The effects of glycemia on breathing movements and plasma prostaglandin E concentrations in the sheep fetus A.L. Fowden, PhD: S. Thian, BA: M. Silver, PhD: M.M. Ralph, PhD; and R. Harding, PhD b Cambridge, England, and Clayton, Victoria, Australia OBJECTIVE: The purpose of this study was to determine the roles of fetal plasma glucose and prostaglandin E in controlling fetal breathing movements. STUDY DESIGN: Five late pregnant ewes with catheterized twin fetuses were fasted for 48 hours; one fetus was kept normoglycemic (by glucose infusion) and the other allowed to become hypoglycemic during this period. Fetal breathing movement and fetal and maternal plasma prostaglandin E and glucose concentrations were measured throughout. Data were analyzed by paired and unpaired t tests. RESULTS: The mean incidence of fetal breathing movement was significantly greater in the normoglycemic fetuses that in the hypoglycemic twins at the end of the fast (p < 0.05), whereas plasma prostaglandin E levels increased significantly (p < 0.05) and to the same extent in both groups of fetuses. CONCLUSION: The reduced incidence of ovine fetal breathing movement that occurs during maternal fasting appears to be primarily caused by fetal hypoglycemia and does not directly involve changes in fetal plasma prostaglandin E. (AM J OBSTET GVNECOL 1992;166:713-9.)

Key words: Fetal breathing, hypoglycemia, prostaglandin E Breathing movements are a normal feature of fetal life. They occur episodically throughout the latter half of gestation and are related to the metabolic and endocrine status of the fetus. 1In particular, the circulating glucose concentration appears to be an important influence on fetal breathing activity in late gestation. I. 2 In the fetus sheep near term, hyperglycemia increases the incidence of fetal breathing movements, whereas hypoglycemia, induced by fasting or insulin infusion, decreases fetal respiratory activity.'·6 Similar observations have been made in the human infant during late gestation. 2 Although fetal breathing activity appears to be closely related to glucose availability in utero, it is still not clear whether these changes in fetal breathing movements are due to variations in the fetal glucose concentration per se or whether other nutritional or hormonal changes are involved. Certainly, infusions of glucose into hypoglycemic fetuses of fasted ewes restores the normal incidence of fetal breathing movements, but the glucose levels achieved in these experiments were twice the normal fetal concentrations. 3 More recent studies have suggested that the low incidence of fetal breathing movements seen during fetal hypoglycemia may be due, in part to a concomitant increase in the prostaglandin E2 (PGE 2 ) concentration in fetal plasma. 6 From the Physiological Laboratory, Cambridge,' and the Department of Physiology, Monash University, Clayton.' Received for publication May 7, 1991; revised August 4, 1991; accepted August 15,1991. Reprint requests: A.L. Fowden, PhD, Physiological Laboratory, Downing Street, Cambridge, England CB2 3EG. 611133388

Prostaglandins have major effects on fetal breathing activity in the sheep.7 Infusion of prostaglandins, particularly PGE 2 , reduces the incidence of fetal breathing movements in sheep, whereas conversely, inhibition of prostaglandin synthesis stimulates fetal breathing activity."·IO Prostaglandin production in utero is also known to be related to maternal nutritional state.'" 12 Increases in uterine prostaglandin synthesis occur during dietary restriction, and an inverse relationship between the plasma prostaglandin and glucose concentrations is observed in the fetus and pregnant ewe when nutrient availability is manipulated during late gestation. 12. 13 Hence in this study the roles of plasma prostaglandin E (PGE) and glucose in controlling fetal breathing movements have been examined more closely by comparing fetal breathing movements and plasma PGE concentrations during maternal fasting in twin sheep fetuses in which one fetus was allowed to become hypoglycemic while the other was maintained in a normoglycemic state by fetal glucose infusion.

