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The Journal of Clinical Endocrinology & Metabolism 87(6):2838 –2842
Copyright © 2002 by The Endocrine Society
Short-Term Effects of Glucocorticoids in the Human
Fetal-Placental Circulation in Vitro
VICKI L. CLIFTON, EUAN M. WALLACE,
AND
ROGER SMITH
Mothers and Babies Research Centre (V.L.C., R.S.), Department of Endocrinology, John Hunter Hospital, University of
Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales 2310, Australia; and Department of
Obstetrics and Gynaecology (E.M.W.), Monash Medical Centre, Monash University, Clayton, Victoria, 3168 Australia
A number of studies demonstrate that both long-term and
short-term exposure to glucocorticoids alters vascular function. We have examined whether the short-term administration of glucocorticoids into the human fetal-placental circulation affects placental arterial pressure and alters vascular
responses to vasoconstrictive and vasodilator agents. Single
lobules of term human placentae were bilaterally perfused in
vitro with Krebs’ solution (maternal and fetal, 5 ml/min Krebs,
95% O2, 5% CO2, 37 C, pH 7.3), and changes in fetal-placental
arterial perfusion pressure were measured. Dexamethasone
(100 nM) infusion for 1 h into the fetal-placental circulation
caused a significant decrease in basal arterial pressure (n ⴝ
19, t test, P < 0.05). Continuous dexamethasone infusion (100
G
LUCOCORTICOIDS PLAY a central role in the regulation of blood pressure and vascular tone. Long-term
administration of glucocorticoids are known to induce hypertension in humans (1). The mechanisms by which glucocorticoids increase vascular resistance have been the subject of many investigations. A number of studies report that
glucocorticoids cause hypertension through the inhibition of
cyclo-oxgenase (2) and nitric oxide (NO) synthase (NOS) (3),
increased synthesis of endothelin-1 (4), up-regulation of dihydropyridine sensitive l-type calcium channels (5) and
other pathways associated with increases in intracellular calcium concentrations (6 –9).
The placental circulation is maintained throughout gestation in a constant state of dilation to optimize the transfer of
oxygen and nutrients to the fetus (10). It would be detrimental to fetal development if placental vascular resistance
increased (11) with the progressive rise in maternal cortisol
concentrations during gestation (12). There are a number of
protective placental mechanisms that regulate the effects of
maternal cortisol on the fetal compartment including 11␤hydroxysteroid dehydrogenase type 2 (11␤-HSD 2), which
inactivates cortisol to cortisone and fetal membrane 11␤-HSD
type 1 that converts cortisone to cortisol (13). However, synthetic glucocorticoids such as dexamethasone or betamethasone are not substrates for these placental enzymes (14) and
could potentially alter vascular function for example through
the increased production of vasoconstrictive prostaglandins
(PGs) (15). In 1999, Wallace and Baker (16) reported that, in
human pregnancies complicated by absent end diastolic flow
of the placental circulation, betamethasone administration
Abbreviations: 11␤-HSD 1 or 2, 11␤-Hydroxysteroid dehydrogenase
type 1 or 2; NO, nitric oxide; NOS, nitric oxide synthase.
nM) did not alter vasoconstrictive responses to PGF2␣ (0.5–120
pM, n ⴝ 12, ANOVA, P > 0.05) or potassium chloride (5– 600 mM,
n ⴝ 12, ANOVA, P > 0.05) or vasodilator responses to CRH
(53–7400 pM, n ⴝ 13, ANOVA, P > 0.05). However when fetalplacental vessels were submaximally preconstricted and then
infused with dexamethasone alone (40 nM–10 ␮M), there was a
dose-dependent decrease in arterial pressure (n ⴝ 8). Dexamethasone-induced dilation was not inhibited by blocking
nitric oxide synthase or cyclo-oxygenase activity. These data
suggest that dexamethasone can cause dilation in the fetalplacental circulation, possibly via an endothelium-independent pathway. (J Clin Endocrinol Metab 87: 2838 –2842, 2002)
was associated with a return of umbilical artery diastolic flow
after 24 h. These studies suggest that synthetic glucocorticoids may have dilatory effects in the fetal-placental circulation. We have examined whether the short-term administration of the synthetic glucocorticoid, dexamethasone, into
the human fetal-placental circulation in vitro affects placental
arterial pressure and alters vascular responses to vasoconstrictor and vasodilator agents.
