Search

Uterine and umbilical uptakes of alanine (Ala) were measured in 10 ewes before (control) and during intravenous infusion of Ala, which increased maternal arterial Ala concentration from 115 +/- 14 to 629 +/- 78 microM (P < 0.001). In 8 of these ewes, placental Ala fluxes were traced by constant intravenous infusion of L-[3,3,3-2H3]Ala in the mother and L-[1-13C]Ala in the fetus. Rates are reported as micromoles per minute per kilogram fetus. Ala infusion increased uterine uptake (2.5 +/- 0.6 to 15.6 +/- 3.1, P < 0.001), umbilical uptake (3.1 +/- 0.5 to 6.9 +/- 0.8, P < 0.001), and net uteroplacental utilization (-0.7 +/- 0.8 to 8.6 +/- 2.7, P < 0.01) of Ala. Control Ala flux to fetus from mother (Rf,m) was much less than the Ala flux to fetus from placenta (Rf,p) (0.17 +/- 0.04 vs. 5. 0 +/- 0.6). Two additional studies utilizing L-[U-13C]Ala as the maternal tracer confirmed the small relative contribution of Rf,m to Rf,p. During maternal Ala infusion, Rf,m increased significantly (P < 0.02) but remained a small fraction of Rf,p (0.71 +/- 0.2 vs. 7.3 +/- 1.3). We conclude that maternal Ala entering the placenta is metabolized and exchanged for placental Ala, so that most of the Ala delivered to the fetus is produced within the placenta. An increase in maternal Ala concentration increases placental Ala utilization and the fetal uptake of both maternal and placental Ala.

Uterine and umbilical uptakes of plasma amino acids were measured simultaneously in eighteen singleton pregnant ewes at 130 +/- 1 days gestation for the purpose of establishing which amino acids are produced or used by the uteroplacenta under normal physiological conditions and at what rates. The branched-chain amino acids (BCAA) had uterine uptakes significantly greater than umbilical uptakes. Net uteroplacental BCAA utilization was 8.0 +/- 2.5 mumol.kg fetus-1.min-1 (P < 0.005) and represented 42% of the total BCAA utilization by fetus plus uteroplacenta. There was placental uptake of fetal glutamate (4.2 +/- 0.3 mumol.kg fetus-1.min-1, P < 0.001) and no uterine uptake of maternal glutamate. Umbilical uptake of glutamine was approximately 61% greater than uterine uptake, thus demonstrating net uteroplacental glutamine production of 2.2 +/- 0.9 mumol.kg fetus-1.min-1 (P < 0.021). In conjunction with other evidence, these data indicate rapid placental metabolism of glutamate, which is in part supplied by the fetus and in part produced locally via BCAA transamination. Most of the glutamate is oxidized, and some is used to synthesize glutamine, which is delivered to the fetus. There was net uteroplacental utilization of maternal serine and umbilical uptake of glycine produced by the placenta. Maternal serine utilization and glycine umbilical uptake were virtually equal (3.14 +/- 0.50 vs. 3.10 +/- 0.46 mumol.kg fetus-1.min-1). This evidence supports the conclusion that the ovine placenta converts large quantities of maternal serine into fetal glycine.

Placental transport and fetoplacental utilization of threonine (Thr) were compared at 130 +/- 1 days gestational age between seven control ewes (C) and six ewes in which intrauterine growth restriction (IUGR) had been induced by exposure to high ambient temperature from 33 +/- 1 to 112 +/- 2 days of gestation. The fluxes were measured using simultaneous intravenous infusions of L-[1-13C]Thr into the mother and L-[U-14C]Thr into the fetus. The IUGR group had less fetal weight (1.27 +/- 0.14 vs. 3.10 +/- 0.10 kg, P < 0.01) and placental weight (120 +/- 17 vs. 295 +/- 14 g, P < 0.01) than the C group. The direct flux of maternal Thr into the fetal systemic circulation was less in the IUGR fetuses, both relative to fetal weight (1.40 +/- 0.19 vs. 2.19 +/- 0.18 mumol.min-1.kg fetus-1, P = 0.0107) and placental weight (1.5 +/- 0.2 vs. 2.3 +/- 0.2 mumol.min-1.100 g placenta-1, P = 0.0187). In both groups, there was excretion of CO2 produced from fetal Thr. The rate of CO2 production from fetal plasma Thr carbon by fetus plus placenta was reduced in the IUGR group (1.50 +/- 0.23 vs. 2.86 +/- 0.32 mumol.min-1.kg fetus-1, P = 0.0065). We conclude that the flux of maternal Thr into the IUGR fetus is markedly reduced because of a reduction in placental mass and because of a weight-specific reduction in Thr placental transport. The reduced flux is routed into fetal Thr accretion via a decrease in fetal Thr oxidation.

Placental transport and fetal utilization of leucine were studied at 130 days of gestation in six control ewes and in seven ewes in which intrauterine growth retardation (IUGR) had been induced by exposure to heat stress. Leucine fluxes were measured during simultaneous intravenous infusion of L-[1-13C]leucine into the mother and L-[1-14C] leucine into the fetus. In the IUGR group, the following leucine fluxes, expressed as micromol/min/kg fetus, were reduced compared with control: net uterine uptake (3.44 vs. 8.56, P<0.01), uteroplacental utilization (0.0 vs. 4.7, P<0.01), fetal disposal rate (6.4 vs. 8.9, P<0.001), flux from placenta to fetus (5.0 vs. 7.1, P<0.01), direct transport from mother to fetus (1.6 vs. 3.4, P<0.01), flux from fetus to placenta (1.5 vs. 3.2, P<0.001), and oxidation of fetal leucine by fetus plus placenta (2.1 vs. 3.2, P<0.02). Uterine uptake, uteroplacental utilization, and direct transport were also significantly reduced per gram placenta. We conclude that maternal leucine flux into the IUGR placenta is markedly reduced. Most of the reduced flux is routed into fetal metabolism via a decrease in placental leucine utilization and a decrease in the leucine flux from fetus to placenta.