Material and methods Animals. Five Welsh Mountain ewes carrying twin fetuses of known gestational age were used. All 10 lambs were alive at delivery, which occurred at a mean gestational age of 143.2 ± 1.2 days (n = 5). Mean birth weight was 2.135 ± 0.063 kg (n = 10). Operative procedures. Between 112 and 117 days of gestation, anesthesia was induced with thiopental and maintained with halothane (1.5% in nitrous oxide and oxygen) after intubation. With established procedures,12. 14 catheters were inserted into the carotid artery, jugular vein, trachea, and amniotic sac of each

714 Fowden et al.

twin fetus and into a uterine vein and dorsal aorta of the ewe. Antibiotics were given intravenously to the fetus (100 mg ampicillin [Penbritin]) and intramuscularly to the mother (10 ml Streptopen) at the end of surgery. Normal feeding patterns were generally restored within 24 to 48 hours of operation, but no experiments were carried until 12 to 21 days after surgery. Experimental procedures. Food but not water was withdrawn from the ewes for 48 hours beginning at 131 to 136 days of gestation at either 9 AM (n = 2) or 5 PM (n = 3). Glucose was infused intravenously into one twin of each pair at 300 mg/hr for the first 24 hours, 600 mg/hr for the next 12 hours, and then at 900 mg/hr for the last 12 hours of the 48-hour fast. The twin to be infused was chosen randomly. During the experimental period, 8 ml blood samples were taken from the uterine vein and fetal and maternal arteries either between 9 and 10 AM (n = 2) or 4 and 5 PM (n = 3) starting 24 hours before the fast was begun and continuing until 24 hours after the animals were refed. A small aliquot of blood (0.5 ml) was used for analyses of pH, Po., Peo., hemoglobin concentration, and oxygen saturation with Radiometer equipment (ABL 330 and OSM2, Radiometer American, Inc., Westlake, Ohio). Blood oxygen content was calculated from the hemoglobin and oxygen saturation values. Two milliliters of blood was added to chilled tubes containing aspirin (1.4 mg) and ethylenediamine tetraacetic acid (0.10 mg) for analysis of PGE. These samples were centrifuged at 4° C, and an equal volume of 0.12 mmollL methoxyamine hydrochloride in sodium acetate buffer (l mollL, pH 5.6) was added to the plasma. Plasma samples with added methoxyamine hydrochloride were left at room temperature for 24 hours then frozen at - 20° C until analysis. The remainder of the blood samples (=5 ml) were added to tubes containing ethylenediamine tetraacetic acid and centrifuged at 4° C. The plasma from these samples was stored at - 20° C until required for metabolite and other hormonal analyses. Recordings of fetal breathing movements were made for 4 to 6.5 hours between 10 AM and 4:30 PM on the day before, the day after, and the 2 days of the 48-hour fast. Tracheal and amniotic fluid pressures were measured in each fetus with standard pressure manometers and displayed on an eight-channel Lectromed recorder together with the electronically derived difference between the tracheal and amniotic pressures. All operative and experimental procedures were approved and licensed by the appropriate authorities. Biochemical analyses. Glucose concentrations were measured in plasma that was deproteinized with zinc sulfate (0.3 mollL) and barium hydroxide (0.3 mol/L) with glucose oxidase. I ' Plasma PGE was assayed by radioimmunoassay against PGE. methyloxime standards with use of an antiserum raised in goats against the

February 1992 Am J Obstet Gynecol

methyloxime of PGE •. I5 Detailed procedures and specificity of the PGE assay for ovine plasma have already been published. I. The limit of sensitivity of the assay was 0.5 nmol/L, and intraassay and interassay coefficients of variation were ::510% and 21.4%, respectively, for the assays required for this study. Because the antiserum did not distinguish between PGE I and PGE., I. plasma PGE concentrations have been expressed as PGE. equivalents. Data analyses. An episode of fetal breathing movements was defined as a series of negative deflections in tracheal pressure, from which amniotic pressure had been subtracted, that were >0.8 mm Hg and lasted longer than 0.5 minute. The incidence of fetal breathing movements was calculated as the total amount of time within a recording period (4 to 6.5 hours) occupied by fetal breathing movements and expressed as a percentage. The amplitude of the negative pressure deflections (tracheal pressure - amniotic pressure) was measured every 20 or 30 seconds during each episode of fetal breathing movements with a Cal Comp digitizing tablet with the Sigma scan program (Jandel Scientific, Corte Madera, Calif.), and the mean value was calculated for all episodes of fetal breathing movements during a recording period in each fetus. Mean ± SEM are used throughout and statistical analyses were made according to the methods of Armitage. 16 Statistical significance was assessed by paired and unpaired t tests. Linear regression was also used to assess the relationship between fetal breathing movements and the plasma concentrations of glucose and PGE. In one glucose-infused fetus the infusion pump became detached for 8 hours during the last 12 hours of the 48-hour period of food withdrawal. Consequently, data obtained from this fetus at 48 hours of fasting have not been included in the mean values for the glucose-infused fetuses at the end of the fast. Results

