Prostaglandin Regulation of Fetal Plasma Adrenocorticotropin and ...

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We infused nimesulide from 9 2 h and vehicle from 8 + 2 h after the onset of labor ... fully characterized. PG endoperoxide synthase (cyclooxygenase) is a bifunc-.
BIOLOGY OF REPRODUCTION 58, 514-519 (1998)

Prostaglandin Regulation of Fetal Plasma Adrenocorticotropin and Cortisol Concentrations in Late-Gestation Sheep' Nobuya Unno, 3 5 Wen Xuan Wu, 3 Chi H. Wong, 3 Phillip R. Bennett, 4 Norio Shinozuka,3 5 and Peter W. Nathanielsz2,3 Laboratory for Pregnancy and Newborn Research,3 Department of Physiology, New York State College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401 Institute of Obstetrics and Gynaecology, 4 Queen Charlotte's and Chelsea Hospital, London, UK Department of Obstetrics and Gynecology,5 Faculty of Medicine, University of Tokyo, Tokyo, Japan ABSTRACT

that eicosanoids, especially cyclooxygenase metabolites, play significant roles in the activation of CRF in the hypothalamo-pituitary axis. In addition, it has been reported that PGs are involved in the regulation of adrenocortical cortisol secretion [8, 9]. In sheep, the activation of the fetal hypothalamo-pituitary-adrenal axis, which promotes fetal organ maturation and triggers the initiation of labor, occurs during the last 3 wk of gestation [10-12]. Involvement of PGE 2 in the parturition-related activation of the fetal hypothalamo-pituitary-adrenal axis and the initiation of labor has been documented [13]. However, effects of inhibition of PG synthesis on the maternal and fetal hypothalamo-pituitary-adrenal axis during parturition have not been fully characterized. PG endoperoxide synthase (cyclooxygenase) is a bifunctional, membrane-bound hemoprotein that catalyzes both the bis-oxygenation of arachidonic acid to form PGG 2 and the peroxidative reduction of PGG 2 to form PGH 2 [14]. Two forms of cyclooxygenase have been isolated [15, 16], one (COX-1, PGH synthase (PGHS)-1) being "constitutive," the other (COX-2, PGHS-2) being mitogen-inducible. PGHS-1 is present in cells under physiologic conditions, whereas PGHS-2 is induced by some cytokines, mitogens, and endotoxin in pathological conditions, such as inflammation [17]. Although PGHS-2 mRNA abundance increases at parturition in the sheep placental cotyledon [18], myometrium, and endometrium [19], there is no available data on the regulation of PG production in the control of the fetal and maternal hypothalamo-pituitary-adrenal axes. Nimesulide (CAS 51803-78-2, N-(4-nitro-2-phenoxyphenyl)-methanesulfonilamide), a nonsteroidal antiinflammatory drug, has been shown not to affect PG synthesis in the bronchial tree [20], in which constitutive PGHS- 1 exerts a bronchoprotective role [21] and preserves mucosal integrity in the gastric mucosa [22-24]. By contrast, nimesulide markedly affects PG production in inflammatory exudate [22] and in inflammatory cells [20], in which PG production is PGHS-2-mediated. Recently, nimesulide has been shown to inhibit PGHS-2, with selectivity over PGHS-1 activity on the order of 70 [25, 26]. It has been shown that the hypothalamo-pituitary-adrenal axis of the sheep fetus is activated in late gestation at the levels of the hypothalamus [27], the pituitary [28], and the adrenal [29]. In the present study, we characterized effects of PG inhibition by nimesulide on the function of the maternal and fetal hypothalamo-pituitary-adrenal axes during spontaneous term labor by administering nimesulide to the laboring ewe. Administration of nimesulide during labor monitored with the precise registration of myometrial activity allowed a clear demonstration of action of the inhibitor on myometrial contractility, a process known to be crit-

