Hemoglobin oxygen dissociation (P50) in bronchopulmonary dysplasia.

A study was devised to determine the P50 in infants with bronchopulmonary dysplasia (BPD). Other factors such as red blood cell 2,3-diphosphoglycerate (2,3-DPG) level proportions of adult (HbA) to fetal (HbF) hemoglobins which could affect P50 were also measured. Fourteen infants with clinical and radiological signs of BPD with a mean post-conceptional age of 42.2 +/- 4.7 weeks born at a mean gestational age of 29.3 +/- 2.0 weeks were evaluated. The percentage of HbF determined in 8 infants was 40.1 +/- 20.3% and the mean 2,3-DPG concentrations was 13.1 +/- 2.2 mumol/g Hb. The P50 was 25.1 +/- 2.7 mm Hg (range 18-29.5 mm Hg). When a HbO2 curve was established based on a large volume of blood consisting of adult blood and newborn cord blood mixed to attain a P50 of 25.1 mm Hg, the PaO2 at 90% O2 saturation was 52 mm Hg. Since there can be a wide range in HbO2 in infants with chronic BPD, pulse oximetry remains the most prudent method of monitoring oxygen therapy in BPD infants.     

Effects of acute hypercapnia on maternal and fetal vasopressin and catecholamine release

Although fetal asphyxia, i.e. hypoxemia, acidosis, and hypercapnia, increases plasma arginine vasopressin (AVP) greater than 40-fold, hypoxemia and metabolic acidosis occurring independently cause only 5-fold and 2-fold increases, respectively. To determine the effects of hypercapnia on AVP release, we examined the effects of acute hypercapnia on AVP secretion in six pregnant sheep and their fetuses at 135 +/- 4 d (chi +/- SD), exposing the ewe successively to room air, 30% O2, 30% O2 plus 10% CO2, 30% O2, and room air, and monitoring uterine blood flow, as well as maternal and fetal mean arterial pressure, heart rate, arterial blood gases, and plasma AVP and catecholamines. Oxygen exposure had no effect on the ewe or fetus. During O2 plus CO2 exposure, the ewes and fetuses developed hypercapnia in the absence of hypoxia, arterial CO2 tension increasing to 8.38 +/- 0.87 kPa (62.9 +/- 6.5 mm Hg) and 10.0 +/- 0.61 kPa (75.2 +/- 4.6 mm Hg) (p less than 0.001), respectively, at 30 min of exposure. Although fetal heart rate and mean arterial pressure were unchanged, maternal values rose 61 and 30% (p less than 0.001), respectively. At 30 min of O2 + CO2 exposure, maternal norepinephrine increased from 2.23 +/- 0.74 to 8.52 +/- 3.97 nmol/L (p = 0.15) and fetal epinephrine increased from 0.27 +/- 0.10 to 2.271 +/- 0.90 nmol/L (p = 0.01); plasma AVP was not significantly increased in the ewe or fetus, although levels rose from approximately 45 to 127 +/- 48 and 137 +/- 64 pmol/L (p = 0.10), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Arterial oxygen tension threshold range for the onset of arousal and breathing in fetal sheep.

Mechanisms for the control of episodic fetal breathing movements or the onset of continuous breathing at birth remain unknown. Lung distension with 100% O2 at a continuous positive airway pressure of 30 cm H2O may induce arousal and continuous breathing. To investigate 1) the threshold range of arterial oxygen tension (PaO2) for the onset of arousal and breathing and 2) the graded response of breathing to various levels of PaO2, we studied 10 fetal sheep between 135 and 142 d of gestation (term = 147 +/- 2 d). Each fetus was instrumented to record sleep states, diaphragmatic electromyogram, arterial pH, and blood gas tensions. PaO2 threshold was determined through an indwelling O2 sensor catheter. Fetal lungs were distended at a continuous positive airway pressure of 40 cm H2O with 100% N2 or with O2 ranging from 40 to 100% via an in situ endotracheal tube. At the onset of arousal (n = 10), PaO2, arterial carbon dioxide tension, and Hb O2 saturation increased from control values of 21.7 +/- 0.75 torr (2.9 +/- 0.09 kPa), 41.8 +/- 1.1 torr (5.47 +/- 0.15 kPa), and 52.9 +/- 2.6% to 65.6 +/- 9.6 torr (8.74 +/- 1.28 kPa), 46.9 +/- 1.3 torr (6.25 +/- 0.17 kPa), and 92.9 +/- 2.06%, respectively, whereas the pH decreased from 7.31 +/- 0.006 to 7.27 +/- 0.009 (mean +/- SEM; p = 0.001, 0.04, 0.002, and 0.001, respectively). Seven of 10 fetuses breathed continuously. In these fetuses, PaO2 and arterial carbon dioxide tension further increased and pH decreased; however, no further significant increase in Hb O2 saturation was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of hypoxia on neurohypophyseal hormone release in fetal and maternal sheep