The hypothesis that glutamine shuttles nitrogen between placenta and fetal liver via interconversion with glutamate was explored by infusing L-[1,2-13C2]glutamine in six fetal sheep chronically catheterized for sampling of the umbilical and hepatic circulations. Fetal plasma glutamine disposal rate was 19.9 +/- 1.3 mumol.min-1.kg fetus-1. Entry of glutamine from the placenta accounted for approximately 60% of the total glutamine entry rate in fetal plasma. Glutamine was taken up by fetal liver, and 45.3 +/- 7.9% of the glutamine taken up was released as glutamate. The fetal liver released large quantities of glutamate, as evidenced by a sixfold increase in plasma glutamate concentration in the blood flowing through the left hepatic lobe and a hepatic glutamate output-to-O2 uptake molar ratio of 0.149 +/- 0.013. In conjunction with a previous study of fetal glutamate metabolism, these data demonstrate that glutamine entering the fetal circulation is converted to glutamate by the fetal liver at a rate of approximately 3-4 mumol.min-1.kg fetus-1.

Plasma serine disposal rate (DR), decarboxylation, and conversion to fetal plasma glycine by the placenta were measured in six fetal lambs at 72 +/- 1 days gestation. L-[1-13C]serine, L-[U-14C]serine, and 3H2O were infused over 3 h into the fetal circulation, the latter for measurement of uterine and umbilical blood flow. The fetal plasma serine DR was 8.7 +/- 1.0 mumol/min or 61.8 +/- 4 mumol.min-1.kg fetus-1. Approximately 90% of the DR represented placental uptake of fetal serine. There was no detectable release of fetal serine into the maternal circulation. The fetal arterial plasma glycine-to-serine enrichment ratio was approximately 0.30. The conversion rate of fetal serine to fetal plasma glycine by the placenta was 5.8 +/- 0.7% of the serine DR. Fetal and placental CO2 production from fetal plasma serine carbon was 1.9 +/- 0.4 and 1.2 +/- 0.4 mumol/min, respectively. Thus, at midgestation, there is a rapid fetoplacental serine exchange that constitutes most of the fetal plasma serine turnover. Placental conversion of serine to fetal glycine and serine oxidation together account for only 10% of the placental uptake of fetal serine.

Glutamate is produced by the fetal liver and taken up by the placenta. To explore the functional meaning of this exchange, the disposal rate (DR), clearance, conversion to glutamine, and decarboxylation rate of fetal plasma glutamate were studied at 129 +/- 2 days of gestation in seven fetal lambs infused via a systemic vein with L-[2,3,3,4,4-2H5]glutamate and L-[1-14C]glutamate. In two experiments, L-[1-13C]glutamate was also infused. The mean glutamate DR and clearance were 11.9 +/- 1.3 mumol.min-1.kg-1 and 200 +/- 8 ml.min-1.kg-1, respectively. The placenta extracted 88.5 +/- 0.8% of the tracer glutamate carried by the umbilical circulation and contributed to 61.3 +/- 3.2% of the glutamate DR. Most of the 14C infused as L-[1-14C]glutamate was converted to 14CO2: 37 +/- 4% by the fetus and 41 +/- 6% by the placenta. Of the labeled glutamate taken up by the placenta, 6.2 +/- 1.5% was returned to the fetus as glutamine. The glutamine-to-glutamate enrichment ratio in fetal arterial plasma was 0.066 +/- 0.008. We conclude that fetal plasma glutamate has an exceptionally high clearance because the flux of glutamate into the placenta is virtually equal to umbilical glutamate delivery rate. The main pathway of fetal plasma glutamate disposal is oxidation by placental and fetal tissues. Placental conversion of glutamate to fetal glutamine is a relatively small component of the placental metabolism of fetal glutamate.

As part of an effort to establish the contribution of different fetal organs to fetal amino acid metabolism, we measured in nine sheep fetuses the uptake of 27 amino acids by the hindlimb under normal conditions and conditions by euglycemic hyperinsulinemia. The fetal hindlimb is representative of nonvisceral tissues, which in the mature fetus account for approximately 70% of fetal weight and 30% of fetal O2 consumption. In the normal condition, there was a significant uptake of 21 amino acids for a net total nitrogen uptake of 132 +/- 21 mg N.day-1 x 100 g-1. The amino acids taken up by the fetal limb included alanine and glutamine. In addition, the fetal limb had significant glutamate and serine uptakes. Because glutamate flows from fetus to placenta and there is no fetal uptake of maternal serine, this indicates production and interorgan transport of these amino acids within the fetus. Insulin infusion significantly decreased the arterial concentration of every amino acid with the exception of cystathionine and significantly increased limb blood flow and glucose uptake. It significantly increased the limb uptake of alanine, asparagine, glycine, isoleucine, methionine, and tyrosine, decreased the uptake of aspartate, and produced no significant change in the net total nitrogen uptake, which remained similar to control (137 +/- 16 mg N.day-1 x 100 g-1).