It is widely recognized that prostaglandins (PGs) are involved in regulation of the hypothalamo-pituitary-adrenal axis and that the activation of the fetal hypothalamo-pituitary-adrenal axis plays a central role in the process of labor in sheep. However, effects of inhibition of PG synthesis on the maternal and fetal hypothalamo-pituitary-adrenal axis during parturition have not been characterized. We examined the effect of inhibiting PG synthesis on the maternal and fetal hypothalamo-pituitary-adrenal axes during spontaneous term labor by using nimesulide, a PGH synthase (PGHS) inhibitor. Under halothane anesthesia, eight pregnant ewes were instrumented with vascular catheters and myometrial electromyogram (EMG) electrodes at 127 3 (mean SEM) days gestation (dGA). After onset of labor as evaluated by EMG, nimesulide was infused to four ewes i.v. (30mg bolus, followed by 6-h infusion at 30 mg/h). Vehicle was infused to the remaining four ewes (controls, CONT). Maternal blood and fetal blood were sampled at 1-h intervals before and during infusion to determine plasma PGE2, ACTH, and cortisol concentrations. Spontaneous labor occurred at 148 0 dGA in nimesulide-treated ewes and at 144 1 dGA in CONT ewes. We infused nimesulide from 9 2 h and vehicle from 8 + 2 h after the onset of labor. Maternal and fetal blood gases and pH remained unchanged in all animals. No significant changes were observed in any plasma hormone concentrations measured in CONT ewes and fetuses before and during vehicle infusion. In nimesulide-treated ewes, maternal plasma PGE2 and ACTH concentrations remained unchanged, while maternal plasma cortisol decreased significantly, recovering to baseline by 3 h. In fetuses of nimesulide-treated ewes, plasma PGE 2 and ACTH levels showed significant sustained decreases after nimesulide infusion. Fetal plasma cortisol decreased significantly and returned to baseline by 5 h. These results suggest that 1) PG synthesis inhibition by nimesulide has differential effects on the ovine maternal and fetal hypothalamo-pituitary-adrenal axes during spontaneous labor, and 2) PG production plays a physiologic role in regulation of the ovine fetal hypothalamo-pituitary-adrenal axis. INTRODUCTION Involvement of prostaglandins (PGs) in regulation of the hypothalamo-pituitary-adrenal axis has been well documented. Both ACTH response to interleukin-1 [1-4] and the induction of corticotropin-releasing factor (CRF) secretion by interleukin- in vitro are blocked by indomethacin [5] in rats. It has been shown that PGs are also involved in the exercise-induced [6] or psychological stress-induced [7] ACTH release in rats. These studies have clearly indicated Accepted September 26, 1997. Received June 24, 1997. 'Supported by NIH HD21350. 2Correspondence. FAX: (607) 253-3455; e-mail: [email protected]

