Vol. 277, Issue 2, H842-H847, August 1999
Effects of selected endothelium-dependent vasodilators on
fetoplacental vasculature: physiological implications
Saral
Amarnani,
Belinda
Sangrat, and
Gautam
Chaudhuri
Departments of Obstetrics and Gynecology and of Molecular and
Medical Pharmacology, University of California, Los Angeles,
California 90095
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ABSTRACT |
The endothelium-dependent vasodilators ACh,
histamine, and bradykinin were studied in the isolated, perfused human
placental cotyledon. Histamine caused a decrease in perfusion pressure
that was attenuated by cimetidine. Bradykinin, at lower concentrations (10
20 to
1014 M), produced a
concentration-dependent decrease in perfusion pressure, whereas at
higher concentrations it produced an increase in perfusion pressure.
ACh was without any effect. The decrease in perfusion pressure observed
with bradykinin was potentiated by captopril and was significantly
attenuated in the presence of HOE-140, the
B2-receptor antagonist, or by
pretreatment with an inhibitor of nitric oxide synthase, but not by an
inhibitor of cyclooxygenase. The decrease in perfusion pressure
observed with bradykinin was potentiated by ANG I but not by ANG II. It is concluded that endothelium-dependent vasodilation can be
demonstrated with histamine and bradykinin in the fetoplacental
vessels, and at least for bradykinin, this is partly mediated by
release of nitric oxide. The potentiation of the bradykinin response in
the presence of ANG I may serve to buffer the vasoconstriction produced by ANG II in the fetoplacental circulation.
bradykinin; human cotyledon perfusion; nitric oxide
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INTRODUCTION |
THE FETOPLACENTAL CIRCULATION is very important for
supplying oxygen and nutrients to the fetus to allow for normal fetal growth and viability. These vessels lack innervation (20), and regulation of vascular tone in the fetal extracorporeal circulation must therefore depend on circulating vasoactive substances that may act
locally in the vasculature to modulate vascular tone. Any impairment in
the circulation could increase the possibilities of growth retardation
of the fetus in utero, fetal distress, and intrauterine fetal death
(2). We (3, 4) and others (22) have previously demonstrated that
histamine, bradykinin, and other endothelium-dependent vasodilators
release nitric oxide (NO) from umbilical artery and vein. It has also
been demonstrated that NO regulates vascular tone in the fetoplacental
vessels (12). However, the actions of endothelium-dependent
vasodilators in eliciting vasodilation of fetoplacental vessels have
been controversial. Although histamine has been demonstrated to release
endothelium-derived relaxing factor (EDRF), now identified as NO (9,
16), from human umbilical vessels and umbilical endothelial cells in
culture (22), endothelium-dependent relaxation of isolated segments of
human umbilical artery has been difficult to demonstrate (11). Similarly, the actions of bradykinin in the fetoplacental vessels have
been conflicting. Some investigators have reported that bradykinin infusion increased perfusion pressure in the placenta (23), whereas
others observed no change (5, 17).
Both histamine (19) and bradykinin (10) are present in the fetal
circulation. We therefore decided to reassess the role of these
endothelium-dependent vasodilators in causing vasodilation of the
fetoplacental vessels. Because both histamine and bradykinin have
vasodilator and vasoconstrictor actions, we decided to utilize much
lower concentrations of these two substances than previously utilized
by other investigators to assess whether endothelium-dependent vasodilation can be demonstrated with very low concentrations. We also
decided to assess the potential mechanism(s) by which bradykinin
modulates tone in these vessels and their physiological implications.
