Showing papers in "Journal of developmental physiology in 1991"

The double-edged role of nitric oxide in brain function and superoxide-mediated injury.

Abstract: Fetal ischemia or hypoxia can lead to cerebral palsy, mental retardation and epilepsy. We propose that the production of nitric oxide and oxygen radicals by neurons when ischemic or hypoxic brain is reperfused may contribute to cerebral injury. Ischemia will depolarize neuronal membranes causing the synaptic discharge of the excitatory neurotransmitter glutamate, which in turn opens the voltage-dependent, N-methyl-D-aspartic acid-specific glutamate receptor/ionophore, allowing calcium to accumulate in the neuron. Calcium in turn activates an oxygen-dependent neuronal nitric oxide synthetase, which oxidizes arginine to produce nitric oxide (.NO) when oxygen is readmitted to brain by reperfusion. Nitric oxide reacts with the oxygen radical superoxide (O2-), also produced by reperfusion, to form peroxynitrite (ONOO-). Peroxynitrite can diffuse for several micrometers before decomposing to form the powerful and cytotoxic oxidants hydroxyl radical and nitrogen dioxide. The hypothesis is consistent with available evidence on the protective action of glutamate antagonists and of oxygen radical scavengers for limiting cerebral infarction following focal ischemia.

Effects of reducing uterine blood flow on fetal blood flow distribution and oxygen delivery.

Abstract: We examined the effect of graded reduction in uterine blood flow on distribution of cardiac output and oxygen delivery to fetal organs and venous blood flow patterns in 9 fetal sheep using the radionuclide-labeled microsphere technique. We reduced uterine blood flow in two steps, decreasing fetal oxygen delivery to 70% and 50% of normal, and compared the results with those from a similar study from our laboratory on graded umbilical cord compression. With 50% reduction in fetal oxygen delivery, blood flow and the fraction of the cardiac output distributed to the brain, heart, and adrenal gland increased and that to the lungs, carcass, skin, and scalp decreased. Oxygen delivery to the brain and myocardium was maintained, while that to the adrenal doubled, and that to the brain stem increased transiently. The decrease in oxygen delivery to both carcass and lower body segment correlated linearly with oxygen consumption (P less than 0.001). The proportion of umbilical venous blood passing through the ductus venosus increased from 44.6% to 53% (P less than 0.05). The preferential distribution of ductus venosus blood flow through the foramen ovale to the heart and brain increased, but that to the upper carcass decreased so that ductus venosus-derived blood flow to the upper body did not change. Hence, the oxygen delivered to the brain from the ductus venosus was maintained, and that to the heart increased 54% even though ductus venosus-derived oxygen delivery to the upper body fell 34%. Abdominal inferior vena caval blood flow and its contribution to cardiac output decreased, but the proportion of the abdominal inferior vena caval blood distributed through the foramen ovale also increased from 23.0 to 30.9%. However, the actual amount of inferior vena caval blood passing through the foramen ovale did not change. There was a 70% fall in oxygen delivery to the upper body segment from the inferior vena cava. A greater portion of superior vena caval blood was also shunted through the foramen ovale to the upper body, but the actual amounts of blood and oxygen delivered to the upper body from this source were small. Thus, graded reduction of uterine blood flow causes a redistribution of fetal oxygen delivery and of venous flow patterns, which is clearly different from that observed previously during graded umbilical cord occlusion.

Growth and metabolism of the placenta after unilateral fetectomy in twin pregnant ewes.

Abstract: Twin-pregnant ewes underwent unilateral fetectomy (Fetx) at 50 days of gestation and were studied at 136 days. Aspects of conceptus growth and placental cellularity and metabolism in vitro were compared to those of unoperated control groups of twin-pregnant or single-pregnant ewes. Mean fetal weight in Fetx ewes tended to be greater than that of twin-pregnant ewes and was similar to that of single-pregnant ewes. Mean placental wet and dry weights were intermediate between those for naturally single- and twin-pregnant animals. Fetectomy caused a significant increase in placental protein:DNA ratio but an unchanged DNA concentration, apparently due to cellular hypertrophy in the placenta of the remaining fetus. Weight-specific rate of oxygen consumption (VO2) of fetal placental tissue in twin-pregnant ewes was higher than in Fetx or singles while maternal placental VO2 in twins tended to be lower than in either of the other two groups. These results highlight the plasticity of placental metabolism and growth, perhaps in response to altered trophic signals from the fetus. Unilateral fetectomy should prove useful in studies designed to identify these signals.

Fetal circulatory responses to oxygen lack.

Abstract: The knowledge on fetal and neonatal circulatory physiology accumulated by basic scientists and clinicians over the years has contributed considerably to the recent decline of perinatal morbidity and mortality. This review will summarize the peculiarities of the fetal circulation, the distribution of organ blood flow during normoxemia, and that during oxygen lack caused by various experimental perturbations. Furthermore, the relation between oxygen delivery and tissue metabolism during oxygen lack as well as evidence to support a new concept will be presented along with the principal cardiovascular mechanisms involved. Finally, blood flow and oxygen delivery to the principal fetal organs will be examined and discussed in relation to organ function. The fetal circulatory response to hypoxemia and asphyxia is a centralization of blood flow in favour of the brain, heart, and adrenals and at the expense of almost all peripheral organs, particularly of the lungs, carcass, skin and scalp. This response is qualitatively similar but quantitatively different under various experimental conditions. However, at the nadir of severe acute asphyxia the circulatory centralization cannot be maintained. Then there is circulatory decentralization, and the fetus will experience severe brain damage if not expire unless immediate resuscitation occurs. Future work in this field will have to concentrate on the important questions, what factors determine this collapse of circulatory compensating mechanisms in the fetus, how does it relate to neuronal damage, and how can the fetal brain be pharmacologically protected against the adverse effects of asphyxia.

