Ovine fetal lung fluid response to atrial natriuretic factor

The fetal lung is an important site of fluid production and is postulated to serve a regulatory role in fetal fluid balance. To assess the role of atrial natriuretic factor on fetal lung liquid production, we studied the effect of intravenous atrial natriuretic factor infusion on tracheal fluid production in fetal sheep with chronic vascular and tracheal catheters. Ovine fetuses (mean gestation = 130 days +/- 1 day) received successive 40-minute intravenous infusions of increasing doses of synthetic fragment 1-28 atrial natriuretic factor (5, 25, and 100 ng/min.kg-1). In response to the 25 ng/min.kg-1 infusion, fetal tracheal fluid production decreased from 1.2 +/- 0.3 ml/10 min to 0.6 +/- 0.2 ml/10 min (p less than 0.05), and remained suppressed during the 100 ng/min.kg-1 infusion (0.5 +/- 0.2 ml/10 min). There was a significant inverse correlation between tracheal fluid production and fetal plasma atrial natriuretic factor levels (r = -0.61, p less than 0.001). Basal tracheal fluid sodium and potassium concentrations (147 +/- 1 mEq/L and 5 +/- 1 mEq/L) and osmolality (291 +/- 3 mOsm) did not change during the atrial natriuretic factor infusion periods. The observation that atrial natriuretic factor acts to decrease fetal lung fluid production suggests that atrial natriuretic factor may be important in the fetal adaptive response to extrauterine life.     

Dehydration increases the renal response to atrial natriuretic peptide in fetal sheep.

OBJECTIVE: In sheep, maternal water deprivation results in urinary natriuresis in spite of suppression of plasma atrial natriuretic factor levels. Near-term fetal sheep also have a urinary natriuresis without change in plasma atrial natriuretic factor during maternal dehydration. This study was designed to explore the role of plasma atrial natriuretic factor levels in fetal dehydration-natriuresis. STUDY DESIGN: Eight chronically instrumented preterm (113 +/- 1 days) ovine fetuses received two atrial natriuretic factor infusions (3 and 15 ng/kg/min) in a euhydrated state and after 48 +/- 1 hours of maternal water deprivation. RESULTS: Dehydration significantly increased maternal plasma osmolality (302 +/- 2 to 313 +/- 2 mOsm/kg water), sodium (148.1 +/- 0.8 to 154.3 +/- 0.4 mEq/L), chloride (112.4 +/- 0.6 to 116.8 +/- 0.9 mEq/L), and arginine vasopressin (4.2 +/- 1.2 to 23.0 +/- 4.0 pg/ml) and significantly decreased plasma atrial natriuretic factor (36 +/- 6 to 19 +/- 4 pg/ml) concentrations. Fetal plasma osmolality (296 +/- 1 to 308 +/- 2 mOsm/kg), atrial natriuretic factor (128 +/- 16 to 241 +/- 36 pg/ml), and arginine vasopressin (3.5 +/- 0.8 to 12.3 +/- 4.8 pg/ml) concentrations and urine osmolality (170 +/- 10 to 253 +/- 10 mOsm/kg), osmolar clearance (0.80 +/- 0.02 to 0.14 +/- 0.02 ml/kg/min), and fractional sodium excretion (3.3% +/- 1.7% to 8.5% +/- 2.1%) increased significantly with dehydration, whereas the plasma atrial natriuretic factor clearance decreased from 127 +/- 27 to 63 +/- 10 ml/kg/min. Dehydration had no effect on fetal hematocrit, vascular pressures, glomerular filtration rate, urine flow, or free water clearance. In euhydrated fetuses plasma atrial natriuretic factor increased from 128 +/- 16 to 287 +/- 46 pg/ml with sequential atrial natriuretic factor infusion, and no significant increases were observed in urine flow, fractional sodium excretion, and glomerular filtration rate. In contrast, atrial natriuretic factor infusion to dehydrated fetuses significantly increased urine flow (0.17 +/- 0.03 to 0.32 +/- 0.07 ml/kg/min), osmolar clearance (0.14 +/- 0.02 to 0.28 +/- 0.06 ml/kg/min), and fractional sodium excretion (8.5% +/- 2.1% to 14.8% +/- 4.0%). CONCLUSION: These results demonstrate that in the fetus at 113 days' gestation plasma atrial natriuretic factor levels increase with dehydration, probably a result of decreased plasma atrial natriuretic factor clearance, and the fetal renal responsiveness to atrial natriuretic factor infusion increases during maternal dehydration.     