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MATERIALS AND METHODS |
Isolated Human Placental Cotyledon Perfusion
Human placentas were collected at the University of California, Los
Angeles, delivery room immediately after normal vaginal delivery or
elective cesarean section and were immediately transported to the
perfusion laboratory. The isolated human placental cotyledons were
dually perfused using the technique described by Glance et al. (6). A
suitable third- or fourth-order chorionic artery and corresponding vein
of an intact cotyledon were cannulated at a point immediately before
passage of the vessels through the chorionic plate. The maternal
intervillous space was cannulated with two butterfly needles inserted
through remnants of the spiral arteries in the basal plate. The
effluent from the intervillous space was collected by gravity into a
Plexiglas cone over which the cotyledon was placed, maternal surface
facing downward. Perfusion medium in most cases was tissue culture
medium 199 containing 5% polyvinylpyrrolidone-40 and 0.1% BSA as
oncotic agents, with 20 IU/ml heparin sodium and 48 µg/ml gentamicin
added. In some experiments, when NO synthase inhibitors were used,
arginine-free medium was utilized. The pH of the medium was 7.4 and was
gassed with 95% O2-5%
CO2 at 37°C. Flow rates were 4 ml/min for the fetal side and 10 ml/min for the maternal side except
where stated. Lateral pressure was measured on fetal and maternal
inflow lines adjacent to the point of cannulation. Data on pressure,
inflow, and outflow were constantly monitored. The
PO2 when sampled ranged from 380 to
500 mmHg. The pH was maintained at 7.4. Because flow was kept constant,
changes in perfusion pressure were reflective of changes in tone of the vessels.
Active tone was induced in the fetal side of the placental vasculature
by adding the thromboxane mimetic agent U-46619 in a final
concentration of 1-5 × 108 M. This
led to an increase in fetoplacental perfusion pressure ranging from 100 to 130 mmHg at a flow rate of 4 ml/min. The endothelium-dependent and
endothelium-independent vasodilators or other agents studied were added
to the perfusion medium directly into the fetal inflow line via an
injection valve, over a wide range of concentrations as indicated in
the respective protocols. In some instances, when antagonists to the
endothelium-dependent vasodilators were utilized as indicated, they
were added to the perfusion medium and allowed to constantly perfuse
the vascular bed of the cotyledon for 30 min before the response to the
endothelium-dependent vasodilators was retested. In all instances, at
the end of the experiment, the responsiveness of the vascular bed was
tested by perfusion of 106
M glyceryl trinitrate (GTN). This concentration of GTN induced maximal
vasodilation and decrease in perfusion pressure in our model system.
The results of the studies were discarded if the vascular bed failed to
respond to GTN at the end of the experimental protocol.
Chemicals and Solutions
ACh, bradykinin, histamine, GTN, captopril, ANG I, ANG II,
N
-nitro-L-arginine
methyl ester (L-NAME), and
L-arginine
(L-Arg) were obtained from Sigma
(St. Louis, MO). Tissue-culture medium and arginine-free medium were
obtained from GIBCO and Specialty Media, respectively. HOE-140
(selective B2 bradykinin receptor antagonist) was obtained from RBI (Natick, MA).
Experimental Protocols
Study I: effects of different concentrations of ACh, histamine, and
bradykinin on the placental perfusion pressure and vascular resistance.
After stabilization of the perfusion pressure after induction of active
tone in the fetal side of the placental vasculature, the test
substances in appropriate concentrations were injected into the fetal
inflow line over a period of 5 min. At least 15 min were allowed to
elapse between each infusion of drug or until a steady baseline was
again achieved. The test substances studied were ACh
(106 to
104 M), histamine
(108 to
106 M), and bradykinin
(1020 to
106 M). The effects of
histamine were assessed in the absence and presence of cimetidine
(105 M). The effects of
bradykinin were assessed in absence or presence of 0.1 µM HOE-140
(the B2-receptor antagonist).
Study II: effect of inhibition of cyclooxygenase and endothelial NO
synthase on the responses to bradykinin.
