Search

Infusion of the angiotensin-converting enzyme inhibitor enalaprilat into fetal sheep caused a profound arterial hypotension within days. Five fetal lambs were infused with enalaprilat for 8 days starting at day 128 of gestation. Total accumulated dose was 0.30 ± 0.11 mg/kg. Arterial pressure decreased from 43.6 to 25.6 mmHg; venous pressure did not change. Biventricular output was not statistically significantly changed; placental blood flow decreased almost in proportion to the decrease in pressure but the increase in somatic flow was not statistically significant. There were no significant changes in pressure 30 min after the initial 50-μg loading dose of enalaprilat. However, the arterial pressure responses to test doses of ANG I were largely abolished. After 1 day, however, there was a significant decrease in somatic vascular resistance, which became stronger with time, but almost no decrease in the placental resistance. We conclude that the fetal somatic circulation exhibits a slow but strong decrease in resistance but that the response to hypotension is weak or absent in the fetal placenta, possibly because it is already fully relaxed.

Almost all water that enters the conceptus of the sheep enters via the placenta. The forces that drive water are hydrostatic and osmotic. The placental channels that allow water to cross into the fetus have not been identified by microanatomic means. Although an "equivalent pore" system can account for the diffusional entry of small hydrophilic solutes, it can be calculated that the filtration coefficient of this system is too small to account for the demonstrated trans-placental water flows. It is possible that a second much less numerous system of large pores permits the flow of water, but that is by no means certain. The placenta does not control the amount of water that enters the conceptus; nor does any other single fetal structure. And water entry is not dependent on the volume of water already present. However, the combined physiological properties of the fetal heart, kidneys, somatic tissues and placenta constitute a consistent explanation of fetal water volume control.

Six singleton fetal sheep of 118-122 days gestational age were instrumented with flow sensors on the brachiocephalic artery, the postductal aorta, and the common umbilical artery and with arterial and venous intravascular catheters. At 125-131 days of gestation, we started week-long continuous recordings of flows and pressures. After control measures had been obtained, the fetuses were given continuous intravenous infusions of adult sheep plasma at an initial rate of 229 ml/day. After 1 wk of infusion, fetal plasma protein concentrations had increased from 34 to 78 g/l, arterial and venous pressures had increased from 42 to 64 and from 2.7 to 3.7 mmHg, and systemic resistance (exclusive of the coronary bed) had increased from 0.047 to 0.075 mmHg.min(-1).ml(-1), whereas placental resistance had increased from 0.065 to 0.111 mmHg.min(-1).ml(-1). Fetal plasma renin activities fell as early as 1 day after the start of infusion and remained below control (all changes P < 0.05). All flows decreased slightly although these decreases were not statistically significant. Thus the increase in arterial pressure was entirely due to an increase in systemic and placental resistances.

Transplacental clearances of Cl-, Na+, SO4(2-), mannitol, raffinose and inulin were measured in anaesthetized rats of 14-19 days gestational age. Water flow across the placenta was calculated from embryonic (74 per cent/day) and extra-embryonic fluid (94 mg/day) growth. Before 16 days, more than half of the tracer contents of the conceptuses were located in the extra-embryonic fluids. Clearances were not demonstrably affected by the presence or polarity of an electrical charge on the tracer. Clearances fell off with increasing molecular weights but faster than the corresponding decreases in the coefficients of free diffusion. The dimensions of the paracellular transplacental passages were calculated with the Patlak equation and equivalent pore theory. Pore radii were not significantly different from 3.3 nm at any gestational age but in the last 2 days, the geometric constant (number of pores per gram x pore area/pore length) increased threefold, to 31 cm/gram placental weight. The calculated parameters were insensitive to deletion of Na+ and Cl- from the data set. In haemochorial placentae, steric restriction does not prevent the entry into the embryo of solutes circulating in maternal blood, except for macromolecules.

1939 and the early 1940s saw the publication of a remarkable series of papers on placental transfer. For the first time, a group of investigators made a quantitative and systematic study of the transfer of a simple, presumably inert physiological solute, the sodium ion, in a number of different species at various gestational ages. The driving force behind these studies was Louis Barkhouse Flexner.

Fetal cardiovascular control is effected by an interaction of the fetal somatic and placental circulations. Three primary regulatory mechanisms are involved: transplacental transfer of extracellular fluid, driven by a difference in hydrostatic and oncotic pressures; modulation of fetal placental and somatic vascular resistances by means of blood pressure controlled production of angiotensin; and somatic autoregulation of flow. A systems analysis incorporates these and other fetal cardiovascular functions and this analysis was modelled for computer simulation. Given physiologically plausible values for known cardiovascular parameters in the fetal sheep, the model reproduced in detail a variety of experimental protocols with known outcomes; these included the normal fetus, the fetus after bilateral nephrectomy, the nephrectomized fetus infused with angiotensin, the intact fetus infused with NaCl solutions, the fetus with lymphatic obstruction and the severely anaemic fetus. The systems analysis demonstrated that fetal cardiac failure constituted the strongest stimulus for the formation of fetal oedema of any tested pathological intervention.