Insulin-like growth factor binding proteins: roles in regulating IGF physiology.

Abstract: Insulin-like growth factor binding proteins (IGFBPs) are soluble proteins present in in extracellular fluids. They have high affinity for IGF-I and -II. Blood concentrations are controlled by nutrition and by hormones in a manner that in most, but not all, instances correlates with plasma concentrations of IGF-I or -II. IGF binding proteins are secreted by a range of cell types in a manner that may serve to modulate the functions of the growth factors in a pericellular environment. IGF binding proteins cxan modify IGF interaction with the type I receptor and may thereby alter IGF signal transduction through this transmembrane signalling unit. Binding proteins may also act as inhibitors or potentiators of biological responsiveness and thereby directly cell type specific responses.

The trigger for parturition in sheep: fetal hypothalamus or placenta?

Abstract: The fetal pituitary-adrenal axis plays a pivotal role in the mechanisms leading to parturition in sheep. Fetal cortisol concentrations gradually increase in the last 15 days before term, with a marked increase occurring in the last 3-4 days. Some mechanism causes a marked increase in the stimulatory drive to the fetal pituitary resulting in increased secretion of ACTH from the pituitary, and subsequent cortisol secretion from the adrenal gland. In this paper we discuss the roles of the hypothalamus and placenta in triggering the onset of labour in sheep. We have shown that prostaglandin E2 can stimulate the release of ACTH and cortisol in the intact fetus and we believe that this could be mediated by the release of CRH and AVP. Although CRH and AVP are present in the fetal hypothalamus and are capable of being released, these factors may not be released until approximately 135 days of gestation. One fundamental question in relation to parturition remains unanswered: how are the high concentrations of cortisol in fetal plasma sustained given that cortisol has an inhibitory feedback effect on the release of CRH and ACTH secretion? We discuss the possibility that the placenta provides an additional trophic drive to both the pituitary and adrenal glands which contributes towards the sustained elevated cortisol concentrations needed to initiate parturition. The placenta may initiate the hypothalamus and PGE2 and/or CRH, secreted by the placenta, may stimulate pituitary ACTH release.

Drug disposition and effects in the fetus.

Abstract: Surveys of drug use in pregnancy demonstrate that a significant proportion of human fetuses are exposed to prescription and non-prescription drugs antenatally or during labor, although recently a decrease in licit drug consumption during pregnancy may have occurred. However, legitimate medical reasons for drug therapy of the mother or fetus remain and there is an increasing problem with illicit drugs. Several approaches are used to examine placental transfer of and fetal exposure to drugs, including studies on pregnant women, the use of chronically catheterized pregnant animals (particularly sheep), acute studies on small animals (e.g. guinea pig and rabbit) and the use of the perfused placenta. Fetal drug exposure is affected by large number of maternal, placental and fetal factors. For long term maternal drug administration, drug binding in maternal and fetal plasma, and fetal drug elimination seem particularly important. Thus, the rate of non-placental clearance of morphine, methadone, acetamionophen, metoclopramide, ritodrine and diphenhydramine in the fetal lamb is comparable to that in the ewe, although the routes of fetal elimination are not fully elucidated. The fetal liver may be of lesser importance in overall drug elimination than in the adult, but conjugated drug metabolites in the fetus may persist because of limited placental transfer. Hence, we have observed that the glucuronide conjugate of ritodrine accumulates in amniotic fluid after intravenous ritodrine administration. Accumulation of intact drugs in amniotic fluid also occurs via fetal renal excretion and perhaps via the fetal membranes. Also, a number of basic amine drugs are also concentrated in fetal tracheal fluid, probably as a consequence of pulmonary uptake, which also takes place in the adult. However, this could result in high fetal lung levels of agents, such as beta 2-adrenergic agonists, that have potent effects on pulmonary function and maturation. When digoxin, metoclopramide and diphenhydramine are injected into amniotic fluid, they are preferentially distributed to the fetus and, for the latter 2 drugs, uptake by the chorioallantoic membranes appears to be important. Thus, there is the possibility of recycling of drugs from amniotic fluid to the fetal circulation and their persistence in the fetus. Many of the therapeutic agents given to pregnant women in late pregnancy have effects on fetal CNS, cardiovascular or metabolic functions. Alterations in fetal behaviour are elicited by prescription sedatives and anesthetics and illicit drugs, and also by the antihistamine, diphenhydramine, present in various nonprescription medications.

Arterial oxygen saturation and breathing movements during the first year of life.

