AMERICAN
JOURNAL
OF PHYSIOLOGY
1971.
Printed
Vol. 221, No. 5, November
in U.S.A.
Effects of bradykinin
on the fetal cirmlation
N. S. ASSALI,
G. H. JOHNSON,
C. R. BRINKMAN
Department of Obstetrics and Gynecology and Physiology, UCLA
Los Angeles, California 90024
ASSALI, N. S., G. H. JOHNSON,
C. R. BRINKMAN III, AND D. J.
HUNTSMAN. Effects of bradykinin on the fetal circulation. Am. J. Physiol.
in the adult animal (8, 16, 29), prompted
us to investigate
its action on the fetal pulmonary,
systemic, and umbilical
circulation.
The intent was to find out if any similarity
exists between
the hemodynamic
action of exogenously
administered
bradykinin
and the circulatory
changes that
occur at birth.
197 1 .-Effects
of bradykinin
on pulmonary,
221(5):
1375-1382.
systemic,
and umbilical
hemodynamics
were studied
in near-term
fetal lambs.
Bradykinin
produced
profound
pulmonary
and sys-
temic vasodilatations; it increased pulmonary blood flow by diverting most of the right ventricular output toward the lung. Left ventricular
aortic
output
increased,
but effective
cardiac
output
(ascending
+ ductus flows) decreased
slightly.
The systemic
vasodilatadid not involve
the umbilicoplacental
circulation
whose blood
tion
flow decreased; a redistribution
of resistances and flows occurred
with
more
blood
shifted
toward
the fetal visceral
Venous
return
to the right heart
and right
ventricular
mained
unimpaired
despite
the decrease
in umbilical
of these circulatory alterations resemble those occurring
flows; resistances; pressure; pulmonary;
arteriosus; cardiac output
circulation.
filling
reflow. Some
at birth.
systemic; umbilical;
ductus
THE MAJOR
CIRCULATORY
CHANGES
that occur at birth are:
a) a fall in pulmonary
vascular resistance and pressure and
a marked increase in pulmonary
blood flow; b) a transient
fall in the systemic arterial pressure followed
by a progressive rise along with a decrease in the effective cardiac output
and an increase in the systemic vascular
resistance;
the
systemic changes become more evident after umbilical
cord
clamping;
c) a rise in both atria1 pressure with a greater
increment
in the left than in the right atrium; d> a constriction and eventual closure of the ductus arteriosus;
and, e)
if the umbilical
cord is not clamped,
a diminution
and
eventual cessation of umbilical
blood flow (1, 3, 12).
The ductus closure and the pulmonary
vasodilatation
have been attributed
partly to the rise in blood PO:! that
follows the onset of breathing
(1, 2, 4, 7) ; but the mechanisms by which oxygen produces these effects are not known.
The transient fall in the systemic arterial pressure has been
related to the changes in the ductus flow direction
which
becomes left to right (3). The subsequent
increase in systemic pressure and resistance and the decrease in the effective cardiac output have been attributed
largely to ductus
closure and to elimination
of the low-resistance
system of the
umbilicoplacental
circulation
(1, 3).
Recent reports have suggested that bradykinin
may play
an important
role in the transitional
circulatory
changes
that occur at birth (10, 17, 26, 28). It has been further
postulated
that the oxygen action on the ductus arteriosus
and on the pulmonary
vessels might be mediated
through
bradykinin
release (17). These hypotheses, together with the
interesting
hemodynamic
properties
of bradykinin
reported
III, AND D. J. HUNTSMAN
School of Medicine, Center for Health Sciences,
MATERIAL
AND
METHODS
A total of 26 near-term pregnant ewes of mixed breed and
their 29 fetal lambs were used in these studies. Each ewe was
fasted for 18-24 hr prior to the experiment.
The ewe was
placed on her left side on the operating
table and, under
local anesthesia, the right carotid artery and jugular
vein
were cannulated.
The carotid
artery catheter served for
recording
maternal
arterial
pressure and for collecting
arterial
blood samples anaerobically.
Anesthesia
was induced with an initial dose of 6-10 mg/kg of pentobarbital
administered
through
the jugular
vein catheter; additional
doses were given as needed to maintain
an adequate
anesthesia. An endotracheal
tube was inserted
through
a
tracheostomy
and the maternal
respiration
was supported
with compressed air using a positive-negative
pressure Bird
respirator.
The pregnant
uterine horn was partially
exteriorized
by
laparotomy
and was marsupialized
to the abdominal
walls
to prevent evisceration.
The fetus was then delivered
by
hysterotomy
and was marsupialized
to the edges of the
uterine incision
to protect the umbilical
circulation.
The
fetal head was covered with a saline-filled
glove to prevent
breathing.
A polyethylene
catheter was inserted into the
fetal femoral artery and was advanced into the descending
aorta; it served for arterial
pressure recording
and for
anaerobic
collections
of blood samples. Another
catheter
was inserted into the femoral vein and served for bradykinin
injections.