It is known that a week-long infusion of angiotensin into fetal sheep produces polyhydramnios. The purpose of the present experiments was to determine whether an increased osmotic force across the placental barrier could account for the excess transfer of water. Six fetuses with indwelling catheters were infused with angiotensin-I and one with angiotensin-II; all, except one fetus in the first group, developed gross polyhydramnios. None of the transplacental concentration differences of the small plasma solutes Na+, Cl-, HCO3-, K+, urea, or glucose showed a demonstrable change and the same was true of the transplacental difference in freezing point osmolality and for the transplacental difference in plasma protein concentration. It is concluded that the infusion of angiotensin at a low dose rate is a reliable protocol for producing polyhydramnios. However, the present findings lend no support to the hypothesis that a primary change in transplacental osmotic force is the cause of the increased transplacental water transfer in this form of polyhydramnios. Alternative hypotheses are discussed in the light of recent discoveries.

1. Maternal blood was made transiently hypertonic by rapid I.V. infusion of a concentrated mannitol solution into pregnant ewes bearing lambs with an indwelling flow sensor and vascular catheters. 2. The transplacental flows of water and of Na+ and Cl- were calculated from the umbilical arteriovenous differences in the concentrations of 125I-labelled albumin and electrolytes, and the fetal placental blood flow. 3. The reflection coefficients of Na+ and Cl- were calculated by means of the Patlak equation and found to be 0.85 +/- 0.04 and 0.68 +/- 0.04 (means +/- S.E.M.). The filtration coefficient was 1.02 x 10(-7) +/- 0.12 x 10(-7) cm5 dyne-1 s-1. 4. The results fitted best to an equivalent pore radius in the placental barrier smaller than the currently accepted 0.44 nm but not less than 0.35 nm.

Transplacental clearances were measured for radiolabelled Cl-, SO4(2-), mannitol, sucrose, raffinose, PEG-900 and inulin. Maternal placental blood flows were measured with radiolabelled microspheres. At 18 days of gestation (term 31 days), the fetuses and extra-fetal fluids were growing at 55 and 32 per cent per day, accounting for a net transplacental filtration rate of 14.2 nl/sec per gram placental weight. Pore theory and a least squares fit of the Patlak equation yielded an equivalent pore radius of 1.75 nm. It was demonstrated that the clearance of the largest tracer, inulin, was 30 times higher than it would have been in the absence of net filtration. Comparison with literature data showed that there was a small increase in placental permeability per gram placenta between 14 and 18 days of gestation but that the increase between 18 and 28 days of gestation was about 14-fold for Cl- and 300-fold for inulin. There was no evidence for a decreasing equivalent pore radius in the course of gestation from 14-18 days.

In pregnancy, the maternal circulating renin-angiotensin system (RAS) and uteroplacental tissue RAS has been thought to support maternal placental flow by raising maternal arterial pressure or changing placental vascular resistance. Also, the placenta or uterus may alter maternal circulating RAS. Recent studies in the authors' laboratory using chronically catheterized rabbits are compared with previous studies on interactions between the RAS and uteroplacental flow. When uterine driving pressure was reduced either mechanically or after converting enzyme inhibition, maternal placental flow decreased in proportion to change in driving pressure; myoendometrial flow did not change. Angiotensin II (AII) infusion to increase pressure by 21 +/- 2 mm Hg decreased placental but not myoendometrial flow. Thus, there is no evidence that maternal placental flow is autoregulated or supported by a specific renin-angiotensin mechanism. Normally, there is no net uterine release or uptake of active plasma renin activity, AI, or AII, but there is a small net release of trypsin-activated plasma renin activity (tPRA), presumably prorenin. Distal aortic occluder inflation produced upper-body hypertension, and uterine release of tPRA increased. There was a significant uterine arteriovenous concentration difference for AII during AII infusion. These methods are adaptable for studying interactions between uteroplacental flow and other vasoactive agents.