Fetal plasma and renal responses to ruminal fluid

Amniotic fluid homeostasis is dependent on a balance of fetal fluid production and absorption. The fetal gastrointestinal tract is believed to resorb 500 to 1000 ml of amniotic fluid per day during 7 to 10 bouts of swallowing activity. However, the impact of ruminal fluid on fetal plasma composition and fluid homeostasis is largely unknown. Seven ovine fetuses (120 +/- 1 day) received intraruminal infusions of 0.9% or 3% saline solution on alternate days. In response to successive 40-minute intraruminal infusions of 0.9% saline solution (0.5 and 1.0 ml/kg/min), there was no change from basal levels of fetal plasma osmolality (295.7 +/- 2.9 mosm), plasma arginine vasopressin (1.45 +/- 0.29 pg/ml), urine osmolality (150 +/- 8 mosm), or urine volume (0.49 +/- 0.10 ml/min). In response to the 3% saline solution infusion, significant increases were noted in fetal plasma osmolality (295.4 +/- 3.1 to 302.6 +/- 2.6 mosm), plasma arginine vasopressin (1.77 +/- 0.31 to 4.84 +/- 0.79 pg/ml), and urine osmolality (157 +/- 13 to 342 +/- 25 mosm), whereas fetal urine volume significantly decreased (0.35 +/- 0.05 to 0.15 +/- 0.06 ml/min). These results indicate that hypertonic, but not isotonic, saline solution infusion into the fetal gastrointestinal tract may affect fetal plasma composition and urine production. Under conditions of significant plasma to luminal osmotic gradients, fetal gastrointestinal water and electrolyte transfer may be more rapid than can be compensated by either fetal renal function or placental equilibration.     

Hemorrhage-induced reductions in plasma atrial natriuretic factor in the ovine fetus.

To investigate the effects of blood volume reduction on fetal plasma atrial natriuretic factor concentrations, chronically catheterized ovine fetuses at 109 to 138 days' gestation were subjected either to withdrawal of two consecutive blood samples or to a moderate hemorrhage. In fetuses from which two blood samples of 3.5 ml each (approximately 1% of fetal blood volume) were withdrawn under basal conditions at 15- to 30-minute intervals, plasma atrial natriuretic factor concentrations in the second sample decreased by 17 +/- 7 pg/ml from 178 +/- 8 pg/ml in the first sample (p less than 0.02). If the fetal blood removed during the first sample was replaced with an equal volume of maternal blood, plasma atrial natriuretic factor concentrations did not change significantly. In these same samples, plasma arginine vasopressin and angiotensin II concentrations were unchanged between the two samples regardless of whether volume was replaced. In fetuses subjected to hemorrhages of 21% +/- 2% over 10 minutes without blood replacement, plasma atrial natriuretic factor concentration at 1.5 hours after hemorrhage was suppressed by 42 +/- 10 pg/ml from basal level of 139 +/- 9 pg/ml (p less than 0.05). Plasma atrial natriuretic factor returned to control levels by 5.5 hours after hemorrhage as blood volume returned to normal. Thus in the ovine fetus a reduction in blood volume results in a decrease in plasma atrial natriuretic factor concentrations. Also, atrial natriuretic factor appears to be more sensitive to changes in blood volume than other vasoactive hormones studied.     