The effect of hypoxemia on arginine vasopressin (AVP) and oxytocin (OT) release was investigated in the chronically catheterized fetus and ewe. During 30 min of 10% maternal oxygen delivery, mean (+/- SEM) arterial PO2 decreased from 105 +/- 10.6 to 48 +/- 3.5 mm Hg in the ewe and from 21 +/- 1.3 to 12 +/- 0.8 mm Hg in the fetus (each P less than 0.001). Arterial PCO2 decreased from 35 +/- 4.4 to 29 +/- 1.0 mm Hg in the ewe, whereas fetal PCO2 decreased from 43 +/- 2.3 to 35 +/- 3.5 mm Hg (P less than 0.05). Blood pH increased from 7.44 +/- 0.03 to 7.56 +/- 0.04 in the ewe (P less than 0.01) and from 7.36 +/- 0.004 to 7.40 +/- 0.006 in the fetuses (P less than 0.01). Baseline mean AVP levels were identical in ewes and fetuses (0.7 +/- 0.1 microU/ml). After 30 min of hypoxia, plasma AVP levels remained unchanged in the ewes (0.9 +/- 0.1), but increased dramatically in the fetuses (47 +/- 21 microU/ml) (P less than 0.001). There was a highly significant correlation between the duration of hypoxia and log fetal AVP concentrations (r = 0.85). The log fetal plasma AVP also was inversely correlated to the log fetal PO2 values (r = 0.83). Mean baseline fetal and maternal plasma OT levels were 2.6 +/- 0.5 microU/ml and 2.2 +/- 0.5 microU/ml, respectively. After 30 min of hypoxia fetal and maternal OT values were 2.9 +/- 0.8 microU/ml (not significant).     

The effect of varying arterial oxygen tension on neonatal acid-base balance.

Acute severe hypoxia, when the arterial partial pressure of O2 (PaO2) is sufficiently reduced, causes a shift from aerobic to anaerobic metabolism and can be fatal to neonates. The ability of the neonate to accommodate this shift, and prevent acidosis, could play a role in its ability to tolerate hypoxia. This study examines the effect of varying degrees of acute hypoxia on acid-base homeostasis in the neonate using a model of right to left shunting where PaO2 is decreased and, if severe, arterial partial pressure of CO2 is increased. Three-d-old swine were anesthetized, intubated, and mechanically ventilated. Ventilation with a gas mixture of medical air and 95% N2:5% CO2 resulted in four groups: 1) normoxia (n = 5); 2) mild hypoxia (n = 4); 3) moderate hypoxia (n = 3); and 4) severe hypoxia (n = 5), with PaO2 of 10.7, 8.0, 5.3, and 2.7 kPa (80, 60, 40, and 20 mm Hg), respectively. Acid-base status was evaluated via changes in arterial blood partial pressure of CO2, pH, HCO3-, and base excess at 0, 30, 60, and 120 min. Only the severe hypoxia group had significantly elevated (p less than 0.0001) arterial partial pressure of CO2 compared to the other groups at 60 and 120 min [8.7 +/- 0.5 and 8.0 +/- 0.5 kPa (65.5 +/- 3.7 and 60.0 +/- 3.7 mm Hg), respectively]. Base excess was unaltered in the normoxic and mild and moderate hypoxic groups, indicating no change in metabolic acid-base status. The severe hypoxic group had progressively decreased HCO3-, base excess, and pH at 60 and 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