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PROSTAGLANDIN REGULATION OF ACTH AND CORTISOL IN FETAL SHEEP ically dependent on PG production. The dose of nimesulide infused prevents the progression of labor [30]. MATERIALS AND METHODS Mature Rambouillet-Columbia cross-bred ewes (n = 8) bred on a single occasion only and carrying a fetus of known gestational age (term 148 days) were used. All procedures were approved by the Cornell University Animal Care and Use Committee. All facilities were approved by the American Association for the Accreditation of Laboratory Animal Care. Care of Animals Surgery was performed under halothane general anesthesia at 127 3 (mean SEM) days gestation (dGA) using basic techniques that have been described in detail before [31]. Briefly, polyvinyl catheters were inserted into a maternal carotid artery and jugular vein and advanced into the descending aorta and superior vena cava, respectively. The fetuses were instrumented with polyvinyl catheters introduced via the carotid artery and jugular vein. An amniotic cavity catheter was also placed for the administration of antibiotics. Multistranded stainless steel wire (Cooner Sales Co., Chatsworth, CA; catalogue No. AS 632) electrodes were sewn to the myometrium. After the surgery, ampicillin (500 mg, AMP-Equine; SmithKline Beecham, West Chester, PA) was administered to the maternal jugular vein catheter twice a day and to the amniotic catheter once a day for 4 days. All the fetuses were allowed to recover for at least 5 days after surgery before being studied. From 5 days after surgery, myometrial electromyographic (EMG) activity was continuously recorded and stored as an average of 8-sec signals throughout the study period in a data acquisition system, as previously described in detail [32]. Study Protocol Baseline measurements. When onset of labor was confirmed by visual analysis of the myometrial EMG activity recording (a characteristic switch of myometrial EMG from low-amplitude, long-lasting (> 3 min), low-frequency (0.53/h) contractures to high-amplitude, short-lived (< 1 min), high-frequency (12-48/h) contractions [33], two fetal and maternal arterial blood samples (5 ml) for PGE 2, ACTH, and cortisol measurements were drawn at 1-h intervals into cold syringes using aseptic techniques and were transferred into polypropylene collection tubes chilled in ice water. These were immediately centrifuged at 4C at 1200 x g for 5 min. Plasma was removed, aliquoted, flash-frozen in liquid N 2, and stored at -20 0 C until assayed. Samples for PGE 2 measurement were placed in tubes containing potassium/EDTA (10 mg/ml) and aspirin (5 mg/ml blood). Additional samples (0.5 ml) were taken for blood gases and pH measurements using a blood gas analyzer (ABL500; Radiometer, Copenhagen, Denmark. Measurements were corrected to 39C). Nimesulide infusion. Nimesulide was prepared in Dulbecco's Minimum Eagle's medium (D-5648; Sigma Chemical Co. St. Louis, MO) (pH 8.0-9.0) at a concentration of 1.2-1.3 mg/ml. Nimesulide solution was infused to four ewes i.v. (30-mg bolus) and then continuously infused at a rate of 30 mg/h for 6 h. After the start of nimesulide infusion, blood sampling was repeated every hour during the study period. Vehicle was infused to the remaining four ewes after the confirmation of onset of labor, and an iden-