Fetal hypoxia elevates plasma atrial natriuretic factor concentration

Acute hypoxia in the fetus is associated with a reduction in fetal blood volume. We hypothesized that atrial natriuretic factor in the fetal circulation may be one of the factors that mediate this blood volume decrease. Thus the present study was designed to determine the effects of hypoxia on circulating concentrations of atrial natriuretic factor in fetal sheep and correlate these changes with fetal blood volume. Hypoxia was induced in chronically catheterized sheep fetuses by infusing nitrogen containing CO2 into the trachea of the ewe for 30 minutes. Fetal arterial PO2 decreased by 10.2 +/- 1.3 (SE) mm Hg. Plasma atrial natriuretic factor concentration rose concurrently with the fall in PO2 such that atrial natriuretic factor increased to 565 +/- 196 pg/ml from a basal level of 127 +/- 13 pg/ml (p less than 0.001). Fetal blood volume was reduced by 7.2% +/- 2.1% and was significantly related to changes in atrial natriuretic factor levels (p less than 0.0001). At the termination of hypoxia, PO2 returned to normal levels before plasma concentrations of atrial natriuretic factor fell to baseline values. Therefore fetal hypoxia appears to be a potent stimulus for elevating plasma concentration of atrial natriuretic factor in the fetus, and this rise in atrial natriuretic factor in the circulation may be partially responsible for the reduction in fetal blood volume observed during hypoxia.     

Renal effects of ovine fetal arginine vasopressin secretion in response to maternal hyperosmolality

Acute increases in maternal plasma osmolality can increase amniotic fluid osmolality. Amniotic fluid is primarily derived from fetal urine production, and arginine vasopressin infusion can affect both fetal urine production and amniotic fluid osmolality. To assess the effect of short-term changes in maternal osmolality on fetal arginine vasopressin secretion and renal function, six ewes of 126 +/- 1 days' gestation received intravenous infusions of 20% mannitol (500 ml/10 min). In response to mannitol infusion, both maternal and fetal plasma osmolality increased significantly (302 +/- 3 to 326 +/- 2 and 300 +/- 1 to 309 +/- 2 mosm, respectively). Increased fetal plasma and urine arginine vasopressin concentrations were associated with significant increases in fetal urine osmolality (146 +/- 12 to 262 +/- 30 mosm) and sodium concentration (35.8 +/- 2.8 to 76.5 +/- 20 mu Eq/ml), but fetal urine production rates did not change (0.68 +/- 0.11 to 0.62 +/- 0.15 ml/min). These conclusions were reached: Acute increases in maternal osmolality can affect fetal arginine vasopressin secretion; arginine vasopressin-induced increases in fetal urine osmolality may contribute to increased amniotic fluid osmolality in response to maternal hyperosmolality.     

Drug accumulation in lung fluid of the fetal lamb after maternal or fetal administration

The pharmacokinetic characteristics of the antiemetic drug metoclopramide and the antihistamine diphenhydramine have been determined in a chronically catheterized pregnant sheep preparation. Metoclopramide and diphenhydramine were administered by separate maternal and fetal intravenous infusions to a steady state as well as by maternal intravenous bolus dosing. Drug concentrations in the maternal and fetal plasma and the amniotic and tracheal fluids were measured by means of capillary gas-liquid chromatographic assay techniques. Both metoclopramide and diphenhydramine were excreted into tracheal fluid in substantial quantities. Tracheal metoclopramide concentrations were found to exceed fetal plasma levels by about fifteen-fold while diphenhydramine attained maximal excretion in tracheal fluid of about five times that seen in fetal plasma. Drug levels were observed to accumulate slowly in amniotic fluid and eventually to exceed tracheal concentrations. The markedly elevated concentrations of these drugs in fetal lung fluid suggests that the fetal lung may be an important route of drug distribution, elimination, and excretion.     