The biologic implications of a rare hemoglobin mutant that decreases oxygen affinity

Blood from seven newborns, a 13-y-old, and seven adult family members with a suspected hemoglobinopathy because of unexplained cyanosis was obtained for analysis to determine Hb oxygen affinity and to characterize and quantify the Hb variants. Their oxygen saturation was 76 to 84%. The P(50) was 30.3 +/- 2.9 for the newborns and 32.5 +/- 2.6 mm Hg for their related adults. In the same order, the plasma erythropoietin was 7.4 +/- 2.9 and 15.9 +/- 3.7 mU/mL, whereas 2,3-diphosphoglycerate was 16.1. +/- 2.9 and 15.9 +/- 3.7 micromol/g Hb. In four of the newborns with increased P(50), the mother had a normal P(50) (27 mm Hg), which indicated a greater maternal oxygen affinity than the fetus with no adverse effects on the fetus. Genetic analysis of alpha-globin genes demonstrated a heterozygous mutation on the alpha2 gene [alpha94(G1)Asp-->His] for each of the newborns and their related adults. The same mutation was found on the alpha1 gene in an adolescent and her father. The mRNA measurements showed that the alpha2- to alpha1-globin mRNA mean ratio was 2.5, alpha2 mutant globin mRNA/total alpha2-globin mRNA was 45.0%, whereas the alpha1 mutant globin mRNA/total alpha1-globin mRNA was 37.8%. The level of alpha2 mutant globin/total alpha-globin was 27.3 +/- 1%, and alpha1 mutant globin/total alpha-globin was 23.8 +/- 1%. The percentage of synthesized alpha2 and alpha1 mutant globins was 27.5 +/- 2 and 26.1 +/- 1, respectively. The ratio of the alpha2/alpha1 mutant globins was 1.1, which corresponded to a ratio at the mRNA level of alpha2/alpha1 of 2.5 +/- 0.5, which suggested that there is a less efficient translation of the alpha2 mRNA than alpha1 mRNA. The reversal of the physiologic fetomaternal oxygen affinity had no effects on fetal development.     

Red cell oxygen affinity, hemoglobin type, 2,3-diphosphoglycerate, and pH as a function of fetal development.

Studies were carried out on fresh cord blood obtained at delivery from nonstressed normal fetuses ranging from 24 to 42 weeks of gestation, to determine the relationship of 2,3-diphosphoglycerate (DPG), the intracellular red cell and extracellular pH, and the proportions of adult and fetal hemoglobin in regulating the position of fetal red cell oxygen affinity in utero. There was a significant positive correlation between P50 and gestational age (r = .62, P less than .001), the linear regression increased from 17.8 to 22.5 mm Hg. There was also a significant positive correlation between P50 and the percentage of adult type hemoglobin (HbA) (r = .67, P less than .001). In contrast gestational age had no effect of 2,3-DPG levels, the mean and SD was 14.86 +/- 2.04 mol/gm of Hb or delta pH between plasma and red cell, the mean was 0.187 +/- SD 0.032. However, there was a significant negative correlation between the intraerythrocyte hydrogen ion concentration and DPG level (r = .5, P less than .025). It is concluded therefore that the decrease in fetal oxygen affinity as gestation progresses is related mainly to the increase in the amount of HbA and the levels of DPG or delta pH between plasma and red cells are not a function of gestational age.     

Theophylline stimulates fetal breathing movements during hypoxia

The respiratory responses to theophylline during normoxia and hypoxia were determined in 13 unanesthetized fetal sheep. Theophylline (plasma levels approximately 111 mumol/L) increased the incidence of fetal breathing movements measured over 120 min from 37.7 +/- 4.8% to 61.1 +/- 5.7% (SEM) in normoxic fetuses. In isocapnic hypoxia (arterial O2 tension approximately 1.86 kPa), theophylline increased the incidence from 20.0 +/- 6.3 to 52.0 +/- 6.1%. Theophylline also resulted in an increase in the slope of inspiration during both normoxia and hypoxia. We conclude that adenosine modulates fetal respiratory drive during normoxia and hypoxia.     