Abstract: Sixteen healthy term infants underwent 12 hour tape recordings of arterial oxygen saturation (SaO2)(Nellcor N100 in beat to beat mode) and breathing movements at around 6 weeks, 3 and 6 months of age. Six of these infants had an additional recording at around their first birthday. Recordings were analysed throughout for pauses in breathing movements of greater than or equal to 4 s (apnoeic pauses), episodes in which SaO2 fell to 80% (desaturations), and (only during regular breathing) baseline SaO2. In the 16 infants studied at 6 weeks, 3 and 6 months, the median frequency of both apnoeic pauses (5.6, 5.7, and 6.1/h, respectively) and desaturations (0.7, 0.4 and 0.5/h, respectively) showed little change. The majority of desaturations followed an apnoeic pause (median 73.2, 86.2 and 93.8% of desaturations). The median proportion of apnoeic pauses followed by a desaturation did not change significantly (9.0, 7.5 and 9.1%), despite an increase in the proportion of apnoeic pauses of greater than or equal to 8 s in duration from 2.0% at 6 weeks to 5.3% at 3 months (P less than 0.01). Baseline SaO2 was 97.3% or higher in all recordings. Median baseline SaO2 increased from 99.6 to 99.9% between 6 weeks and 3 months (P less than 0.02) and remained unchanged thereafter. In the subgroup of infants studied also at one year of age, again no significant differences were found with increasing age in the frequency of either apnoeic pauses or desaturations. The data show that in healthy subjects no major changes occur between 6 weeks and 1 year of life in apnoeic pause frequency or arterial oxygenation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular responses to acute, severe haemorrhage in fetal sheep.

Abstract: In adults, the responses to acute haemorrhage vary greatly depending on the amount of blood lost. While many studies have documented fetal responses to mild haemorrhage, fetal responses to severe haemorrhage are not known. In this study we examined the effect of acute, severe haemorrhage in fetal lambs. Despite the severity of haemorrhage, we found that mean arterial blood pressure was restored within 2 min, and heart rate was restored within 30 min. This restoration of blood pressure and heart rate was facilitated by an increase in peripheral vascular resistance mediated in part by secretion of catecholamines and plasma renin. In addition, about 40% of the shed blood volume was restored within 30 min by fluid from either the fetal interstitium or placenta. The PO2 of umbilical venous blood increased from 33 +/- 9 mmHg to 49 +/- 17 mmHg 2 min post-haemorrhage, and to 47 +/- 15 mmHg 30 min post-haemorrhage. However, this increase was not sufficient to offset the fall in both haemoglobin concentration and umbilical-placental blood flow, so that oxygen delivery decreased from 21.1 +/- 5.5 ml/min per kg to 9.1 +/- 5.2 ml/min per kg 2 min post-haemorrhage, and 14.1 +/- 9.2 ml/min per kg 30 min post-haemorrhage. Because of this decrease in oxygen delivery, oxygen consumption fell and a metabolic acidemia ensued. Nevertheless, oxygen delivery to the heart and brain was maintained because hepatic vasoconstriction diverted more of the well oxygenated umbilical venous return through the ductus venosus. Although the fetus was able to tolerate acute loss of 40% of blood volume, larger volumes of haemorrhage resulted in fetal death.

ECG waveform, short term heart rate variability and plasma catecholamine concentrations in response to hypoxia in intrauterine growth retarded guinea-pig fetuses.

Abstract: After unilateral uterine artery ligation in midpregnancy twelve guinea-pig does were anesthetized at 63 days of gestation. The ST waveform of the fetal electrocardiogram and the short term heart rate variability were studied during normoxia and in response to acute hypoxia in growth retarded fetuses (n = 12, mean +/- SEM, 58.5 +/- 3.9 g) and their normal sized littermates (n = 12, 94.3 +/- 3.5 g). Hypoxia was induced by letting the doe breathe a low-oxygen gas mixture. After 10 min of hypoxia fetal blood was sampled by decapitation and blood gases, acid-base status and catecholamine concentrations were analyzed. The does responded to decrease in inspired oxygen concentration with changes in oxygen tension (13.8 +/- 0.8 to 4.3 +/- 0.2 kPa) and oxygen saturation (99.9 +/- 0.1% to 70.5 +/- 1.8%). Fetal blood gases and plasma catecholamine concentrations did not differ between the groups. In the growth retarded group standard bicarbonate was significantly lower compared to controls. The T/QRS ratio (the quotient between T wave height and QRS peak to peak amplitude) was normal and similar in both groups prior to the hypoxic period. In response to hypoxia T/QRS ratio increased in the normal sized group and T/QRS was correlated to carbon dioxide tension, oxygen saturation, pH, lactate, standard bicarbonate concentration, standard base excess and plasma noradrenaline concentration, respectively. The growth retarded fetuses presented a completely different pattern where 7 out of 12 fetuses showed a biphasic ST waveform during hypoxia with depression and downward sloping of the ST segment and negative T wave.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of heat stress on ovine placental growth in early pregnancy.

Abstract: Ditocous Dorset ewes were fed to predicted requirements and kept in environmental chambers at 21 degrees C (n = 6) or 40 degrees C (n = 5) between days 50 and 75 of gestation. Ewes were slaughtered and the pregnant uterus was dissected for measurement of conceptus weights and in vitro estimations of placental mitotic activity. Heat caused a 19% reduction in placental weight but did not affect fetal weight. Placental DNA and protein concentrations and protein/DNA were similar in both groups. Total placental DNA content was significantly reduced in the heated ewes, suggesting a reduction in cell number; however, DNA synthetic rate tended to be higher. These results are consistent with the hypothesis that fetal growth retardation in chronically heat-stressed ewes occurs in late pregnancy as a consequence of a primary reduction in placental growth in early gestation.

