Gary K. Oakes

Effect of propranolol infusion on the umbilical and uterine circulations of pregnant sheep

Propranolol was infused intravenously for 60 minutes to five ewes (4 mug per kilogram per minute) or five fetal sheep (10 mug per kilogram per minute). The umbilical blood flow was significantly decreased by 18 per cent from control at 60 minutes with either maternal or fetal propranolol infusion. Uterine blood flow and maternal and fetal mean arterial pressure did not significantly change. Maternal and fetal heart rates decreased 18 and 9 per cent from control, respectively, during maternal propranolol infusion. With propranolol to the fetus, fetal heart rate decreased 15 per cent and maternal heart rate did not change. During all infusion, maternal and fetal arterial pH, PCO2 and PO2 remained within normal physiologic limits.

The Effect of Hypoxia on Neurohypophyseal Hormone Release in Fetal and Maternal Sheep

Summary: The effect of hypoxemia on arginine vasopressin (AVP) and oxytocin (OT) release was investigated in the chronically catheterized fetus and ewe. During 30 min of 10% maternal oxygen delivery, mean (±SEM) arterial Po2 decreased from 105 ± 10.6 to 48 ± 3.5 mm Hg in the ewe and from 21 ± 1.3 to 12 ± 0.8 mm Hg in the fetus (each P < 0.001). Arterial Pco2 decreased from 35 ± 44 to 29 ± 1.0 mm Hg in the ewe, whereas fetal Pco2 decreased from 43 ± 2.3 to 35 ± 3.5 mm Hg (P < 0.05). Blood pH increased from 7.44 ± 0.03 to 7.56 ± 0.04 in the ewe (P < 0.01) and from 7.36 ± 0.004 to 7.40 ± 0.006 in the fetuses (P < 0.01).Baseline mean AVP levels were identical in ewes and fetuses (0.7 ± 0.1 µ μ U/ml). After 30 min of hypoxia, plasma AVP levels remained unchanged in the ewes (0.9 ± 0.1), but increased dramatically in the fetuses (47 ± 21 µ μU/ml) (P < 0.001). There was a highly significant correlation between the duration of hypoxia and log fetal AVP concentrations (r=0.85). The log fetal plasma AVP also was inversely correlated to the log fetal Po2 values (=0.83).Mean baseline fetal and maternal plasma OT levels were 2.6 ± 0.5 µ μU/ml and 2.2 ± 0.5 µ μU/ml, respectively. After 30 min of hypoxia fetal and maternal OT values were 2.9 ± 0.8 µ μU/ml (not significant).

Arginine Vasopressin and Arginine Vasotocin Inhibit Ovine Fetal/Maternal Water Transfer

Summary: After the infusion of 500 ml 20% mannitol to 12 pregnant ewes, we studied maternal and fetal plasma osmolality and maternal hematocrit responses and monitored blood pressure, heart rate, blood gas, and pH in chronically catheterized fetal lambs at 129–140 days gestation. To examine the effect of arginine vasotocin (AVT) and arginine vasopressin (AVP) on fetal/maternal water transfer, the mannitol infusion was repeated 1 day before or after the baseline mannitol study during a 2-h fetal infusion of AVT (7 μU · kg−1 · min−1) or AVP (20–400 μU · kg−1 · min−1) in eight and five animals, respectively. Mannitol was administered to the ewe after 1 h of the 2-h AVT or AVP infusion. The fetal and maternal osmolality and hematocrit responses were compared to the baseline mannitol responses in the same sheep. Maternal and fetal blood gases and pH were measured throughout the study periods during the AVT studies. In four of the ewes, an identical (sham) study was performed substituting 500 ml normal saline for the mannitol infusion to the ewe.Fetal AVP infusion alone produced a significant decrease in fetal plasma osmolality (P < 0.001; two-way analysis of variance) and a slight increase in maternal osmolality (P < 0.05). Fetal AVP or AVT infusion significantly obtunded the fetal osmolality increment induced by maternal mannitol (each P < 0.001); moreover, there was a greater decrease in maternal hematocrit after mannitol alone than after mannitol with AVT (P < 0.05). Fetal hematocrit was maintained unchanged by transfusion with heparinized maternal blood. Maternal and fetal heart rates and maternal blood pressure remained unchanged during the studies. But during the fetal AVT infusion, fetal blood pressure increased from 64 ± 3 to 75 ± 2 mniHg (P < 0.01); fetal and maternal Po2 and pH remain unchanged; and fetal Pco2 increased from 30 ± 2 to 37 ± 4 (P < 0.05). Normal saline (sham protocol) produced no change in any parameter.The data indicate that fetal blood levels of AVP and AVT can influence transplacental water flow. Fetal AVP infusion produces a net gain in fetal water by inhibiting baseline fetal to maternal water flow. Both AVP and AVT infusion inhibit fetal to maternal water transfer after an osmotic stimulus to the ewe.

