Cynthia T Barrett

Studies on the Circulation of the Previable Human Fetus

Extract: The circulation was studied in 33 previable human fetuses (12–272 g) delivered by hysterotomy, while the placenta was still attached. The umbilical vein (UV) and in some instances umbilical or carotid artery (FA) were cannulated. Fetal and maternal pH, PO2, and PCO2 were measured. Radionuclide-labeled microspheres (50 μ in diameter) were injected into the UV on one or more occasions from 1 to 36 min after delivery of the fetus. The distribution of the cardiac output (CO) was calculated from the relative amounts of radioactivity in each organ. In 11 fetuses, FA blood samples were withdrawn during microsphere injection, and CO and actual organ blood flows were measured.With advancing gestational age (10–20 weeks) there was an increase in total inferior vena caval return from 64 to 75% of CO. The proportion of CO to the placenta increased from 17 to 33% and to the gut from 5.5 to 9.2%. Superior vena caval return decreased from 32 to 23%, and the percentage of CO to the kidneys fell from 6.5 to 3.2%. In those fetuses in which repeated observations were made, there was a fairly uniform decrease in proportion of CO distributed to the placenta, probably owing to umbilical vessel constriction. This deterioration was not reflected by UV blood gases which in fact showed a decrease in PCO2 and rise of PO2, when FA showed a rise of PCO2 and fall in PO2 and pH. Associated with the fall in FA pH there was an increase in the proportion of CO to the brain, myocardium, and adrenals. The proportion of CO to the brain increased significantly with increase of FA PCO2.Speculation: The circulation of the previable human fetus may be studied at the time of hysterotomy. It is most important to realize that, even though umbilical venous blood gases may appear to reflect good physiological function, umbilical flow may be markedly decreased. This must be taken into account in all attempts to study placental function.

Experimental intrauterine growth retardation in the sheep

Abstract This report describes a procedure for investigation of the pathophysiology of fetal growth retardation in the sheep. In ewes with single fetuses (96 to 125 days gestation) a polyvinyl catheter was inserted into a distal branch of the uterine artery supplying the pregnant horn and cdvanced retrograde to the main uterine artery. Catheters were also placed in fetal blood vessels. Gradual embolization of the uteroplacental vascular bed was accomplished by injecting carbonised microspheres, 15 μ in diameter, into the uterine artery daily, if fetal blood gases were normal. When compared with control fetuses, the embolication group showed a mean decrease of 30 per cent in weight, variable decreases in certain organ weights, and a significant increase in the brain-to-liver weight ratio. In the embolization group, mean fetal Po 2 decreased 11 and 18 per cent, respectively, in each of the last two weeks of the study.

Role of adenosine 3', 5'-monophosphate in maturation of fetal lungs.

Extract: Fetal lung cyclic AMP phosphodiesterase, cyclic AMP, phosphatidyl choline, and incorporation of precursors into phosphatidyl choline were measured in rabbits after maternal administration of hydrocortisone phosphate and aminophylline. Both agents inhibited lung phosphodiesterase activity and augmented cyclic AMP concentrations (Table 1). Aminophylline administration was associated with a significant increase in lung saturated phosphatidyl choline (Table 2). Incorporation of [14C]choline and [3H]methionine was increased by both aminophylline and hydrocortisone (Table 3).Speculation: Aminophylline, which inhibits cyclic AMP phophodiesterase as its primary mode of action, has effects similar to hydrocortisone on incorporation of labeled precursors into phosphatidyl choline. Cyclic AMP, therefore, may be a mediator of maturation of lung phosphatidyl choline synthesis and/or secretion in the fetus, and pharmacologic agents which enhance cyclic AMP levels in the lungs may also enhance synthesis of phosphatidyl choline.

Regulation of fetal lung phosphatidyl choline synthesis by cortisol: role of glycogen and glucose.