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tical blood-sampling regimen was performed on these animals as controls (CONT). In addition, the time of onset of labor was retrospectively determined by changes in contraction power (the power in the frequency window of 0.20.8 cycles/min in the power spectral analysis following the fast Fourier transform of EMG signals [30]. RIAs. Plasma ACTH and cortisol concentrations were determined by specific RIAs as previously described [34]. Assay sensitivity for ACTH and cortisol were 9.0 pg/ml and 4.9 ng/ml, respectively. Plasma PGE 2 concentrations were determined by using an antibody, kindly provided by Dr. Leslie Myatt, generated in rabbits to a PGE 2-bovine serum albumin conjugate. The cross-reactivities of this antibody with PGE 2, PGD 2, PGF2, 6-keto-PGE, and TXB 2 were 100%, 1.8%, 1.5%, < 2.2%, and < 1%, respectively [35]. Plasma (100 dl) was equilibrated with acid for 2-3 h, extracted twice with diethyl ether, and reconstituted with 500 pl of 0.1% gelatin in 0.1 M PBS. Aliquots (100 Il) of reconstituted samples were assayed in duplicate. Tritiated PGE 2 served as the labeled ligand (Dupont NEN, Boston, MA), and dextran-charcoal PBS solution was used to separate bound from free ligand. PGE2 standard (Cayman Chemical Co., Ann Arbor, MI) used at 3.13-400 pg/tube was diluted in the assay buffer (0.1% gelatin, 0.1 M PBS). Tritiated PGE 2 at 5000 cpm and PGE2 antiserum diluted 1:15 000 were added in 100 -JLl aliquots each to the standards and extracted samples, and incubated at 4°C overnight. A 15-min incubation with 1 ml dextran-charcoal solution at 4°C was followed with centrifugation at 2400 x g for 15 min at 4°C. The supernatant containing the bound ligand was decanted into scintillation vials, scintillation fluid was added, and both were counted. Extraction recovery of tritiated PGE2 added to plasma was 79.5 ± 2.1% (n = 6), and the solvent blank was negligible. Assay values were not corrected for recovery. Plasma pools were made by adding 0.5, 1, 2, and 8 ng/ml exogenous PGE 2 to charcoalextracted pooled sheep plasma. When aliquots of 100 Il of these levels were extracted and assayed, 0.58 ± 0.11, 0.74 + 0.09, 1.61 0.13, and 5.69 0.41 ng/ml were measured, respectively (n = 10). The assay sensitivity was 3.13 pg per tube, which is equivalent to 0.157 ng/ml when 20 pl1 of plasma was extracted. The intraassay coefficient of variation (CV) and the interassay CV were 8.8% and 8.1%, respectively. Statistical analysis. Analysis was performed on absolute values for all measurements except PGE2. Since PGE 2 values demonstrated considerable variability between animals, the two baseline samples obtained before infusion of nimesulide or vehicle were averaged, and subsequent values for each animal were expressed as a percentage of baseline for that animal. Data were expressed as mean ± SEM. Values that represent baseline were calculated as an average of two baseline measurements. Differences in gestational age and baseline PGE2 concentrations between the control and nimesulide-infused groups were evaluated by Student's nonpaired t-test. All other data were analyzed with two-way repeated measures analysis of variance followed by the Student-Neuman-Keuls test. Statistical significance was set at p < 0.05. RESULTS Arterial Blood Gas Status Spontaneous labor occurred at 148 0 dGA in nimesulide-infused ewes and at 144 + 1 dGA in CONT. Although pregnant ewes were chosen at random for the two groups, the time of onset of labor was significantly later in nimesulide-infused ewes than in CONT. Nimesulide infusion began 9 2 h after the labor onset, and vehicle in-