For these studies, L-Arg-free
perfusion medium was used. The effects of bradykinin
(1016 to
1014 M) were initially
ascertained followed by a 30-min infusion of indomethacin
(105 M) to inhibit
cyclooxygenase. This concentration of indomethacin was selected because
it is known to completely inhibit cyclooxygenase (4). After this, the
effects of different concentrations of bradykinin in the presence of
indomethacin were reassessed. After this,
L-NAME
(104 M) was added to the
perfusion medium, and the concentration of U-46619 was adjusted to
ensure that the perfusion pressure was similar to that obtained before
the addition of L-NAME. The
effects of bradykinin were again retested.
Study III: effects of bradykinin in the presence and absence of
captopril, ANG I, and ANG II.
In this series of experiments, we initially assessed whether the
effects of bradykinin were modified in the presence of captopril, a
converting enzyme inhibitor. We then assessed whether a similar modification of bradykinin action occurred in the presence of ANG I
which gets converted by the converting enzyme to ANG II.
Initially, the responses to bradykinin
(1018-1014
M) were elucidated in the absence of captopril. After this, captopril
(107 M) was added to the
perfusion medium and was perfused for at least 30 min before the
responses to bradykinin in the presence of captopril were reassessed.
This concentration of captopril was selected because it has been
previously shown to significantly inhibit the converting enzyme in the
fetoplacental vasculature (1).
In separate experiments, the same protocol was utilized, but instead of
captopril, ANG I (3 × 109 M) or ANG II (2 × 108) was used. The
concentrations of ANG I and ANG II perfused were selected on the basis
of their reported concentrations in the fetal circulation (14, 15).
Data Analysis
Decrease in mean perfusion pressure was measured as the percent
decrease in mean pressure below the stable perfusion pressure elicited
by inducing active tone in the fetoplacental vessels by U-46619.
Increase in mean perfusion pressure above the stable perfusion pressure
was measured as the percentage of increase in perfusion pressure
elicited by inducing active tone with U-46619. Values are expressed as
means ± SE. Comparisons of means were made by using Student's
t-test or ANOVA with repeated
measurements where appropriate. If a significant
F-value was found, a Bonferroni comparison between means was performed. Differences were considered to
be significant at P < 0.05. Four to
seven placentas were used for each experimental protocol.
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RESULTS |
Study I: Effects of Different Concentrations of ACh, Histamine, and
Bradykinin on the Placental Perfusion Pressure and Vascular Resistance
ACh (106 to
104 M) was without any
effect on the fetoplacental vasculature (data not shown). Histamine
(108 to
106 M) led to a
concentration-related relaxant effect (Fig.
1), and this was partially abolished by
cimetidine (Fig. 2). Bradykinin caused a
biphasic response. Usually at low concentrations
(1020 to
1016 M), there was a
concentration-dependent relaxation. This was followed by a diminution
in the relaxant effect followed by contraction (Fig.
3). However, there was considerable
interplacental variation in the response of the fetoplacental vessels
to bradykinin. The concentration of bradykinin when a biphasic response
was first observed also varied between different placentas. The effects of low concentrations of bradykinin
(1020 to
1016 M) were significantly
attenuated in the presence of HOE-140, the
B2 receptor antagonist (Fig.
4).
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Fig. 1.
Tracing showing effects of different concentrations of histamine (Hist)
on perfusion pressure in isolated, perfused human placental cotyledon.
Histamine administration to fetal side of placental vasculature led to
a concentration-dependent decrease in perfusion pressure.
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Fig. 2.
Effect of different concentrations of histamine in decreasing perfusion
pressure in absence and presence of
H2-receptor antagonist cimetidine.
Values are expressed as percent decrease in mean perfusion pressure ± SE. * Significantly different from corresponding
concentrations of histamine in absence of cimetidine
(P < 0.05).
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Fig. 3.
Effect of different concentrations of bradykinin in modulating
perfusion pressure. Values are expressed as percent change in mean
perfusion pressure ± SE. Lower concentrations decreased mean
perfusion pressure, whereas higher concentrations increased mean
perfusion pressure.