Basal values. Before the fast, fetal blood gas tensions, pH, and oxygen content were within the normal range of values, 14 as were the plasma concentrations of glucose and PGE in the fetus (Table I) and ewes (2.98 ± 0.26 mmol/L and 11.60 ± 1.11 nmollL, respectively, n = 5). The incidence and amplitude of fetal breathing movements before the fast were also similar to values reported previously for fetal sheep in late gestation (Table 1).1 Before the fast began, there were no significant differences in plasma glucose, PGE, blood gas status, or incidence or amplitude of fetal breathing movements between the pairs of fetuses that were subsequently glucose infused or uninfused during the fast (Table I). Effects of nutritional manipulation Metabolite and hormone concentrations. Fasting significantly reduced plasma glucose levels in the mother and

Glucose, prostaglandin E, and breathing in fetal sheep 715

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Table I. Values (mean ± SE) for arterial blood gas tensions, pH, oxygen content, plasma concentrations of glucose and PGE, and mean incidence and amplitude of fetal breathing movements before fasting in twin sheep fetuses that were subsequently uninfused (n = 5) or infused with glucose (n = 5) during a 48-hour period of maternal fasting Arterial plasma concentration

Animals

Uninfused Glucoseinfused

Glucose (mmollL)

PGE (nmoll L)

0.74 ± 0.10 0.79 ± 0.09

4.62 ± 1.31 3.57 ± 1.32

Arterial

Fetal breathing movements

pH

P0 2 (mm Hg)

Peo2 (mm Hg)

Oxygen content (mmol/ L)

Incidence (%)

Amplitude (mm Hg)

7.367 ± 0.009 7.364 ± 0.006

19.0 ± 0.7 21.7 ± 1.2

48.2 ± 1.3 46.6 ± 1.2

3.50 ± 0.28 3.79 ± 0.24

47.7 ± 5.7 44.4 ± 5.4

3.9 ± 0.4 4.7 ± 0.9

Table II. Values (mean ± SE) for arterial plasma concentrations of glucose and PGE before, during, and after 48-hour period of food withdrawal begun at time 0 in ewes and their twin fetuses, which were either glucose infused or uninfused during fast Time from food withdrawal

Glucose (mmoIlL) Uninfused fetuses Infused fetuses Mothers PGE (nmoIlL) Uninfused fetuses Infused fetuses Mothers

No. of animals

-24 hr

o hr

24 hr

5 4 5

0.70 ± 0.12 0.83 ± 0.12 3.05 ± 0.28

0.77 ± 0.10 0.84 ± 0.08 2.92 ± 0.34

0.51* ± 0.06 0.68 ± 0.07 1.89* ± 0.18

0.48*t ± 0.06 ± 0.06 0.81 1.76* ::!: 0.18

0.65 ± 0.08 0.66 ± 0.08 2.72 ± 0.48

4 4 4

5.14 ::!: 2.44 4.15 ± 2.04 10.10 ± 0.85

6.44 ::!: 2.24 3.30 ± 1.65 11.13 ± 1.33

6.91 ::!: 1.51 5.46 ± 1.87 13.51 ± 0.27

8.30* ::!: 2.54 6.60* ± 1.92 18.19 ± 2.57

6.24 ± 1.51 4.49 ± 1.76 16.55 ± 2.70

48 hr

72 hr

*Significantly different from time 0 value, p < 0.05 (paired t test). tSignificantly less than value in infused fetuses, p < 0.01 (paired and unpaired t test).