Summary: Twenty pregnant rabbits were studied in pairs. Half were given cortisol subcutaneously on days 24. 25, and 26 of gestation in dosage of 2 nig/kg/day. Half served as controls and received saline. The fetal lungs were studied on the 27th day of gestation by incubating lung slices in the presence of [6-14C]glucose. Glucose consumption significantly increased in the tissues from animals treated with cortisol, 17.61 ± 5.56 (SD) μmol/g wet lung versus 14.28 ± 5.78 (SD) μmol/g in the controls (P < 0.05). The glycogen content of tissues treated with cortisol was significantly reduced compared to the controls, 2.42 ± 0.97 (SD) mg/g wet lung versus 3.81 ± 1.05 (SD) mg/g (P < 0.05). Treatment with cortisol resulted in significantly enhanced incorporation of the 14C label into glycogen and phosphatidl choline (Tables 3 and 4). These data suggest that glucocorticoids affect fetal lung phosphatidyl choline production by promoting glycogenolysis and increasing glucose incorporation into phosphatidyl choline.Speculation: Diminished glycogen content of the fetal lung in the latter part of gestation may reflect increasing utilization for phosphatidyl choline synthesis. Adenosine 3′,-5′-monophosphate (cyclic AMP) increases which occur after glucocorticoid administration may be responsible for activation of glycogen phosphorylases in the lung as they are in the liver. If insulin inhibits glycogenolysis in the lung as it does in the liver, insulin may inhibit phosphatidyl choline synthesis in the lung by preventing glycogen and glucose From serving as precursors.

Phospholipid synthesis in fetal lung organotypic cultures and isolated type II pneumocytes

Type II pneumocytes from fetal rabbit lungs were grown in an organotypic system and used to study surfactant phospholipid synthesis. This organotypic system was further employed as a means for isolating purified type II cells which were grown in monolayer cultures. Phospholipid synthetic properties for these purified type II cells at different stages of culture were studied using the radioactivity labeled substances: palmitate, choline and acetate. Additionally, fibroblasts were recovered from the organotypic system and grown in isolated cultures or in combination with type II cells. A comparison of the phospholipid composition and biosynthesis for these cell preparations indicated that in all instances, with the exception of fetal lung fibroblasts, the cultures were capable of producing saturated phosphatidylcholine as a major phospholipid product. The relative molar incorporation into phospholipids for the substrates studied differed depending on the type cell preparation being examined. The formation of surfactant phospholipids appeared most similar for the organotypic system and mixed fibroblast/type II cell preparations. Furthermore, a mixed culture of fibroblasts and type II cells produced larger proportions of surfactant phospholipids than type II cells alone. These observations indicate that the organotypic system is a useful model for examining fetal lung surfactant phospholipid synthesis and may also be employed as a simple means or isolating fetal type II pneumocytes.

Inhibition of Surfactant Production by Insulin in Fetal Rabbit Lung Slices

Summary: Incorporation of labeled glucose and fatty acid residues into saturated phosphatidylcholine was significantly reduced in lung slices from 27.5 days of gestation fetal rabbits during 90 min incubation in the presence of 100 μU/ml insulin. When 14C-glucose was used as substrate, incorporation into both phosphatidylcholine and saturated phosphatidylcholine was reduced by insulin. This occurred despite an increase in overall glucose utilization by the lung from 11.3 ± 3.9 to 16.3 ± 5.2 nmole/g tissue in the presence of insulin (P < 0.05). A decrease in incorporation of fatty acid residues into saturated phosphatidylcholine was also observed when 14C-paImitate was used as substrate, from 102 ± 4 to 90 ± 5 nmole palmitate/g tissue (P < 0.01). In the presence of insulin, there were significant reductions of both substrates appearing in lysophosphatidylcholine, a precursor of saturated phosphatidylcholine. There was no significant change in incorporation of glucose residues into glycogen or lactate under these conditions.Speculation: Hyperinsulinemia appears to be responsible for respiratory distress syndrome (RDS) in infants of diabetic mothers (IDM) and infants of gestational diabetic mothers (IGDM). Control of the maternal diabetic state to a degree which inhibits development of fetal hyperinsulinism reduces the incidence of RDS in IDM and IGDM by removing excess quantities of the factor, insulin, that is responsible for inhibition of surfactant production.