The fetal chest was entered
through
the fourth
leftintercostal
space and the main pulmonary
artery,
the
ascending
aorta, and the ductus arteriosus *were exposed.
The left phrenic and vagus nerves were kept intact in the
majority
of the animals.
The technical
steps described
above were performed
on
all animals. Additional
surgical procedures were carried out
according
to the experimental
protocol as follows:
A) Five fetal lambs served for the study of the effects of
bradykinin
on the pulmonary
circulation
only. In these
animals, the main pulmonary
artery and the ductus arteriosus were fitted with electromagnetic
flow transducers
and
their blood flows were recorded
simultaneously;
net pul1375
1376
monary
blood flo*w was estimated
from the difference
between these two flows (1). Pulmonary
artery pressure was
recorded
through
a Rochester-type
catheter inserted into
the pulmonary
artery and secured in situ with a pursestring suture. A similar catheter was inserted into the left
atrium and served for atria1 pressure measurement.
Right
atria1 pressure was monitored
through a catheter placed in
the right atrium through a jugular
vein.
B) Five fetuses served for studying
the effects of bradykinin on the fetal effective cardiac output only. In these, the
ascending aorta and the ductus arteriosus were fitted with
flow transducers and their blood flows were measured simultaneously. Fetal effective cardiac output was estimated from
the algebraic sum of these two flows (1).
C) Six other fetuses served for studying
the effects of
bradykinin
on both pulmonary
and systemic circulations
concommitantly.
In each of these animals, the three great
vessels namely, the main pulmonary
artery, the ascending
aorta, and the ductus arteriosus were fitted with flow transducers and their blood flows -were monitored
simultaneously.
This procedure
allowed estimation
of net pulmonary
flow,
effective cardiac output, and foramen ovale flow in the same
animal (1, 3). Pulmonary
artery and atria1 pressures were
recorded as in the series described under A.
D) In seven additional
animals, the effects of bradykinin
on the umbilica 1 circu la tion and the umbilical
fraction of
the
cardiac
output
were invest] .gated. In each animal,
intraperitoneal
segment of the main umbilical
vein was
exposed prior to its entrance into the liver and was fitted
with a flow transducer
to measure total umbilical
blood
flow. Flow transducers were also placed around the ascending aorta and ductus arteriosus to measure simultaneously
the effective cardiac output. A catheter was inserted into a
cotyledonary
branch
of the umbilical
vein and was advanced into one of the two main umbilical
veins where it
served to monitor umbilical
vein pressure. Systemic pressure
was measured through a catheter in the umbilical
artery or
aorta. In three of the seven animals, the inferior vena cava
pressure was measured
through
a catheter
introduced
through a femoral vein and placed in the vena cava past the
liver as previously described (9). The location of the catheter
was checked at the end of the experiment.
E) To test whether
the changes in ductus blood flow
elicited by bradykinin
were due to a direct action of this
substance on the ductus itself or were secondary to changes
in the pulmonary
vascular bed (see RESULTS), the following
two series of experiments
were performed:
in three fetuses
after exposing the great vessels, the circulation
to the lungs
was bypassed by introducing
a shunt with a polyethylene
tube between the left branch of the main pulmonary
artery
and the left fetal jugular
vein. The right branch
of the
pulmonary
artery was ligated.
Blood flows in the main
pulmonary
artery, ductus arteriosus,
and ascending aorta,
as well as systemic and pulmonary
artery pressures, were
monitored
continuously.
This preparation
eliminated
the
variables connected with the pulmonary
vascular bed.
In another three lambs, the ductus arteriosus was ligated.
Main pulmonary
a rtery a.nd ascending aortic flows as well
vascular pressures were monias svstemic and pulmonary
tored. These last experimen ts allowed testing of bradykinin
ASSALI,
JOHNSON,
BRINKMAN,
AND
HUNTSMAN
action on the pulmonary
circulation
in the absence of the
ductus arteriosus.
All blood flows were measured using cuff-type, balancedfield electromagnetic
flow transducers
and amplifiers
previously described
(3 1). Each transducer
was selected to fit
each vessel snugly but without
undue constriction.
The
transducers
were calibrated
in vitro, and a calibration
factor obtained for each as described in detail elsewhere (5).
Blood flow rate in each vessel was calculated
from the
product
of the calibration
factor of that particular
transducer and the integrated
flow deflection (electronic
integrator) elicited on the Dynograph.
The error in this method
for any given flow in the great fetal vessels is no more than
zt 5%.
Vascular pressures were measured with matched Statham
DB-23 strain gauges calibrated
to a common zero base line.
Phasic and integrated
pressure and flow signals were recorded on an Offner Dynograph
and on an Ampex magnetic tape. Net pulmonary
blood flo’~, effective cardiac
output, and pulmonary,
systemic, and umbilical
vascular
resistances were computed
by formula previously described
(1, 3). Heart rate was obtained from the phasic pressure or
flow records. Maternal
and fetal blood pH, POT and Pcoz
were analyzed
using the Radiometer
acid-base
analyzer
with
a microblood-gas
(type PHM7 1), in conjunction
apparatus.