uninfused fetus at 24 and 48 hours (Table II). Infusion of glucose into the other fetus of the pair maintained normoglycemia; plasma glucose levels were not significantly different from prefasting values at 24 and 48 hours and were significantly greater than those in the uninfused fetuses after 48 hours of fasting (Table II). In the fetus in which glucose infusion failed, the plasma glucose level was maintained for the first 24 hours of maternal fasting but had fallen to a value similar to that in the uninfused fetuses by the end of the 48-hour fast. After refeeding was carried out for 24 hours, plasma glucose levels in the mothers and uninfused fetuses were not significantly different from prefasting values (Table II). Maternal fasting led to increases in plasma PGE concentrations in the ewes and uninfused, hypoglycemic fetuses, as reported previously. 12 The increment in maternal arterial plasma PGE during fasting varied widely between individuals (range 2.90 to 15.16 nmoIlL), and hence the mean change in plasma PGE was not significant, even at the end of the 48-hour period of fasting (P > 0.05, Table II). Significant increases in fetal plasma PGE levels were observed at the end of the fast in both the uninfused and glucose-infused fetuses (Table II). The increment in fetal plasma PGE from

the mean prefasting value was similar in the uninfused (+ 2.52 ± 0.53 nmollL, n = 4) and glucose-infused (-t. 2.80 ± 0.74 nmollL, n = 4) fetuses. There were also no significant differences in the absolute PGE concentrations between the two groups of fetuses at any time during the experimental period (Table II). Refeeding the ewes lowered plasma PGE concentrations in the mother and both groups of fetuses; the values observed 24 hours after refeeding were not significantly different from those measured before fasting began (Table II). No significant changes in fetal blood gas tensions, pH, or oxygen content occurred during maternal fasting in either the glucose-infused or uninfused groups of fetuses (p > 0.05 all cases). Fetal breathing movements. In common with previous studies 3 . 12 the incidence of fetal breathing movements decreased significantly during maternal fasting in the fetuses that became hypoglycemic (Fig. I). The mean reduction in the incidence of fetal breathing movements during the 48-hour period of fasting was 58% ± 11.0% (p < 0.01) in these five fetuses. By contrast, there was no significant change in the incidence of fetal breathing movements during maternal fasting in the glucose infused fetuses (Fig. 1); the mean inci-

716

Fowden et al.

February 1992 Am J Obstet Gynecol

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nificant positive correlation between the incidence of fetal breathing movements and the arterial plasma glucose concentration in the individual fetuses (Fig. 2). No significant correlation was observed between the incidence of fetal breathing movements and the fetal plasma PGE level (r = -0.120, n = 32, P > 0.05) or between the latter values and the fetal arterial concentration of plasma glucose (r = -0.166, n = 32, p> 0.05).

o

24 48 72

0 24 48 72

TIME (h)

Fig. 1. Incidence and amplitude (mean ± SE) of fetal breathing movements (FBM) (dotted bars) before, during, and after 48-hour period of maternal food withdrawal (solid horizontal bars) and mean changes in value (hatched bars) from time 0 in fetuses uninfused (n = 5) or infused with glucose during fast (n = 5, except at 48 hours when n = 4). Asterisk, Significant change from time 0 value, p < 0.05; Dagger, Significantly different from infused fetuses, p < 0.05. dence of fetal breathing movements in these fetuses was therefore significantly greater than that in the uninfused fetuses at the end of the fast (Fig. 1). After refeeding for 24 hours, the incidence of fetal breathing movements was not significantly different from prefasting values in either uninfused or glucose-infused groups of fetuses (Fig. I). In the fetus in which glucose infusion failed, the incidence of fetal breathing movements was maintained at a normal value (38.2%) at 24 hours of fasting but had fallen to a value (13.7%) similar to that in the uninfused, hypoglycemic fetuses at the end of the fast (Fig. 1). In contrast to earlier findings,I2 there was no apparent change in the amplitude of fetal breathing movements during maternal fasting in the hypoglycemic fetuses (Fig. 1). Nor was there any significant change in amplitude in the glucose-infused fetuses during the 48hour period of maternal fasting (Fig. 1). Relationship between fetal breathing movements and plasma concentrations of glucose and PGE. When the data from all the fetuses were combined, irrespective of the day or type of treatment, there was a sig-