Transplacental transfer of aldosterone and its effects on renal function in the fetal lamb.

Summary: Seven chronically catheterized fetal lambs between 100 and 130 days gestation (term, 140 to 145 days) and five newborn lambs were infused with d-aldosterone monoacetate, 100 μg/kg bolus, and 100 μg/kg over 60 min. Fetal lamb plasma aldosterone levels increased from a mean and S.E. baseline of 4.5 ± 0.3 μg/dl to >100 μg/dl. Maternal plasma aldosterone concentrations increased from 10.2 ± 0.8 to 26.2 ± 2.4 μg/dl after 15 min (P < 0.05) of the infusion. Amniotic fluid levels increased from 13.3 ± 0.8 to 23.8 ± 2.3 μg/dl (P < 0.05) after 15 min of the infusion. There was no change in plasma renin activity levels in the fetus or pregnant ewe. Urine sodium excretion decreased from 0.87 ± 0.09 to 0.34 total mEq (P < 0.05), and urine potassium increased from 0.25 ± 0.06 to 0.38 ± 0.07 total mEq (P < 0.05) between 60 and 90 min after the start of the infusion in the fetal lamb. There was no change in creatinine clearance or urinary sodium and potassium excretion in the newborn lamb. These data show that aldosterone crosses the placenta during the last trimester in the fetal lamb and can control sodium and potassium transport in the distal renal tubule. Lack of distal tubular responsiveness to aldosterone in the newborn is not due to maturational factors.Speculation: Aldosterone can cross the placenta during the last trimester in the sheep, but the fetal adrenal cannot be stimulated. Sodium balance in the fetus is dependent on sodium balance in the mother.

Perinatal Primate Parathyroid Hormone Metabolism

Near-term fetal and neonatal parathyroid gland function has been studied in the Rhesus monkey. Fetal serum ionized calcium (Ca++) levels are significantly greater than simultaneously obtained maternal levels. Fetal serum parathyroid hormone (PTH) was undetectable both in the basal state and in association with EDTA-induced fetal hypocalcemia. Induced maternal hypocalcemia was associated with increased maternal serum PTH levels and no change in fetal basal serum Ca++ or PTH levels. Only a minimal decrease in simian neonatal serum Ca++ occurred over the first 48 h of life. Normal adult levels of serum PTH were present as early as 6 h of neonatal life. Induced hypocalcemia at 12 h of age resulted in a significant increase in serum PTH levels.

Glucagon metabolism in nonhuman primate pregnancy

Abstract Rhesus monkey basal plasma glucagon levels in the nonpregnant female adult, near-term mother, fetus, and neonate are in the same range reported in human subjects. Glucagon does not cross the placenta in the third trimester in either the maternal-to-fetal or fetal-to-maternal direction. Although the maternal and neonatal pancreatic alpha cells respond to glucagonogenic stimuli of intravenous alanine and insulin-induced hypoglycemia, the fetal alpha cells do not. The causes for the change in both pancreatic beta- and alpha-cell responsiveness to physiologic stimuli in the transition from fetal to newborn life are not known.