Exercise and fetal health.

Abstract: This is a brief review of current information dealing with the impact of maternal exercise on the well-being of the human embryo and fetus. It discusses the theoretical concerns and exercise variables involved in the interaction between exercise and fetal health and focuses on five areas of fetal health where some information is available describing the interaction in the human. These include embryonic development, fetoplacental growth, prematurity, indices of fetal stress/distress, and condition during labor and at birth. It concludes that well-conditioned women who continue a regular running or aerobics regimen in the peri-conceptual period and throughout pregnancy at levels that exceed current guidelines do not experience an increase in the incidence of failure to conceive, abortion, congenital abnormalities, abnormal placentation, premature rupture of the membranes or preterm labor. Although all their fetuses demonstrate a brisk elevation in heart rate post-exercise throughout pregnancy, they have a significant reduction in the incidence of 4 clinical markers of fetal stress/distress during labor. In addition, at the time of delivery, their % body fat is less than that of the control offspring (11 vs 16%) which accounts for over 70% of the observed 300 g reduction in birthweight. Finally, there is little evidence to suggest that the other exercise regimens studied to date have an adverse effect on fetal health.

Lack of maternal to fetal transfer of 125I-labelled erythropoietin in sheep.

Abstract: We administered tracer quantities of biologically active 125I-labelled recombinant human erythropoietin by intravenous bolus injection to seven late gestation pregnant ewes. Maternal and fetal blood was sampled over the subsequent six hours and assayed for erythropoietin-specific radioactivity. Despite the expected increase in maternal plasma immunoprecipitable 125I-labelled erythropoietin radioactivity, fetal plasma levels remained unchanged throughout the study. In addition, erythropoietin receptors were not detected in ovine and human placental tissue. We conclude that biologically active 125I-labelled erythropoietin does not cross the placenta from mother to fetus in measurable quantities in sheep, and likely in humans. Thus, these data indicate the levels of erythropoietin measured in fetal plasma are reflective of fetal, and not maternal, erythropoietin production and elimination.

Role of plasma adenosine in breathing responses to hypoxia in fetal sheep.

Abstract: The importance of plasma adenosine in hypoxic inhibition of breathing movements was determined in chronically catheterized fetal sheep (greater than 0.8 term). Preductal arterial blood for adenosine measurements was withdrawn using a double lumen catheter to mix blood entering the catheter with a solution to stop adenosine metabolism. In 6 fetuses, isocapnic hypoxia (delta PaO2 congruent to -10 Torr) increased the average plasma adenosine concentration from 1.1 +/- 0.2 (SEM) to 2.0 to +/- 0.4 microM. During hypoxia, plasma levels of adenosine were inversely related to preductal arterial O2 content (CaO2) with values ranging between 1.6 and 4.0 microM when CaO2 was less than 3 ml/dl. Hypoxia also significantly reduced the incidence of fetal breathing and rapid eye movements. In other experiments, adenosine (0.36 +/- 0.03 mg/min/kg) was infused for one hour into the inferior vena cava of 5 fetuses. During this infusion, mean plasma concentration of adenosine was 2.8 +/- 0.3 microM, a value about 2.5 times the control average. Adenosine also significantly reduced the incidence of low voltage electrocortical activity, rapid eye movements and breathing activity. We conclude that hypoxic inhibition of fetal breathing most likely arises from an increase in central adenosine production, although during severe O2 deprivation (CaO2 less than 3 ml/dl) blood-borne adenosine could also contribute.

Thyroid hormone differentially regulates development of beta-adrenergic receptors, adenylate cyclase and ornithine decarboxylase in rat heart and kidney.

Abstract: In mature animals, thyroid hormone produces parallel up-regulation of beta-adrenergic receptor binding sites and their linkage to adenylate cyclase; during development, these same processes may be critical in establishing the set-point for subsequent adrenergic reactivity. In the current study, we administered triiodothyronine to neonatal rats for the first five days postpartum and evaluated [125I]pindolol binding capabilities and adenylate cyclase activity in membrane preparations from heart and kidney. In the heart, hyperthyroidism elicited an initial increase in receptor density, with subsequent deficits and an eventual return to normal values by young adulthood. In contrast, the ability of isoproterenol, a beta-adrenergic agonist, to stimulate adenylate cyclase was enhanced regardless of whether receptor numbers were increased or decreased; the same effects were also present for basal adenylate cyclase activity and non-receptor-mediated stimulation by forskolin. Enhanced cyclase activity involved both increases in the magnitude of response as well as accelerated onset of the postweaning peak of enzyme activity, results which suggest a direct impact of thyroid status on the ontogenetic expression of adenylate cyclase itself. The kidney, which possesses less efficient beta-receptor coupling to adenylate cyclase in the neonate, was less drastically affected by triiodothyronine for either beta-receptor binding sites or enzyme activity. As we had previously shown that neonatal hyperthyroidism uncouples beta-receptors from growth-related enzymes, such as ornithine decarboxylase, we also evaluated whether the promotion of adenylate cyclase responses was mechanistically linked to effect on ornithine decarboxylase; administration of cyclic AMP analogs to 5 days-old rats led to inhibition of the enzyme in the heart, whereas the same treatment in 9 days-old animals was ineffective. These data suggest that thyroid hormone differentially regulates the development of beta-receptors as well as adenylate cyclase and ornithine decarboxylase, with preferential effects on tissues, such as the heart, that already possess efficient linkage of the receptors to cell transduction mechanisms at birth.