This study demonstrates that the reduction in the incidence of fetal breathing movements observed during maternal fasting is due primarily to the fall in glucose concentration in the fetal plasma. The degree of fetal hypoglycemia produced by fasting and the reduction in breathing activity observed in the hypoglycemic fetuses in the current study were similar to those reported previously, as were the increments in plasma PGE. 3,4,6. 12 When fetal normoglycemia was maintained during the fast by fetal glucose infusion, there was no reduction in the incidence of fetal breathing movements in spite of an increase in fetal plasma PGE similar to that seen in the hypoglycemic fetuses. These observations indicate that, contrary to previous suggestions,6 PGE is not directly involved in regulating fetal breathing movements during maternal fasting, although any effects of PGE may have been obscured by glucose administration in the fetus. Role of prostaglandins. In other circumstances prostaglandins, including PGE, are known to affect the incidence of fetal breathing movements in the sheep. 7 Reducing the circulating prostaglandin levels in the fetus by treatment with prostaglandin synthetase inhibitors (aspirin, indomethacin, meclofenamate) leads to an increased incidence of fetal breathing movements, which can be restored to its normal value by PGE infusion. 7• 10 Intrafetal infusion of prostaglandin, particularly PGE, to levels similar to those seen during labor also causes a rapid reduction in the normal incidence of fetal breathing movements.1O In the current study the percentage increase in fetal plasma PGE observed during fasting was smaller than that during infusions of PGE sufficient to reduce the incidence of fetal breathing movements. IO Furthermore, fetal plasma PGE concentrations observed at the end of the fast in this study were less than those measured during labor. 12 These observations suggest that there may be a critical circulating concentration of PGE above which inhibition of fetal breathing movements occurs. The finding that the relationship between the incidence of fetal breathing movements and the dose of PGE 2 infused into meclofenamate-treated fetuses is not linear supports this suggestion. 1O Previous studies have shown that the concentrations of plasma glucose and PGE are both significant influ-

Glucose, prostaglandin E, and breathing in fetal sheep

Volume 166 Number 2

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ences on the incidence of fetal breathing movements in the sheep fetus after 130 days of gestation. 10. 12 Under normal nutritional conditions, PGE may be the more important factor physiologically as fetal PGE levels rise toward term, whereas fetal plasma glucose levels vary very little during late gestation in well-fed animals. l7 · 18 However, even under these conditions, PGE is unlikely to be the only influence on fetal breathing movements because the decrease in breathing activity observed toward term still occurs when the normal prepartum increase in fetal plasma PGE is abolished by meclofenamate treatment. '" Certainly in the current study fastinginduced rises in plasma PGE did not inhibit fetal breathing activity when they were accompanied by fetal normoglycemia, which suggests that plasma glucose may be the more important factor regulating fetal breathing movements during adverse nutritional conditions. Central mechanisms. The mechanism whereby hypoglycemia reduces the incidence of fetal breathing movements is still unclear but may involve changes in cerebral metabolism and acid-base balance!' '. 7 Fetal hypoglycemia, induced by insulin administration, reduces cerebral glucose utilization and leads to changes in the acid-base status of the peripheral circulation. J. 6 On the other hand, hypoglycemia induced by fasting has no apparent effect on cerebral glucose consumption, although there is a reduction in sagittal sinus Peo 2 and H+ ion levels, which suggests that less carbon dioxide is being produced by the fetal brain under these

circumstances.' Certainly, when glucose is infused into hypoglycemic fetuses of fasted ewes, there is a rise in cerebral glucose utilization that is accompanied by central acidosis and an increase in fetal breathing activity. 3 These observations suggest that fetal glycemia may alter fetal breathing activity by changing the chemical environment of the central chemoreceptors. These receptors are responsive in utero and known to be active in the control of ovine fetal breathing movements during late gestation!0.21 It has also been postulated that central chemoreceptors mediate the respiratory effects of prostaglandins in the fetus. 7.21. 22 Infusions of prostaglandin synthetase inhibitors produce central acidosis in the sheep fetus, whereas PGE infusion may cause cerebral vasodilatation and lead to central alkalosis as a consequence. 22 Changes in the fetal concentrations of PGE and glucose may therefore act on fetal breathing movements through a common pathway, which, in the case of maternal fasting, would have additive effects at the chemoreceptors and lead to a reduced incidence of fetal breathing movements. However, the effect of the increment in PGE induced by fasting must be relatively small, as no change in fetal breathing movements was observed in the current study when fetal PGE levels increased in the absence of any change in fetal glucose concentrations. Whatever the central mechanisms involved, these findings show that the respiratory effects of fetal hypoglycemia, induced by fasting. are not mediated through changes in fetal plasma PGE.