Effect of mild hypothermia and hypoxia on blood flow and oxygen consumption of the fetal sheep brain

This study was undertaken to measure the effects of mild hypothermia on cerebral blood flow and metabolism and cardiovascular responses to hypoxia in the fetal sheep. Near-term fetal sheep were chronically instrumented with laser Doppler flowmetry in the parietal cortex for measurement of relative changes in cerebral blood flow, as well as with arterial and sagittal sinus catheters for measurement of oxygen extraction by the brain and a cooling coil around the fetal thorax. Fetuses were studied during cooling alone, cooling with superimposed maternal hypoxia to achieve a fetal arterial Po2 of 1.33 to 1.60 kPa, or hypoxia alone. In response to cooling alone [1.6 degrees +/- 0.1 degrees C (mean +/- SEM) decrease in brain temperature], fetal blood pressure and heart rate both increased significantly whereas cerebral blood flow decreased 14 +/- 4%, commensurate with a 24 +/- 8% decline in cerebral metabolic rate. Administration of moderate hypoxia during cooling resulted in a significant increase in cerebral blood flow, decreased heart rate, and no further increase in blood pressure. In response to hypoxia alone, fetal blood pressure was significantly increased, heart rate was decreased, and cerebral blood flow increased by 24 +/- 8%, whereas cerebral metabolic rate decreased by 38 +/- 13%. Arteriovenous oxygen extraction was unchanged by cooling alone but increased significantly in response to hypoxia administered during cooling. We therefore conclude that oxygen delivery to the fetal sheep brain remains coupled to metabolic rate during hypothermia and that hypothermia does not impair the compensatory cardiovascular responses of the fetus to acute moderate hypoxia.     

The inhibition of the postnatal rise of 2,3-diphosphoglycerate in newborn lambs as a result of glucose perfusion

Due to the abrupt increase in 2,3-diphosphoglycerate (2,3-DPG) concentration in the newborn lamb, which begins soon after birth, this interval in development was considered an excellent period to test the hypothesis that glucose perfusions could inhibit 2,3-DPG synthesis. Ten newborn lambs were divided into two groups and perfused either with glucose (15 mg/kg/min) or physiologic saline (45% NaCl) for 10 days. Blood gases, electrolytes, glycemia, O2 pressure at 50% Hb saturation, and 2,3-DPG levels were compared in the two groups. Glucose levels remained significantly elevated during the first 3 days in the glucose perfused group. The O2 pressure at 50% Hb saturation increased in both groups but was significantly lower in the glucose perfused group when determined on day 5 and 8. The postnatal increase in 2,3-DPG was significantly diminished in the glucose infused lambs, which suggests that glucose perfusion has an inhibiting effect on erythrocyte 2,3-DPG synthesis.     

Pituitary-adrenal responses to acute hypoxemia during and after maternal dexamethasone treatment in sheep

The effects of maternal dexamethasone treatment on hypothalamic-pituitary-adrenal axis function were determined during basal and hypoxemic conditions in maternal and fetal sheep. Under halothane, ewes and their fetuses were catheterized at 117 d gestation (term = 145 d). Starting at 124 d, the ewes received i.m. injections of two doses of either dexamethasone (12 mg) or saline at 24-h intervals. All animals experienced one episode of hypoxemia when the dexamethasone was present in the maternal and fetal circulations [125 +/- 1 d (H1)] and a second episode of hypoxemia when the steroid was no longer detectable in either the maternal or fetal circulations [128 +/- 1 d (H2)]. The fall in partial pressure of oxygen in arterial blood in response to hypoxia was similar in the two episodes in both the fetal and the maternal blood. Maternal dexamethasone treatment diminished maternal and fetal basal plasma cortisol but not ACTH during the normoxic period of H1 but not H2. In control animals, hypoxemia induced increases in fetal but not maternal ACTH and cortisol concentrations. In dexamethasone-treated animals, maternal ACTH and cortisol concentrations also remained unchanged from baseline in both H1 and H2. In contrast, fetal plasma ACTH and cortisol responses to hypoxemia were significantly suppressed during H1 but not H2. Correlation of fetal plasma ACTH and cortisol concentrations suggested diminished cortisol output without a change in adrenocortical responsiveness in dexamethasone-treated fetuses during H1 but not H2. Maternal treatment with dexamethasone transiently suppressed maternal and fetal basal hypothalamic-pituitary-adrenal axis function and the fetal plasma ACTH and cortisol responses to acute hypoxemia in sheep.     