Technical
details of the surgical procedures
as
well as those of measuring
flows, pressures, and blood gases
have appeared
in several publications
(2, 3, 4, 9, 19).
The experimental
protocol comprised
the following :
A control period of 30 min was observed during which
flows and pressures were allowed
to stabil .ize and were
recorded continuously;
blood gases were analyzed at IO-min
intervals.
A drug-testing
period then followed during which bradykinin was administered
intravenously
in single-bolus
injections in progressively
increasing
amounts. At the conclusion
of each experiment,
the fetal weight was obtained
and the
amounts of the drug used were converted
on the basis of
body weight; a dosage range of Z-700 rig/kg of fetal body
wt was obtained.
Each dose was tested at least 12 times and
the effects of each injection
on flows and pressures were
monitored
continuously.
Adequate
time was allowed
between subsequent injections for the pressures and flows to
return to control values. Blood respiratory
gases and pH
were analyzed every 5 min during this period.
In addition
to single intravenous
doses, the effects of
continuous
infusion of bradykinin
were tested. In these
cases, the drug was administered
via the femoral vein at
rates of 5-10 rig/kg per min for 3-5 min. Flows and pressures were monitored
continuously
before, during, and after
interruption
of the infusion.
In a few lambs, the effects of small doses of bradykinin
injected into the main pulmonary
artery were tested.
RESULTS
Control data. Average
values for blood flows, vascular
pressures, and blood respiratory
gases and pH recorded
after completion
of surgery and prior to bradykinin
administration
are listed in Table 1. These figures are within
the range of values obtained
by us in previously
published
experiments
(1, 2, 3, 19).
BRADYKININ
AND
FETAL
1377
CIRCULATION
TABLE
1. Values for fetal blood jaws, vascular pressures, and
blood respiratory gases and PH recorded in control period after
completion of surgery and prior to bradykinin injection
65
70
111
96
142
46
181
22
43
7.28
Systemic
arterial
pressure,
mm Hg
Pulmonary
artery
pressure,
mm Hg
Ascending
aorta flow, ml/kg
per min
Ductus
arteriosus
flow, ml/kg
per min
Main pulmonary
artery
flow, ml/kg
per min
Net pulmonary
flow, ml/kg
per min
Effective
cardiac
output,
ml/kg
per min
Aortic
blood Paz, mm Hg
Aortic
blood Pco~, mm Hg
Aortic
blood pH
Values
are means
parentheses.
& 1
Number
SD.
zt
rt
zt
zt
=t=
zt
rfr
zt
=t:
=t
of measurements
4 (70)
6 (35)
16 (35)
22 (56)
18 (35)
22 (35)
24 (35)
6 (70)
8 (70)
.08 (70)
is given
in
+60
Pulmonary
Arterlul
tory changes produced
by injection
of bradykinin
into the
main pulmonary
artery were not significantly
different
from those observed after administration
by the femoral
vein.
Ductus arteriosus blood flow decreased invariably
following the in.jections of bradykinin
(Figs. 2 and 3). The response of this vessel -was also progressive up to 20-30 rig/kg;
thereafter increasing
the dose produced
no further decrease
in ductus blood flow (Fig. 7).
In order to assess the maximum
response of the pulmonary
circulation
including
the ductus arteriosus
to bradykinin,
the changes in all animals included
in series A and C (see
MATERIALS
AND
METHODS)
observed after doses of 40-700
rig/kg (the flat portion
of the dose-response
curve) were
pooled together
and were plotted
as percent
of control
values (Fig. 4). Maximum
decrease in pulmonary
artery
pressure averaged
40 % while the maximum
increase in
main pulmonary
artery flow averaged about 80%. Mean
ROW
Exp No. 9
Aug. 19, 1970
Fetus 5.1 kg
km 7
/- ---,_
‘.
504
.---I
AORTIC
PRESSURE
mm Hq
--
4m
-.-.
1,
..
--
-
\
^
--
-----
O-
20”, ,, 40,
60,
80,
100”
, ,,
Dose (Nanogram
,
,
,
,
,
200
300
400
500
600
,
700
1 kg)
100
PULMONARY
ARTERY
PRESSURE
mm Hg
7
5oj
.
DUCTUS
;;iV;RIOSUS
ml / min
-30
-4ol-
1. Dose-response
pressure and flow.
FIG.
tery
PULMONARY
ARTERY
FLOW
ml / min
-
P ulmonory
relationship
Ar fer-ii/
Pressure
of bradykinin
4 nangr
in pulmonary
ar
E$ects on pulmonary and ductus arteriosus circulation. The response of the pulmonary
vascular bed to progressively
increasing doses of bradykinin
is illustrated
in Fig. 1. The
data in this figure ‘were those collected from the experiments
listed under A and C (see MATERIALS
AND
METHODS).
