Role of prostaglandins in the metabolic responses of the fetus to hypoxia

Role of prostaglandins in the metabolic responses of the fetus to hypoxia Stuart B. Hooper, PhD, Richard Harding, PhD, Jan Deayton, BSc, and Geoffrey D. Thorburn, MD Clayton, Victoria, Australia OBJECTIVE: The effect of inhibiting prostaglandin synthesis on the fetal metabolic response to hypoxemia was examined by infusing indomethacin during periods of reduced maternal uterine blood flow. STUDY DESIGN: In seven fetal sheep we administered a 6-hour infusion of either indomethacin (n = 5), indomethacin plus prostaglandin E2, or a vehicle solution (n = 5). The last 4 hours of each infusion period coincided with a period of fetal hypoxemia induced by reduced maternal uterine blood flow. RESULTS: During reduced maternal uterine blood flow indomethacin infusions caused a significantly greater reduction in pHA (reduced from 7.36 ± 0.01 to 7.10 ± 0.02) than both the vehicle (from 7.36 ± 0.01 to 7.20 ± 0.03) and indomethacin plus prostaglandin E2 infusions (from 7.36 ± 0.01 to 7.18 ± 0.02). Before reduced maternal uterine blood flow was induced, indomethacin significantly elevated fetal plasma glucose and lactate concentrations from 0.6 ± 0.04 and 2.2 ± 0.1 to 1.3 ± 0.2 and 6.7 ± 0.7 mmol/L, respectively. During reduced maternal uterine blood flow indomethacin caused a significantly greater increase in plasma glucose and lactate concentrations than the vehicle; plasma glucose and lactate concentrations increased to a maximum of 1.8 ± 0.2 and 22.7 ± 0.8 mmol/L, respectively, during indomethacin infusions compared with 1.1 ± 0.1 and 15.7 ± 1.7 mmol/L, respectively, during vehicle infusions. The addition of prostaglandin E2 to the indomethacin infusion prevented the enhanced increase in glucose and lactate concentrations during reduced maternal uterine blood flow and caused a significant increase in fetal plasma insulin concentrations from 12.6 ± 0.7 to 60.9 ± 28.1 ILU/ml. CONCLUSION: The inhibition of prostaglandin synthesis during fetal hypoxemia alters the metabolic response of the fetus, leading to a severe metabolic acidosis. (AM J OBSTET GVNECOL 1992;166:1568-75.)

Key words: Fetus, hypoxia, asphyxia, indomethacin, glucose, lactate, insulin Fetal hypoxia is a common cause of fetal morbidity and mortality and can result from a number of causes, including umbilical cord occlusion, maternal cigarette smoking, and reduced uteroplacental circulation. The blood gas and pH changes and many of the endocrine, biophysical, and cardiovascular responses that occur in the fetus during acute periods of hypoxemia are not sustained if the hypoxemia is prolonged. 1-4 In particular the fetal arterial acidosis, which develops initially after reducing maternal uterine blood flow, is corrected after 12 to 16 hours.t" We have suggested that this correction in fetal blood pH results from a metabolic adaptation to the hypoxemia': our study is directed toward an understanding of the mechanisms involved in this adaptation. Prostaglandin E2 (PGE.) is considered to be an im-

From the Department of Physiology, Monash University. Supported by the National Health and Medical Research Council of Australia. Receivedfor publication August 16, 1991; revised December 4, 1991 ; accepted December 30, 1991. Reprint requests: S.B. Hooper, PhD, Department of Physiology, Monash University, Clayton, Victoria 3168, Australia. 6/1 136035