Effects of alcohol (ethanol) on the fetus.

Abstract: Alcohol (ethanol) use during pregnancy can produce a wide spectrum of effects in the developing embryo/fetus that are dependent on the maternal drinking pattern. The effects of chronic ethanol exposure on the developing conceptus are reviewed with primary focus on ethanol teratogenesis, manifesting in the human as the fetal alcohol syndrome or fetal alcohol effects. The effects of acute ethanol exposure on the near-term fetus are described, including suppressed fetal breathing movements, electrocorticographic (ECoG) activity and electrooculographic (EOG) activity. The ethanol-induced suppression of fetal breathing movements is a very sensitive index of acute exposure of the near-term fetus to ethanol, and appears to involve a direct mechanism of action rather than an indirect mechanism involving suppression of electrocortical activity. The disposition of ethanol and its pharmacologically active proximate metabolite, acetaldehyde, and the activity of alcohol dehydrogenase and aldehyde dehydrogenase in the near-term maternal-fetal unit are described, and a pharmacokinetic model is proposed. The effects of short-term ethanol exposure on the near-term fetus include the development of tolerance to the ethanol-induced suppression of fetal breathing movements, low-voltage ECoG activity and EOG activity. The development of tolerance occurs more rapidly to the latter two fetal biophysical activities. The mechanism of tolerance development appears to be pharmacodynamic (functional) in nature, as there is no increase in the rate of ethanol elimination from the maternal-fetal unit. The role of prostaglandins (PGs) in the mechanism of the ethanol-induced suppression of fetal breathing movements is described. In the near-term fetus, there is a direct relationship between fetal blood ethanol concentration and fetal plasma PGE2 concentration, and an inverse relationship between the incidence of fetal breathing movements and each of fetal plasma and fetal cerebrospinal fluid (CSF) PGE2 concentrations. Indomethacin, a PG synthetase inhibitor, selectively blocks and reverses the ethanol-induced suppression of fetal breathing movements. These data support the postulates that the ethanol-induced suppression of fetal breathing movements is mediated by increased PGE2 concentration in the near-term fetus and that the ability of indomethacin to antagonize the ethanol-induced suppression of fetal breathing movements is due to its biochemical action to decrease fetal PGE2 concentration.(ABSTRACT TRUNCATED AT 400 WORDS)

Identification of the hyperpolarization-activated inward current in young embryonic chick heart myocytes.

Abstract: Whole-cell voltage-clamp experiments were performed to examine the underlying currents flowing during the pacemaker potential of spontaneously-beating embryonic chick ventricles. The holding potential was -30 mV. Long-duration (3 s) hyperpolarizing pulses were applied to -40 to -120 mV, in increments of 10 mV. A marked hyperpolarization-activated inward current (If) was produced. In cells from 3-day-old hearts, the threshold potential for the inward current was -50 to -60 mV. In 17-day-old cells, there was almost no If current. At -120 mV, the inward current was -93.8 +/- 6.3 pA (n = 5) in 3-day-old cells and -15.7 +/- 2.8 pA (n = 5) in 17-day-old cells. The average capacitances were 10.1 +/- 2.0 pF (n = 17) in 3-day-old cells, and 6.9 +/- 1.2 pF (n = 14) in 17-day-old cells. The reduction of If paralleled the decrease in spontaneous activity. In the presence of 3 mM CsCl, the inward current was blocked completely, and the tail current was reduced. In addition, 3 mM CsCl depressed the spontaneous action potentials and had a negative chronotropic effect. These results indicate that the hyperpolarization-activated inward If current exists in young embryonic chick heart cells, and decreases during development. This If current may contribute somewhat to the electrogenesis of the pacemaker potential.

Developmental and hormonal regulation of surfactant protein A (SP-A) gene expression in fetal lung.

Abstract: Pulmonary surfactant is a developmentally-regulated lipoprotein synthesized and secreted by the type II cells of the pulmonary alveolus where surfactant glycerophospholipids and proteins act to reduce surface tension at the alveolar air-liquid interface. Surfactant protein A (SP-A), the major surfactant-associated protein, appears to serve an important role in surfactant function and reutilization by type II cells. SP-A synthesis and gene expression are initiated in fetal lung tissue in concert with the developmental induction of surfactant glycerophospholipid synthesis. In studies using midtrimester human fetal lung explants maintained in organ culture, we have observed that cyclic AMP and glucocorticoids have pronounced effects on morphologic development and on the levels of SP-A gene expression. Cyclic AMP analogues act primarily to induce SP-A gene transcription; whereas, glucocorticoids have complex effects at both the transcriptional and posttranscriptional levels. We also have found that human fetal lung in vitro secretes into the culture medium relatively large amounts of prostaglandins (PG) PGE2 and PGF2 alpha and the PGI2 and thromboxane A2 metabolites, 6-keto-PGF1 alpha and TxB2, respectively. The prostaglandin synthesis inhibitor, indomethacin, markedly inhibits SP-A gene expression and cyclic AMP formation by human fetal lung in culture; the inhibitory effect of indomethacin on SP-A gene expression can be prevented by simultaneous incubation with either Bt2cAMP or PGE2. These findings are suggestive that prostaglandins acting through cyclic AMP also may serve an important role in the regulation of SP-A gene expression in human fetal lung tissue.