The relationship between uterine driving pressure and maternal placental blood flow was studied after inflation of an aortic occluder previously placed between the renal and ovarian arteries in 10 conscious pregnant rabbits at 28 +/- 1 (mean +/- SEM) d of a 30- to 31-d gestation to test the hypothesis that there is autoregulation of maternal placental blood flow. After control measurements, the femoral artery pressure was reduced 22 +/- 3% from 83 +/- 5 mm Hg and clamped at 65 +/- 4 mm Hg (p < 0.001) for 54 +/- 4 min by servo control. Carotid artery pressure increased from 86 +/- 5 to 98 +/- 6 mm Hg (p < 0.01). There was no change in cardiac output (839 +/- 78 vs 814 +/- 64 mL/min; NS), upper-body flow (651 +/- 62 vs 671 +/- 55 mL/min; NS), or renal flow (111 +/- 14 vs 104 +/- 8 mL/min; NS). Blood flow to tissues below the occluder decreased from 188 +/- 18 to 143 +/- 14 mL/min for the lower body (p < 0.05), 153 +/- 15 to 116 +/- 11 mL/min for the hindquarters (p < 0.05), and 17.7 +/- 1.9 to 12.9 +/- 1.4 mL/min for 13 pregnant uterine horns (p < 0.05). Placental flow to live fetuses per horn decreased from 13.0 +/- 1.9 to 8.9 +/- 1.2 mL/min (p < 0.01), whereas there was no significant change in myoendometrial flow (4.0 +/- 0.3 vs 3.5 +/- 0.5 mL/min; NS). Uterine oxygen consumption was unchanged (1.15 +/- 0.16 vs 1.06 +/- 0.13 mL/min; NS).(ABSTRACT TRUNCATED AT 250 WORDS)

The clearances of a series of hydrophilic probes (radii of 2-10 A) were determined in rabbit placentas of 13-15 days of gestation (term, 31 days). Maternal placental blood flows were measured by means of radiolabeled microspheres. None of the transfers of the tracers were limited by maternal or embryonic arteriovenous differences in the placenta, and the clearances decreased with increasing molecular radius. The transplacental water filtration rate calculated from conceptual growth was comparable in magnitude to the clearances of the largest tracers. Application of Patlak's modification of the Hertzian equation and pore theory suggested an equivalent pore radius of 17 A. Placental permeability surface area products computed from this value decreased much more steeply with increasing molecular dimension than the measured clearances, suggesting a highly significant contribution by filtration despite the very large diffusional gradients that existed under the experimental conditions. The results indicate that the size selectivity of the hemochorial embryo placenta in vivo is not very significant, and that under normal conditions filtrate of maternal plasma constitutes a major contributor to embryonic supply.

One of the most typical complications following chorionic villae sampling (CVS) is vaginal bleeding shortly or some days after the intervention, resulting in abortion in some cases. We report on a case of intraplacental haematoma (pathology: massive subtotal acute haemorrhagic placental infarct), followed by acute placental insufficiency in the 29th week of pregnancy. Therefore, we decided on an emergency caesarean section.

Uterine renin may regulate uteroplacental blood flow locally through changes in vascular resistance or systemically by supporting arterial blood pressure. Captopril (5 mg/kg) was given i.v. to 14 conscious pregnant rabbits at day 27.5 +/- 0.3 of gestation for the purpose of investigating the effects of angiotensin converting enzyme inhibition on uteroplacental blood flow and oxygen consumption. Control measurements (mean +/- S.E.M.) were compared to measurements made at 1 hr (n = 14) and at 3 to 4 hr (n = 7). Arterial blood pressure decreased from 80 +/- 3 to 66 +/- 3 mm Hg, P less than .01, and then declined further to 56 +/- 4 mm Hg, P less than .01. Cardiac output was unchanged at 1 hr, 799 +/- 79 vs. 705 +/- 61 ml/min, but was decreased to 634 +/- 29 ml/min by 3 to 4 hr, P less than .01. There was no change in renal blood flow from 102 +/- 13 ml/min. Total uterine blood flow decreased from 37 +/- 5 to 29 +/- 5 ml/min, P less than .01, and then to 23 +/- 1 ml/min, P less than .01, whereas placental blood flow decreased from 25 +/- 4 to 19 +/- 3 to 15 +/- 3 ml/min, P less than .01; there was no significant change in myoendometrial flow. Oxygen delivery per uterine horn decreased from 2.4 +/- 0.3 to 1.8 +/- 0.4 to 1.6 +/- 0.2 ml/min, P less than .005. Oxygen consumption per horn decreased from 1.31 +/- 0.14 to 1.05 +/- 0.15 ml/min by 1 hr, P less than .05, and there was no further decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Four pregnant ewes were operated on at 121-126 days of gestation. An electromagnetic flow sensor and an inflatable occluder were placed on the maternal common internal iliac artery. The ovarian arteries and veins were ligated. Indwelling catheters were placed in a maternal femoral artery and uterine vein and in the amniotic and allantoic fluids. An inflatable occluder was placed around the umbilical cord, close to the fetal abdomen. 2. Eight to nine days after surgery, the cord was occluded, the fetus killed and uterine blood flow reduced to one-quarter of its control value. The rate of water loss from the uterine circulation was calculated from blood flow and the venoarterial difference in blood osmolality. The amniotic and allantoic fluids were made hypertonic by infusion of 2 l into each sac of a solution of 1.5 mol of mannitol per litre of saline. The rate of water loss from the maternal uterine circulation was then measured five times over the next 4.5 h. 3. The combined filtration coefficient surface area product of the interfaces between maternal blood and the amniotic and allantoic sacs, normalized per kilogram fetal body weight, was (2.8 +/- 0.5) x 10(-6) cm3 s-1 kPa-1 kg-1 (mean +/- S.E.M).