Transplacental, amniotic, urinary, and fetal fluid dynamics during very-large-volume fetal intravenous infusions

With rapid intravenous infusion of very large volumes of isotonic saline solutions into the fetus, the fluid could stay within the fetal body, thereby creating hydrops fetalis, be transferred into the amniotic fluid through the fetal kidneys, thereby creating polyhydramnios, or be transferred across the placenta into the maternal circulation. This study was designed to explore these possibilities. After a 1-hour control period, 10 near-term chronically catheterized ovine fetuses were infused intravenously with 4 L (greater than 100% of fetal weight) of either isotonic saline solution or lactated Ringer's solution over 4 hours. Fetal arterial pressure was significantly elevated by 7 mm Hg throughout the infusion (p less than 0.00001). Venous pressure underwent a transient rise (4.8 mm Hg) at 20 minutes of infusion and remained elevated (2.7 mm Hg) during the rest of the infusion (p less than 0.00001). Fetal urine flow increased by an average of 5.7 +/- 0.4 ml/min throughout the infusion (p less than 0.00001) and accounted for 34.1% +/- 2.6% of the infused volume. Estimated fetal extracellular fluid volume increased by 17.7% +/- 1.8% of the infused volume. Because fetal fluid retention, urine flow, and amniotic fluid volume changes accounted for only half of the infused fluid, the remainder of the infused volume must have crossed the placenta and entered the maternal circulation. Given the above changes in vascular pressures, this requires a filtration coefficient of the placenta 50 to 100 times the previously reported values. Thus we conclude that relatively small changes in fetal vascular pressures dramatically alter the filtration capacity of the ovine placenta and transplacental volume flow.     

Plasma endothelin-1 and atrial natriuretic peptide levels during prolonged (24-h) non-acidemic hypoxemia in fetal goats.

OBJECTIVE: The purpose of this study was to investigate the effects of prolonged (24-h) non-acidemic hypoxemia on plasma endothelin-1 and atrial natriuretic peptide (ANP) in fetal goats. METHODS: During continuous infusion of nitrogen into the maternal trachea, fetal plasma endothelin-1 and ANP levels were measured in nine chronically instrumented goat fetuses at 117-129 days' gestation. Endothelin-1 and ANP were measured by radioimmunoassay. RESULTS: Fetal arterial pO(2) decreased significantly from 23.1 +/- 1.0 mmHg (control) to 15.2 +/- 0.9 mmHg during the first 2 h of hypoxemia and to 15.7 +/- 1.1 mmHg at the end of the experimental period of hypoxemia. The plasma endothelin-1 concentration increased from 10.6 +/- 1.9 pg/ml to 20.4 +/- 4.3 pg/ml (p < 0.05) during the first 2 h and was 19.7 +/- 2.4 pg/ml (p < 0.01) at the end of the experimental period. The plasma ANP concentration also increased, from 20.3 +/- 5.5 pg/ml to 23.0 +/- 4.7 pg/ml in the first 2 h and then to 58.0 +/- 8.8 pg/ml (p < 0.05) at the end of the experimental period. There was a significant negative correlation between fetal plasma endothelin-1 and pO(2), but no significant correlation was found between fetal plasma ANP and pO(2). CONCLUSIONS: Prolonged non-acidemic hypoxemia induces a continuous increase in fetal plasma endothelin-1 and ANP levels. Fetal plasma ANP increases time-dependently but endothelin-1 remains constant during hypoxemia.     

Atrial natriuretic factor maternal and fetal concentrations in severe preeclampsia

There is a reduction in intravascular volume in patients with preeclampsia. Since the secretion of atrial natriuretic factor by human atrial myocytes is stimulated by increased intraatrial pressure or atrial distention, we sought to determine whether circulating maternal plasma atrial natriuretic factor concentrations were lower in patients with preeclampsia compared to normal pregnant women. The level of alpha-human atrial natriuretic factor was measured by a specific radioimmunoassay. Maternal venous concentrations of a alpha-human atrial natriuretic factor were higher in patients with severe preeclampsia (116.12 +/- 13.37 pg/ml) than in normal pregnant women (80.30 +/- 4.02 pg/ml). Umbilical artery alpha-human atrial natriuretic factor concentrations were higher in fetuses born to patients with severe preeclampsia (197.68 +/- 29.10 pg/ml) than normal control subjects (118.00 +/- 12.52 pg/ml). Umbilical artery alpha-human atrial natriuretic factor concentrations were higher than umbilical or maternal venous concentrations. In cases of severe preeclampsia, despite the presumed volume changes, maternal atrial natriuretic factor concentrations are higher than in normal pregnant women. The fetus appears to produce its own atrial natriuretic factor. Umbilical artery atrial natriuretic factor concentrations in fetuses born to preeclamptic mothers are higher than those seen in normal control subjects.     