1568

portant circulating fetal hormone released by the placenta."? Fetal plasma PGE 2 concentrations gradually increase in an exponential-like manner toward term" and can be precociously elevated by fetal hypoxemia" hypoglycemia.v" and hyperthermia." In addition, PGE 2 is thought to play an important metabolic role in the fetus by regulating insulin release,'? and PGE. has recently been identified as the placental factor that prevents catecholamine-mediated brown fat metabolism in the fetus." In a previous study we suggested that correction of fetal arterial acidosis, which occurred during prolonged hypoxia, primarily resulted from an increase in the uptake and metabolism of glucose and lactate by the fetus! Because we also observed that the increase in fetal arterial pH during prolonged hypoxemia closely followed the increase in fetal plasma PGE 2 concentrations, the aim of the present study was to determine the role of PGE 2 in the fetal metabolic adaptation to hypoxemia. In particular we wished to determine the effect of inhibiting prostaglandin release during fetal hypoxemia on fetal plasma glucose, lactate, and insulin concentrations. We hypothesized that the gradual increase in circulating PGE. concentrations in the fetus

Volume 166 Number 5

during hypoxemia plays an important metabolic role by reducing fetal blood glucose and, hence, lactate concentrations. Material and methods

Animal preparation. Surgery was performed under aseptic conditions on seven Border Leicester X Merino ewes between 110 and 117 days of gestation (term is 145 days). Anesthesia was induced with 5% thiopental sodium in water (intravenously) and was maintained after tracheal intubation with 1.5% halothane (oxygen/nitrous oxide, 50: 50 vol/vol). In all ewes polyvinyl catheters (SV 116, Dural Plastics, Sydney, Australia) were implanted into the maternal jugular vein and amniotic cavity. An adjustable clamp" was placed around the maternal common internal iliac artery to produce controlled reductions in maternal uterine blood flow.13. 14 In each fetus polyvinyl catheters (SV65, Dural Plastics) were implanted into the carotid artery and jugular vein. A polyvinyl catheter (SVI16) was also implanted into the trachea of the fetus to detect fetal breathing movements. Antibiotics (2 ml Streptopen intramuscularly, Glaxovet, Australia) were administered to each fetus before the uterine incision was closed. Fetal catheters and the control cable for the vascular clamp were exteriorized through an incision in the right flank of the ewe. The ewes were allowed to recover for at least 5 days after surgery before experimentation. Experimental protocol. Three separate 8-hour experiments were performed, each consisting of a 6-hour infusion period and a 2-hour recovery period. The last 4 hours of the 6-hour intravenous infusion corresponded to a period of moderate fetal asphyxia induced by reducing maternal uterine blood fIoW. 14 The three experiments differed by the type of infusion administered to the fetus: (a) a vehicle solution, (b) indomethacin (17 gm/min), or (c) indomethacin (17 gm/min) plus PGE. (2 gm/min). Fetal arterial blood samples were collected before the infusion (- 2 hours), immediately before the period of reduced maternal uterine blood flow (0 hours), and at 0.5, 1,2,4, and 6 hours after the onset of reduced maternal uterine blood flow for the measurement of Pao., Paco., pH A , fetal arterial blood oxygen saturation (Sao-), and glucose and lactate concentrations. Fetal arterial blood samples were also collected for the measurement of insulin concentrations at - 2, 0, 2, and 4 hours. Fetuses were allowed to recover for ~5 days between experiments. Fetal Pao., Paco., and pH A were measured with a blood gas and acid base analyzer (ABL30, Radiometer, Denmark); fetal Sao. was measured with a hemoximeter (OSM2, Radiometer). Fetal arterial pressure and heart rate were recorded continuously on a polygraph