Transfer of lidocaine across the sheep placenta to the fetus: Hemodynamic and acid-base responses of the fetal lamb☆

Placental transfer of lidocaine administered to pregnant sheep and removal of the drug from the fetal circulation were determined. Responses of the hemodynamic and acid-base state in the mother and fetus were also studied. Lidocaine readily crossed the placenta and appeared in the fetal blood as early as one minute following injection. Disappearance of lidocaine in the asphyxiated fetus tended to be slower than in the normal one. Lidocaine produced a transient fall in the fetal heart rate which was accompanied by a decrease in blood pH and oxygenation. Lidocaine also reduced umbilical blood flow and, in some instances, uterine blood flow. Decrease in umbilical blood flow was more pronounced in the initially asphyxiated fetus.

Alpha and beta adrenergic receptor activity in fetal sheep

Abstract Fetal circulatory responses to infusions of isoproterenol and methoxamine were measured in 16 fetal sheep with weights between 138 grams and 4.75 kilograms. During isoproterenol infusion in 9 animals, heart rate increased from a mean of 196 to 247 and mean umbilical blood flow increased from 211 to 269 ml. per kilogram per minute. Cardiac output, measured by radionuclide labeled microspheres, did not change significantly but was redistributed with preferential flow to the placenta and myocardium. During methoxamine infusion in 7 studies, mean arterial pressure increased from a mean value of 46 mm. Hg to 56 mm. Hg and mean unbilical blood flow decreased from 217 to 177 ml. per kilogram per minute. Cardiac output decreased in all animals (mean decrease, 22.5 per cent). Renal blood flow decreased out of proportion to the change in cardiac output; the proportion of cardiac output supplying the lungs increased, and in 6 animals actual flow to the lungs also increased.

Enhancement of Fetal Lung Surfactant Production by Aminophylline

Summary: Antepartum administration of aminophylline to pregnant rabbits resulted in accelerated formation of phospholipids regarded to be important components of pulmonary surfactant. Increases in the tissue content and synthesis of saturated phosphatidylcholine and phosphatidylinositol were found in lung slice preparations obtained from fetuses previously treated with aminophylline. Synthesis of phospholipids was measured using labeled palmitate, oleate, and glucose as precursors. The results showed increased de novo production of these lipids, and that glucose and glycogen may serve as important precursors. There was a significant reduction in triglyceride content while free fatty acids increased suggesting increased lipolysis in the aminophylline-treated groups, but this did not measurably affect the rate of labeled palmitate incorporation into total phospholipids.Speculation: Prenatal treatment with aminophylline may prove to be an effective means of preventing idiopathic respiratory distress syndrome. This method could be an effective and safe means of accelerating pulmonary surfactant production before premature delivery.

Adenylate Cyclase Activity in Immature Rabbit Lung

Extract: Adenylate cyclase activity of lung homogenates from fetal and neonatal rabbits is considerably higher than that found in adult animals. This activity does not change significantly between 21 and 31 days postconception, but maturational changes are observed in responses of adenylate cyclase activity to incubation with epinephrine, glucagon, and NaF. Epinephrine stimulated adenylate cyclase activity at all ages studied, 21, 24, 27, 30 and 31 days postconception. NaF depressed adenylate cyclase activity at 21 and 24 days but thereafter stimulated it at 27, 30, and 31 days. Glucagon stimulated adenylate cyclase activity only after delivery. We conclude that hormonally mediated responses in formation of adenosine 3′, 5′-monophosphate (cyclic AMP) occur in the lung of the fetal animal.Speculation: Adenylate cyclase may be important in regulating pulmonary phospholipid biosynthesis in fetal animals. Activity of adenylate cyclase can be augmented by epinephrine in fetal lung homogenates and may mediate growth of the lung or premature formation of pulmonary surface active phospholipids.