Pharmaceutical Sciences
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P a g e | 759 DISCUSSION
above 12500 mg/kg b.w. and the seeds infusion of Securigera securidaca (Fabaceae)
Toxicological studies showed that doses of
with a LD50 of 1260 mg/kg b.w.19,24
BpF2 ranging from 215 to 740 mg/kg b.w. induced a decrease in mobility. This fact
BpF2 caused a dose-dependent decrease in
can suggest that BpF2 had an effect on the
the
locomotion
the
mechanical activity of the isolated rat heart.
nervous system. In that range of doses, the
The cardioinhibitory effect induced by this
mortality
dose-
fraction F2 was strongly reduced in the
dependent manner to reach 100% at a dose
presence of increasing doses of atropine.
of 740 mg/kg b.w. The LD50 values of BpF2
However, the negative chronotropic and
determined according to the graphic mode
inotropic effects did not completely vanish.
(429.14 ± 28.11 mg/kg b.w.) and the
These results were highly similar to those
calculation mode (452.50 ± 23.10 mg/kg
obtained
b.w.) are quite similar. According to the
acetylcholine, suggesting the presence in
defined classification, substances that have
this extract of cardioactive cholinomimetic
a
substances
LD50
system rate
less
and
therefore
increased
than
5
in
mg/kg
a
b.w.
are
amplitude
and
with
frequency
the
of
the
administration
acting
via
of
muscarinic
considered highly toxic. In contrast, those
cholinoceptors. These
which have a LD50 greater than 5000
similar to those of aqueous extracts of
mg/kg
plants such as total leaf extract and the
b.w.
are
called
non-toxic
fraction
very toxic substances (5 < LD50 < 50 mg/kg
(Euphorbiaceae) on the isolated rat heart,
b.w.), toxic substances (50 < LD50 < 500
bulbs extract of Hypoxis hemerocallidea
mg/kg b.w.), or weakly toxic substances
Fisch & Mey (Hypoxidaceae) and the leaf
(500 < LD50 < 5000 mg/kg b.w.) can be
extract
distinguished.22
According
(Lauraceae)
classification,
BpF2,
this
administered
of
from
Persea
on
atrium.25,26,27,28
Mareya
also
substances. Between these two extremes,
to
F2
effects were
the
micrantha
americana
isolated
Mill
guinea-pig
The effects of acetylcholine
intraperitoneally, is not highly or very toxic
on the heart activity are well known in
but simply toxic. This toxicity is relatively
mammals. According to some studies, the
low
plant
predominating muscarinic receptors are
extracts. Indeed, BpF2 is less toxic than the
those of the type M2.29,30 Several authors
aqueous extracts of root bark of Swartzia
indicate that their stimulation leads to a
madagascariensis (Caesalpiniaceae) with a
decrease
LD50 equals to 5.99 mg/kg b.w. and the
activation
of
adenyl
leaves of Sesamum radiatum (Pedaliaceae)
activation
of
a
which LD50 is 184.2 ± 21 mg/kg b.w.21,23
potassium
BpF2 is more toxic than the methanol
consequences are hyperpolarization and
extract from the stem bark of Erythrina
decreased opportunities for transmission of
Senegalensis
action
compared
to
that
(Fabaceae)
of
other
which
LD50
is
in
contractile G
cyclase protein
channels.
potentials,
force
Thus,
which
by
the
and
the
coupled the
limit
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final
calcium
PHARMANEST - An International Journal of Advances in Pharmaceutical Sciences Volume 4 Issue 4 July-August 2013 Available online: www.pharmanest.net
to
P a g e | 760 influx.31,32,33,34.
However,
other
authors
However,
BpF2
did
not
influence
observed positive inotropic effects by the
significantly the duration of QT interval. A
use of muscarinic receptor agonists, and
series of studies advocate drug evaluation
according
to
them,
these
were
against the risk of induction of arrhythmias
receptors.30,35,36,37
due to torsades de pointes in humans. This
Through the results obtained with BpF2 on
requires an assessment of QT interval
isolated rat heart, it is likely that the
which extension is a risk.42,43 The effects of
cholinomimetic substances in this fraction
acetylcholine on the ECG of guinea pig also
act via M2 receptors. A study showed that
were highlighted by an Ivorian reseracher.25
in
Thus,
mediated by M1 and M3
isolated
effects
human
myocardium,
the
presence
of
cholinomimetic
acetylcholine had a biphasic effect resulting
substances in BpF2 could justify its effects
in a negative inotropic effect at low doses
on rabbit ECG.
(10-9 to 10-6 M) through M2 receptors and
CONCLUSION
positive inotropic effect at high doses (10-6 to 10-3 M) via M1 receptors.38
The active fraction F2 of the aqueous leaf extract of Bidens pilosa L. is toxic when
On rabbit ECG, BpF2 induced a sharp
administered
reduction of P wave, QRS complex and T of
PQ
interval
and
had
medicine which should nevertheless be
no
done with caution. The study of the effects
significant effect on QT interval. These
of BpF2 on the isolated rat heart showed
results revealed that BpF2 could decrease the
depolarization
of
the
atria
However,
this cannot impede its use in traditional
wave. However, this fraction elicited a slight increase
intraperitoneally.
that this fraction caused cardioinhibition
and
which was
ventricles, ventricular repolarization and
linked to
cholinomimetic
heart rate. The outcome of the whole action
electrical
of BpF2 indicated an inhibitory effect of this
the
substances.
activity
of
rabbit
presence On
the
heart,
the
diminution of the activity was due to the
substance on the global electrical activity of
inhibitory
the rabbit heart. These results were similar
parameters,
to those of acetylcholine on the ECG.
effect
of
except
BpF2 QT
on
interval.
ECG This
observation seemed particularly interesting
Indeed, some authors revealed that on a
since an extension of QT interval could be a
heart-lung preparation of dog, acetylcholine
factor
caused a slowing of the pacemaker, a
of
arrhythmia
cardioinhibitory
blockade of atrio-ventricular conduction
effects
induction. of
BpF2
These could
explain, at least in part, the hypotension
associated with prolongation of PR interval
induced by this fraction by cholinomimetic
and a decrease in ventricular activity.39,40,41
substances in rabbits.
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