Fetal plasma alanine disposal rate (DR) and decarboxylation rate were measured at 132 +/- 1 days gestation in nine fetal lambs infused with L-[1-14C]alanine via a brachial vein. In five experiments, L-[1-13C]alanine was added to the infusate. Using L-[1-14C]alanine, we found mean DR to be 15.5 +/- 1.8 mumol.min-1 . kg-1. DR was significantly correlated to both arterial plasma alanine and whole blood lactate concentrations. Placental uptake of fetal plasma alanine accounted for 19 +/- 4% of DR. Fetal and placental production of CO2 from the first carbon of alanine were 61 +/- 2 and 16 +/- 2% of DR, respectively, for a total uterine excretion of 77 +/- 3%. Net alanine flux from placenta to fetus was 5.2 +/- 0.5 mumol.min-1 x kg-1, which was less than fetal plasma alanine decarboxylation (9.4 +/- 1.2 mumol.min-1 x kg-1) plus fetal alanine accretion (2.4 mumol.min-1 x kg-1). Utilizing L-[1-13C]alanine, we found DR to be 14.2 +/- 0.8 mumol.min-1 x kg-1, not significantly different from the 14C data. We conclude that both the umbilical uptake of alanine from the placenta and fetal alanine synthesis contribute to fetal alanine supply and that oxidation is the main route of fetal plasma alanine disposal.

In a study of the metabolic implications of the large placental-to-fetal mass ratio that characterizes early fetal development, fetal plasma lactate disposal rate and CO2 production from fetal plasma lactate by fetus and placenta were measured in six midgestation (71-80 days) pregnant sheep. A constant fetal intravenous infusion of L-[U-14C]lactate and 3H2O was given to establish fetal steady-state lactate specific activity and to measure uterine and umbilical blood flows. Fetal and placental weights were 158.6 +/- 19.7 and 441.9 +/- 32.7 g, respectively. There was a significant net lactate flux into the uterine circulation (31 +/- 4.3 mumol/min, P < 0.01) but no measurable umbilical uptake. Fetal plasma lactate disposal rate was 21.2 +/- 2.7 mumol/min, approximately one-half of which represented fetal lactate flux into the placenta (9.9 +/- 1.9 mumol/min). The oxidation rate of tracer lactate carbon to 14CO2 by placenta plus fetus was 72.6 +/- 4.7% of the infused tracer and was fairly evenly distributed between the placenta and the fetus (42.4 +/- 3.9 vs. 30.3 +/- 2.2%). The midgestation placenta metabolizes and produces fetal plasma lactate at rapid and nearly equal rates. This contrasts with the late-gestation placenta, which makes a small contribution to fetal lactate disposal and is a major net source of fetal lactate.

To test the hypothesis that an important aspect of the fetal response to severe, nonlethal hypoxia is a relatively large reduction in oxidative metabolism and small increase in lactate production by organs whose O2 supply is selectively reduced, net fluxes of O2, glucose, pyruvate, lactate, and CO2 derived from fetal plasma lactate carbon [(CO2)PL] were measured across the hindlimb and umbilical circulations in six sheep fetuses before and at 200-260 min of hypoxia. During hypoxia, blood lactate reached a high but steady level (15.2 +/- 2.2 vs. 1.7 +/- 0.2 mM; P < 0.001). Hypoxia was induced by reducing uterine blood flow. Limb O2 uptake and (CO2)PL decreased (P < 0.01) and lactate output increased (P < 0.05) (-83.1 +/- 13.9, -28.6 +/- 5.0, and +35.7 +/- 13.7 nmol.min-1 x g-1, respectively), while pyruvate and glucose uptakes remained similar to control. The increase in limb glycolysis was approximately 10% of the value that would compensate for the decrease in oxidative energy metabolism. The ratio of limb O2 uptake to fetus O2 uptake decreased significantly (0.247 +/- 0.029 vs. 0.447 +/- 0.036; P < 0.01). In contrast to fetal limb (CO2)PL, fetal (CO2)PL did not decrease. During severe, nonlethal hypoxia, fetal survival depends on uneven and counterbalancing organ O2 uptake and lactate metabolism.

Eleven studies of fetal serine fluxes were performed in chronically catheterized fetal lambs by continuous infusion of [1-13C]- and [U-14C]serine into a fetal brachial vein. At tracer serine steady state, samples were collected from the fetal abdominal aorta, umbilical vein, fetal hepatic vein, and fetal femoral vein and from the maternal femoral artery and uterine vein. Analyses were performed for plasma serine and glycine concentration, for serine and glycine 13C mole percent enrichment, and for whole blood 14CO2 and O2 concentrations. Uterine and umbilical blood flows were also measured. The placenta had a significant net uptake of fetal serine (2.1 +/- 0.5 mumol.min-1.kg-1, P < 0.01). Fetal plasma serine disposal rate (DR) was 42.5 +/- 3.9 mumol.min-1.kg-1.CO2 production from decarboxylation of fetal plasma serine represented 7.9 +/- 0.5% of DR, or 10.1 +/- 1.2 mumol CO2.min-1.kg-1. Fetal plasma glycine enrichment was 59.7 +/- 4.9% of fetal plasma serine enrichment. There was a significant loss of tracer serine from the fetal circulation into the placenta accounting for approximately 45% of infused tracer. Fifteen percent of this was converted to glycine and released into the umbilical circulation. There was a significant uptake of tracer serine by both fetal liver and fetal hindlimb with a significant CO2 production by both sites with serine oxidation predominantly in the carcass. These results indicate a high fetal serine disposal rate in the lamb, with rapid fetoplacental serine exchange, resulting in a net uptake of fetal serine by the placenta.(ABSTRACT TRUNCATED AT 250 WORDS)

In six ewes heat stressed from 39 to 125 days gestation and studied in a normothermic environment at 135 days, fetal and placental masses were less than in control sheep (1,645 vs. 3,112 and 149 vs. 356 g, respectively, P less than 0.01). Umbilical glucose uptakes (Rf,UP) were measured keeping maternal arterial plasma glucose at 70 mg/dl at spontaneously occurring fetal plasma glucose values (state A) and at two additional fetal glucose levels, to determine the transplacental glucose difference (delta) vs. Rf,UP relation. At normal delta of 49.2 mg/dl, Rf,UP was less in the experimental group (3.2 vs. 5.6 mg.min-1.kg fetus-1, P less than 0.05). Differences in placental perfusion and glucose consumption could not account for this result, thus indicating a reduced placental glucose transport capacity. In state A, fetal hypoglycemia enlarged significantly (P less than 0.01) the delta to 56.7 mg/dl and increased Rf,UP approximately 50% over the Rf,UP at a normal delta. In heat-induced fetal growth retardation, fetal hypoglycemia increases the flux of maternal glucose across a placenta with reduced glucose transport capacity.