The purpose of the computer simulation was to use experimentally measured parameters of placental water transfer to compute conceptual water acquisition during the last third of ovine pregnancy and to evaluate the possible role of each of these parameters in the pathophysiology of polyhydramnios. Total conceptual water at birth was almost insensitive to the value of the placental filtration coefficient. It was more sensitive to fetal and maternal placental blood flows, the concentrations of actively transported or metabolically produced solutes in fetal plasma (bicarbonate, fructose, alpha-amino acids, urea, lactate), and the hydrostatic pressure difference across the placental barrier. It was quite sensitive to the NaCl reflection coefficient and permeability. We conclude that the actively transported or produced solutes in fetal plasma constitute a primary driving force. The opposing diffusion gradient of NaCl, and to a much lesser extent that of glucose, are essential to restrain the process. The causes of polyhydramnios in this species are, in order of probability, an increase in the placental diffusion permeability of NaCl, a decrease in the placental reflection coefficient for NaCl, or an increase in the concentration of an osmotically effective solute in fetal plasma, by active transport or metabolic production.

Prenatal transfer of hydrophilic materials was studied in chronic guinea pig preparations of ca. 30-65 days gestation. In most preparations the vitelline (yolk sac placenta) circulation of one of the fetuses was ligated between 1 and 20 days before the experiment. Fetal and maternal serum protein concentrations were recorded as a function of the number of days after ligation. Prenatal transfer of hydrophilic materials of 60-5,500 daltons molecular wt was consistent with diffusion, with some evidence of steric restriction of the larger molecules. There was no difference between operated and sham-operated or control fetuses. However, the transfer of radiolabeled homologous gamma globulin ceased after ligation of the yolk sac vessels. The transfer in control fetuses accounted for most of the prenatal requirements of this protein, as calculated from the increases in fetal weight and serum gamma globulin concentrations as a function of gestational age. There was evidence of a nonspecific suppression of yolk sac function by surgery but no evidence of fetal catabolism of gamma globulin.

Fetal plasma is known to be hyperosmotic with respect to maternal plasma. Although some solutes are actively transported across the placenta and occur in higher concentrations in fetal than in maternal plasma, the total concentration difference is reversed by an opposite difference in the concentrations of electrolytes. Calculations on the basis of the Kedem and Katchalsky equations for a homogeneous membrane demonstrate that active solute transfer and a physiologically plausible hydrostatic pressure difference account for the known rates at which water and electrolytes are accumulated in the fetus. Best estimates of the membrane parameters (per kilogram fetal weight) are PSNa, Cl = 0.23 ml-min-1-kg-1, LpS = 5-10(-6) cm5-min-1-kg-1-dyne-1, and sigma NaCl approximately equal to 0.5. (where PS is the permeability-surface area product, LpS is the filtration coefficient, or sigma is the Staverman reflection coefficient). The driving forces for water and electrolyte transfer (active transfer and hydrostatic pressure) are not used as regulators. Rather, electrolyte permeability, which is the major constraint on fetal growth, and which continuously increases during gestation, makes possible the exponential increase in fetal weight during gestation.

Inulin was administered to eight volunteer patients at term gestation over a period of 3 hours before cesarean section. Inulin concentrations were repeatedly measured in maternal plasma, in fetal plasma, and in amniotic fluid at the time of delivery. Total inulin uptake of the conceptus was taken to be the sum of the inulin in the amniotic fluid and in the newborn infant. Amniotic fluid volumes were measured by ultrasound examination, and the distribution volume of inulin in the neonate was assumed to be 180 ml/kg on the basis of animal experiments. The mean permeability was 0.15 microliter/(s.g) placenta. This value and the previously measured permeability for cyanocobalamin delimit a range of molecular weights from 1350 to 5200 daltons. In this range permeability to lipid-insoluble molecules is roughly proportional to the coefficients of free diffusion in water without further discrimination of molecular size by the placental barrier.