Materials and Methods
Subjects
The following experiments were formally approved by the Hunter
Area Health Service Research Ethics Committee and The University of
Newcastle Human Research Ethics Committee, and written informed
consent was obtained from women donating their placentas. Normal,
term placentas (n ⫽ 38, 38 – 42 wk gestation) were obtained within 20 min
of vaginal or Caesarean delivery from women (20 –37 yr, mean 29.7 ⫾
1 yr), who had uncomplicated pregnancies. Some, but not all patients,
had received one or more of the following drugs during labor: oxytocin
(2 IU over 6 – 8 h), pethidine hydrochloride (100 mg, im), promethazine
maleate (12.5–25 mg, im) or inhaled 70% N2O and 30% O2. These drugs
have no apparent effects on responses of the fetal vascular tissues under
conditions used (10). Placentas from women with blood pressures of
more than 140/90 mm Hg or who had experienced an increase of more
than 20 mm Hg diastolic pressure during pregnancy or who smoked
more than 10 cigarettes per day were not used.
Placental perfusion protocol
Placental lobules were perfused within 45 min of delivery by the
technique originally described by Penfold et al. (1981) (17), as modified
by Mak et al. (1984) (10). A suitable paired artery and vein, typically third
or fourth branches of the chorionic plate vessels, to a peripheral placental
lobule were chosen. The artery was cannulated with polyethylene tubing
and the vein cut at a convenient point to allow blood and perfusate to
escape. The cannula, which was inserted to the point where the artery
disappeared below the surface of the chorionic plate, was connected to
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Clifton et al. • Glucocorticoid Effects on the Human Placental Circulation
a Gilson Minipuls 3 (Gilson Medical Electronics, Villiers-le Bel, France)
peristaltic pump and the lobule perfused at 5 ml/min with Krebs’
solution containing (mmol/liter) NaCl, 97.0; NaHCO3, 24.3; KCl, 3.0;
KH2PO4, 1.2; CaCl2, 1.89; MgSO4, 1.0; d-glucose, 5.5 (pH 7.3) (all chemicals were obtained from BDH Laboratory Supplies, Victoria, Australia),
maintained at 37 C and equilibrated with 95% O2; 5% CO2. The corresponding maternal sinus to the lobule was also perfused with Krebs’
solution, under identical conditions to those used for perfusion of the
fetal circulation, except that perfusate was delivered via a single cannula
inserted into a remnant of one of the spiral arterioles of the basal plate
for the purpose of hydration of the lobule. The effluent was allowed to
drain from the remaining vessels and bathe the placenta.
Experimental design
Changes in fetal-placental vascular resistance were monitored by
recording the inflow pressure to the lobule, using a Gould Statham P23D
transducer (Cleveland, OH), connected via a T-junction to the fetal
arterial perfusion line. Signal conditioning and amplification were performed by a J-RAK (Melbourne, Victoria, Australia) PA-2 module and
displayed on a Kontron Instruments Ltd. W⫹W 330 flat-bed recorder
(Basel, Switzerland). Inflow pressure at the commencement of perfusion
was 80 –100 mm Hg, declining to a stable baseline pressure between 20
and 40 mm Hg within a period of 1 h. Preparations having baseline
pressures greater than 60 mm Hg were discarded. Effects of vasoactive
agents were measured after the baseline perfusion pressure had become
constant.
Upon obtaining a stable baseline pressure between 20 – 40 mm Hg,
dexamethasone (100 nm) or the vehicle were infused for 1 h and basal
arterial pressure measured. Dexamethasone was infused continuously
while constrictive agents, KCl (19.3–504 mm) or PGF2␣ (0.4 –151 pm)
(Pharmacia-Upjohn, New South Wales, Australia), were infused via a
peristaltic pump (Gilson Minipuls 3, Gilson Inc.) in a series of semilog
doses of increasing concentrations until a maximum increase in perfusion pressure was obtained. The infusion rate of KCl and PGF2␣ was not
increased until an equilibrium response had occurred in response to the
previous concentration. The mean equilibration time between doses was
96.85 ⫾ 8.39 min (n ⫽ 6). Each experiment was completed within a 4to 6-h period. These studies were also repeated in the absence of dexamethasone infusion.