The net transfer rate of glucose to the fetus from the placenta (Rf,up) increases approximately 10-fold over the second half of pregnancy. To examine the mechanism underlying this increase, we measured Rf,up at different glucose concentration gradients between maternal arterial (GA) and umbilical arterial (Ga) glucose and at three fetal ages: midgestation (76.0 +/- 0.6 days, n = 6), late gestation (131.5 +/- 2.1 days, n = 8), and an intermediate age (103.3 +/- 1.9 days, n = 4). The GA -- Ga gradient was varied by changing Ga below and above control values with fetal insulin and glucose infusions, respectively, while GA was kept constant at 70 +/- 2 mg/dl by a glucose clamp procedure. The slope of the line relating Rf,up to GA -- Ga increased from 0.15 to 1.01 dl/min in the 76- to 131.5-day period, while the intercept in the GA -- Ga axis remained approximately constant at 34 mg/dl. This indicates a fivefold increase in the ability of the placenta to supply glucose to the fetus at fixed values of maternal and fetal glucose concentration (placental glucose transfer capacity). Concomitant with this increase, there was a significant (P less than 0.001) decrease in control Ga from 26.7 +/- 1.3 to 20.3 +/- 0.3 mg/dl, leading to a significant increase in the GA -- Ga gradient and an 11-fold increase in control Rf,up (from 1.53 to 16.77 mg/min). We conclude that, in the second half of pregnancy, fetal glucose demand grows much more rapidly than placental glucose transfer capacity and requires a decrease in fetal glucose concentration to balance glucose supply and demand.

Placental O2 transport was studied in seven fetal lambs before and after occluding one of the two umbilical arteries. Ethanol was used to measure uterine and umbilical blood flows using the steady-state transplacental diffusion method. Blood samples were drawn from umbilical artery, umbilical vein, both uterine veins, and maternal artery and analyzed for blood flow indicator, O2 content, PO2, PCO2, and pH. Occlusion reduced the placental mass and the uterine blood flow, which was available for transplacental exchange, to 49.5 and 46.5% of control, respectively. After occlusion, fetal blood pressure increased 38%, total umbilical blood flow decreased 25%, total fetal O2 uptake decreased 26%, fetal blood flow to the unoccluded placenta increased 52%, and the O2 flux from unoccluded placenta to fetus increased 49%. This increased flux was accompanied by a decrease in the PO2 of maternal venous blood from the unoccluded placenta and an enlargement of the transplacental PO2 gradient, resulting in a marked drop in umbilical venous PO2 (28.3 to 17.7 Torr). This evidence supports the hypothesis that placental O2 diffusing capacity is a limiting factor in placental O2 transport and agrees with other studies indicating the absence of homeostatic mechanisms for preventing acute changes of PO2 in the placental circulation.

[1-13C]- and [1-14C]glycine were infused into chronically catheterized fetal lambs via a brachial vein. At tracer glycine steady state, samples were collected from the fetal abdominal aorta, umbilical vein, and fetal hepatic vein and from the maternal femoral artery and uterine vein. The samples were analyzed for plasma glycine and serine, for glycine and serine 13C atom% excess (APE), and for whole blood 14CO2 and O2 concentrations. Fetal plasma glycine disposal rate (DR) was 12.4 +/- 0.8 mumol.min-1.kg fetus-1.CO2 production from decarboxylation of fetal plasma glycine was 1.63 +/- 0.16 mumol.min-1.kg fetus-1 and represented 12.3 +/- 0.7% of DR. Approximately 50% of infused tracer glycine was taken up by the fetal liver with the release of labeled serine and CO2 in the fetal circulation. There was no detectable efflux of tracer glycine from the placenta into the maternal circulation. The tracer production of serine and CO2 accounted for 23 and 17%, respectively, of the hepatic tracer glycine uptake. The labeled CO2 released by the liver was a large fraction (approximately 70%) of the labeled CO2 produced by the fetus. The serine-to-glycine APE ratio in fetal plasma was approximately 5%. These results indicate that the fetal liver is the major site of fetal plasma glycine decarboxylation and of serine synthesis from plasma glycine.