The molecular weight of cyanocobalamin is well suited to distinguish the two patterns of size discrimination found in the hemochorial and epitheliochorial placentas. The concentrations of cyanocobalamin that were used ensured that nondiffusional transport was negligible, and experiments on guinea pigs confirmed that the diffusion permeabilities measured with cyanocobalamin were the same as those expected for inert hydrophilic substances of similar molecular weight. All human studies were performed on volunteers who were scheduled for elective cesarean section under spinal or epidural anesthesia. Endogenous plasma concentrations of cobalamin were measured in 10 pregnant volunteers and their newborns. Ten additional volunteers were given 1 mg of cyanocobalamin by intramuscular injection 44 min before delivery. Placental permeability, calculated as the ratio of fetal uptake and the concentration-time integral between maternal and fetal plasmas, was 14.3 microliter X min-1 X g placental wt-1. The permeability of the human placenta parallels that of the histologically similar guinea pig placenta, at a slightly higher level, up to molecular weights of 1,355.

We measured plasma concentrations of Na+, K+, Mg2+, Cl-, Ca2+, HCO3-, phosphate, lactate, glucose, total amino acids, and total protein, and also the total (freezing point depression) osmolality and the colloid osmotic pressures. Conversion of chemically measured concentrations to osmolalities showed that unrecognized solute (s) were present in maternal (7 mM) and fetal (12 mM) plasma. Statistically reliable transplacental gradients existed only for calcium ion, phosphate, and amino acids, Ionic Na, K Mg, Cl, Ca, HCO3 and lactate were in electrochemical equilibrium at potential differences of -4.2 to +1.3 mV. Total plasma osmolalities were not significantly different in maternal and fetal plasmas in preparations in good condition, but fetal plasma osmolalities rose due to lactate secretion in asphyxiated fetuses. Colloid osmotic pressures were about 5 cmH2O higher in maternal plasmas before 45 days gestation and about 6 cmH2O higher in fetal plasmas after 60 days gestation. In the guinea pig, colloid osmotic pressures are at least as important as intravascular pressures in the regulation of transplacental water flow.

Salts of sulfate, lithium, and bromine were injected or infused intravenously into ewes in the last trimester of gestation. Ewes and fetuses had indwelling catheters; most fetuses were nephrectomized. Concentrations were measured in paired maternal and fetal samples over periods of 4--14 days. Maternal excretion of sulfate was too rapid to permit near equilibration of fetal and maternal plasma concentrations; the results, however, did not support the existence of a large potential difference across the exchange barrier. The concentrations of Li+ (given by continuous infusion) and 82Br- in maternal plasma did not change rapidly. The concentrations of these tracers in fetal plasma rose until they were nearly equal to the maternal plasma concentrations. Steady-state transplacental potentials, calculated by use of the Nernst equation, were 5.2 +/- 2.0 (SEM) mV (n = 26) for Li+ and -2.2 +/- 0.8 (SEM) mV (n = 10) for Br-. Nernst potentials calculated from previously measured maternal and fetal plasma concentrations of Na+, K+, Mg2+, and Cl- were +0.4, +3.6, +0.5, and -1.4 mV. We concluded that, of the total potential difference of about -50 mV (fetus negative) between the fetal lamb and the ewe, only a few mV are dropped across the placental exchange barrier.

An electromagnetic flow sensor was placed on the distal fetal aorta (umbilical flow fraction 78.1 +/- 1.6 SEM, %), an inflatable occluder was tied around the umbilical cord, and catheters were placed in distal branches of an umbilical artery and vein, a uterine vein, and in the amniotic cavity. An inflatalbe occluder was tied around the vagina of some of the ewes. Control values 3 days after surgery were (mean +/- SE): fetal femoral artery pH, 7.37 +/- 0.01; umbilical blood flow, 186 +/- 14 ml-min-1 .kg fetus-1; fetal arterial blood pressure, 39 +/- 3 mmHg; and umbilical venous pressure, 7.4 +/- 1.0 mmHg (above intrauterine pressure). Fetal weight at autopsy was 3.1 +/- 0.3 kg, n = 11. Small increases in umbilical vein pressure caused immediate decreases in placental blood flow without decreases in fetal arterial blood pressure. The relation between venous pressure and umbilical blood flow at constant arterial pressure was that of an inert system, i.e., no evidence of a surrounding pressure (Starling resistor effect or waterfall phenomenon) could be found with increases in venous pressures of 2-40 mmHg. The results were not affected by increases in uterine vein pressure between 2 and 30 mmHg, nor by anesthesia and supine position of the ewe, nor by ganglionic blockade of the fetal ANS. It was concluded that surrounding pressures in the fetal placental circulation could not be demonstrated.

Inflatable occluders were placed on the distal aorta of 11 fetal lambs. After 1 wk of control measurements, fetal placental blood flow was reduced to about two-thirds of its control value for an average period of 2 wk. No allowance was made for fetal growth. During the period of flow restriction, fetal growth was 2%/day. Femoral arterial blood pressure was reduced from a control value of 41 to 27 mmHg (P less than 0.001). There was an insignificant increase in carotid arterial blood pressure from 48 to 50 mmHg. Placental resistance to flow did not decrease more than could be accounted for by the increase in gestational age in the course of the experiment. It is concluded that fetal placental blood flow is not under feedback control, since neither of the determinants of flow (i.e., driving pressure and resistance) responded to its chronic reduction.