Hypoxemia and reoxygenation with 21% or 100% oxygen in newborn pigs: changes in blood pressure, base deficit, and hypoxanthine and brain morphology.

To study whether room air is as effective as 100% O2 in resuscitation after hypoxia, hypoxemia (PaO2 2.3-4.3 kPa) was induced in newborn pigs (2-5 d old) by ventilation with 8% O2 in nitrogen. When systolic blood pressure had fallen to 20 mm Hg, animals were randomly reoxygenated with either 21% O2 (group 1, n = 9) or 100% O2 (group 2, n = 11) for 20 min followed by 21% O2 in both groups. Controls (group 3, n = 5) were ventilated with 21% O2 throughout the experiment. Base deficit peaked at 31 +/- 5 mmol/L (mean +/- SD) for both hypoxic groups at 5 min of reoxygenation and then normalized over the following 3 h. There were no statistically significant differences between the two groups during reoxygenation concerning blood pressure, heart rate, base deficit, or plasma hypoxanthine. Hypoxanthine peaked at 165 +/- 40 and 143 +/- 42 mumol/L in group 1 and 2 (NS), respectively, and was eliminated monoexponentially in both groups with an initial half-life for excess hypoxanthine of 48 +/- 21 and 51 +/- 27 min (NS), respectively. Blinded pathologic examination of cerebral cortex, cerebellum, and hippocampus after 4 d showed no statistically significant differences with regard to brain damage. We conclude that 21% O2 is as effective as 100% O2 for normalizing blood pressure, heart rate, base deficit, and plasma hypoxanthine after severe neonatal hypoxemia in piglets and that the extent of the hypoxic brain damage is similar in the two groups.     

Monitoring of cerebral oxygenation during hypoxic gas management in congenital heart disease with increased pulmonary blood flow

In the preoperative management of congenital heart disease (CHD) with increased pulmonary blood flow, hypoxic gas management to control pulmonary blood flow is useful. However, the cerebral oxygenation state has rarely been studied, and there is concern about neurologic development. In eight infants with CHD accompanied by increased pulmonary blood flow, hypoxia was induced after a 1-h baseline period in room air (FiO2, 0.21). The infants were simultaneously monitored in both the front-temporal region and the right-brachial region for 90 min using near-infrared spectroscopy (NIRS). The minimum SaO2 (pulse oximetry) after hypoxic gas administration was 80.8 +/- 2.9% when the minimum FiO2 was 16.2 +/- 1.1%. With a decrease in SaO2, oxy-Hb (O2Hb) decreased and total Hb [cHb: O2Hb + deoxy-Hb (HHb)] increased in both regions in the majority of infants. HHb increased in both regions with a decrease in SaO2. The maximum change in the tissue oxygenation index (TOI: O2Hb/cHb x 100) was -8.3 +/- 2.6% in the front-temporal region and -3.6 +/- 2.3% in the right-brachial region. Cerebral oxygenation decreased despite an increase in cerebral blood flow during hypoxic gas management. The change in TOI was < or =10% when the SaO2 was > or =80%. Safer control of SaO2 should be maintained over 80% for hypoxia management in CHD based on the results of the present study.     