Fetal and placental metabolism of leucine (Leu) and ketoisocaproic acid (KIC) were studied in seven fetal lambs at 132 +/- 1.3-days gestation. Fetal infusions of [1-13C]Leu, [1-14C]Leu, and antipyrine were carried out for 4 h. Uterine and umbilical blood flows were measured using the antipyrine steady-state diffusion technique. Leu and KIC concentrations, [14C]Leu-specific activities, 14CO2, [13C]Leu, and [13C]KIC enrichment (mole percent enrichment) were measured in the maternal artery, uterine vein, and umbilical artery and vein to calculate net fluxes of tracee and tracer molecules between fetus and placenta and between the uteroplacenta and the maternal circulation. There were net Leu and KIC fluxes into the fetus from the placenta with the KIC flux equal to approximately 19% of the combined Leu plus KIC flux. In addition, there was a net KIC flux into the uterine circulation. The fraction of infused tracer Leu escaping the placenta into the mother was small (approximately 6%). By contrast, there was a rapid exchange of tracer Leu carbon between placenta and fetus resulting in a significant flux of labeled KIC from placenta to fetus. Approximately 20% of the infused tracer carbon was converted to CO2 within the fetus. This rate of conversion was greater than 80% of the total fetoplacental conversion rate and significantly higher than the flux of KIC tracer carbon from placenta to fetus. Fetal KIC decarboxylation rate, calculated from the fetal KIC enrichment data, was 2.83 +/- 0.40 mumol.min-1.kg fetus-1 and approximately 60% of the combined net Leu and KIC flux into the fetus from the placenta.(ABSTRACT TRUNCATED AT 250 WORDS)

Net ovine uteroplacental glucose consumption (Ro,up) and transfer rates to the fetus (Rf,up) were measured at different concentrations of maternal (GA) and fetal (Ga) arterial plasma glucose that were set and maintained independently by a glucose clamp procedure. Five GA/Ga combinations were studied: 70/15, 70/20, 70/30, 50/14, and 50/24 mg/dl. Rf,up was inversely related to Ga both at GA = 70 and GA = 50. Linear regression analysis of Rf,up vs. Ga for the GA = 70 and GA = 50 groups of observations revealed similar slopes (-0.286 +/- 0.012 vs. -0.217 +/- 0.028 dl.min-1.kg fetus-1) but a significantly higher intercept for the GA = 70 group (10.3 +/- 0.12 vs. 5.5 +/- 0.47 mg.min-1.kg fetus-1). In contrast, Ro,up increased significantly in response to an increase of Ga and had no significant dependence on GA. These results indicate that uteroplacental glucose metabolism occurs primarily in tissues that have direct access to glucose molecules carried by the umbilical circulation and that the glucose transport capacity of the placental barrier is greater on its fetal than its maternal surface. Uteroplacental glucose metabolic rate and its dependence on fetal glucose concentration are major factors that determine the magnitude and variability of the glucose concentration gradient (and thus the rate of net glucose transfer) between maternal and fetal plasma.

Experiments were conducted in late-gestation, conscious, pregnant ewes to measure maternal glucose production and the net glucose uptake by the uterus, fetus, uteroplacenta, and nonuterine maternal tissues. Glucose concentration in the ewes varied naturally or decreased in response to fasting. Normoglycemic ewes (63.8 +/- 8.7 mg/dl) had a glucose production rate of 178.7 +/- 44.5 mg/min compared with a rate of 76.9 +/- 20.6 mg/min for hypoglycemic ewes (34.7 +/- 7.4 mg/dl). Uterine glucose uptake (56.5 +/- 16.8 mg/min), fetal glucose uptake (15.7 +/- 5.2 mg/min), uteroplacental glucose uptake (40.8 +/- 13.4 mg/min), and nonuterine maternal glucose uptake (122.2 +/- 27.7 mg/min) in the normoglycemic ewes were significantly greater than in the hypoglycemic ewes (28.7 +/- 5.4, 7.5 +/- 4.4, 21.2 +/- 6.6, and 48.2 +/- 15.2 mg/min, respectively). The fractional distribution of maternally produced glucose among nonuterine maternal tissues, the fetus, and the uteroplacenta was not altered markedly by hypoglycemia despite a 57% reduction in maternal glucose production.

The effect of variations of uterine blood flow (F) on placental transfer was examined in six chronic sheep preparations by measuring the placental clearances of ethanol (CE) and antipyrine (CA) at different levels of F. Norepinephrine infusion, hemorrhage, and occlusion of the terminal aorta were used to reduce F below normal. The reduction of F had no appreciable effect on umbilical blood flow (f). In each ewe, CE significantly correlated with F. The CE vs. F relationship at constant f was curvilinear with convexity toward the clearance axis. Regression analysis showed that the equation 1/CE = 1/.911 F + 1/.831 f could account for most of the CE variance (r2 = 0.97). Implicit in this relation is the concept that, given a certain level of placental perfusion, an F/f ratio congruent to 1 is optimal for the exchange of highly diffusible inert molecules between mother and fetus [CE/(F + f) was maximum at F/f = 0.955]. CA was not significantly different from CE at low clearance level but became smaller than CE at clearance values greater than 300 ml/min. This suggests that a high rates of perfusion placental permeability was a factor in limiting CA.

The relationships between arterial plasma insulin, glucose, and fructose concentrations during the fed and fasted state were studied in seven fetal lambs and their mothers. A significant correlation between insulin and glucose concentration was noted in all fetal lambs and in their mothers. Fetal sensitivity to glucose, as measured by the slopes of the insulin-response curves, was equal to that of the adult although the fetal response was shifted to the left of the maternal. Glucose infusion in four fetal lambs caused significant insulin elevations but no early insulin response (phase I). Maternal fasting caused no alteration in glucose-induced response in the fetus. Similar glucose infusions in newborn and 1-mo-old lambs demonstrated significant early-phase insulin secretion. Basal insulin to glucose ratios were consistent with an adult pattern as early as 3 days after birth.