Prostaglandins and fetal hypoxemia 1569

(7D, Grass) throughout each experiment. Arterial pressures were recorded after subtraction of amniotic fluid pressure. These experiments adhere to the Monash University guidelines on the care and use of experimental animals. Insulin assay. Fetal plasma insulin concentrations were measured with a human insulin radioimmunoassay kit (code IM.78, Amersham, United Kingdom) modified for ovine fetal plasma. The antisera to human insulin, human insulin standards (range 0 to 320 /-LU /ml), iodine 125-labeled insulin, and assay buffers were provided with the kit. The manufacturer's protocol was used except for the following modifications: to increase the sensitivity of the assay, the concentration of antisera and 1.5I-labeled insulin was one quarter and one half, respectively, of the concentration recommended; the assay was incubated overnight at 4° C, and bound and free insulin was separated with polyethylene glycol 6000 (10%; 0.03% sodium azide). All assay tubes were centrifuged at 2500 rpm for 20 minutes at 4° C (BeckmanJ6B) before the supernatant was aspirated off. The radioactivity remaining in the pellet was quantified using a gamma counter (Crystal 5400, Packard, USA). The intraassay coefficient of variation was 11.1 % (n = 16) at an insulin concentration of 72.8 ± 2.0 /-LU/ml of fetal plasma. No significant deviation from parallelism (p > 0.1) was found between a standard curve in buffer, a standard curve in plasma, and different volumes of a single plasma sample. A significant (p < 0.005) correlation was found between the amount of insulin added to plasma and the amount measured by the assay (y = 0.98x + 0.58, r = 0.998). Plasma PGE 2 glucose and lactate concentrations. Fetal plasma PGE. concentrations were measured by radioimmunoassay with antisera and procedures previously described.' Fetal plasma glucose concentrations were measured enzymatically by a previously described method." Fetal plasma lactate concentrations were also measured enzymatically with a glucose-lactate analyzer (2300GL, Yellow Springs Instruments). Statistical analysis. The results are presented as mean ± SEM. Data on fetal blood gases and pl-l, and fetal plasma, PGE., glucose, lactate, and insulin concentrations (after log transformation) were analyzed by a three-way analysis of variance with treatment (type of infusion), time, and animals as factors. All three experiments were completed in only four of the seven animals studied. Analyses of variance were performed only with these four fetuses. If a significant effect of treatment was found between any of the treatments, the significant treatment was analyzed separately by a two-way analysis of variance with animals and time as factors. This analysis was followed by a Student-Newman-Keuls multiple-range test for differences between time periods. Differences between treatments for a

1570

Hooper et a!.

May 1992

Am J Obstet Gynecol

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Time (h) Fig. 1. Fetal plasma PGE2 concentrations expressed as a percentage of preinfusion control values during either a fi-hour vehicle (open circles), indomethacin (solid circles), or indomethacin plus PGE, (triangles) infusion. The period of reduced maternal uterine blood flow (hatched bar) coincided with the last 4 hours of the 6-hour infusions (open bar).

given time period were analyzed by a nonpaired Student's t test. Unless otherwise stated, the level of significance reported in the text is p < 0.05. Results Fate of fetuses. All fetuses survived to or near term (140.1 ± 0.8 days), at which time the ewes and fetuses were killed by an overdose of pentobarbital sodium. All fetuses were classified as being healthy at the start of each experiment as judged by their blood gas and acidbase status. Fetal plasma PGE, concentrations. The vehicle infusion alone did not significantly affect fetal plasma PGE" concentrations, whereas inducing reduced maternal uterine blood flow during the vehicle infusion caused an increase in PGE, concentrations from a mean control value of 4.3 ± 1.1 nmol! L to a maximum of 5.8 ± 1.0 nmol!L after 4 hours of reduced maternal uterine blood flow (Fig. I). The infusion of indomethacin caused a significant reduction in fetal plasma PGE, concentrations from a mean control value of 5.7 ± 1.7 nmol! L to below the sensitivity of the assay (in all except one experiment) 2 hours after starting the infusion. The addition of PGE, to the indomethacin infusion maintained fetal plasma PGE 2 concentrations at preinfusion levels; PGE, concentrations were similar before the start of the infusion (4.2 ± 1.4 nmol/L) compared with 6 hours after the start of the infusion (5.1 ± 1.6 nmoI!L). Two hours after the completion of the indomethacin plus PGE, infusion fetal plasma PGE, concentrations had significantly decreased to 1.2 ± 1.0 nmol/L.