To study the effect of dexamethasone on placental vascular dilatation
by CRH (Auspep, Victoria, Australia), dexamethasone (100 nm) was
infused for 1 h and then submaximal vasoconstriction was induced with
KCl (50 –100 mmol/liter) (BDH Laboratory Supplies) to an arterial pressure between 80 and 120 mm Hg. Under normal conditions, fetal-placental basal arterial pressure in vitro is too low to observe responses to
dilator agents, thus submaximal constriction is required. Dexamethasone and KCl were infused continuously into the artery via a peristaltic
pump (Gilson Minipuls 3) for the duration of the experiment (4 – 6 h).
CRH was added in a semilog series of increasing concentrations. Intermediate concentrations in the response curve were not increased until
the perfusion pressure had reached an equilibrium. These studies were
also repeated in the absence of dexamethasone infusion. A time control
was conducted where constriction in the vessel was induced, and then
saline was infused instead of CRH. This allowed us to determine if there
are significant changes in vascular arterial pressure over time. Vasodilatation was expressed as a percentage of the induced vasoconstriction
induced by KCl. Each agonist was examined in a single placental lobule
only. Experiments with different agonists were often examined in individual lobules of the same placenta. In these cases, lobules were
selected to be located as far apart as possible.
To study the effect of dexamethasone alone on placental vascular
function, vessels were preconstricted to a submaximal pressure with KCl
(50 –100 mmol/liter) and dexamethasone was infused (40 nmol/liter to
10 ␮mol/liter) in semilog doses as described above for the CRH experiments. A time control was also conducted with saline as previously
described.
Placental vessel viability was assessed at the end of each experiment
by the addition of a single dose of a dilator agonist (sodium nitroprusside 100 nm) if the vessels were previously constricted or a constrictor
(PGF2␣ 10 nm) if the vessel had been dilated. This allowed for the
assessment of functional capacity of the vessel by the end of the exper-
J Clin Endocrinol Metab, June 2002, 87(6):2838 –2842 2839
iment. Those vessels that did not respond were excluded from the final
analysis.
Statistical analyses
Placental blood flow data were analyzed using a custom designed
macro analysis program on an Excel spreadsheet (Microsoft Corp., Redmond, WA). Differences in the linear portions of the curves were compared by linear regression analysis and compared and tested for significant displacement and deviation from parallelism as described by
Bowman and Rand (1980) (18). Differences between the response curves
were calculated by determining the degree of displacement between
parallel concentrations in the curve where appropriate. Nonparallel
curves and multiple comparisons of means were tested with one-way
ANOVA and Tukey-Kramer for post analysis tests using GraphPad
Instat Software (1990 –1993, Version 2.04a) (GraphPad Software, Inc.,
San Diego, CA). t tests were used for comparison of subject parameters
and basal arterial pressure before and after dexamethasone infusion. All
values are expressed as means ⫾ sem unless otherwise stated. P value
less than 0.05 were considered significant.
Results
Placentae from women with normal, term pregnancies
used in this study had a mean basal fetal-placental arterial
perfusion pressure of 17.1 ⫾ 3.4 mm Hg (n ⫽ 19) during the
in vitro studies. Basal fetal-placental arterial perfusion pressures were significantly reduced to 12.5 ⫾ 2.4 mm Hg (n ⫽
19) following infusion of dexamethasone (100 nm) for 1 h (t
test P ⬍ 0.05, Fig. 1).
Responses to vasodilators in vitro in the presence and
absence of dexamethasone
The responses to CRH (17–5300 pmol/liter) during submaximal vasoconstriction with KCl (50 –100 mmol/liter) in
the presence and absence of dexamethasone are shown in
Fig. 2. A concentration-dependent vasodilatory response to
CRH was observed in both groups. The vasodilatory response to CRH was not significantly altered by the infusion
of dexamethasone (Fig. 3) when compared with the control
placentae (P ⬎ 0.05, ANOVA, regression analysis).