Uniformly labeled [14C]lysine was infused at constant rate into the inferior vena cava of eight ovine fetuses with gestational ages ranging from 110 to 145 days. The infusion lasted 9 to 13 h and produced a steady-state specific activity of free lysine in the fetal plasma. In the steady state, approximately 9% of the infused radioactivity was excreted by the fetus as 14CO2, indicating fetal catabolism of lysine. At the end of the infusion, the fetal carcass was analyzed for its total content of labeled and unlabeled lysine. The rate of protein synthesis was calculated from the carcass-to-plasma lysine specific activity ratio. The fractional rate constant (Ks) for the unidirectional flux of lysine into fetal proteins was inversely related (r = -0.88) to fetal age: Ks = 0.584 - 0.0036 age (days). In each fetus, Ks was 2-4 times greater than the estimated fractional rate of fetal protein accretion (KG). The discrepancy between Ks and KG demonstrates that a large fraction of protein synthesis in the ovine fetus is devoted to protein turnover.

Seventeen studies were performed in 12 pregnant sheep to examine the relationship among simultaneously measured glucose uptake via the umbilical circulation, fetal glucose utilization (mg X min-1 X kg-1), and maternal arterial glucose (Gm, mg/dl). Fetal glucose utilization was measured by means of tracer glucose infused into the fetus or both mother and fetus. By fasting the ewe, Gm was varied in the 62-22 range. A decrease in Gm was accompanied by a significant (P less than 0.001) decrease in umbilical uptake (uptake = 0.09 Gm - 0.96, r = 0.82) and in fetal utilization, measured either by [U-14C]glucose (utilization = 0.062 Gm + 0.91, r = 0.90) or [6-3H]glucose (utilization = 0.065 Gm + 0.51, r = 0.91). At uptake greater than 3 mg X min-1 X kg-1, utilization and uptake were not significantly different. At lower uptakes, utilization did not decline as much as uptake. The results demonstrate that maternal fasting decreases both the umbilical uptake and the fetal utilization of glucose and suggest that fetal glucogenesis increases when the availability of exogenous glucose is markedly reduced.

Blood flow measurements were made using radioactive microspheres in 14 unstressed, conscious, pregnant guinea pigs with gestational age ranging between 34 and 67 days. Within each litter placental blood flow (PBF) was positively correlated to fetal weight (FW), even after correcting for placental weight differences. Although the largest littermate was, on the average, only 30% larger than the smallest, its material placental blood flow was 95% greater. The PBF vs. FW relationship could be described by the allometric equation: PBF = Ai FW2.89 where Ai is a litter-specific coefficient. This study demonstrates that the placenta of the largest littermate is "hyperperfused" compared with its smaller siblings.

Tracer glucose was infused simultaneously into mother ( [6-3H]glucose) and fetus ( [U-14C]glucose) in pregnant sheep in the last month of gestation to study the exchange of glucose molecules between maternal and fetal blood. Net rates of entry and exit of tracer glucose via the uterine and umbilical circulations were measured by application of the Fick principle under steady-state conditions. The net flux of fetal tracer to the uteroplacenta from the fetus was 53.4 +/- 3.1% of the fetal tracer infusion. The net flux of fetal tracer into maternal blood was 43.8 +/- 5.0% of the net flux of fetal tracer to the uteroplacenta from fetal blood. The net flux of maternal tracer to the uterus from the mother was 31.7 +/- 2.8% of the maternal tracer infusion. The net flux of maternal tracer into fetal blood was 40.5 +/- 4.4% of the net flux to pregnant uterus from maternal blood. This evidence demonstrates that the uteroplacental tissue mass constitutes a glucose pool that is interposed between the maternal and fetal glucose pools and rapidly metabolizes glucose molecules derived from both maternal and fetal blood. Calculations based on a three-pool model show that the fetal glucose pool contributes approximately 40% of the glucose that is metabolized by the placenta. The comparison of the three-pool model with a previously proposed two-pool reversible model shows that the latter lumps the placental utilization of fetal glucose with fetal glucose utilization and overestimates the rate of fetal glucose metabolism by approximately 60%.

Mammary blood flow was measured in conscious, unanesthetized ewes with electromagnetic flow probes prior to spontaneous labor (four animals) or during the induction of premature labor (four animals) by administration of dexamethasone, 1 mg/24 h, to the fetus. In all animals an increase in mammary blood flow was noted prior to delivery. Dexamethasone administered to one mother in the same dose did not induce labor or produce an increase in mammary blood flow. These results suggest that the fetal adrenal gland influences maternal mammary blood flow prior to delivery.

The cerebral uptakes of glucose, oxygen, lactate, pyruvate, acetoacetate and beta-hydroxybutyrate were compared in the adult, the fetal, and the newborn sheep. Beginning 1-2 days after surgery, we withdrew samples simultaneously from an artery and from the sagittal sinus for up to 2 wk. At all ages glucose was the only substrate taken up in significant quantity relative to oxygen. The glucose-oxygen quotients were 0.98 less than 1.03 less than 1.08 in adults; 0.92 less than 0.99 less than 1.06 in lambs; 0.92 less than 0.98 less than 1.03 in fetuses. These quotients were not significantly different. There was a significant (P less than .05) arteriovenous difference for lactate in the adult (-0.031 mM), but not in the lamb or fetus. A significant (P less than .05) arteriovenous difference pyruvate was found in the adult (-0.013 mM) and in the fetus (-0.020 mM). The findings of a glucose-oxygen quotient of approximately 1 and the lack of significant lactate production in fetal sheep brain are consistent with the hypothesis that anerobic glycolysis is unimportant to the steady-state cerebral metabolism of the fetal sheep.