1. We measured the differences in electrical potential between mother and fetus in the guinea-pig. The fetus was 33 +/- 2 (S.E. of mean) mV negative with respect to the mother. 2. Salts of bromine, sulphate, rubidium, and lithium were injected into pregnant sows and blood samples were obtained from the sows and their fetuses at various times after injection. The transplacental electrical potentials at which each of these ions would be in electrochemical equilibrium across the placental exchange barrier were calculated from the Nernst equation and the concentrations in maternal and fetal plasmas. 3. The differences in transplacental electrical potential calculated from the steady-state concentrations of these ions in maternal and fetal plasmas were within 1 mV of zero. 4. These observations are consistent with a very small difference in electrical potential across the placental exchange barrier itself, and the generation of a potential difference between mother and fetus at a site other than the exchange barrier.

Fetal growth in utero demands a continuous flow of water and solutes across the placental barrier. We investigated the membrane parameters that control the influx of solutes that are not actively transported and the influx of water. The osmotic conductivity, and the Na+ and Cl- permeabilities of the membrane were measured in chronically instrumented fetal sheep. Transplacental salt flow and water flow were augmented by drainage of fetal urine to the exterior over extended periods of time. Calculation showed that the membrane parameters are: deltaNaCl = 0.83, P.SNaCl = 8.0 10-3 ml.sec-1 kg-1, and LPS = 4.7 10-8 cm5.dyne-1.sec-1.kg-1 (placental surface area S being expressed per kg fetal weight). The chronic infusion of vasopressin into the fetuses at 8 to 11 units per day per kg fetal weight reduced the reflection coefficient deltaNaCl to a mean of 0.63 (P less than 0.03). We concluded that the characteristics of the influx of NaCl and water are compatible with those of a diffusion filtration process, that fetal growth is constrained by the diffusional permeability of the placenta for inert electrolyte and that in the long run fetal growth can only accelerate because placental electrolyte permeability increases. Vasopressin appears to reduce the salt reflection coefficient of the placenta thus enabling the fetus to exert some short term control over its acquisition of water and electrolyte.

Experiments were performed on unanaesthetized ewes in the last third of pregnancy. Fetuses and ewes had indwelling vascular catheters. In some of the experiments fetal urine was drained to the exterior by means of an indwelling vesicular catheter. Placental diffusion permeabilities were measured with 22Na+ and 36Cl- injected into eight fetuses. Volumes of distribution of Na+ and Cl- in the conceptus were Na+: 548 +/- 24, Cl-: 760 +/- 51 (ml/kg fetal wt +/- SEM). Diffusion permeabilities were Na+: 5.2 X 10(-3) +/- 0.3 X 10(-3), Cl-: 9.8 X 10(-3) +/- 0.9 X 10(-3) (ml.s-1.kg-1 +/- SEM). Ultrafiltration-reflection-coefficients of Na+ and Cl- in the placental exchange barrier were measured 17 times in seven fetuses with vesicular catheters. The transplacental e.m.f. was estimated from these results, on the assumption that the individual reflection-coefficients of Na+ should correlate with those of Cl-. The best estimate was -1.0 mV (fetus negative), and the best estimates of the placental reflection-coefficients were Na+: 0.83 and Cl-: 0.79. There was a reliable negative correlation (P < 0.01) between the calculated reflection-coefficients and the osmolality of the urine secreted by the fetus. This suggested that the concentration of vasopressin in fetal plasma affects the membrane characteristics of the placenta. The mean total osmotic force across the placental barrier of the sheep in these experiments was calculated to be 260 Pa (2 mmHg).

An electromagnetic flow sensor was placed on the distal aorta of sheep fetuses in utero, and catheters were placed in a femoral artery and the common umbilical vein. Catheters were also placed in a carotid artery and a uterine vein of the pregnant ewe. Three days postoperatively maternal plasma was hyperosmotic with respect to fetal plasma by all methods: +5.8 +/- 1.4 SE by vapor-pressure osmometry, +2.2 +/- 0.7 SE by freezing-point depression osmometry corrected for bicarbonate loss; and +3.26 mosmol/liter by chemical measurement of plasma constituents. Maternal or fetal plasma was made hypertonic in vivo by infusion of concentrated solutions of mannitol, sucrose, or NaCl. Transplacental water flux was calculated from placental blood flows and arteriovenous differences in water content of the blood. The apparent osmotic conductivity of the placenta was 61 ml2-mosmol-1-kg-1, but this value should be divided by an unknown reflection coefficient to yield the true osmotic conductivity. Separate measurements were made of the placental diffusional permeability of Na+ and Cl- in five chronically prepared sheep fetuses: PSNa+ =0.20 +/- 0.04, PSCl- = 0.27 +/- 0.04 ml/(min-kg fetus). There was a highly significant positive regression between (total) placental permeability and fetal weight.