718

Fowden et al.

Uteroplacental prostaglandin synthesis. Hypoglycemia in either the mother or fetus appears to be a potent stimulus to prostaglandin synthesis in the pregnant ewe. When maternal glucose levels fall during fasting or insulin administration, there are increases in the maternal concentrations of PGE and 13,14-dihydro-15-keto-prostaglandin F2a (PGFM), the main metabolite of prostaglandin F2a ."· 13 Similarly, when the fetus becomes hypoglycemic, its prostaglandin levels rise even when there is no change in maternal glycemia."·'3 The most likely source of this PG is the uteroplacental tissues, because there are significant arteriovenous concentration differences in PG across both sides of the ovine placenta. II. '2.23 Furthermore, these concentration differences across the uterine circulation widen during hypoglycemia."·'3 The present finding that fetal plasma PGE levels increased during fasting in both twins, irrespective of their glucose concentrations, appears to suggest that maternal glucose levels may have the more dominant role in regulating utero placental PG production. However, when glucose is infused into single fetuses to maintain normoglycemia during maternal fasting, no rise in maternal plasma PGFM occurs in spite of sustained hypoglycemia in the ewe. 24 Although neither PGF 2a nor PGE was measured in this study,"4 these findings suggest that uteroplacental prostaglandin production can be inhibited by glucose infusion into a single fetus. However, infusion of glucose into one of a pair of fetuses, even at rates higher than its normal use, clearly is not sufficient to overcome the combined effects of hypoglycemia in its mother and uninfused twin. Increased PGE production therefore occurs in the uteroplacental tissues of the uninfused twin and leads directly to elevated PGE levels in the ewe and hypoglycemic fetus. Because PGE crosses the ovine placenta 25 and maternal PGE concentrations are invariably higher than those in the fetus, the high plasma PGE level found during fasting in the normoglycemic fetus could be due merely to transplacental passage of PGE down its concentration gradient from the ewe. The way in which glycemia affects prostaglandin synthesis remains unknown, although the results of this and previous studies indicate that the rate of placental glucose consumption is probably a key factor in determining prostaglandin production by the uteroplacental tissues. '2. 24 However, further studies of uteroplacental prostaglandin output in different nutritional conditions are required before the role of placental glucose consumption and the relative importance of fetal and maternal glucose in controlling prostaglandin synthesis can be ascertained fully. It may be that changes in the availability of other metabolites such as fatty acids, which accompany the changes in glycemia induced by