Each
datum represents the mean I-+ 1 SE of all the tests made for
each dose. The response of a given circulatory
parameter
to
each dose was taken as the maximum
change observed after
the injection. This value ‘was then plotted as percent of the
average of several control readings taken prior to the injection. Figure 2 illustrates
a typical example of phasic and
integrated
responses in the systemic and pulmonary
artery
pressure and in the ductus and main pulmonary
artery
flows to different doses of bradykinin.
Figure 3 illustrates an
example in which pulmonary
artery, ductus, and ascending
aortic flows were recorded
simultaneously
with the atria1
and vascular pressures.
Intravenous
administration
of single doses of bradykinin
consistently
produced
a prompt
and equal fall in systemic
and pulmonary
artery pressures. Pulmonary
artery blood
flow increased
simultaneously
with the fall in pressure
#(Figs. l-3). The dose-response relationship
of the pulmonary
Ocirculation was nearly linear between 2 and cit. 20 rig/kg.
Within
this dose range, the increase in pulmonary
blood
flow
was greater than the decrease in pulmonary
artery
pressure (Fig. 1). Dosages from 20 to 700 rig/kg produced no
greater response than that of 20 rig/kg (Fig. 1). The circula-
chart
speed
mm /set
/ kg
8 nangr
/kg
16 nangr
/kg
40
nangr
/ kg
5
FIG.
2. Segments
of a record
depicting
effects of various
intravenous tdoses of bradykinin
on pulmonary
artery and aortic pressures
and on 1 pulmonary
artery
and ductus arteriosus
flow.
PdJd_-rME;~ARY
PRESSURE
m m Hg
AORTIC
PRESSURE
m m Hg
RIGHT
ATRIAL
PRESSURE
m m Hg
LEFT
ATRIAL
PRESSURE
m m Hg
f”Lff;NARY
FLOW
ml / min
DUCTUS
;FM&RIOSUS
ml / min
ASCENDING
t%iA
ml / min
?
t
92 nangr / kg
chart speed:
mm /set
I
369 nangr / kg
5
FIG. 3. Segments
of a record showing effects of 2 different
doses of
bradykinin
on pulmonary
and systemic
circulations
including
left
and right atrial pressures. Note reciprocal
changes in pulmonary
and
ductus flows. Note also greater rise in left than right atria1 pressure,
1378
ASSALI,
Pulm.
t-
Pulm.
Art. Flow
Net Pulm.
-120
L. Atrial
/SE
I
-100
I
-80
I
-60
1
-40
-I
Ductus
Flow
Pulm.
Vast.
Flow
R. Atrial
I---
Press.
1-b
4-1
I
Art.
Press.
-
Press.
---
Res.
I
I
I
-20
0
I
+20
I
+40
I
+60
+80
l//l
+lOO
+200
I
+300
I
+400
% CHANGES
FIG. 4. Maximum
changes in pulmonary
hemodynamics
and atria1
pressures in response to 40-700
r&kg
of bradykinin.
Note marked
increase
in net pulmonary
blood flow and decrease
in pulmonary
vascular
resistance.
Note also difference
between
left and right atria1
pressure increments.
TABLE
2. Changes in pulmonary and systemic circulations
response to 15-20 rig/kg of bradykinin when ductus was
occluded or when pulmonary vascular bed was bypassed
JOHNSON,
BRINKMAN,
AND
HUNTSMAN
the dose-response
relationship
of the systemic circulation
including
the response of the ductus arteriosus. The systemic
arterial pressure responded
in a manner similar to that of
the pulmonary
artery
pressure. A progressive
decrease
occurred between doses of 2-20 rig/kg. Thereafter,
increasing the dose produced
no further systemic arterial pressure
decrement
(Fig. 7).
Ascending
aortic flow increased
progressively
up to 20
rig/kg; but thereafter the dose-response
curve became flat
(Fig. 7). For any given dose, the increment
in ascending
aortic flow was significantly
less than that of the pulmonary
flow (Figs. 1 and 7). Ductus arteriosus blood flow decreased
in a manner similar to that observed in the series of pulmonary studies (Fig 7).
Figure 8 presents the maximum
systemic hemodynamic
changes produced
by doses of 40 rig/kg and above in all
animals in which ascending aortic and ductus blood flows
in
Bradykinin
Systemic
Pressure
mmHg
Arterial
I.V.