Fetal pancreatic glucagon responses in glucose-intolerant nonhuman primate pregnancy

Rhesus monkey pancreatic alpha-cell function in streptozotoc-induced glucose-intolerant pregnancy is similar to that in normal primate pregnancy. Specifically, basal maternal and fetal plasma glucagon levels equate, and the fetal alpha cell does not respond to the glucagonogenic stimulus of either intravenous alanine or insulin-induced hypoglycemia. This contrasts with the accelerated maturation of the fetal beta cell in glucose-intolerant pregnancy, and does not support the concept of functional coupling of the pancreatic islet by a common glucose-based process. Fetal plasma glucagon levels do increase after L-dopa injection to the fetus. These data indicate that alpha cell unresponsiveness is a function of the glucagon-releasing mechanism rather than inadequate hormonal synthesis.

LECITHIN SYNTHESIS IN FETAL PRIMATE TISSUES AS MEASURED in vivo.

The choline incorporation pathway (I) accounts for >95% of de novo lecithin synthesis in fetal monkey lung slices. This in vivo study examined the incorporation of 3H-choline and 14C-ethanolamine into lecithin. Isotopes were injected into 140-148 day fetal Rhesus monkeys via an interplacental venous catheter maintaining the integrity of the amniotic cavity and the circulation. After 2 hrs, 3H/14C labeling in TLC-isolated lecithin was measured in various organs. Results (% transported precursor incorporated into lecithin) from 4 fetusesindicate that pathway I predominates over pathway II (phosphatidyl ethanolamine methylation) in these tissues. 3H-lecithin was present in fetal plasma after 2 hrs but not in tracheal or amniotic fluid. Maternal treatment with IM betamethasone 48 hrs prior to delivery resulted in greater than normal incorporation of 3H-choline into lecithin in lung, but not liver, brain, or kidney in 2 fetuses examined thus far. Additionally, one acidotic fetus showed a reduced pathway I rate in all organs except brain. Therefore, the choline incorporation pathway of fetal primate lung a) is predominant in synthesis of lecithin, and b) may be enhanced by corticosteroids and depressed by acidosis.

262 ARGININE VASOTOCIN INHIBITS OVINE FETAL|[sol]|MATERNAL WATER TRANSFER

Arginine vasotocin (AVT) is found in the mammalian fetal pineal and was previously shown to decrease water flow across guinea pig placental membranes in vitro. To examine this effect in vivo we infused mannitol (Osmitrol 500 ml in a 20% solution) into 6 chronically catheterized ewes (129-144 days gestation). Fetal and maternal blood gases, pH, blood pressure (BP), heart rate (HR), hematocrit (Hct), and osmolality (Osm) were measured at eight 10 minute intervals before and after the mannitol. One day later an identical amount of mannitol was infused into the ewe during a 2hr infusion of AVT into the fetal circulation,with similar blood sampling. In 4 control ewes 500 ml normal saline (NS) was infused in place of the mannitol.Maternal mannitol infused without fetal AVT evoked a greater rise in mean (±SEM) fetal osm (baseline 291 ± 2.1 mOsm/kg vs post mannitol 313 ± 6.1 mOsm/kg) than did maternal mannitol during fetal AVT infusion (289 ± 1 vs 297 ± 3.1 mOsm/kg; p<.05).During the AVT infusion fetal HR, pH and pO2 remained unchanged; fetal pCO2 increased from 30 ± 2 to 37 ± 4 (p<.05). Fetal BP increased from 64 ± 3 to 75 ± 2 mmHg (p<0.01). NS infusion produced no change in any parameter.Thus: 1)AVT in the fetal circulation diminishes water transfer from fetus to mother in response to a maternal osmolar stimulus; 2)This effect may be mediated by decreased fetal/placental blood flow or by a direct AVT effect on placental water transfer.