Cortisol infusion blocks adrenocorticotropic hormone but not vasopressin responses to hypotension in fetal lambs

In eight experiments in which a paired crossover design was used, we studied the ability of physiologic levels of cortisol to block adrenocorticotropic hormone (ACTH) and vasopressin responses to hypotension in fetal lambs. On different days, each fetus received a 4-hour infusion of cortisol or ethanol-saline solution vehicle, and then hypotension was induced with nitroprusside. Mean levels of ACTH before manipulation were 20 +/- 10 pg/ml and 18 +/- pg/ml in the saline solution- and cortisol-treated animals, respectively. Mean values of ACTH increased significantly to 70, 88, and 127 pg/ml at 2.5, 5, and 10 minutes of hypotension after pretreatment with saline solution. Cortisol pretreatment abolished the fetal ACTH response to hypotension. Mean levels of vasopressin during the control period were similar in the two groups of animals (5.7 +/- 1.5 pg/ml versus 5.9 +/- 1.3 pg/ml) and rose to comparable levels (69.4 +/- 15.6 pg/ml versus 65.2 +/- 7.7 pg/ml) during hypotension. Thus, increases in plasma cortisol levels within a physiologic range can suppress hypotension-induced ACTH but not vasopressin release in the fetus.     

Fetal blood volume, urine flow, swallowing, and amniotic fluid volume responses to long-term intravascular infusions of saline

The purpose of this study was to determine the effects of a long-term infusion into the fetal circulation on fetal and amniotic fluid dynamics. In 10 chronically catheterized fetal sheep averaging 130 +/- 1 (SE) days' gestation, a balanced, isotonic electrolyte solution (Isolyte S) was infused continuously for 5 days into a fetal vein at a rate of 0, 1, 2, 4, and 0 L/day, respectively. During the infusion, fetal blood volume increased by a maximum of 6.4 +/- 2.0% (p less than 0.001), and the daily swallowing of amniotic fluid doubled (p less than 0.001). Fetal urine flow increased (p less than 0.0001) above preinfusion rates by a volume equal to the infusion rate plus the increase in swallowing, whereas renal excretion of sodium and chloride increased by the amount infused. The increase in the plasma concentration of atrial natriuretic factor (p less than 0.0001) and the decrease in arginine vasopressin (p less than 0.05) were not linearly related to urine flow changes. Amniotic fluid volume increased (p less than 0.0001) by 20% of the infused volume. All values returned to normal on day 5 except amniotic fluid volume, which remained elevated. Estimated allantoic fluid volume at the end of day 5 was 800 ml above normal. Thus it appears that on a long-term basis, the ovine fetus eliminates infused water and electrolytes through its kidneys rather than across the placenta. Although all of the infused volume left the fetus through its kidneys, only 30% of the infused volume remained in the amniotic and allantoic fluid compartments, suggesting transfer to the mother by unknown mechanisms.     