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TABLE 1. Maternal and fetal arterial pH and blood gases (mm Hg) following nimesulide or vehicle (CONT) infusion (mean + SEM; n = 4 except * n = 3). Nimesulide Sample

pH

CONT

PCO2

P02

Maternal artery Baseline 1h 2h 3h 4h 5h 6h

7.46 7.46 7.47 7.48 7.48 7.46 7.47

± ± ± ± ± ± ±

0.01 0.01 0.00 0.01 0.01 0.02* 0.02

33.8 34.1 34.9 33.4 35.3 32.1 34.3

± 2.1 ± 0.9 + 1.9 ± 0.6 ± 1.1 ± 3.7* ± 2.5

118.6 120.7 114.0 116.0 115.9 112.7 107.9

Fetal artery Baseline 1h 2h 3h 4h 5h 6h

7.33 7.34 7.36 7.36 7.36 7.36 7.35

+ ± ± ± ± ± +

0.01 0.02 0.01 0.01 0.01 0.01* 0.01

51.6 52.3 52.2 51.8 52.7 49.2 49.5

± ± + ± ± ± ±

4.0 2.2 1.3 2.0 0.7 4.1' 1.3

18.2 19.2 18.8 19.6 18.3 18.2 17.4

pH

P02

+ 5.7 ± 3.6 ± 3.4 ± 3.1 ± 4.2 ± 3.8* ± 7.5

7.46 7.47 7.45 7.45 7.45 7.45 7.47

± ± ± ± ± ± ±

0.03 0.03 0.03 0.03 0.02 0.02* 0.02*

35.2 35.9 35.6 37.5 35.4 35.8 35.0

± ± ± ± + ± ±

2.0 1.4 0.7 2.6 0.8 0.8* 0.4*

103.0 109.5 104.8 111.2 101.2 100.3 100.2

1.2 1.0 0.9 0.6 0.8 1.1* 1.3

7.36 7.36 7.37 7.35 7.36 7.36 7.35

± ± ± ± ± + ±

0.02 0.02 0.03 0.02 0.03 0.03* 0.03*

52.1 55.6 53.6 54.0 55.3 54.9 54.6

+ ± ± ± ± ± ±

2.2 1.3 2.5 2.1 1.7 1.7* 1.3*

20.0 18.0 17.2 18.2 17.5 16.7 16.0

± ± ± ± ± ± ±

fusion began 8 + 2 h after the onset of labor in CONT. After nimesulide or vehicle infusion, maternal and fetal blood gases and pH remained unchanged throughout the infusion period (Table 1). Changes in Maternal and Fetal PGE2 Maternal plasma PGE 2 concentrations did not show change during infusion either in nimesulide-infused ewes or CONT, although baseline PGE 2 concentration in treated ewes (0.51 + 0.10 ng/ml) was significantly lower than in CONT (1.28 + 0.30 ng/ml). Fetal plasma PGE2 concentra0.10 tion at baseline in nimesulide-infused ewes (1.86 ng/ml) and CONT (1.52 + 0.12 ng/ml) were not statistically different from each other. Fetal plasma PGE 2 concentrations in CONT remained unchanged during vehicle infusion, while fetal plasma PGE 2 concentrations decreased significantly during nimesulide infusion (Fig. 1). This decrease was sustained during the infusion period.

± 3.7 ± 11.3 ± 4.5 ± 5.0 + 1.3 ± 4.3* ± 6.5* ± ± ± ± + ± ±

1.9 1.4 0.7 1.8 1.4 1.4* 1.3*

Changes in Maternal and Fetal Plasma ACTH and Cortisol Baseline maternal plasma ACTH and cortisol concentrations were similar in CONT and nimesulide-infused ewes. Maternal plasma ACTH concentrations remained unchanged in both groups. In contrast, in nimesulide-treated ewes, maternal cortisol levels decreased significantly (p < 0.05) and recovered to baseline by 3 h (Fig. 2),, whereas no change occurred in plasma cortisol concentrations in CONT. In CONT, fetal plasma ACTH concentrations showed no consistent change during vehicle infusion. In contrast, fetal plasma ACTH levels in nimesulide-treated ewes showed a sustained decrease during nimesulide infusion. Plasma cortisol concentrations in CONT fetuses remained unchanged during the study period. In nimesulide-treated fetuses, plasma cortisol concentrations decreased significantly after nimesulide infusion began and recovered to baseline by 5 h (Fig. 3).

240

80

-

60

160

2

PCO2

40 0

o

80

0

n;