Nicotine delays arousal during hypoxemia in lambs

A decreased ability to arouse from sleep in response to arterial hypoxemia may lead to severe asphyxia and has been proposed as a mechanism of sudden infant death syndrome. Based on previous observations that nicotine exposure, a major environmental risk factor for sudden infant death syndrome, may impair hypoxic defense in neonates, we hypothesized that a short-term infusion of nicotine could impair hypoxic arousal through interference with oxygen-sensing mechanisms. Seven chronically instrumented unanesthetized lambs were studied at the age of 4.6 +/- 1.3 d during normoxia and acute hypoxia (0.1 fraction of inspired oxygen) for 5 min. Ventilation, transcutaneous Hb oxygen saturation, blood pressure, heart rate, and time to arousal were compared during a control saline infusion and during a 0.5 microg x kg(-1) x min(-1) nicotine infusion. Activity states, i.e. wakefulness and quiet sleep as well as arousal, were defined by EEG, nuchal electromyogram, and electrooculogram. Each lamb acted as its own control. Arousal from quiet sleep occurred significantly later during nicotine infusion compared with control (177 +/- 93 versus 57 +/- 41 s, p < 0.01) and at a lower transcutaneous Hb oxygen saturation (60 +/- 12 versus 79 +/- 12%, p < 0.01) (paired t test). The ventilatory response to hypoxia in wakefulness was similar during both conditions but was significantly attenuated in quiet sleep during nicotine infusion (p < 0.001, 2-way ANOVA repeated-measures design). Blood pressure and heart rate responses were similar during both conditions. These results suggest that a brief nicotine exposure blunts oxygen sensitivity in young lambs, a finding of potential relevance for sudden infant death syndrome.     

The effect of prolonged intrauterine hyperinsulinemia on iron utilization in fetal sheep

Newborn infants of poorly controlled insulin-dependent diabetic mothers demonstrate a redistribution of iron from serum and tissue stores into red blood cells. These changes may be due to increases in iron utilization during augmented Hb synthesis, which compensates for chronic intrauterine hypoxemia induced by prolonged fetal hyperinsulinemia. We tested this hypothesis by measuring plasma iron, total iron-binding capacity, percent iron-binding capacity saturation (total iron-binding capacity saturation), Hb concentration, total red cell Hb, and total red cell iron in the arterial blood of 11 chronically instrumented fetal sheep after 7-12 d of infusion with 15 U/day of insulin (n = 5) or placebo (n = 6). The insulin-infused fetal sheep had higher mean +/- SD plasma insulin concentrations (448 +/- 507 versus 11 +/- 8 mU/L; p less than 0.001) and lower arterial oxygen saturations (38 +/- 7 versus 54 +/- 9%; p less than 0.02). The insulin-infused group had a lower mean plasma iron concentration (20.8 +/- 10.9 versus 42.1 +/- 14.7 microM/L; p less than 0.02) and total iron-binding capacity saturation (36 +/- 20 versus 64 +/- 22%; p less than 0.02) and a higher total red cell Hb (45.4 +/- 8.7 versus 32.6 +/- 8.8 g; p less than 0.02) and total red cell iron content (154 +/- 29 versus 111 +/- 29 mg; p less than 0.02) when compared with the placebo group. Seven to 12 d of intrauterine hyperinsulinemia decreases serum iron and increases total red cell iron, most likely by stimulating increased Hb synthesis in response to low arterial oxygen saturation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of maternal oxygen inhalation on the fetus with growth retardation

Decreased nutrient and oxygen transfer to the fetus accounts for fetal growth retardation in pregnancies complicated by severe uteroplacental insufficiency. A model of uteroplacental insufficiency was produced by ligation of the uterine artery of one horn in pregnant rats at 17 days of gestation. The pregnant rats were assigned to environmental chambers containing a gas mixture of either an increased fractional inspired oxygen concentration of 0.40 (O2) or room air from day 17 through 21 of gestation. Supplemental oxygen inhalation resulted in increased survival of the fetuses from the ligated horn [34 +/- 6% in intrauterine growth retardation (IUGR)-room air versus 57 +/- 8% in IUGR-O2] and an increase in fetal weight, expressed as a percentage of nonligated appropriate for gestational age control littermates (67 +/- 2% in IUGR-room air versus 74 +/- 2% in IUGR-O2). A role for hypoxia in the suppression of fatty acid synthesis in IUGR fetal tissues had been postulated; however, maternal oxygen inhalation did not result in any increase in fatty acid content or specific activity in liver, lung, or carcass of IUGR fetuses. These data indicate that supplemental maternal oxygen inhalation improves survival and growth of fetuses compromised by uteroplacental insufficiency, but it has no apparent effect on lipogenesis at term.     