Blood gas and pH measurements. No effect of infusion type was found on the changes in fetal Sao" Pao, and Paco, in response to reduced maternal uterine blood flow, indicating that the level of hypoxemia was similar in all three groups (Fig. 2). During the vehicle infusion reduced maternal uterine blood flow significantly decreased fetal Pao, and Sao, from control values of 23.5 ± 0.2 mm Hg and 57.3% ± 3.0% to 14.7 ± 1.1 mm Hg and 23.9% ± 1.8%, respectively, after I hour. Similar decreases were observed during the other two infusions. In contrast, a significant effect of infusion type was found on the changes in pH A in response to reduced maternal uterine blood flow. Before reduced maternal uterine blood flow was induced the indomethacin and indomethacin plus PGE" infusions, but not vehicle infusions, caused a significant reduction in pH A compared with respective preinfusion control values (Fig. 2). During vehicle infusions reduced maternal uterine blood flow caused a significant reduction in pH A from a control value of 7.36 ± 0.01 to a minimum of 7.20 ± 0.03 after 2 hours. Compared with vehicle infusions indomethacin infusions resulted in a lower pH A at 1, 2, and 4 hours after inducing reduced maternal uterine blood flow (Fig. 2); fetal pl-l, decreased from a mean control value of 7.36 ± 0.0 I to a minimum of 7.10 ± 0.02 after 2 hours of reduced maternal uterine blood How. The addition of PGE" to the indomethacin infusion reversed the effects of indomethacin alone during reduced maternal uterine blood flow (Fig. 2). During the indomethacin plus PGE, infusions, fetal pl-I; decreased from a control value of 7.36 ± 0.0 I to a minimum of 7.18 ± 0.02 at

Prostaglandins and fetal hypoxemia

Volume 166 Number 5

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4 hours after inducing reduced maternal uterine blood

Row. Fetal plasma glucose concentrations. A significant effect of infusion type was found on the changes in fetal plasma glucose concentrations. During vehicle infusions reduced maternal uterine blood Row caused a significant elevation in fetal plasma glucose concentrations from a preinfusion control value of 0.60 ± 0.09 mmol/L to a maximum of 1.1 ± 0.1 mmol/L after 30 minutes of reduced maternal uterine blood flow. Fetal plasma glucose concentrations remained elevated for the duration of the experiment (Fig. 3, A). Before reduced maternal uterine blood Row was induced, both the indomethacin and indomethacin plus PGE 2 infusions, but not vehicle infusion, caused a significant increase in fetal plasma glucose concentrations. During indomethacin infusions, glucose concentrations increased from a mean control value of 0.6 ± 0.04 to 1.3 ± 0.2 mmol/L (Fig. 3, A). Inducing reduced maternal uterine blood Row during the indomethacin infusion caused a further significant increase in fetal plasma glucose concentrations to a maximum of 1.8 ± 0.2 mmol/L after 1 hour of reduced maternal uterine blood Row. The addition of PGE. to the indomethacin infusion prevented the additional increase in

glucose concentrations that occurred during reduced maternal uterine blood Row (Fig. 3, A). Fetal plasma lactate concentrations. The three types of infusion had significan'lly different effects on fetal plasma lactate concentrations (Fig. 3, B). During vehicle infusions, fetal plasma lactate concentrations were significantly elevated by reduced maternal uterine blood Row from a control value of 2.4 ± 0.2 mmol/L to a maximum of 15.7 ± 1.7 mmol/L after 4 hours. The infusion of indomethacin before the induction of reduced maternal uterine blood Row caused a significant elevation in fetal plasma lactate concentrations from a preinfusion control value of 2.2 ± 0.1 to 6.7 ± 0.7 mmol/L. The induction of reduced maternal uterine blood Row during the indomethacin infusion caused a further significant elevation in fetal plasma lactate concentrations to a maximum of22.7 ± 0.8 mmol/L after 4 hours of reduced maternal uterine blood Row. The addition of PGE. to the indomethacin infusion prevented the indomethacin-induced increase in fetal plasma lactate concentrations during normoxia and reduced the increase in lactate concentrations observed during an indomethacin infusion in the presence of reduced maternal uterine blood Row. The increases in fetal plasma lactate concentrations during reduced ma-