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Fig. 4.
Effect of lower concentrations of bradykinin (Bk) in decreasing mean
perfusion pressure in absence and presence of
B2-receptor antagonist HOE-140.
Values are expressed as percent decrease in mean perfusion pressure ± SE. * Significantly different from corresponding values in
absence of HOE-140 (P < 0.05).
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Study II: Effect of Inhibition of Cyclooxygenase and Endothelial NO
Synthase on the Responses to Bradykinin
Bradykinin at 1016 M
produced a vasodilator response followed by a biphasic response at
1014 M. There was initially
a decrease in perfusion pressure with 1014 M bradykinin, and this
was followed by an increase in perfusion pressure. After pretreatment
with indomethacin, the decrease in perfusion pressure at the two
concentrations was unaltered. However, the increase in perfusion
pressure observed with 1014
M bradykinin was significantly attenuated (Fig.
5). After addition of
L-NAME, there was significant
attenuation of the decrease in perfusion pressure observed with both
concentrations of bradykinin when compared with the values observed in
the absence of L-NAME (Fig. 5).
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Fig. 5.
Effect of lower concentrations of bradykinin in decreasing mean
perfusion pressure in absence and presence of cyclooxygenase inhibitor
indomethacin (IND) and nitric oxide synthase inhibitor
N-nitro-L-arginine
methyl ester (L-NAME). Values
are expressed as percent decrease in mean perfusion pressure ± SE.
* Significantly different from corresponding values obtained in
presence of any inhibitor (P < 0.05).
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Study III: Effects of Bradykinin in the Presence and Absence of
Captopril, ANG I, and ANG II
The vasodilator action of bradykinin
(1016 to
1014 M) was significantly
potentiated in the presence of captopril (Figs.
6 and 7).
Similarly, the effects of lower concentrations of bradykinin (1020 to
1016 M) were potentiated in
the presence of ANG I but not in the presence of ANG II (Fig.
8).
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Fig. 6.
Tracing showing decrease in perfusion pressure in isolated perfused
human placental cotyledon by low concentrations of bradykinin in
absence and presence of an angiotensin-converting enzyme inhibitor,
captopril (Capt). In presence of captopril, effects of bradykinin were
potentiated. GTN, glyceryl trinitrate.
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Fig. 7.
Effect of low concentration of bradykinin in decreasing mean perfusion
pressure in absence and presence of angiotensin-converting enzyme
inhibitor captopril. Values are expressed as percent decrease in mean
perfusion pressure ± SE. * Significantly different from
corresponding values in absence of captopril
(P < 0.05).
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Fig. 8.
Effect of different concentrations of bradykinin in decreasing mean
perfusion pressure in absence and presence of ANG I and ANG II.
* Significantly different from corresponding values in absence of
ANG I (P < 0.05).
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DISCUSSION |
The objectives of the present study were to reassess the effects of
some selective endothelium-dependent vasodilators on the fetoplacental
vessels and their potential physiological role with special relevance
to bradykinin. We utilized the dually perfused, isolated human
placental cotyledon for this study because this would allow the
endothelium-dependent vasodilators to initially come in contact with
the endothelium when these substances are added to the perfusate. This
would be more physiological than utilizing isolated strips of vessels
set up in organ baths where the vasodilators may have actions on both
the endothelium, releasing an endothelium-derived vasodilator, and a
direct contractile action on the vascular smooth muscle, thereby
producing opposing actions that may not have physiological relevance.