&
6o
0.3 pg
Fetal weight 4.1 kg
Experiment
1A LUNGS
BYPASSiD
0
Ductus Occluded
Systemic
arterial
pressure
Pulmonary
artery
pressure
Main
pulmonary
artery
flow
Ascending
aorta flow
Ductus
arteriosus
flow
Heart
rate
-25
-30
+27
+18
=f=
It
rt
rt
2
2
8
6
(18)
(15)
(15)
(15)
Lungs Bypassed
-28
-26
3-18
+16
+20
0 (1%
Values
are net percent
changes
from
Number
of tests is given in parentheses.
control
values
=f= 3 (15)
=t 5 (12)
zt: 9 (12)
=t 8 (12)
xt 10 (12)
0
=t
1
Pulmonary
Pressure
mmHg
Arterial
60
0
SE.
decrease in ductus blood flow also was about 80 %. Net
pulmonary
blood
flow (main
pulmonary
artery-ductus
flow) rose, and pulmonary
vascular resistance decreased
strikingly
(Fig. 4). Both right and left atria1 pressures increased, but the increment was greater in the left than in the
right atrium (Figs. 3 and 4).
In view of the fact that the decrease in ductus flow was of
the same magnitude
as the increase found in the pulmonary
blood flow, we designed the experimental
protocol described
under E (see MATERIALS
AND METHODS)
to investigate whether
the ductus changes produced
by bradykinin
were primary
or secondary to the blood shift caused by the pulmonary
vasodilatation.
When the pulmonary
vascular bed was bypassed, bradykinin produced
the usual equivalent
fall in systemic and
pulmonary
artery pressures (Table
2 and Fig. 5). Ductus
blood flow, however,
instead of decreasing
as previously
described, increased consistently;
the increment
was of the
same magnitude
as that of the main pulmonary
artery blood
flow (Table 2 and Fig. 5). It is of interest that, in the absence
of the pulmonary
circulation,
the action of bradykinin
lasted longer (Fig. 5).
In the experiments
in which the ductus arteriosus was
occluded,
bradykinin
produced
the typical
decrease in
systemic and pulmonary
pressures and the increase in main
pulmonary
artery and ascending
aortic blood flow as observed in the other animals (Table 2 and Fig. 6).
Effects on systemic circulation. Figure 7 presents the data on
820
Main Pulmonary
Arterial
Flow
mlimin
410
p
0 :
FIG. 5. A representative
example
of effects of bradykinin
in a fetus
with lung vasculature
bypassed.
Note that ductus arteriosus
flow increased instead of decreasing.
Increase
was largely
in diastolic
flow.
Note also more prolonged
action of bradykinin
(see text).
120
Bradykinin
r
Pulmonary Arterial
Pressure
mmHg
I.V. 0.5 ug
G
Fetal weight 4. 7 kg
Experiment 4A DUCTUS OCCLUDED
OL
Systemic Arterial
Pressure
mmHg
ASC. Aortic Flow
mllmin.
360
0
6. A typical
example
of effects of bradykinin
ductus
arteriosus
occluded.
Note that pulmonary
fell and main pulmonary
artery flow increased despite
tus circulation
(see text).
FIG.
in a fetus with
artery
pressure
absence of duc-
BRADYKININ
AND
+4ok
FETAL
CIRCULATION
1379
Ascending
;lSE.
Dose (Nanogram/kg
Ductus
Aorflc
)
Flow
FIG. 7. Dose-response relationship of bradykinin
circulation including ductus arteriosus.
l-1
1
-i30
-80
Flow
in fetal systemic
monary artery flow exceeded the sum of OAA and QD.
Foramen
ovale flow decreased by about 50% and became
negative, i.e., from left to right.
Effects on umbilical circulation and on inferior vena cava pressure.
Figure 9 illustrates
a representative
example of the effects
of bradykinin
on systemic arterial (equivalent
to umbilical
arterial)
and venous pressures and on the blood flows in the
umbilical
vein, ascending
aorta, and ductus arteriosus.
Figure 10 presents the average changes in these circulatory
parameters
including
those in the inferior cava pressure.
Intravenous
administration
of bradykinin
decreased the
pressure in the umbilical
artery and vein in a similar manner
and by an equivalent
amount (about 40 %) (Figs. 9 and 10).
Total umbilical
blood flow also decreased by an average of
40%, umbilical
vascular resistance did not change significantly (Fig. 10). Effective cardiac output fell only slightly
but the fraction
of the cardiac output
destined for the
placenta decreased markedly
(Fig. 10).
Heart Rate
S.E.
/
I
-60
I
-40
,
-20
I
0
+20
I
+40
!
+60
1
+80
I
+I00
% CHANGES
FIG. 8. Maximum
changes
in aortic
pressure,
ductus
and
aortic
flows, effective cardiac output, systemic vascular resistance, and
heart rate in response to doses of bradykinin, 40-700 rig/kg. Note
marked
decrease
in systemic
vascular
resistance.
Effective
cardiac
output changed
very little because decrease in ductus flow was offset
by increase in ascending
aortic flow.
were measured simultaneously
(series B and C). Systemic
arterial pressure decreased by an average of about 40%,
and ductus flow decreased by an average of 80 %. Maximum
increase in ascending aortic flow averaged about 70 % (Fig.
8). Because of the opposite changes in ductus and ascending
aortic flows, the effective cardiac output of the fetus (ascending aortic + ductus flows) decreased only slightly but the
changes were not significant;
fetal systemic vascular resistance fell markedly
(Fig. 8).