February 1992 Am J Obstet Gyneco1

fasting, are also important in determining prostaglandin production in utero. II We thank Mrs. D. Houlton and Mr. P. Hughes for their help during surgery and sampling, Mr. I. Cooper and Mr. D. Clarke for their care of the animals, and Miss L. Mundy and Miss D. Brouwer for their assistance with the biochemical analyses. REFERENCES 1. Harding R. Fetal breathing. In: Beard R, Nathanielsz PW, eds. Fetal physiology and medicine. New York: Marcel Dekker, 1984:255-86. 2. Natale R. Maten1al plasma glucose concentration and fetal breating: a review. Semin Perinatol 1980;4:287-93. 3. Richardson BS, Hohimer AR, Bissonnette ]M, Machida CM. Cerebral metabolism in hypoglycaemic and hyperglycaemic fetal Iambs. Am] PhysioI1983;245:R730-6. 4. Richardson BS, Hohimer AR, Bissonnette ]M, Machida CM. Insulin hypoglycaemia, cerebral metabolism, and neural function in fetal lambs. Am ] Physiol 1985;248:R72-7. 5. Bissonnette ]M, Hohimer AR, Richardson BS, Machida CM. Effect of acute hypo glycaemia on cerebral metabolic rate in fetal sheep.] Dev Physiol 1985;7:421-6. 6. Fowden AL, Harding R, Ralph MM, Thorburn CD. Nutritional control of respiratory and other muscular activities in relation of plasma prostaglandin E in the fetal sheep.] Dev Physiol 1989; 11 :253-62. 7. Kitterman ]A. Arachidonic acid metabolites and control of breathing in the fetus and newborn. Semin Perinatol 1987; 11 :43-52. 8. Kitterman ]A, Liggins CC, Clements ]A, Tooley WHo Stimulation of breathing movements in fetal sheep by inhibitors of prostaglandin synthesis. ] Dev Physiol 1979; 7 :453-66. 9. Kitterman ]A, Liggins CC, Fewell ]E, Tooley WHo Inhibition of breathing movements in fetal sheep by prostaglandins.] Appl Physiol 1983;54:687-92. 10. Wallen LD, Murai DT, Clyman RI, Lee CH, Mauray FE, KittermanJA. Regulation of breathing movements in fetal sheep by prostaglandin E2 • ] Appl Physiol 1986;60:52631. 11. Fowden AL, Silver M. The effect of nutritional state on uterine prostaglandin F metabolite concentrations in the pregnant ewe during late gestation. Q ] Exp Physiol 1983;68:337-49. 12. Fowden AL, Harding R, Ralph MM, Thorburn CD. The nutritional regulation of plasma prostaglandin E concentrations in the fetus and pregnant ewe during late gestation.] Physiol 1987;394: 1-12. 13. Fowden AL, Silver M. The effects of food withdrawal on uterine contractile activity and on plasma cortisol concentrations in ewes and their fetuses during late gestation. In: Jones CT, Nathanielsz PW, eds. Physiological development of the fetus and newborn. London: Academic Press, 1985:157-61. 14. Comline RS, Silver M. The composition offoetal and maternal blood during parturition in the ewe. ] Physiol 1972;222:233-56. 15. Kelly RW, Amato F, Seamark RF. N-acetyl-S-methoxykynureanamine, a brain metabolite of melatonin is a potent inhibitor of prostaglandin biosynthesis. Biochem Biophys Res Commun 1984;121:372-9. 16. Annitage P. Statistical methods in medical research. Oxford: Blackwell, 1971. 17. Bassett ]M, Madill D. The influence of maternal nutrition on plasma hormone and metabolite concentrations.] Endocrinol 1974;61:465-77.

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Glucose, prostaglandin E, and breathing in fetal sheep 719

18. ChallisJRG, Dilley SR, RobinsonJS, Thorburn GO. Prostaglandins in the circulation of the fetal lamb. Prostaglandins 1976;11:1041-52. 19. Wallen LD, Murai DT, Clyman RI, Lee CH, Mauray FE, Kitterman JA. Effects of meclofenamate on breathing movements in fetal sheep before delivery. J Appl Physiol 1988;64:759-66. 20. Hohimer AR, Bissonnette JM, Richardson BS, Machida CM. Central chemical regulation of breathing movements in fetal lambs. Respir PhysioI1985;52:99-111. 21. Koos BJ. Central stimulation of breathing movements in fetal lambs by prostaglandin synthetase inhibitors. J Physiol 1985;362:455-66. 22. Hohimer AR, Richardson BS, Bissonnette JM, Machida CM. The effect of indomethacin on breathing movements and cerebral blood flow and metabolism in the fetal sheep . .I Dev Physiol 1985;7:217-28.

23. Andrianakis P, Walker OW, Ralph MM, Thorburn GO. Effect of inhibiting prostaglandin synthesis in pregnant sheep with 4-amino antipyrine under normothermic and hyperthermic conditions. AM J OBSTET GV;\IECOL 1989;161:241-7. 24. Binienda Z, Rosen ED, Kelleman A, Sadowsky OW, Nathanielsz PW, Mitchell MD. Maintaining fetal normoglycaemia prevents the increase in myometrial activity and uterine 13,14 dihydro-15-keto-prostaglandin F'a production during food withdrawal in late pregnancy in the ewe. Endocrinology 1990; 127:3047-51. 25. Rankin JHG, Phernetton TH. Circulatory responses of the near term sheep fetus to prostaglandin E,. Am J PhysioI1976;231:760-5.

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The effects of glycemia on breathing movements and plasma prostaglandin E concentrations in the sheep fetus.

The purpose of this study was to determine the roles of fetal plasma glucose and prostaglandin E in controlling fetal breathing movements...
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