The diaphragm of the newborn infant: anatomical and ultrasonographic studies.

Abstract: In the newborn infant, the diaphragm seems badly adapted to perform the burden of respiratory work. Indeed, due to the large angle of insertion on the rib cage and the small area of apposition, the flat diaphragm of the newborn infant seems better designed to suck in the rib cage rather than air. To better understand this paradox, and get insight in the structure-function relationship, the anatomical connections between the diaphragm and the rib cage were studied in 16 infants of various postmenstrual and postnatal ages. It was concluded (1) that the diaphragm inserts on the rib cage border only in the anterior costo-diaphragmatic triangle. From antero-laterally to posteriorly it inserts at increasingly greater distance from the rib cage border; (2) that the dorsal diaphragm ends its free course at the 11th rib and continues caudally as a spur ending between the 12th rib and the crista iliaca. From echographic studies of the right diaphragm with simultaneous measurement of the caudad displacement of the diaphragm and abdominal circumference change, the dynamics of the diaphragmatic movements could be better understood. It was concluded that, in contrast with the adult diaphragm, acting as a piston within the rib cage, the diaphragm of the newborn infant acts as a below moving mainly in the posterior part.(ABSTRACT TRUNCATED AT 250 WORDS)

Persistent influence of neonatal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment on glucocorticoid receptors and on the microsomal enzyme system.

Abstract: Neonatal treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) accounted for a considerable decrease in the number of thymic glucocorticoid receptors in both male and female rats, as assessed at 6 weeks of age. TCDD also gave rise to a marked and prolonged increase in microsomal enzyme activity in the female rats but had practically no such effect on the males. These experimental observations attract attention on to the lasting microsomal inducer effect of the herbicide contaminant dioxin which damages foreign receptors and substantiate the chemical imprinting potential of aromatic hydrocarbons.

Catecholamine concentrations in plasma and organs of the fetal guinea pig during normoxemia, hypoxemia, and asphyxia.

Abstract: To examine the responses of the sympatho-adrenal system to reduced oxygen supply we studied plasma and tissue concentrations of catecholamines during normoxemia, hypoxemia, and asphyxia in 22 fetal guinea pigs near term. Fetal blood was obtained by cardiopuncture in utero under ketamine/xylazine-anesthesia. Catecholamines were determined in plasma and tissue of 15 organs and 14 brain parts by HPLC-ECD. During normoxemia (SO2 54 +/- 4 (SE) %, pH 7.36 +/- 0.02, n = 5) plasma catecholamine levels were low (norepinephrine 447 +/- 53, epinephrine 42 +/- 12, dopamine 44 +/- 6 pg/ml). During hypoxemia (SO2 27 +/- 3%, pH 7.32 +/- 0.01, n = 6) and asphyxia (SO2 24 +/- 2%, pH 7.23 +/- 0.02, n = 11) tissue catecholamine concentrations changed with changing blood gases and with increasing plasma catecholamines. Norepinephrine concentrations increased in both skin and lung and decreased in liver, pancreas, and scalp; those of epinephrine increased in the heart, lung liver, and scalp and decreased in the adrenal. There were only minor changes in brain catecholamine concentrations except for a 50% reduction in dopamine in the caudate nucleus. Concentrations of dopamine catabolite 3,4-dihydroxyphenylacetic acid decreased in many brain parts, suggesting that cerebral catecholamine metabolism was affected by hypoxemia and asphyxia. We conclude that the sympatho-adrenal system of fetal guinea pigs near term is mature and that its stimulation by reduced fetal oxygen supply leads to changes in both plasma and tissue catecholamine concentrations.

Development of gastric proteases in fetal pigs and pigs from birth to thirty six days of age. The effect of adrenocorticotropin (ACTH).

Abstract: Development of the synthesis and secretion of gastric proteases was studied in 55 Large White x Landrace pigs from 22 days before birth (93 days gestation) to 36 days of age. The pigs came from eight litters and were 0.4 - 13.5 kg body weight. Littermate pairs were treated with either saline or adrenocorticotropin (ACTH) from three days of age. Secretion of protease activity (milk-clotting and general proteolytic activity) was investigated in anaesthetized pigs by a gastric perfusion technique using intravenous infusion of pentagastrin at dose rates of 4 and 8 micrograms/h per kg body weight. In addition, concentrations of protease zymogens (prochymosin, pepsinogen A, progastricsin) were measured in fundic tissue extracts by rocket immunoelectrophoresis. Prochymosin was present in fundic tissue at 22 days before birth, reached peak concentrations at birth and decreased in concentration during the subsequent 36 days. Pepsinogen A and progastricsin were absent or present in trace amounts in the first week after birth, but thereafter concentrations of both zymogens increased rapidly. Development of the pentagastrin-stimulated secretion of protease activity reflected the changes of zymogen concentrations in fundic tissue. Chronic treatment of pigs with ACTH from three days of age significantly increased the concentration of prochymosin in fundic tissue at 9-11 days and the concentrations of pepsinogen A and progastricsin at 34-36 days of age. Hormones such as ACTH and glucocorticoids may therefore play a regulatory role in the ontogeny of porcine gastric proteases.

Control of glucose metabolism in the perinatal period.

