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Short-Term Effects of Glucocorticoids in the Human Fetal-Placental Circulation in Vitro

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

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.

Abstract

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 = 19, t test, P < 0.05). Continuous dexamethasone infusion (100 nM) did not alter vasoconstrictive responses to PGF₂ (0.5–120 pM, n = 12, ANOVA, P > 0.05) or potassium chloride (5–600 mM, n = 12, ANOVA, P > 0.05) or vasodilator responses to CRH (53–7400 pM, n = 13, ANOVA, P > 0.05). However when fetal-placental vessels were submaximally preconstricted and then infused with dexamethasone alone (40 nM–10 µM), there was a dose-dependent decrease in arterial pressure (n = 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 fetal-placental circulation, possibly via an endothelium-independent pathway.

GLUCOCORTICOIDS 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, 7, 8, 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 11ß- hydroxysteroid dehydrogenase type 2 (11ß-HSD 2), which inactivates cortisol to cortisone and fetal membrane 11ß-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 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 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 4- to 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 µmol/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 experiment. 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).

View larger version (14K): [in this window] [in a new window]   Figure 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.

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).

View larger version (15K): [in this window] [in a new window]   Figure 2. A, The vasoconstrictor effects of PGF2 (0.4–151 pmol/liter) in normal placentae in the presence () (n = 6) and absence () (n = 6) of dexamethasone (100 nM). B, The vasoconstrictor effects of KCl (19–504 mmol/liter) in normal placentae in the presence () (n = 6) and absence () (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.

View larger version (16K): [in this window] [in a new window]   Figure 3. The vasodilator effects of CRH (17–5300 pmol/liter) in normal placentae in the presence () (n = 6) and absence () (n = 7) of dexamethasone (100 nM). Placental vessels were submaximally constricted with KCl (50–100 mmol/liter). All values are expressed as mean ± SEM.

Dose-dependent vasoconstriction to KCl (19–504 mM) and PGF₂ (0.4–151 pM) were examined in placentae in the presence 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).

Effect of dexamethasone alone on preconstricted placental vessels

Because we observed a decrease in basal arterial pressure with the infusion of dexamethasone, we examined dose-dependent effect of this steroid in preconstricted vessels. The responses to dexamethasone (40 nmol/liter to 10 µmol/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 µM). 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.

View larger version (16K): [in this window] [in a new window]   Figure 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.

View larger version (13K): [in this window] [in a new window]   Figure 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.

Infusion of N-nitro-L-arginine, an NOS inhibitor, (100 µmol/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 µmol/liter, n = 4) also had no effect on the dexamethasone-induced vasodilatation (data not shown). The cyclo-oxygenase inhibitor, indomethacin (3 µmol/liter), did not inhibit the response to dexamethasone (P > 0.05, ANOVA, regression analysis, n = 4, data not shown).

Discussion

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), 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 µM. 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 11ß-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 pathways. 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

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.

Footnotes

This work was generously supported by the Hunter Medical Research Institute and the NSW Government.

Abbreviations: 11ß-HSD 1 or 2, 11ß-Hydroxysteroid dehydrogenase type 1 or 2; NO, nitric oxide; NOS, nitric oxide synthase.

Received July 3, 2001.

Accepted February 25, 2002.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clifton, V. L. Articles by Smith, R. Search for Related Content PubMed PubMed Citation Articles by Clifton, V. L. Articles by Smith, R.