Elevated plasma corticotrophin release factor levels and in utero meconium passage

Intrauterine meconium (MEC) passage and aspiration may result in significant newborn morbidity, though there is little understanding of the physiologic mechanisms for MEC passage. We hypothesized that stress induces fetal MEC passage via corticotrophin releasing factor (CRF), a known mediator of colonic motility in adult rats. Pregnant rats at e22 were subjected to acute hypoxia or normoxia for 35 min, after which rats were anesthetized and fetuses operatively delivered. Amniotic fluid bilirubin and intestinal alkaline phosphatase were measured as markers for MEC passage, and fetal and maternal plasma CRF and corticosterone levels determined. Hypoxic stress induced defecation in all dams and provoked visible MEC passage in all fetuses. Amniotic fluid bilirubin content was significantly higher in hypoxic fetuses versus controls (1.064 +/- 0.101 versus 0.103 +/- 0.003 O.D. at 410 nm) and intestinal alkaline phosphatase was consistently elevated in MEC stained amniotic fluid. Hypoxia significantly increased plasma CRF (maternal, 82 +/- 5 to 196 +/- 14 pg/mL; fetal, 284 +/- 15 to 1523 +/- 185 pg/mL) and corticosterone (maternal, 417 +/- 50 to 1150 +/- 50 ng/mL; fetal, 96 +/- 5 to 182 +/- 10 ng/mL) compared with controls. In view of the known action of CRF in adult colonic motility, these results suggest that hypoxic stress-mediated MEC passage in term fetal rats is mediated by a CRF dependent pathway.     

Fetal hind limb oxygen consumption and blood flow during acute graded hypoxia

Hind limb blood flow and O2 uptake, mean blood pressure, and heart rate were measured in six fetal sheep at 127-141 d gestation in the control state and at different levels of hypoxia that were induced by partial occlusion of the maternal terminal aorta. Blood flow was measured by an ultrasonic flow transducer. Control fetal arterial O2 content ([O2]a) in the descending aorta was 3.25 + 0.17 mM. In response to graded acute hypoxia, blood flow first increased (22.2 versus 19.9 mL.min-1.100 g-1, p = 0.003) and then decreased abruptly at approximately 1.5 mM [O2]a.O2 uptake decreased about 12% (14.74 versus 16.71, p = 0.03) as [O2]a decreased to 1.5 mM, and then fell markedly, tending toward zero for [O2]a = 0.9 mM. In the 2.7- to 1.5-mM [O2]a range, heart rate increased above control (194 versus 169 min-1, p = 0.0024), whereas mean blood pressure did not change significantly. For [O2]a less than 1.5 mM, heart rate decreased to 148 min-1 (p = 0.0005) and mean blood pressure increased above baseline (55 versus 47 torr, p = 0.0001). In conjunction with previous evidence, these results define a state of acute moderate hypoxia in which the whole fetus can sustain a relatively high rate of oxidative metabolism, and a state of acute severe hypoxia ([O2]a between 1.5 and 1.0 mM) in which O2 uptake by some fetal organs is selectively and markedly decreased.     

TBC3711, an ET(A) receptor antagonist, reduces neonatal hypoxia-induced pulmonary hypertension in piglets