1. Experiments were performed on pregnant guinea-pigs with gestations of about 44 days to term (65 days). Under anaesthesia, one fetus in each litter was given a volume equal to 1.31% of estimated body weight (v/w) of a 40% solution of 60k-90k dextran in Ringer solution by I.P. injection. One control litter-mate received the same amount of Ringer solution, but without dextran. Other litter-mates served as non-injected controls. 2. At 20.4 (+/- 4.7 S.D.) hr later, the sow was re-anaesthetized and all fetuses were removed and weighed. They were then dried to constant weight. Wet weights and dry weights were corrected for the weights of the injected materials. 3. Wet weights were normalized by dry weights to account for differences in body size. The average normalized wet weight of the fetuses injected with the dextran solution was 10.9% greater than that of the injected controls and 16.0% greater than that of the non-injected controls. 4. The results were not affected by the removal of all amniotic fluid at the time of the injections. 5. The results could not have been due to non-colloid osmotic forces. The Ringer solution was slightly hypo-osmotic compared to guinea-pig plasma and the dextran contained negligible amounts of non-colloids. 6. The applied colloid osmotic pressure of less than 20 torr caused the transfer of a physiologically significant volume of water in a period of 1 day.

The permeability of the placenta was measured with unlabelled inulin in unanaesthetized guinea pigs. Inulin was injected into the sows and the plasma concentrations were recorded at regular intervals. The inulin contents of the conceptuses were calculated from fetal weights, fetal plasma inulin concentrations and a measured inulin distribution volume of 180 ml/kg fetus. From fetal inulin contents and the time integral of the difference in maternal and fetal plasma concentrations, we calculated a mean inulin permeability of 29 +/- 9 (s.e.m.) nl/s per gram placental weight. The inulin permeability per gram placental weight rose statistically significantly with increasing fetal weight. Comparison with a similar rise observed for the smaller cyanocobalamin molecule studied previously led to the conclusions that in the last ten days of gestation the transplacental passages narrow while at the same time there are apparent changes in the numbers and/or lengths of these passages that suffice to increase the unrestricted permeability fourfold.

This paper reviews some of the equations that apply to the electrophysiology of the extrafetal membranes, and stresses the limitations that may apply to the use of these equations. A literature review of experimental data on potential differences between the fetus, the extrafetal fluid compartments and the mother leads to the conclusion that the transplacental potential difference is no more than a few millivolts and that, in some species, there is an electrical generator outside the placenta.

Ferritin was injected into the fetal or the maternal circulation of 27-29-day-pregnant rabbits. After the occurrence of a quasi-steady state, the placentas were prepared for electron microscopy. Ferritin particles were counted in the electron micrographs in the fetal capillaries, in the maternal blood spaces, and in the two interstitial compartments of the three-layered placenta. Under the circumstances of the experiments (excessively elevated plasma ferritin concentrations), no evidence was found for nondiffusional transport of radiolabeled ferritin. Comparison of the standing concentration gradients in the placentas, recorded after maternal and after fetal injection, showed that the interstitial spaces "excluded" ferritin; the plasma-interstitial space ferritin partition coefficients were 10 in the basement membrane space and 3 in the space between the cyto- and syncytiotrophoblasts. 55% of the total concentration gradient across the rabbit placenta occurred across the fetal endothelium, about 45% across the cytotrophoblast, and less than 5% across the syncytiotrophoblast. These figures are believed to reflect the relative contributions of these three layers to the total diffusional resistance in the rabbit placenta. When compared to previous data on the relative contributions of these three layers for small ions and molecules, the present data lead to the conclusion that discrimination of molecular size is a function of the fetal capillary endothelium alone.

Published and new data on steady-state exchange of tracers and oxygen are characterized by marked species differences. When the placenta is treated as an ideal diffusion cell of unknown vessel geometry and permeability, the exchange characteristics of oxygen can be used to prove that the exchange of tracers such as acetylene, nitrous oxide, tritiated water and antipyrine is entirely flow limited. The recorded patterns of transfer of flow-limited tracers reveal that some placentas are as effective as counter-current exchangers whereas others mimic the behavior of the less effective types of exchangers. These species differences in apparent geometry are unrelated to the histologic nature of the barrier. The patterns of flow-limited transfer are so similar to those of oxygen transfer that the diffusion resistance to oxygen must be small. The exchange of diffusion-limited (hydrophilic) tracers mimics exchange across capillary membranes in some species and exchange across cell membranes in others. These species differences in diffusion-limited transfer are clearly related to the histologic nature of the barrier and are independent of vessel geometry.