Responses to vasoconstrictors in vitro in the presence and
absence of dexamethasone
Dose-dependent vasoconstriction to KCl (19 –504 mm) and
PGF2␣ (0.4 –151 pm) were examined in placentae in the pres-
FIG. 1. Comparison of basal arterial pressure before (n ⫽ 19) and 1 h
after (n ⫽ 19) the infusion of dexamethasone (100 nM) in normal
placentae. There was a significant decrease in arterial pressure after
dexamethasone infusion (t test, P ⬍ 0.05). All values are expressed as
mean ⫾ SEM.
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J Clin Endocrinol Metab, June 2002, 87(6):2838 –2842
Clifton et al. • Glucocorticoid Effects on the Human Placental Circulation
Effect of dexamethasone alone on preconstricted
placental vessels
Because we observed a decrease in basal arterial pressure
with the infusion of dexamethasone, we examined dosedependent effect of this steroid in preconstricted vessels. The
responses to dexamethasone (40 nmol/liter to 10 ␮mol/liter)
during submaximal vasoconstriction with KCl (50 –100
mmol/liter) are shown in Fig. 4. A weak but significant
concentration-dependent vasodilatory response to dexamethasone was observed with 40% inhibition of the induced
vasoconstriction being observed at the highest concentration
of dexamethasone (10 ␮m). A representative chart recording
of dexamethasone-induced dilation in the fetal-placental circulation and the time control with saline infusion conducted
in the adjacent lobule are depicted in Fig. 5.
Effect of inhibition of NOS and cyclo-oxygenase on
dexamethasone-induced dilation
Infusion of N␻-nitro-l-arginine, an NOS inhibitor, (100
␮mol/liter), did not affect the response to dexamethasone
(P ⬎ 0.05, ANOVA, regression analysis, n ⫽ 5, data not
shown). The inactive D isomer of N␻-nitro-l-arginine (100
␮mol/liter, n ⫽ 4) also had no effect on the dexamethasoneinduced vasodilatation (data not shown). The cyclo-oxygenase inhibitor, indomethacin (3 ␮mol/liter), did not inhibit the
response to dexamethasone (P ⬎ 0.05, ANOVA, regression
analysis, n ⫽ 4, data not shown).
Discussion
FIG. 2. A, The vasoconstrictor effects of PGF2␣ (0.4 –151 pmol/liter) in
normal placentae in the presence (f) (n ⫽ 6) and absence (⽧) (n ⫽ 6)
of dexamethasone (100 nM). B, The vasoconstrictor effects of KCl
(19 –504 mmol/liter) in normal placentae in the presence (f) (n ⫽ 6)
and absence (⽧) (n ⫽ 6) of dexamethasone (100 nM). Vasoconstriction
is expressed as cumulative increase in placental arterial pressure
(mm Hg). All values are expressed as mean ⫾ SEM.
This study demonstrates in vitro that short-term administration of the synthetic glucocorticoid, dexamethasone
causes dilation when administered alone and does not alter
vascular responses to dilator or constrictor agents. These
findings are in agreement with the in vivo study of Wallace
and Baker 1999 (16), suggesting that antenatal betamethasone administration reduces placental vascular resistance in
pregnancies complicated by absent end diastolic flow of the
umbilical artery as demonstrated by Doppler ultrasound.
Conversely, multiple doses of dexamethasone over a 6-d
period to pregnant women with uncomplicated pregnancies
did not alter umbilical artery flow velocity waveforms (19),
FIG. 3. The vasodilator effects of CRH (17–5300 pmol/liter) in normal
placentae in the presence (f) (n ⫽ 6) and absence (⽧) (n ⫽ 7) of
dexamethasone (100 nM). Placental vessels were submaximally constricted with KCl (50 –100 mmol/liter). All values are expressed as
mean ⫾ SEM.
ence and absence of dexamethasone (Fig. 3). Dexamethasone
infusion did not significantly alter the vasoconstrictor response to either KCl or PGF2␣ (ANOVA, regression analysis,
P ⬎ 0.05, Fig. 3).