Our observations that ACh did not produce any decrease in perfusion
pressure, reflecting an absence of vasodilatory action in the
fetoplacental vessels, is similar to that reported by other investigators (25) and most likely reflects an absence of the muscarinic receptors of ACh on endothelial cells. In this regard, these
vessels appear to be different from adult vessels where the ACh
receptors are invariably present on endothelial cells and ACh produces
relaxation of both conduit and resistance vessels. The physiological
implications for the absence of ACh receptors on fetoplacental
endothelial cells is not known. Histamine, on the other hand, produced
a concentration-related decrease in perfusion pressure in the isolated,
perfused human placental cotyledon preparation similar to that reported
by others (13), indicating that histamine is able to relax
fetoplacental vessels. This action of histamine is most likely due to
its ability to release EDRF, now known as NO (9, 16), as has been
previously demonstrated by us and others (3, 22). Our observations
indicate that this vasodilation produced by histamine is most likely
mediated by the H2 receptors, because cimetidine, an H2-
receptor antagonist, was able to significantly attenuate this action of
histamine. One group of investigators demonstrated the ability of
histamine to release EDRF from perfused human umbilical artery, vein,
and umbilical vascular endothelial cells in culture but failed to
observe any relaxation of umbilical vascular preparations by histamine
when these preparations were mounted for isometric tension recording
precontracted with 5-hydroxytryptamine. On this basis, these authors
suggested that the umbilical arteries may have poor relaxant response
to cGMP-mediated vascular relaxation (22). This does not appear to be
the case, because we (3, 4) and others (12) have previously
demonstrated that fetoplacental vessels do relax by cGMP-mediated
mechanisms and that NO is more potent than prostacyclin in relaxing
fetoplacental vessels. The most likely explanation may be that in our
experiments histamine added to the perfusate initially came in contact
with the endothelial cells, leading to release of NO and thereby
producing vascular relaxation. On the other hand, when isolated tissues
in organ baths were utilized, the endothelial cells and vascular smooth muscles were simultaneously exposed to histamine, and the histamine, acting via H1 receptors, may have
produced constriction of the vessels that may have counteracted any
actions of NO released by endothelial cells. Other investigators have
also reported a decrease in perfusion pressure with histamine using the
dually perfused, isolated human placental cotyledon (13).
The actions of bradykinin on the fetoplacental vessels are
controversial. Some investigators have reported that bradykinin infusion increased perfusion pressure in the placenta (23), whereas
others (5, 17) observed no change. On this basis, we elected to assess
the effects of very low concentrations of bradykinin on the
fetoplacental vessels. Our observations are interesting that bradykinin
at very low concentrations decreases perfusion pressure, indicating a
vasorelaxant effect, and that at higher concentrations increases
perfusion pressure, indicating a vasoconstrictive action. Bradykinin
and related kinins act via two receptors designated as
B1 and
B2 receptors (18). Bradykinin has
a high affinity for binding to the
B2 receptors and a low affinity
for binding to B1 receptors (21).
At low concentrations, when perfused intraluminally, bradykinin comes
in contact with the endothelial cells and leads to a release of NO.
This action of bradykinin was mediated by the
B2 receptors because the actions of bradykinin were significantly attenuated when bradykinin was perfused in the presence of the
B2-receptor antagonist HOE-140. This vasodilator action of bradykinin was mediated by release of NO and
not by the vasodilator prostanoids because the vasodilator action of
bradykinin was significantly attenuated only in the presence of
L-NAME but was not affected by
indomethacin, an inhibitor of cyclooxygenase. As higher concentrations
of bradykinin were perfused, a biphasic response was observed over
certain concentration ranges followed by a vasoconstrictor response.
The concentrations at which this biphasic response was observed varied
slightly from one placenta to the other and most likely represent
variation in response to bradykinin in different placentas. The
abolition of a slight vasoconstrictor response to bradykinin observed
after pretreatment with indomethacin was most likely due to inhibition of thromboxane A2 release since
this was abolished by indomethacin. The vasoconstrictor response
observed with higher concentrations of bradykinin may be due to the
bradykinin being able to diffuse through the endothelial cell barrier
and coming in contact with the vascular smooth muscle, leading to
vascular smooth muscle contraction and thereby negating the
vasorelaxant effects of any NO released by bradykinin from the
endothelial cells. Our studies therefore indicate the importance of
using very low concentrations of endothelium-dependent vasodilators and
perfusing these substances intraluminally to demonstrate
endothelium-dependent vasodilation in fetoplacental vessels. These
factors may be the potential explanation for the contradictory
observations by other investigators where much higher concentrations of
bradykinin have been utilized in studies with perfused isolated human
placental cotyledons or in studies utilizing isolated vascular strips
of fetoplacental vessels in organ baths.