Epinephrine inhibits tracheal occlusion induced lung growth in fetal sheep

OBJECTIVE: Although the mechanisms responsible for lung growth following tracheal occlusion (TO) are not fully understood, lung fluid accumulation is a requirement for growth to occur. It is known that betamimetics such as epinephrine (Epi), terbutaline, and ritodrine inhibit fetal lung fluid production late in gestation. We hypothesized that continuous infusion of Epi would have a detrimental effect on lung growth following TO in the fetal sheep model. METHODS: Twenty fetal lambs were divided into four groups. Group 1: no TO without Epi (n = 4); group 2: TO without Epi (n = 4); group 3: no TO with Epi (n = 5), and group 4: TO with Epi (n = 7). TO was performed on days 130-134 of gestation (full term = 145 days). In groups 3 and 4, Epi was infused into the fetus at a rate of 2 microg/min using a miniosmotic pump implanted subcutaneously at the time of TO. The fetuses were sacrificed after 4 days, and lung volume (LV, ml/kg), drained lung fluid (LF, ml/kg), wet lung weight/body weight ratio (LW/BW, %), whole right-lung dry weight per body weight ratio (dRLW/BW, g/kg), volume density of lung parenchyma (v(Vp)), and right-lung DNA and protein contents were compared among the four groups by one-way Anova. RESULTS: LW/BW and dRLW/BW of group 4 (3.91 +/- 0.52 and 2.10 +/- 0.28, mean +/- SD) were significantly lower than those of group 2 (5.18 +/- 0.57 and 2.67 +/- 0.15) and were not statistically significantly different from those of group 1 or 3. LV, LF, V(Vp), and DNA and protein contents all showed a similar trend. CONCLUSIONS: Continuous infusion of Epi to the fetus results in less fluid accumulation within the TO lungs and abolishes significant lung growth after TO in the late-gestation fetal lamb. Drugs affecting lung fluid secretion may have a major impact on TO-induced lung growth.     

Propranolol inhibits the maturational effect of adrenocorticotropin in the fetal sheep lung

We reported previously that metyrapone inhibited the maturational effect of adrenocorticotropin in the fetal sheep lung, even in the presence of exogenous glucocorticoids. To examine the role of beta-adrenergic input in this response we examined lung maturation in fetal sheep treated for 100 hours in vivo with adrenocorticotropin (66 ng/min for 15 minutes every 2 hours, n = 5); adrenocorticotropin plus propranolol (40 micrograms/min, n = 4), or saline solution (n = 8). Pulmonary maturation was assessed by pressure-volume curves, phospholipid content, and morphologic features. The basal cortisol level rose from less than 5 to 32.0 +/- 12.1 and 83.5 +/- 8.0 ng/ml in the adrenocorticotropin and adrenocorticotropin plus propranolol groups, respectively. The adrenal:body weight ratio (X 10(-4)) rose from 1.43 +/- 0.12 in the saline solution group to 2.90 +/- 0.16 and 2.51 +/- 0.14 in the adrenocorticotropin and adrenocorticotropin plus propranolol groups, respectively. Lung distensibility (milliliters of air per gram of lung) rose from 1.10 +/- 0.14 to 1.90 +/- 0.20 in the adrenocorticotropin group but was unchanged (0.98 +/- 0.24) in the adrenocorticotropin plus propranolol group. Phosphatidylcholine (milligrams per gram of lung) in the lung lavage rose from 0.07 +/- 0.02 to 0.23 +/- 0.11 in the adrenocorticotropin group but was not significantly changed (0.12 +/- 0.06) in the adrenocorticotropin plus propranolol group. We conclude that propranolol inhibits the maturational effects of adrenocorticotropin on the fetal lung, which implies that the mechanism of pulmonary maturation is not solely dependent on endogenous cortisol and must be mediated, at least in part, through adrenergic responses.     

The increase in fetal hemoglobin synthesis in the fetal lamb during hyperglycemic hypoxemia

To determine whether fetal hypoxemia induced by hyperglycemia has any effect on the proportions of fetal and adult hemoglobin synthesized during fetal development, hemoglobin synthesis was determined after a period of hyperglycemic hypoxemia in the fetal lamb. These experiments were carried out at a time in gestation during the switch from fetal to adult hemoglobin. Twelve catheterized fetal sheep were included in this study. Seven were made hyperglycemic by glucose infusions during 5 days (group I) and five were control animals (group II) that received saline solution infusions (0.45 gm/dl). In group I, glycemia increased from 14.7 +/- 5.0 to 54.6 +/- 16.4 mg/dl (p less than 0.001), whereas oxygen content decreased from 8.5 +/- 1.7 to 6.4 +/- 2.2 ml/dl (p less than 0.01). Red blood cells obtained before and after 5 days of glucose or saline solution infusions were incubated in an amino acid mixture containing 14C-leucine. The hemoglobins were then subjected to polypeptide chain elution with carboxymethyl cellulose chromatography. The amount of fetal hemoglobin synthesized was determined by the ratio of radioactive gamma-chain to total of radioactive non-alpha-chains. The data demonstrated that the hyperglycemic fetus synthesizes more fetal hemoglobin than expected for the period of fetal development (78.0% +/- 10.9% versus 59.8% +/- 11.3%, p less than 0.02).     