1572 Hooper et al.

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infusion. The period of reduced maternal uterine blood flow with the last 4 hours of the 6-hour

(hatched bar) coincided infusions (open bar).

ternal uterine blood flow were similar during vehicle infusions and indomethacin plus PGE. infusions. Fetal plasma insulin concentrations. The three types of infusion had significantly different effects on the concentration of insulin in fetal plasma. The infusion of indomethacin alone had no significant effect on fetal plasma insulin concentrations during normoxia. During vehicle infusions, reduced maternal uterine blood flow caused a small reduction in fetal plasma insulinconcentrations from a control value of 9.5 ± 0.7 ""V I ml to a minimum of 5.9 ± 0.3 ""V I ml after 4 hours of reduced maternal uterine blood flow (Fig. 4). Similarly, inducing reduced maternal uterine blood flow during indomethacin infusions caused a decrease in fetal plasma insulin concentrations from a control value of 14.7 ± 2.2 to a minimum of6.5 ± 0.3 ""Vlmlafter 2 hours of reduced maternal uterine blood flow. The addition of PGE. to the indomethacin infusion caused a large increase in fetal plasma insulin concentrations during normoxia from a preinfusion control value of 12.6 ± 0.7 to 60.9 ± 28.1 ""Vlml after 2 hours. In the subsequent reduced maternal uterine blood flow period fetal plasma insulin concentrations decreased to

Comment

In this study we have obtained evidence to support the contention that increased placental PGE. production plays an important role in the metabolic adaptation of the fetus to prolonged hypoxia. We have demonstrated that the inhibition of prostaglandin synthesis enhances the increase in fetal plasma glucose and lactate concentrations that occur during reduced maternal uterine blood flow. The enhanced increase in plasma lactate concentrations undoubtedly contributes to the severe reduction in fetal pH A which, if sustained, causes fetal death (Hooper SB, Harding R, Thorburn GD. Unpublished observations). The addition of PGE. to the indomethacin infusion, however, prevented this augmented fetal acidemia, hyperglycemia, and hyperlacternia during reduced maternal uterine blood flow and stimulated a large increase in fetal plasma insulin concentrations. During vehicle infusions PGE. concentrations were significantly elevated after 4 hours of reduced maternal uterine blood flow, which supports our earlier observation! The infusion of indomethacin, a potent inhibitor of prostaglandin synthesis," rapidly decreased fetal plasma PGE. concentrations; they remained low during the subsequent reduced maternal uterine blood flow period. The addition of PGE. to the indomethacin infusion maintained circulating fetal plasma PGE. concentrations at preinfusion levels for the duration of the infusion (Fig. I). However, it is unlikely that the dose of PGE. administered was sufficient to sustain the normal delivery of PGE. to some tissues (e.g., liver) and, more importantly, to increase the delivery to a level that would occur during reduced maternal uterine blood flow! The major source of circulating PGE. in the fetus is the placenta," 7 and umbilical vein PGE. concentrations are much higher than the concentrations circulating in the fetus.' Because 75% of the blood supply to the fetal liver is derived from the umbilical vein," the fetal liver is therefore normally exposed to higher concentrations of PGE. than the concentrations that circulate in fetal blood. This could explain why PGE. did not reverse all of the effects of insulin administration. The infusion of indomethacin during reduced maternal uterine blood flow caused a much greater reduction in pH A than when the vehicle was infused. During reduced maternal uterine blood flow the reduction in pH A most probably results from the elevation in Paco, (respiratory acidosis), the elevation in blood lactate, and possibly fatty acid concentrations (metabolic acidosis), although these were not measured. The greater reduction in pH A during reduced maternal