Foramen ovale flow. Blood flow through the foramen ovale
(OFO)
was estimated in the animals included
in ..series C
(see
MATERIALS
AND
METHODS)
using
the formula:
QFO =
(OAA .+ GDA) - QPA; where Q&A = ascending aortic
flow, QD = ductus arteriosus
flow, and QPA
= main
control
values for this
pulmonary
artery flow. Average
series of experiments
was 5? f 15 ml/kg per min. In the
control period, the sum of QAA and QD was greater than
QPA, and foramen flow was from right to left. After bradykinin injections,
left atria1 pressure increased much more
than right atria1 pressure and the decrement
in ductus flow
was greater than the increment
in ascending
aortic flow.
Consequently,
in the majority
of instances, the main pul-
FIG. 9. Segments
of a record
illustrating
simultaneous
effects of
bradykinin
on systemic
and umbilical
circulations.
Note
parallel
fall in systemic
and umbilical
vein pressures
and umbilical
blood
flow.
Inf. vena cava press.
-
Umb V Press
i Unk
b--lS.E
I
-80
I
-60
-40 ’
Vast. Res.
-217
hk~orzkz&
% CHAhGES
FIG.
10. Maximum
changes in umbilical
circulation
and in umbilical
fraction
of cardiac
output
in response
to bradykinin.
Note
unchanged
umbilical
vascular
resistance and marked
fall in umbilical
fraction.
Note also divergent
effects on umbilical
vein and inferior
vena cava pressures.
1380
While bradykinin
decreased umbilical
vein pressure, it
increased consistently the pressure in the inferior vena cava,
between the ductus venosus and right atrium, by an average
of over 75 % (Fig. 10).
of instances,
E$ects on heart rate. In the great majority
intravenous
administrations
of single doses of bradykinin
up
to 700 rig/kg did not alter the heart rate appreciably.
However, in occasional
animals, a bradycardia
occurred
after
large doses. Such a bradycardia
was unpredictable
and not
reproducible.
When it did occur, however, all pressures and
flows in the pulmonary
and systemic circulations
decreased.
E#ects of continuous infusion. The pattern of the circulatory
changes produced
by continuous
intravenous
infusion of
bradykinin
was similar to that of a single rapid injection.
However,
pressures and flows tended
to return
toward
control values after 2-3 min despite continuation
of the
infusion. These findings are in agreement with other reports
(8, 16, 29).
E$ects on blood respiratory gases andpH. Neither single intravenous injections nor continuous
infusion of bradykinin
had
any effect on fetal blood POT, Pco~, or PH.
DISCUSSION
The available
information
indicates that the circulatory
effects of bradykinin
vary according
to: a) animal species,
b) the vascular bed under observation,
c) the dose, d) the
interaction
of bradykinin
with other vasoactive substances,
and e) the integrity of the autonomic
nervous system (8, 16,
28, 29). Despite the variation,
it is generally
agreed that,
in the adult animal, bradykinin
produces a fall in the systemic vascular pressure and resistance and an increase in
the cardiac output (8, 16, 28, 29). Bradykinin
also produces
coronary, cerebral, and splanchnic
vasodilatation
(20, 30).
The action of bradykinin
on the pulmonary
circulation
of the adult animal is somewhat more complex than that on
the systemic circulation.
Pulmonary
vascular resistance may
not change or may decrease somewhat,
but pulmonary
artery pressure may rise slightly depending
on the animal
species (8, 16, 18, 2 1). The decrease in pulmonary
vascular
resistance has been attributed
to the increase in cardiac
output and pulmonary
blood volume (8, 16, 18, 2 1).
The reports on the response of the venous system to
bradykinin
are not consistent.
Some authors (6, 14, 18)
have observed venous constriction
following
bradykinin;
others believe the primary
action is venous dilatation
(28).
In the neonatal
period, endogenously
generated
bradykinin is believed to promote the pulmonary
vasodilatation
and the ductus arteriosus constriction
that occur with initiation of breathing
( 10, 17, 26, 28). Blood concentrations
of
bradykinin
have been found to be higher in the neonatal
than in the fetal lamb ( 17, 26) ; higher concentrations
were
also observed in fetal lambs whose blood Paz was raised with
hyperbaric
oxygenation
( 17). Isolated
observations
on
exogenous administration
of bradykinin
(4-10 ng) to fetal
lambs showed a rise in pulmonary
blood flow ( 10, 17).
The present studies carried out on fetal lambs with intact
umbilical
circulation
and unexpanded
lung show that
bradykinin
action
is
somewhat
different
from
that observed
,
in adult animals.
Pulmonary circulation. Unlike in the adult animal
bradv-
ASSALI,
JOHNSON,
BRINKMAN,
AND
HUNTSMAN
kinin in the fetus invariably
produced
a marked fall in
pulmonary
vascular pressure and resistance and a striking
increase in net blood flow. This pulmonary
vasodilatation
occurred irrespective
of the dose and site of injection.