Ovine fetal breathing and swallowing activity in response to plasma glucose changes.

Fetal swallowing activity generally occurs simultaneously with fetal breathing movements (FBM) in sheep. The present study investigated the FBM and swallowing responses to altered fetal plasma glucose. Fetal lambs were chronically prepared with laryngeal, esophageal and diaphragm electromyogram (EMG) wires, an esophageal flow probe and vascular catheters. Beginning at 138 +/- 1 day, FBM and swallowing were monitored during control periods and in response to intravenous glucose infusions (14 mg/kg/min for 120 min) to fetuses of fed and fasted ewes. Glucose infusions to fetuses of fed ewes resulted in significant increases in fetal plasma glucose (21.2 +/- 0.7 to 40.5 +/- 1.9 mg/dl) and time breathing (46.2 +/- 6.3 to 60.0 +/- 9.5 min/2 h). In response to maternal fasting, fetal glucose levels (13.4 +/- 1.0 mg/dl) and time breathing (23.0 +/- 7.2 min/2 h) decreased significantly. Glucose infusion to fetuses of fasted ewes resulted in significant increases in time breathing (50.3 +/- 13.4 min/2 h) and diaphragmatic EMG activity (1,295 +/- 654 to 3,012 +/- 1,182 spikes/2 h). There was no change from basal levels of fetal EMG swallows (83.2 +/- 4.3 swallows/2 h) or esophageal flow (40.8 +/- 7.9 ml/2 h) in response to maternal fasting or fetal glucose infusions.     

Ovine fetal cardiorespiratory response to nicardipine

Nicardipine, a calcium antagonist associated with decreased uterine blood flow in near-term pregnant rabbits and fetal asphyxia after maternal administration in the rhesus monkey and sheep, was infused directly to the fetus in six chronically prepared pregnant ewes at 128 days' gestation. Changes in fetal mean arterial and diastolic blood pressure levels at 2 and 30 minutes after bolus injection of 50 micrograms were minimal; by 60 minutes these values had returned to preinfusion levels. No significant changes were observed after infusion of 100 micrograms of nicardipine. Fetal heart rate, fetal arterial blood gas values, and maternal cardiovascular variables did not change at either dose. Fetal plasma concentrations of nicardipine were 78 +/- 28 ng/ml and 114 +/- 48 ng/ml at 30 minutes after infusion of 50 micrograms and 100 micrograms, respectively, well within the range previously reported to be associated with fetal asphyxia. These data suggest that the previously reported fetal acidosis from maternal infusion of nicardipine may be primarily due to a decrease in maternal uterine blood flow rather than a direct fetal effect of the drug.     

Detection of C-type natriuretic peptide in fetal circulation

C-type natriuretic peptide (CNP) belongs to the natriuretic peptide family that plays an important role in the control of blood pressure, renal function and volume homeostasis. In contrast to the atrial natriuretic peptide and brain natriuretic peptide, CNP acts in an autocrine/paracrine fashion and is considered to be the endothelial component of the natriuretic peptide system. CNP has a high expression and tissue-specific regulation in reproductive organs. Using a radio-immunoassy for CNP-22 we measured for the first time CNP in fetal blood. Samples were taken by cordocentesis in a group of fetuses with rhesus isoimmunisation (10.74 +/- 2.81 pg/ml), fetuses with rhesus isoimmunisation after intravascular transfusion (10.03 +/- 4.01 pg/ml) and a group with structural anomalies (12.9 +/- 5.67 pg/ml). A group of healthy fetuses was used as controls (11.64 +/- 4.32 pg/ml). In contrast to ANP, the fetal CNP-plasma concentrations remain stable in the investigated fetal diseases and after volume load during intravascular transfusion. Moreover, fetal CNP-plasma levels are higher than previously measured maternal concentrations in normal pregnancies. Therefore, the fetus expresses CNP independently of the maternal circulation.     