1. Fifteen sheep foetuses of 1.5-5.2 kg body weight were prepared with indwelling arterial and venous catheters for experimentation one to six days later.2. Unanaesthetized foetuses were found to have mean arterial and central venous blood pressures of 40 +/- 1.5 (S.E. of mean) and 2.0 +/- 0.3 (S.E. of mean) mm Hg respectively, compared to intra-uterine pressure. Intra-uterine pressure was 16 +/- 0.8 (S.E. of mean) mm Hg with respect to atmospheric pressure at mid-uterine level.3. Mean placental blood flow of the foetuses was 199 +/- 20 (S.E. of mean) ml./(min.kg body wt.). Mean cardiac output in eleven of the foetuses was 658 +/- 102 (S.E. of mean) ml./(min.kg).4. Mean foetal and maternal colloid osmotic pressures were 17.5 +/- 0.7 (S.E. of mean) and 20.5 +/- 0.6 (S.E. of mean) mm Hg respectively at 38 degrees C.5. Intravenous infusions into six ewes of 1.8 mole of mannitol and 0.4 mole of NaCl resulted in significant increases in foetal plasma osmolarity, sodium, potassium, and haemoglobin concentrations, without detectable transfer of mannitol to the foetal circulation.6. In the sheep placenta there is osmotic and hydrostatic equilibration of water. As a consequence, there should be an interaction between foetal placental blood flow and foetal water exchange with the maternal circulation. It was concluded that this interaction tends to stabilize foetal placental blood flow.

1. The permeability of the endothelial cell layer of the foetal capillaries of the rabbit placenta was measured by the tracer-dilution method. Isotopically labelled water, urea, chloride and sodium ions, and inulin were used. Radio-iodinated human serum albumin served as reference tracer. The measurements were made in in situ placentas of 27-29 days gestation of which the foetal circulation was perfused with homologous blood.2. The permeability of water was found to be 1.7 ml. min(-1).g(-1), the permeabilities of urea, chloride ions and sodium ions were in the range of 0.28-0.42 ml. min(-1).g(-1) and the permeability of inulin was 0.053 ml. min(-1).g(-1). These values may be underestimates, particularly the value of water.3. The approximate maternal blood space, foetal blood space, and extravascular sodium space were determined in rabbit placentas of 27-29 days gestation and found to be 0.16, 0.07, and 0.48 ml./g respectively.4. The permeabilities of the endothelial layer were compared to those published for the entire placenta and found to be far greater. The resistance to diffusion of the endothelial layer is only a small part of the total resistance to diffusion. Most of the resistance is localized in the syncytioand/or cellular trophoblasts.5. It was concluded that lipid insoluble molecules diffuse through the interstitial water spaces of the trophoblast in few, relatively wide channels but that diffusing water can make use of intracellular as well as extracellular paths.

Fetal volume control is driven by an equilibrium between fetal and maternal hydrostatic and oncotic pressures in the placenta. Renal contributions to blood volume regulation are minor because the fetal kidneys cannot excrete fluid from the fetal compartment. We hypothesized that an increase in fetal plasma protein would lead to an increase in plasma oncotic pressure, resulting in an increase in fetal arterial and venous pressures and decreased angiotensin levels. Plasma or lactated Ringer solution was infused into each of five twin fetuses. After 7 days, fetal protein concentration was 71.2 ± 4.2 g/l in the plasma-infused fetuses compared with 35.7 ± 6.3 g/l in the lactated Ringer-solution-infused fetuses. Arterial pressure was 68.0 ± 3.6 compared with 43.4 ± 1.9 mmHg in the lactated Ringer solution-infused fetuses (P < 0.0003), whereas venous pressure was 4.8 ± 0.3 mmHg in the plasma-infused fetuses compared with 3.3 ± 0.4 mmHg in the lactated Ringer solution-infused fetuses (P < 0.036). Six fetuses were studied on days 0, 7, and 14 of plasma protein infusion. Fetal protein concentration increased from 31.1 ± 1.5 to 84.8 ± 3.8 g/l after 14 days (P < 0.01), and arterial pressure increased from 43.1 ± 1.8 to 69.1 ± 4.1 mmHg (P < 0.01). Venous pressure increased from 3.0 ± 0.4 to 6.2 ± 1.3 mmHg (P < 0.05). Fetal heart rate did not change. Angiotensin II concentration decreased, from 24.6 ± 5.6 to 2.9 ± 1.3 pg/l, after 14 days (P < 0.01). Fetal plasma infusions resulted in fetal arterial and venous hypertensions that could not be corrected by reductions in angiotensin II levels. [ABSTRACT FROM AUTHOR]