Our observation that bradykinin at low concentrations leads to
vasodilation of fetoplacental vessels may have important physiological implications. Concentrations of free bradykinin are higher in umbilical
venous and arterial cord blood than in maternal venous blood (10).
Bradykinin causes pulmonary vasodilation in the fetus, and it has been
shown that bradykinin is released following oxygenation of the fetal
lungs and that it is responsible at least in part for the normal
pulmonary vasodilation seen in the transition from fetal to
extrauterine life (8). It is possible that bradykinin is also
responsible for maintaining the fetoplacental vessels in a vasodilated
state. These vessels are not innervated (20); therefore, endogenous
circulating vasodilators must play an important role in modulating tone
in these vessels. Angiotensin-converting enzyme in the fetoplacental
vascular bed plays a key role in the regulation of fluid balance in the
fetus by converting ANG I to ANG II. This enzyme also inactivates
bradykinin (5). Our observation that the vasodilator effects of low
concentrations of bradykinin were potentiated by captopril, an
inhibitor of the converting enzyme, indicates that bradykinin is
degraded by this enzyme in the fetoplacental circulation. Other
investigators who have utilized higher concentrations of bradykinin and
observed a constrictor response have reported that captopril
potentiated the vasoconstrictor action of bradykinin in the human fetal
placental circulation (5). These findings support our observation that
converting enzyme is present in the fetal placental vascular bed.
Our observation that ANG I at concentrations present in the fetal
circulation but not ANG II (14, 15) potentiated the vasodilator effect
of bradykinin in the fetoplacental vessels may also have important
physiological implications. It has been demonstrated (14, 15) that the
level of plasma ANG II is higher in cord blood than in the maternal
circulation after vaginal delivery. The fetal pulmonary circulation has
a high vascular resistance and low blood flow because of the
cardiopulmonary bypasses through the ductus arteriosus and foramen
ovale. Thus it is not likely that the fetal lung is responsible for the
conversion of ANG I to ANG II. The placenta is one of the likely sites
for this conversion (24). However, the ANG II produced in the
fetoplacental circulation could lead to vasoconstriction and increase
in perfusion pressure as has been demonstrated in the isolated perfused
human placental cotyledon (7). However, if bradykinin competes with ANG
I for the converting enzyme leading to decreased degradation of
bradykinin and thereby potentiating the vasodilatory action of
bradykinin, this could then serve as a buffering mechanism to
counteract the simultaneous vasoconstriction produced by ANG II formed
from ANG I by the converting enzyme. Such a local buffering mechanism
must exist to counteract uncontrolled vasoconstriction in these
noninnervated fetoplacental vessels by the ANG II produced in order for
the fetus to survive.
In conclusion, our results indicate that selective
endothelium-dependent vasodilators can cause endothelium-dependent
vasodilatation in fetoplacental vessels. The action of these
vasodilators, specifically bradykinin, may have important physiological
relevance in maintaining vasodilation in the fetoplacental circulation.
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ACKNOWLEDGEMENTS |
This work was supported in part by National Institute of Child
Health and Human Development Grants HD-31467 and HD-31467-S.
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FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. Chaudhuri,
Dept. of Obstetrics and Gynecology and Molecular and Medical
Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095-1740 (E-mail: gchaudhu{at}obgyn.medsch.ucla.edu).
Received 11 December 1998; accepted in final form 23 March 1999.
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