Prostaglandins and fetal hypoxemia 1573

Volume 166 Numbe r 5

100

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uterine blood flow in indomethacin com pared with vehicle infusions must have been metabolic in origin because the elevation in Paco, was similar in both experiments, whereas blood lactate concentrations were gr eater with indomethacin. The add ition of PGE. to the indomethacin infusion prevented this enhanced acidosis, presumably by preventing the increase in lactate concentrations; howev er, it is also possible that PGE. red uced fatty acid concentrations by decreasing lipolysis in adipose tissue. I S If reduced maternal uterine blood flow and the indomethacin infusions were continued for a longer period of time (>6 hours), these fetuses would probably have died. In two preliminary experiments we considered it appropriate to induce reduced maternal uterine blood flow during an indomethacin infusion for at least 12 hours becau se PGE. increases relatively slowly during reduced maternal uterine blood flow and is significant onl y aft er 4 hours.' In these preliminary ex periments both fetu ses became severely acidoti c (p H 6.9 to 7.0) and died between 6 and 8 hours after inducing reduced maternal uterine blood flow (Hooper, Harding, and Thorburn, unpublished observations). This observation and those presented in our study clearl y demonstrate the detrimental effects that indomethacin has on a hypoxemic fetu s. Furthermore, these effects could explain the unaccounted fetal deaths th at have occurred in utero after the ad ministration of indomethacin to prevent premature labor in human beings. ' 9 The control of blood glucose concentrations in the fetus is primarily dependent up on maternal blood glucose concentrations, insulin pr oduction by the fetal

pancreas, fetal glucose use, and glucose production or storage by the liver." Gluconeogenesis is a very important source of blood glucose in ad ult ruminants;' but although the fetal shee p liver has all the necessary en zymes it is believed that this metabolic pathway do es not operate until after birth! ···3 It is not known, however, whether this pathway can be activated during fetal hypoxemia. The finding in thi s stud y that an indomethacin infusion during normoxia causes an elevation in fetal plasma glucose con centrations has been reported previously." The mechanism underlying this increase is not known although it probably results from an incr ease in glucose release from the liver because insulin concentrations were not altered by indomethacin . PGE. failed to reverse the effect of indomethacin on fetal blood glucose co ncent rations during normoxia, which could mean th at (1) the dose of PGE. administered was insufficient to increase PGE. concentrations in the umbilical vein to normal levels, (2) PGE. is the wrong prostaglandin, or (3) the failure was due to a side effect of indomethacin unrelated to prostaglandin synthesis. One known side effect of indomethacin is the inhibition of phosphodiesterase activity, although this o nly occurs at mu ch higher doses than that used in our study." Inhibition of ph osphodiesterase activity would cau se a sustained elevation in intracellular cyclic ade nosine monophosphate (cAMP) concentrations by preventing the breakdown of cAMP. As discussed below, an increase in intracellular cAMP concentrations in liver tissue would decrease glycolysis and promote gluconeogenesis and glucose release." Other known