Fetal umbilical glucose uptake was compared with simultaneous measurements of glucose turnover and utilization rates in 12 pregnant sheep, at a mean of 137 days gestational age (range, 118-146 days). Umbilical glucose uptake was calculated by application of the Fick principle. Fetal glucose turnover rate was measured by a primed-constant infusion of [14C]- and [3H]glucose (glucose turnover rate = tracer infusion rate divided by fetal glucose sp act). The calculation of fetal glucose utilization rate required substraction of the loss of tracer to the placenta from the tracer infusion rate, thus defining the net tracer entry into the fetus for direct comparison with the net umbilical glucose uptake. In fed, normoglycemic sheep, these measurements demonstrated statistical equivalence of umbilical glucose uptake rate (4.77 mg.min-1.kg-1 +/- 0.34 SE) and glucose utilization rate ([14C]glucose, 5.58 mg.min-1.kg-1 +/- 0.54 SE; and [3H]glucose, 7.19 mg.min-1.kg-1 +/- 1.24 SE) when tested by two-way analysis of variance (P greater than 0.1). In three fasted, hypoglycemic sheep, the umbilical glucose uptake rate fell to 1.43 mg.min-1.kg-1 +/- 0.56 SE, which was considerably lower than the simultaneous glucose utilization rate ([14C]glucose, 4.78 mg.min-1.kg-1 +/- 0.48 SE; and [3H]glucose, 6.81 mg.min-1.kg-1 +/- 2.19 SE). Thus, in the normoglycemic, late-gestation fetal lamb, there appears to be little glucogenesis, whereas glucogenesis may become significant during fasting-induced fetal hypoglycemia.

Uterine and umbilical blood flows, the placental clearance of 3H2O, uterine and umbilical uptakes of oxygen, glucose, and lactate were measured in conscious, pregnant sheep at 71-81 days gestation. Fetal weight was 210 +/- 20 g and less than half placental weight. In relation to fetal weight, umbilical flow was 468 +/- 57 ml X min-1 X kg-1, more than double normal values for the mature fetus. Clearance of 3H2O was approximately 12% of the late pregnancy value but high in relation to fetal weight (280 +/- 23 ml X min-1 X kg-1). Fetal oxygen uptake was 10.9 +/- 0.6 ml X min-1 X kg-1, approximately 40% greater than in late gestation. Umbilical uptake of glucose was also relatively high, whereas lactate uptake was low. Uteroplacental tissues consumed more than 80% of the oxygen and glucose taken up by the pregnant uterus. However, uteroplacental utilization rates of oxygen and glucose as well as net lactate production were lower (approximately 50, 30, and 25%, respectively) than in late pregnancy, despite a larger placental mass (486 +/- 22 vs. 302 +/- 12 g).

Amino acid and ammonia concentrations as well as oxygen content were measured in either the right or left hepatic vein, the umbilical vein, and the umbilical artery in 13 fetal lambs in late gestation. There was an uptake of all of the essential and most of the nonessential amino acids by both lobes of the fetal liver. The umbilical venous-hepatic venous amino acid concentration differences were similar in the two hepatic lobes. While glutamine and glycine were taken up by both hepatic lobes, their metabolically related amino acids, glutamate and serine, were released by the fetal liver into the systemic circulation. There was a reciprocal net placental uptake from the umbilical circulation of glutamate and serine and a net fetal of glutamine and glycine, suggestive of interorgan cycling of these amino acids between the placenta and fetal liver. Total fetal umbilical nitrogen uptake was 0.91 g N.kg-1.day-1. The umbilical venous-hepatic venous differences of ammonia were positive and not significantly different in the two lobes. There was a significant umbilical uptake of ammonia (12.8 +/- 1.8 microM; 0.0078 microM NH3/microM O2). However, 0 the ratios of NH3 to O2 were much higher in each lobe (right, 0.060; left, 0.079; each P less than 0.01) than in the umbilical circulation.

To study the effect of genetic differences in the maternal oxyhemoglobin dissociation curve on fetal O2 supply, we compared eight pregnant ewes homozygous for high O2 affinity hemoglobin (A) with eight pregnant ewes homozygous for low O2 affinity hemoglobin (B). Each ewe carried a single fetus. Fetal weights were not significantly different (A, 3,000 +/- 170 g; B, 3,070 +/- 270 g). The A ewes had significantly higher arterial O2 saturation (95 vs. 89.4%), uterine blood flow per kilogram of fetus (464 vs. 374 ml/min), uterine venous O2 saturation (78.1 vs. 67.5%), and placental-to-fetal weight ratio (0.107 vs. 0.085). Uterine venous PO2 was significantly less in A ewes (41.7 vs. 47.6 Torr), but umbilical venous and arterial PO2 and fetal O2 uptake were virtually equal in the two groups. We conclude that the difference in O2 affinity between A and B hemoglobins is fully compensated for by differences in arterial O2 saturation, in the rate of perfusion of the pregnant uterus, and in the degree of PO2 equilibration between the uterine and umbilical circulations so that the single fetuses of A and B hemoglobin carriers have equal levels of oxygenation.

We studied the effect of varying umbilical blood flow (F) on transplacental diffusion of ethanol and O2 before and during partial occlusion of the fetal abdominal aorta. At steady state, samples of umbilical and uterine arterial and venous blood were drawn simultaneously from chronically indwelling catheters and analyzed for the concentration of ethanol. O2 capacity, O2 saturation, PO2, PCO2, and pH. A decrease in F from 507 to 289 ml/min (P less than 0.001) was associated with a significant (P less than 0.02) increase of the umbilical-uterine venous ethanol concentration difference. This increase was indicative of a 25% diffusional shunt for ethanol on the fetal side of the placenta. The decrease in F caused a decrease in the umbilical O2 delivery-to-control O2 uptake ratio from 3.1 to values between 2.2 and 0.8 and was associated with a decrease in fetal O2 uptake to values between 94 and 56% of control. Uterine venous PO2 increased in response to the decrease in fetal O2 uptake. Umbilical venous PO2 correlated with uterine venous PO2 (r = 0.8, P less than 0.02). The response of fetal O2 uptake to decrease in umbilical O2 delivery was nonlinear and confirmed previous studies, showing that the normal umbilical O2 delivery rate exceeds approximately twofold the minimum necessary to sustain a normal rate of fetal oxidative metabolism.