FIG. 4. Dexamethasone induced dilation in the human fetal-placental circulation. Normal term placentae were submaximally constricted with KCl (50 –100 mmol/liter) and then infused with increasing doses of dexamethasone (40 –10,000 nmol/liter) (n ⫽ 8). All values
are expressed as mean ⫾ SEM.
Clifton et al. • Glucocorticoid Effects on the Human Placental Circulation
FIG. 5. A representative chart recording of changes in fetal-placental
arterial pressure (A) in the presence of increasing concentrations of
dexamethasone or (B) a saline control. Adjacent arteries of the same
placenta were submaximally preconstricted with KCl (50 –100 mmol/
liter) and infused with increasing concentrations of dexamethasone
(40 –10 000 nmol/liter) or saline.
J Clin Endocrinol Metab, June 2002, 87(6):2838 –2842 2841
ways. Chaney et al. (1999) (25) reported that the administration of methylprednisolone to patients undergoing cardiac
surgery resulted in decreased systemic vascular resistance.
Antenatal treatment with betamethasone was associated
with augmented NO-induced dilation in ovine pulmonary
arteries (26). These studies indicate that glucocorticoids have
multiple effects in different vascular beds and can act either
directly or indirectly to reduce vascular tone.
In summary, our study has demonstrated that short-term
administration of dexamathasone causes dilatation in the
human fetal-placental circulation in vitro and suggests that
the placental vascular bed may not be adversely affected by
the administration of this drug in pregnancies complicated
by preterm delivery. However, the long-term effects of this
drug on the placental vascular bed could not be examined
using this experimental model. The mechanism by which
dexamethasone causes dilation requires further investigation. However, evidence from this study suggests that the
mechanism does not involve endothelial-derived products,
PGI2, and NO and may therefore be an endothelium-independent mechanism.
Acknowledgments
suggesting that glucocorticoid vasodilator effects in the fetal
placental circulation may only be apparent when there is an
increase in vascular resistance.
The mechanism by which dexamethasone exerts its vasodilator effects in the human fetal-placental circulation remains to be identified. Our study found that dexamethasone
does not cause dilatation via NO or cyclo-oxygenase-derived
prostanoids. In a previous study, using the same methodology, we were able to block the vasodilator effects of CRH
using the NOS inhibitor, N␻-nitro-l-arginine (20). This provides evidence that using this model, we are able to inhibit
the NO pathway. Gude et al. (1990) (21) has demonstrated
that the cyclo-oxygenase pathway can be blocked using indomethacin at a concentration of 3 ␮m. The data from this
work suggest that dexamethasone may act via a nongenomic,
endothelial-independent pathway to cause dilation in the
human fetal-placental circulation.
Our study has demonstrated that the short-term administration of dexamethasone does not alter vascular responses
to vasoconstrictors and vasodilators. This finding is not in
agreement with previous studies in other human vascular
beds. Short-term administration of cortisol to the human
foreman vasculature after 11␤-HSD activity had been inactivated, caused a significant increase in noradrenaline induced vasoconstriction (22). Furthermore short-term administration of dexamethasone to normal healthy males
impaired insulin-induced vasodilation under conditions of
physiological hyperinsulinaemia (23).
The finding that dexamethasone is a vasodilator in the
placental circulation in vitro is novel and supports the work
of Wallace and Baker (1999) (16). In contrast, many studies
report that glucocorticoid infusion alters vascular function
by causing hypertension in humans (1). However, work in
other animal models have demonstrated that glucocorticoids
can act as vasodilators in some vascular beds. De Matteo and
May (1999) (24) demonstrated that cortisol caused dilation in
the sheep renal vessels via the prostacyclin and NO path-
We thank Philip Hempenstall for technical assistance and the help of
the clinical staff at the Delivery Suite at the John Hunter Hospital for
assistance in the collection of placentae.
Received July 3, 2001. Accepted February 25, 2002.
Address all correspondence and requests for reprints to: Dr. V. L.
Clifton, Department of Endocrinology, John Hunter Hospital, Locked
Bag 1, Hunter Region Mail Center, Newcastle, New South Wales 2310,
Australia.
This work was generously supported by the Hunter Medical Research
Institute and the NSW Government.
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