Plasma levels of atrial natriuretic peptide during normal pregnancy and in pregnancy complicated by hypertension

To clarify a possible role for atrial natriuretic peptide in the pathophysiology of pregnancy complicated by hypertension, we studied plasma levels of atrial natriuretic peptide in 176 pregnant women with or without hypertension. Plasma atrial natriuretic peptide levels in normal pregnant women showed a gradual increase as pregnancy advanced, but the mean (+/- SD) concentrations in women in each trimester (34.8 +/- 14.7 pg/ml in the first trimester, n = 35; 38.7 +/- 12.2 pg/ml in the second trimester, n = 34; and 43.1 +/- 20.0 pg/ml in the third trimester, n = 71) did not differ statistically from the mean plasma atrial natriuretic peptide level in nonpregnant women (38.2 +/- 13.6 pg/ml, n = 44). In contrast, plasma atrial natriuretic peptide levels were elevated in 9 of the 12 women who had hypertension. The mean plasma atrial natriuretic peptide concentration in these patients (162 +/- 95.2 pg/ml) was significantly (p less than 0.01) higher than in normal pregnant women and in nonpregnant controls. On the other hand, 11 pregnant women with proteinuria or edema but without hypertension had normal plasma atrial natriuretic peptide levels. These results suggest that plasma atrial natriuretic peptide levels are normal in women during uncomplicated pregnancy, while the levels are elevated in pregnancy complicated by hypertension. Increased atrial natriuretic peptide secretion in the latter condition may reflect a mechanism of compensation that operates in response to water and sodium retention.     

Discordant accelerated pulmonary maturation after adrenocorticotropic hormone-induced labor in twin sheep fetuses

To examine the role of parturition on lung maturation in sheep, we studied parameters of lung development in singleton fetuses treated with pulsatile adrenocorticotropic hormone or saline solution from day 127 or twin pregnancies in which one fetus only received pulsatile adrenocorticotropic hormone from day 127 until labor occurred. These parameters were compared with those of term fetuses (145 days). Pulsatile adrenocorticotropic hormone provoked labor in a mean (+/- SEM) of 102.6 +/- 6.6 and 181.0 +/- 18.0 hours in single and twin pregnancies, respectively. Adrenal/body weight ratios increased similarly in adrenocorticotropic hormone-treated single and twin fetuses at delivery, and basal cortisol levels were two- to threefold higher prepartum in adrenocorticotropic hormone-treated fetuses. Little change in plasma cortisol levels occurred in singletons treated with saline solution or in twins not infused with adrenocorticotropic hormone. The lung weight/body weight was not altered in any group. Lung distensibility and stability were doubled to term values in fetuses treated with pulsatile adrenocorticotropic hormone compared with controls and untreated twins. Mean lavage phosphatidylcholine levels rose from 0.07 to 0.11 mg/gm in saline solution-treated or untreated fetuses to 0.20 to 0.23 mg/gm in pulsatile adrenocorticotropic hormone-treated singletons or twins, compared with 0.63 mg/gm at term. Phosphatidylcholine production increased from 0.51 dpm/gm/hr in saline solution-treated fetuses to 0.73 and 0.89 dpm/gm/hr in the single and twin pulsatile adrenocorticotropic hormone-infused fetuses, respectively; phosphatidylcholine production was 0.62 dpm/gm/hr in the noninfused twin. Lungs of twins treated with pulsatile adrenocorticotropic hormone were morphologically more mature than those of untreated twins. We conclude that fetal endocrine responses to exogenous adrenocorticotropic hormone, rather than the stimuli associated with labor per se, are responsible for lung maturation in the fetal sheep.