The effects on fetal cerebral blood flow (Qc) of changes in the carotid arterial and sagittal sinus venous PO2, PCO2, and oxygen content were studied in the chronically catheterized ovine fetus in utero at 130-140 days of gestation. Forty-seven measurements of Qc were made in 20 fetuses with radioactive microspheres. In 11 of these animals, 84 measurements of cerebral arteriovenous differences of oxygen content were performed, permitting an indirect measurement of cerebral blood flow (Qc*), assuming a constant cerebral metabolic rate. Arterial and, in 11 animals, sagittal sinus blood was withdrawn for analysis of PO2, PCO2, oxygen content, and pH at the time of the flow measurements. Preliminary analysis showed the best predictor of Qc and Qc* to be the reciprocal of the arterial oxygen content (1/CaO2). Multiple linear regression analysis combining the effects of 1/CaO2 with arterial PCO2 (PaCO2) gave the following equations: Qc = 458.8 (1/CaO2) + 2.68 PaCO2 - 107.93 (R2 = 0.68); Qc* = 435.54 (1CaO2) + 2.20 PaCO2 - 75.03 (R2 = 0.86). As a result of the hyperbolic relationship between Qc (and Qc*) and CaO2, changes in CaO2 at the low levels found during intrauterine life exert an important influence on the fetal cerebral circulation.

To study mechanisms by which variations in fetal oxygen demand alter fetal oxygen saturation and PO2, we measured uterine and umbilical blood flow and transplacental oxygen diffusion rate in eight chronically prepared pregnant ewes before and during fetal neuromuscular blockade with pancuronium bromide (0.2 mg/kg). Uterine and umbilical blood flows were measured by applying the steady-state method using ethanol as the test substance. Fetal oxygen uptake decreased 7.5% (P less than 0.05). Umbilical blood flow increased 6% (P less than 0.05), whereas uterine blood flow did not change significantly. Fetal arterial oxygen saturation increased markedly (54.8-60.9%; P less than 0.001). There were also significant increases in umbilical vein oxygen saturation (83.6-86.9%; P less than 0.01), uterine vein oxygen saturation (70.7-72.2%; P less than 0.01), umbilical vein PO2 (29.4-32.1 Torr; P less than 0.001), and uterine vein PO2 (49.4-50.7 Torr; P less than 0.01). The uterine-umbilical venous PO2 difference decreased significantly (20.0-18.6 Torr; P less than 0.001), whereas there was no significant change in the uterine-umbilical venous PCO2 difference or in the umbilical ethanol shunt. The data indicate that follows a small decrease in fetal oxygen demand is caused by two aspects of placental oxygen transport: 1) umbilical and uterine blood flow do not react homeostatically to prevent the rise of PO2 in the placental circulation, and 2) the decrease in oxygen flux from placenta to fetus is associated with a decrease in the transplacental PO2 gradient.

To determine the effects of duration of hypoxia on fetal pulmonary blood flow and vasoreactivity, we studied the response of the fetal pulmonary vascular bed before, during, and after prolonged (2-h) and more brief (30-min) exposures to acute hypoxia in 19 chronically instrumented unanesthetized fetal lambs. Left pulmonary arterial blood flow was measured by an electromagnetic flow transducer. Fetal PO2 was lowered by delivering 10-12% O2 to the ewe. During 2-h periods of hypoxia left pulmonary arterial blood flow decreased, and main pulmonary arterial and pulmonary vascular resistance increased. The increase in pulmonary vascular resistance was sustained throughout the 2-h period of hypoxia. After the return of the ewe to room air breathing, pulmonary vascular resistance remained elevated for at least 1 h despite the rapid correction of hypoxemia and in the absence of acidemia. In contrast, after 30 min of hypoxia, left pulmonary arterial blood flow, pulmonary arterial pressure, and pulmonary vascular resistance returned to base-line values rapidly with the termination of hypoxia. The persistent pulmonary hypoperfusion after 2 h of hypoxia was attenuated by alpha-adrenergic blockade and was characterized by a blunted vasodilatory response to increases in fetal PO2. When fetal PO2 was elevated during the posthypoxia period in the presence of alpha-blockade, pulmonary blood flow still remained unresponsive to increases in fetal PO2. We conclude that 2-h periods of acute hypoxia can decrease fetal pulmonary vasoreactivity, and we speculate that related mechanisms may contribute to the failure of the normal adaptation of the pulmonary circulation at birth.

The rate of O2 delivery to the pregnant uterus (FaO2) was decreased in chronic sheep preparations by mechanical occlusion of uterine blood flow. The relationship of uterine venous O2 saturation (SVO2) to FaO2 was curvilinear with convexity toward the SVO2 axis. As SVO2 decreased, there was a decrease in uterine and umbilical venous O2 tension (PO2), with no appreciable reduction of the PO2 difference between the two veins and a decrease in the umbilical vein O2 delivery rate. Fetal O2 uptake and base excess remained normal as the umbilical vein O2 delivery rate was reduced from 1.1 to 0.6 mmol . min-1 . kg-1 but decreased markedly at an O2 delivery rate less than 0.5. Umbilical venous CO2 tension (PCO2) was higher than, and strongly correlated with, uterine venous PCO2 (R = 0.954). These observations support a venous equilibration model of ovine placental exchange and demonstrate that under normal physiological conditions the O2 supply to the fetal lamb is approximately twice the value necessary to maintain an adequate fetal O2 uptake and a normal fetal base excess.