1574 Hooper et al.

side effects of indomethacin are 0Iigohydramnios,9. 27 possibly caused by reduced fetal urine production, a reduction in cerebral blood flow in fetal sheep ," and an increase in vascular tone of the ductus arteriosus." Fetal plasma catecholamine concentrations are elevated by fetal hypoxia whether it is induced by maternal hypoxia" or reduced maternal uterine blood flow.' The increase in fetal plasma catecholamine concentration is believed to be responsible for the increase in glucose concent ration during fetal hypoxemia." Catecholamines promote an increase in glucose release by the liver, which is mediated by ~-adrenergic receptors and an increase in cAMP levels." Catecholamines also inhibit insulin release from the pancreas, an action mediated by a-adrenergic receptors and a decrease in cAMP levels." The increases in fetal plasma glucose concentrations we observed during reduced maternal uterine blood flow (vehicle infusion) are similar to those reported previously during fetal hypoxia caused by maternal hypoxia. " The infusion of indomethacin, however, caused a greater increase in fetal blood glucose concentrations after the induction of reduced maternal uterine blood flow. The mechanism. by which indomethacin enhances this increase in fetal blood glucose during reduced maternal uterine blood flow is not known . It is highly likely, however, to be mediated by an inhibition of PGE2'synthesis because the addition of PGE2 to the indomethacin infusion prevented this increase. We suggest that PG~ may antagonize some of the biochemical actions of the catecholamines in utero by exerting opposing actions on tissue levels of cyclic adenosine monophosphate. For example, we speculate that PGE2 acts on the fetal liver to lower tissue cAMP concentrations. Increased cAMP levels in the liver decrease glycolysis and promote an increase in gluconeogenesis and glycogenolysis , leading to increased hepatic glucose release. If PGE 2 acts on the fetal liver as it do es in adipose tissue ," increased PGE2 concentration s would promote a reduction in liver cAMP levels; this would enhance glycogen synthesis and glycolysis and inhibit glycogenolysis and gluconeogenesis, thereby de creasing glucose release. Thus reducing circulating PGE2 concentrations during reduced maternal uterine blood flow would lead to an unopposed action of the cate cholamines on liver cAMP levels, leading to increased glucose production. The concept that PGE2 can oppose the action of catecholamines in utero is supported by the finding that PGE. release from the placenta prevents brown-fat metabolism (nonshivering thermogenesis) in the fetus ." In newborn lambs brown-fat metabolism is activated by adrenergic stimulation and is mediated by ~-adrenergic receptors, which increase cAMP concentrations." PGE 2 is known to inhibit lipolysis in adipose tissue by reducing cAMP concentrations" and probably has a similar

May 1992 Am J Obstet Gyn eco l

action on brown adipose tissue to prevent nonshivering thermogenesis in the fetus. I I In our study, in which fetal PGE2 concentrations were reduced by indomethacin and sympathoadrenal activity was increased by reduced maternal uterine blood flow" it seems likely that lipolysis would have been stimulated and that the release of fatty acids would have contributed to the observed acidosis. The action of catecholamines on the ~-islet cells of the pancreas to inhibit insulin release is mediated by aadrenergic receptors leading to a reduction in cAMP concentrations." In these experiments PGE 2 stimulated a large increase in insulin concentrations, again demonstrating an opposing action to the catecholamines. We speculate that PGE 2 acts on membrane-bound aden ylcyclase receptors, resulting in an increase in cAMP concentrations and thus insulin rele ase. The indomethacin infusion during normoxia caused an increase in fetal plasma lactate concentrations, which probably resulted from the increase in plasma glucose concentrations. The addition of PGE2 to the indomethacin infusion prevented this increase in lactate concentr ations, probably because of the large increase in plasma insulin concentrations and possibly also because of the suppression of glycogenolysis. In creased plasma insulin concentrations would promote the uptake of glucose for oxidative metabolism or storage as glycoge n. During fetal hypoxia the increase in fetal plasma glucose concentrations is believed to be largely responsible for the increase in fetal blood lactate concentrations because of the anaerobic metabolism of fetal glucose primarily by the placenta." Thus the increased fetal blood glucose could account for the enhanced increase in circulating fetal plasma lactate concentrations caused by indomethacin during reduced maternal uterine blood flow. The addition of PGE. prevented this effect of indomethacin during reduced maternal uterine blood flow, probably by elevating insulin concentrations and suppressing glucose production. We have demonstrated that during fetal hypoxemia indomethacin has profound metabolic effects on the fetus ; if the hypoxia or infusion is prolonged, the fetus is at risk of fatal acidemia. A similar finding has been observed after the inhibition of prostaglandin synthesis during another form of fetal stress, hyperthermia." During hyperthermia the infusion of 4-aminoantipyrine, a prostaglandin synthetase inhibitor, caused a large increase in fetal plasma glucose concentrations and a rapid decrease in fetal pH ; 4 of 10 fetuses died from this treatment." We contend, therefore, that an elevation in placental prostaglandin synthesis, probably PGE 2 , plays an integral role in the fetal metabolic adaptation to stress, possibly by leading to a gradual suppression of the metabolic actions of the catecholarnmes.

Volume 166 Number 5

We are indebted to K. Billings for her expert technical assistance and to A. Satragno for surgical assistance.

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