The pulmonary vasculature of newborns with persistent pulmonary hypertension is characterized by active vasoconstriction and vascular remodeling. It has been suggested that endothelin-1 (ET-1), a potent vasoconstrictor and growth promoter, may be involved in the pathogenesis of persistent pulmonary hypertension of the newborn. To determine whether treatment with an ET(A) receptor antagonist can reverse pulmonary hypertension in the neonate, 1-d-old piglets were exposed to hypoxia for 3 d to induce pulmonary hypertension and then treated for the remainder of the 14 d with an orally active, nonpeptidic ET(A) antagonist (TBC3711, 22 mg x kg(-1) x d(-1)). At the end of the exposure, Hb, pulmonary artery pressure, right ventricle to left ventricle plus septum weight ratio, percentage wall thickness, ET-1 circulating levels, perfusion pressure, and dilator response to the nitric oxide (NO) donor, SIN-1 (3-morpholinosydnonimine-N-ethylcarbamide) in isolated perfused lungs were determined. Exhaled NO and hemodynamic variables were also examined in an intact anesthetized animal preparation that had undergone the same treatment. By 3 d of exposure to hypoxia, piglets had already developed significant pulmonary hypertension as estimated by their pulmonary artery pressure (24.0 +/- 1.3 mm Hg versus 14.2 +/- 3.4 mm Hg) and percentage wall thickness (26.6 +/- 5.9% versus 18.7 +/- 2.4% for vessels 0-30 microm). Whereas further exposure to hypoxia for 14 d did not enhance the increase in pulmonary artery pressure and percentage wall thickness, it did augment the right ventricle to left ventricle plus septum weight ratio (0.71 +/- 0.09 versus 0.35 +/- 0.01). ET-1 circulating levels were increased only when exposure to hypoxia was prolonged to 14 d (5.1 +/- 2.4 pg/mL versus 1.0 +/- 0.4 pg/mL). Treatment with TBC3711 from d 3 to d 14, once pulmonary hypertensive changes were established and while hypoxic exposure persisted, caused significant reduction in the right ventricle to left ventricle plus septum weight ratio (0.60 +/- 0.06), pulmonary artery pressure (20.0 +/- 4.8 mm Hg), and percentage wall thickness (18.5 +/- 3.3%) and restored the dilator response to the NO donor SIN-1. Prolonged hypoxia markedly reduced exhaled NO concentrations (0.3 +/- 0.6 ppb), although treatment of hypoxic animals with TBC3711 restored the concentration of exhaled NO (4.4 +/- 2.8 ppb) to the level of normoxic controls (4.9 +/- 3.0 ppb). Lastly, treatment with TBC3711 increased ET-1 circulating levels in both the normoxic (5.4 +/- 2.8 pg/mL) and hypoxic (13.0 +/- 6.3 pg/mL) groups. In conclusion, the specific ET(A) receptor antagonist, TBC3711, can significantly ameliorate the morphologic changes encountered in hypoxia-induced pulmonary hypertension in the newborn piglet and may improve the dilator response to NO.     

Chronic moderate hypoxia and protein malnutrition both induce growth retardation,but have distinct effects on arterial endothelium-dependent reactivity in the chicken embryo

Deviations in the rate of intrauterine growth may change organ system development, resulting in cardiovascular disease in adult life. Arterial endothelial dysfunction often plays an important role in these diseases. The effects of two interventions that reduce fetal growth, chronic hypoxia and protein malnutrition, on arterial endothelial function were investigated. Eggs of White Leghorn chickens were incubated either in room air or in 15% O2 from d 6 until d 19 of the 21-d incubation. Protein malnutrition was induced by removal of 10% of the total albumen content at d 0. In vitro reactivity of the femoral artery in response to vasodilators was measured at d 19. Both chronic hypoxia and protein malnutrition reduced embryonic body weight at d 19 by 14% without affecting relative brain weight. Chronic hypoxia or protein malnutrition did not change sensitivity to the exogenous nitric oxide donor, sodium nitroprusside (5.74 +/- 0.15 versus 5.85 +/- 0.23 and 6.05 +/- 0.18 versus 6.01 +/- 0.34, respectively). Whereas protein malnutrition did not modify arterial sensitivity to acetylcholine (7.00 +/- 0.10 versus 7.12 +/- 0.05), chronic hypoxia reduced sensitivity to this endothelium-dependent vasodilator (6.57 +/- 0.07 versus 7.02 +/- 0.06). In the presence of Nomega-nitro-l-arginine methyl ester, this difference in sensitivity to acetylcholine was no longer apparent (6.31 +/- 0.13 versus 6.27 +/- 0.06), indicating that chronic exposure to hypoxia reduced sensitivity to acetylcholine by lowering nitric oxide release. In additional experiments, a decrease in basal nitric oxide release in arteries of 3- to 4-wk-old chickens that had been exposed to in ovo chronic hypoxia was observed (increase in K+ contraction: -0.16 +/- 0.33 N/m versus 0.68 +/- 020 N/m). Protein malnutrition and chronic hypoxia both induce disproportionate growth retardation, but only the latter impairs arterial endothelial function. Intrauterine exposure to chronic hypoxia induces changes in arterial endothelial properties that may play a role in the development of cardiovascular disease in adult life.