Abstract: The central importance of glucose as a fuel for energy metabolism and growth of the fetus is clear as is the role of insulin in coordinating its utilisation by many fetal tissues. What is less clear is the qunatitative nature of the interaction between the fetus and placenta in organising glucose metabolism. Increasingly there is evidence that the fetus coordinates some of the supply of glucose to the placenta and that this is particularly important when uterine blood flow is reduced. It is unclear how this is regulated, but substrate cycles of glucose and lactate appear to make a significant contribution to carbohydrate metabolism in fetus and placenta. Another area as yet unresolved in the control of fetal glucose metabolism is the coordination of the changes that occur around the time of birth. Notable of these is the activation of glycogen mobilisation and of glucose synthesis and changes in the setting of glucose regulatory mechanism. These are briefly reviewed.

Hypoxia reduces oxygen consumption of fetal skeletal muscle cells in monolayer culture

Abstract: In a previous study on acute asphyxia in unanesthetized fetal sheep near term we showed that reduced oxygen delivery to peripheral organs reduces total oxygen consumption, suggesting that oxygen itself may be a determinant of oxygen consumption (Jensen, Hohmann & Kunzel, 1987). To test this hypothesis we developed an in vitro perfusion model, which enabled us to measure the oxygen consumption of fetal skeletal muscle cells in monolayer culture in a control period (at approximately 145 mmHg) and during various degrees of hypoxia (6-140 mmHg). In 57 experiments on 57 cultures the mean oxygen consumption at a mean 'entry PO2' of 145.3 +/- 10.4 mmHg was 10.3 +/- 9.3 (SD).10(-6) mul O2 per h per skeletal muscle cell. These measurements were made after an average of 4.2 +/- 2.3 transfers of the cells and at a cell density of 2.0 +/- 1.2.10(5) cells per cm2. In 54 of these experiments hypoxia was induced. There was a close positive correlation between the PO2 of the perfusate entering the Petri-dish ('entry PO2') and the change of the oxygen consumption of the cells (y = 5.17 - 0.54x + 0.03x2 - 0.00016x3, r=0.97, p<0.0001). When oxygen tension fell, there was a concomitant fall in cellular oxygen consumption. We conclude that oxygen is a determinant of cellular oxygen consumption. Thus, hypoxia may reduce oxygen consumption of skeletal muscle cells, and oxygen may be preserved to maintain oxidative metabolism in central fetal organs. This powerful and protective cellular mechanism may warrant both intact survival of the fetus during hypoxia and optimal cell function at any given state of oxygenation, be it during recovery from hypoxia or during transition from fetal to postnatal live.

Induction of parturition by cortisol: effects on negative feedback sensitivity and plasma CRF.

Abstract: In fetal sheep, plasma concentrations of both adrenocorticotropic hormone (ACTH) and cortisol increase at the end of gestation. The increase in fetal plasma cortisol concentration induces placental 17 alpha-hydroxylase and 17, 20 lyase activities and therefore stimulates the placenta to secrete relatively more estrogen and relatively less progesterone. The resultant increase in the estrogen-to-progesterone ratio is thought to increase uterine contractility and initiate labour. We had previously demonstrated that the efficacy of cortisol-induced suppression of ACTH secretion at the end of gestation was reduced. We hypothesized that cortisol-induced stimulation of placental steroidogenesis promoted the secretion of a steroid hormone which reduced negative feedback efficacy, and therefore allowed both ACTH and cortisol secretion to increase simultaneously. Others had proposed that cortisol stimulates the placental secretion of corticotrophin releasing factor, which might also stimulate fetal ACTH secretion. This study was designed to test the hypotheses that cortisol reduces its own feedback efficacy or stimulates CRF secretion. Five pregnant ewes with twin pregnancies were studied after chronic catheterization. One fetus was subjected to infusion of hydrocortisone sodium succinate (10 micrograms/min, iv) and the other to infusion of saline. After 5 and 53 h of infusion, each fetus was subjected to a period of hypotension produced by infusion of sodium nitroprusside. The infusion of hydrocortisone sodium succinate decreased plasma progesterone concentrations in the fetal circulation into which the steroid was infused, and in the maternal circulation. Fetal plasma CRF concentrations were increased on the third day of infusion, the day in which the fetuses went into labour.(ABSTRACT TRUNCATED AT 250 WORDS)

Cortisol induces perinatal hepatic gluconeogenesis in the lamb.

Abstract: To examine the influence of a prenatal increase in plasma cortisol concentration on perinatal initiation of hepatic gluconeogenesis, we infused cortisol into seven fetal sheep at 137-140 days gestation. 14C-Lactate provided tracer substrate for estimation of gluconeogenesis. We measured hepatic blood flow using radionuclide-labeled microspheres. After delivery, fetal arterial blood glucose concentration (1.33 +/- 0.4 mmol/l) increased transiently, but returned to fetal levels within 1 h after delivery. Substantial hepatic gluconeogenesis was induced in the fetus after cortisol infusion, averaging 23.4 +/- 12.2 mumol/min/100 g liver (7.8 +/- 4.4 mumol/min/kg fetal weight). Fetal hepatic glucose output was 44.4 +/- 17.7 mumol/min/100 g liver. Hepatic glucose output did not change after delivery; estimated gluconeogenesis decreased immediately, then increased by 6 h after delivery. Lactate supply to the liver fell substantially, from 1.1 +/- 0.4 mmol/min/100 g in the fetus to 0.24 +/- 0.09 at 1 h after delivery. Lactate flux across the liver decreased from 75.3 +/- 23 mumol/min/100 g in the fetus to 20.2 +/- 15.7 at 1 h after delivery. Hepatic lactate flux was significantly related to gluconeogenesis (r = 0.734, P = 0.0001). We conclude that cortisol induces substantial hepatic gluconeogenesis in fetal sheep near term. After delivery, there appears to be a transient decline in gluconeogenesis from lactate, which may be secondary to limited hepatic oxygen and substrate supply. Onset of gluconeogenesis in the fetus fails to sustain increases in either fetal or postnatal blood glucose concentrations.