i LIL

240 -


II n [cthe localization * of PGHS activity in the hypothalamus or the pituitary in the sheep fetus. Evaluation of circulating nimesulide concentrations in the fetus would have been baseline 2 3I 4 I6 useful in determining potential paracrine effects. Unfortubaseline 1 2 3 4 5 6 nately, we were unable to measure circulating concentrah of infusion tions of nimesulide in fetal or maternal plasma. FIG. 3. Feta I (Fet) plasma ACTH (upper) and cortisol (lower) concentraIt is not clear why maternal baseline plasma PGE 2 conSEM; centrations were different between CONT and nimesulidetions during nimesulide or vehicle infusion. Values are mean closed bars indicate data from nimesulide-treated ewes, and open bars treated ewes. This difference may possibly be explained by indicate data from CONT; n = 4 in each group. *p < 0.05 compared to differences in gestation length when labor began. The baseline and corresponding CONT; + p < 0.05 compared to baseline. abrupt decrease in maternal plasma cortisol concentrations without an observed change in maternal plasma ACTH levels indicates that nimesulide has a suppressive effect on the DISCUSSI(ON hypothalamo-pituitary-adrenal axis at the adrenal level in the ewe. Since it has been shown that PGE 2 does not have Althoug,h it has been well described that PGE 2 is a potent stimul ant of the hypothalamo-pituitary-adrenal axis in a direct stimulatory effect on adrenocortical cortisol secretion in vitro [48], and we did not find any significant the late ge:station sheep fetus [13, 36-39], the various studchanges in maternal plasma PGE 2 concentrations after niies conduc ted to date do not clearly indicate the level (or he axis at which PG stimulation occurs [40-43]. mesulide infusion, it is not likely that the decrease in malevels) in t No studies have addressed effects of inhibition of PG proternal cortisol levels after nimesulide infusion was due to the changes in circulating PGE 2. Therefore, it is more likely duction oni the fetal ovine hypothalamo-pituitary-adrenal that PGs produced within the adrenal may have a regulatory axis. In thee present study, administration of nimesulide to the ewe during labor decreased fetal PGE 2 by 50% and effect on the adrenal activity via paracrine or autocrine resulted in suppression of both fetal plasma ACTH and cormechanisms. In addition, it is also possible that nimesulide tisol. Althc)ugh placental production of corticotropin-releashas a direct suppressive effect on the adrenal via a mechanism other than PG pathways. It is interesting that nimeing hormoxne and ACTH has been documented by several sulide infusion did not cause an increase in plasma ACTH research groups in both pregnant women and nonhuman levels in the ewes despite the decreased cortisol levels. This primates, Fproduction of both of these peptides in the ovine failure of maternal ACTH to rise when negative feedback placenta is much more controversial [44]. According to our decreases may indicate that cortisol feedback mechanisms results, it is i likely that the effects of the reduction in PG in the hypothalamus and/or the anterior pituitary were also production are exerted at the fetal hypothalamo-pituitaryadrenal axiis at both the pituitary and adrenal levels. altered by nimesulide. At baselline measured just after the onset of labor, fetal Since PGHS-2 mRNA abundance increases significantly in the sheep placenta during late gestation, while PGHS-1 plasma AtCTH and cortisol concentrations were elevated above the baseline levels normally measured at 130-140 abundance remains unchanged [18, 49], it is likely that the dGA. The sustained suppression of ACTH in the fetuses of increase in PGHS-2 production is responsible for the innimesulidel-treated ewes clearly indicates the inhibitory efcreased PGHS enzyme activity [50] and the increased plasfect of ni:imesulide on the hypothalamo-pituitary-adrenal ma PGE 2 concentrations observed at parturition. Several axis at the levels of the hypothalamus and/or the pituitary. studies have reported that nimesulide is a selective PGHSThis effect on plasma ACTH concentrations was observed 2 inhibitor [25, 26]. If so, our findings indicate that in labor, immediately ly after nimesulide infusion and was sustained fetal PGHS-2 plays a major role in regulating hypothalamopituitary-adrenal activity at the hypothalamic and/or pituithroughout the infusion period. In contrast, the suppression tary levels. In contrast to the fetus, in the ewe PGHS-2 may of plasma cortisol concentration lasted only for 4 h. These results suglgest that, although PG pathways are a major regplay a more significant role in regulation of adrenocortical ulator for the t parturition-related activation of the fetal hyactivity compared to regulation at the hypothalamic and/or pothalamo--pituitary-adrenal axis, there may be other compituitary levels. Further studies are required to elucidate the pensatory mechanisms at the adrenal level that can stimuinvolvement of PGs in mechanisms responsible for this diflate adreno)cortical activity even in the presence of marked ferential regulation of fetal and maternal hypothalamo-pisuppressionn of PG production. Recent studies have demtuitary-adrenal activity. onstrated that sympathetic nerve stimulation via the In conclusion, maternal administration of the PGHS insplanchnic nerve regulates adrenocortical activity [45]. It is hibitor nimesulide has significant effects on the ovine matherefore p ossible that the splanchnic nerve-mediated pathternal and fetal hypothalamo-pituitary-adrenal axis during way is alsoo involved in the regulation of the parturitionlabor. The inhibitory effect of nimesulide on circulating .-

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ml +5

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tI

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PGE2 concentration observed in the present study is compatible with a physiological role for PGHS-2 in the sheep parturition. ACKNOWLEDGMENTS We are grateful for the expert surgical assistance of Dr. Xiu-Ying Ding, to Stella Vincent for performing the PGE assay, and to Andrew C. Yen 2 for ACTH and cortisol assays.

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