It could be argued that : I) the fall in the fetal pulmonary .
artery pressure produced
by bradykinin
is secondary
to,
the systemic hypotension
since the two vascular beds are
connected
by the ductus arteriosus;
and 2) the increase in.
net pulmonary
blood flow is secondary to a shift of blood
from the ductus arteriosus which was primarily
constricted
by bradykinin.
Since ductus occlusion did not eliminate the
pressure fall or the flow increase, it 1s obvious th .at the
changes in pulmona ry hemodynamic
s are caused by an,
active dilatation
of the pulmonary
vascular bed by bradykinin.
The reasons for the difference between the adult and fetal
pulmonary
vascular responses to bradykinin
are not clear.
Campbell- and his co-workers
( 10) observed a considerably
smaller pulmonary
response to bradykinin
in 5- to 14-weekold (newborn)
than in fetal lambs; the response of the
neonatal
lamb became greater when the lungs were collapsed and pulmonary
vascular resistance increased. These
authors suggested that the magnitude
of changes depends
a great deal on the initial status of the pulmonary
vessels.
Since in the neonate and in the adult animal the pulmonary
vessels are already widely dilated and the pressure is low,
the response to bradykinin
is less. This plausible hypothesis
may explain
a smaller response; it may not be sufficient,
however, to explain a reversal of pressure effect, namely, a
rise in the pulmonary
artery pressure as often observed in
the adult animal as opposed to the profound
pulmonary
hypotension
of the fetus.
Ductus arteriosus circulation. Bradykinin
decreased ductus
blood flow consistently
by an amount
equivalent
to the
increase in the main pulmonary
artery blood flow. The
decrease was not related to changes in such factors as the
pressure gradient
across the ductus, the blood POT or the
right ventricular
output since the first two factors were not
altered and the latter increased. The decrease in ductus flow
produced
by bradykinin
could then be due to either an
active ductus constriction
or passive contraction
secondary
to the pulmonary
vasodilatation.
The data obtained
from
the experiments
in which the pulmonary
vascular bed was
bypassed show a reversal of ductus response to bradykinin.
In every instance,
an increase instead of a decrease in
ductus blood flow occurred
and the increment
was similar
to that which occurred in the main pulmonary
artery blood
flow. These observations
seem to indicate
that the fall in
ductus flow produced
by bradykinin
is most likely to be
secondary
to a shift of blood to the dilated
pulmonary
vessels.
True, in vitro observations
have shown that the ductus
arteriosus
contracts
under the action of bradykinin
(22).
But similar
ductus contractions
have been observed in
vitro in response to a variety of stimuli (23, 25). When some
of these stimuli are tested in vivo, however,
the hemodynamic effects on the systemic and pulmonary
circulation
render the ductus response so complex
that it may not
correspond
to the simple in vitro system (4, 27).
Systemic circulation. The present data show that the systemic vasodilatation
produced
by bradykinin
in the fetus is
BRADYKININ
AND FETAL
CIRCULATION
closely similar to that observed in the adult animal (8, 16,
29). However,
comparison
of the effects of bradykinin
on
the cardiac output of the fetus and the adult animal cannot
be made for reasons of anatomic and physiologic
differences.
In the fetus, because of the ductus arteriosus,
we define
effective cardiac output as the algebraic
sum of ascending
aortic flow (roughly
left ventricular
output)
and ductus
flow ( 1, 3). Since, in the present experiments,
ductus blood
flow decreased by an amount greater than the increase in
ascending aortic flow, the effective cardiac output decreased
slightly. The increase in left ventricular
output produced
by
bradykinin
was obviously caused by the marked increase in
blood returning
from the lungs to the left side of the heart.
But the increment
in ascending aortic flow was always less
than that of the net pulmonary
blood flow. The discrepancy
could be due to one or a combination
of the three following
factors: a) Bradykinin
increased
fetal pulmonary
blood
volume through a rise in vascular compliance.
b) Bradykinin
dilated
the fetal coronary
circulation
and increased
the
coronary fraction of the cardiac output. Such an increase
would have been missed since our method of measuring
left
ventricular
output does not include coronary flow. c) Some
of the blood returning
from the lungs passed through
the
foramen ovale to the right side of the heart. This latter
possibility will be discussed further below. At any rate, as in
the adult, bradykinin
must have acted on the peripheral
vascular resistance to produce
the systemic vasodilatation
seen in the fetal lamb. But the regional site of the peripheral
vasodilatation
is considerably
more complex than that of the
adult circulation.
Umbilical circulation and venous return. The complexity
is
related to the interesting
effects of bradykinin
on the umbilicoplacental
circulation.
The equivalent
fall in the arterial
and umbilical vein pressures and in the total umbilical
blood
flow indicates an unaltered
umbilical
vascular resistance
following bradykinin
administration.