The blood supply to the heart and brain in the growth retarded guinea pig fetus.

Abstract: Blood flow to the heart and brain of 31 control and 15 growth retarded (IUGR) guinea pig fetuses was measured between 60-64 days of pregnancy by the microsphere technique. The animals were anaesthetized with diazepam and pentobarbitone. Brain weight was reduced by 11% in IUGR fetuses from 2.61 +/- 0.03 to 2.33 +/- 0.05 g and heart weight by 39% from 0.42 +/- 0.01 to 0.25 +/- 0.01 g, compared to a decrease in body weight of 42% from 83.6 +/- 2.3 to 48.2 +/- 2.2 g. The myocardial blood flow of control animals was negatively correlated to arterial O2 content (r = 0.78, P less than 0.001) and arterial pH (r = 0.68, P less than 0.001). Brain blood flow was inversely correlated to arterial O2 content in control fetuses (r = 0.79, P less than 0.001). Eight regions of the brain were examined: cerebral hemispheres, caudate nucleus, hippocampus, thalamus + hypothalamus, cerebellum, pons, and medulla. Regional blood flows were significantly correlated to fetal oxygenation in the controls. Growth retarded fetuses were characterized by poor oxygenation (arterial O2 content less than or equal to 2.5 mM) and were frequently acidaemic (pH less than 7.20). No relation could be demonstrated between the myocardial or cerebral blood flows of IUGR fetuses and arterial O2 content or pH. It is concluded that growth retarded fetuses are unable to maintain O2 delivery to the brain and myocardium by increases in blood flow. Although O2 extraction could be increased to meet the O2 requirements of the heart, IUGR fetuses had a lower rate pressure product, suggesting a decline in myocardial O2 consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of severe reduction in maternal placental blood flow on blood flow distribution in the sheep fetus.

Abstract: To test the hypothesis that fetal lambs are able to maintain oxygen delivery to myocardial, brain and adrenal tissues during reduction in uterine blood flow to 25% of control, we performed experiments on five ewes and their fetuses. A snare occluder was placed around the maternal common hypogastric artery and catheters were placed for measurement of blood pressures, flows, blood gas tensions, pH and oxygen content. After a five day recovery period, control measurements were made. The snare occluder was then closed until the artery was fully occluded. The arterial occlusion caused uteroplacental blood flow to fall to 32 +/- 4% and maternal placental blood flow to fall to 25 +/- 3% of control values. This level of asphyxia was maintained for 19 +/- 3 minutes, when maternal and fetal blood flows were measured again. In response to occlusion, fetal ascending aortic PO2 fell from 21 +/- 2 (SEM) to 13 +/- 2 mmHg (P less than or equal to 0.01), oxygen content from 4.3 +/- 0.3 to 1.4 +/- 0.2 mM (P less than or equal to 0.01) and pH from 7.37 +/- 0.01 to 7.21 +/- 0.05 (P less than or equal to 0.01). PCO2 rose from 48 +/- 1 to 62 +/- 3 mmHg (P less than or equal to 0.01). Fetal arterial blood pressure increased from 51 +/- 3 to 61 +/- 3 mmHg (P less than or equal to 0.001) and heart rate decreased from 172 +/- 10 to 104 +/- 4 beats.min-1 (P less than or equal to 0.01). The heart, brain and adrenals showed vasodilation in response to the asphyxic stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of breathing at birth.

Abstract: The factors which regulate the transition to lung gas exchange in the newborn are not well understood. The transition begins within seconds of birth with the newborn's first breath and is largely complete by 30 min of age at which time breathing is continuous, and arterial blood gas tensions and pH approach stable newborn values. Experiments indicate that sensory stimulation caused by cutaneous cooling or sciatic nerve stimulation can result in the initiation of breathing within seconds. Thus, massive sensory stimulation of the newborn caused by labour and delivery probably plays an important role in promoting the rapid onset of lung ventilation. Any delay in the onset of lung gas exchange causes a rise in arterial PCO2 and fall in pH which would stimulate breathing probably via stimulation of the central chemoreceptors. Since an impairment of CO2 elimination is usually observed after birth, a rise in arterial PCO2 likely stimulates breathing in the newborn. However, this impairment is transient and is usually corrected within 30 min to 2 h of age. Recent experiments suggest that placental perfusion inhibits the fetal central respiratory system and that this effect may be mediated by a placentally-produced respiratory inhibitor. Thus, withdrawal of a respiratory inhibitor from the circulation may play an important role in maintaining breathing in the newborn after sensory stimulation wanes and arterial PCO2 returns to normal fetal levels.