This puzzling
action is
not in keeping with the marked fall in the total fetal systemic
resistance to which the umbilicoplacental
vascular bed contributes a great deal. The fall in the umbilical
artery pressure
reflects the overall systemic arteriolar
dilatation;
it is not,
however,
consistent with the in vitro observations
which
show that bradykinin
constricts the human umbilical
artery
(11, 15). Th is d iscrepancy could be due either to the difference in sensitivity to bradykinin
between the human and
the sheep umbilical
artery (24) or to the inherent differences
in the in vivo and in vitro experimental
results. The fall in
the umbilical
vein pressure indicates
either dilatation
of
these vessels by bradykinin
or relaxation
of the ductus
venosus or both. At any rate, in the presence of such a
massive umbilical
arterial
and venous relaxation,
one
would expect an increase in flow. Yet, umbilical
blood flow
decreased instead of increasing.
This decrease can be explained on the basis of either pooling
of blood in the placenta, or redistribution
of blood
flows and resistances
between the placenta and other fetal organs. In view of the
marked decrease in the fraction of cardiac output destined
to the placenta, we are inclined to believe that bradykinin
produces a marked vasodilatation
in other parts of the fetal
organism
(most likely the visceral
circulation)
; hence,
blood flow is redistributed
and is shifted from the placenta
toward these other dilated regions. This hypothesis receives
1381
further support from the fact that, despite the decrease in
the umbilicoplacental
blood flow, the inferior vena cava
and the right atria1 pressures increased along with the right
ventricular
output. These changes indicate an unimpaired
venous return to the right heart. Of course, it is possible
that bradykinin,
while dilating
the umbilical
veins, constricted the other parts of the venous system, including
the
vena cava, maintaining,
thereby, a normal venous return.
Or, that the rise in the inferior vena cava and right atria1
pressures was caused by a passage of blood from the left to
the right atrium through
the foramen ovale. This passage
would be facilitated
by the marked rise in the left atria1
pressure secondary to the increased pulmonarv
blood flow.
We realize that our estimates of foramen ovale flow involve
a large error due to multiple
flow measurements.
Nevertheless, they do suggest a reversed flow, i.e., from left to right.
Similar changes in left and right atria1 pressures have been
observed after fetal lung expansion
with air or oxygen
despite a marked decrease in umbilical
flow (3, 13). There is
no obvious reason to believe that the foramen ovale flow
would be always unidirectional,
that is from right to left,
and that this shunt should close promptly
and totally upon
raising the left atria1 pressure.
The increase in right ventricular
output (main pulmonary
artery blood flow) observed when the lungs were bypassed
seems to suggest a positive inotropic
effect on the fetal heart.
Such an action has been observed in the adult animal (8, 16,
29). The increase could also be secondary to the systemic
vasodilatation
since the two vascular beds are connected by
the ductus arteriosus.
In attempting
to integrate all these hemodynamic
alterations produced ‘by bradykinin
in the fetus, we can state that
this substance produces a profound
pulmonary
vasodilatation, diverting,
thereby, most of the right ventricular
output
toward the lungs. This leads to an increase in the left venOn the systemic side, bradykinin
also
tricular
output.
produces a marked vasodilatation
which is directed more
toward the visceral than the umbilical
circulation.
A redistribution
of flows and resistances occurs through which blood
is shifted from the placenta
toward
the rest of the fetal
circulation.
This seems to insure an adequate venous return
to the right side of the heart and a higher than normal right
ventricular
output.
In comparing
the circulatory
changes produced by bradykinin to those occurring
during the transitional
period of
neonatal life, similarities
definitely exist. The changes in the
pulmonary
and umbilical
circulations
and in the cardiac
functions produced
by bradykinin
are not greatly different
from those observed after lung expansion with air or oxygen
(1,3, 12). The only obvious difference is the decrease in the
systemic vascular
resistance
and pressure produced
by
bradykinin
-which usually does not occur after birth. But
here the situation is complicated
by the presence of an intact
umbilicoplacental
circulation.
In the fetal lamb, expansion
of the lungs without
clamping
the umbilical
cord produces
a transient fall in the aortic pressure (1 y 3). Although
this
fall has been attributed
to the change in the direction
of
ductus flow, there is no reason to believe that it cannot be
due to other factors. The arterial pressure rises after clampelimination
ing the cord; but under these circumstances,
of the low resistance of the placenta plays a major role. If
the cord is not clamped for several minutes after lung ven-
1382
tilation,
the blood flow through
the umbilicoplacental
vascular bed decreases progressively
and is shifted to the
visceral vasculature
which undergoes
a dilatation
(1, 3).
These changes are again similar
to those produced
by
bradykinin.
ASSALI,
JOHNSON,
BRINKMAN,
AND
HUNTSMAN
The authors are indebted
to Sandoz Pharmaceuticals
for the supply
of bradykinin
and to Mr. R. Cutait for his technical
assistance.
This study was supported
by National
Heart and Lung Institute
Grant HE O1755*
Received
for publication
‘23 April
1971.
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