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.     

Chronic in utero plasma hyperosmolality alters hypothalamic arginine vasopressin synthesis and pituitary arginine vasopressin content in newborn lambs

OBJECTIVE: Arginine vasopressin is synthesized in the hypothalamus and secreted by the posterior pituitary gland in response to plasma hypertonicity. Previous studies suggest that in utero and neonatal exposure of rat pups to prolonged alterations of plasma osmolality may permanently alter (imprint) arginine vasopressin synthesis and secretion, thus adult responses to osmotic challenges. Little is known, however, of the potential for imprinting of neuroendocrinologic systems in precocial species. In view of the frequent occurrence of altered maternal and fetal plasma tonicity (eg, maternal dehydration, hyperemesis), we sought to determine the effect of prolonged maternal hypertonicity on arginine vasopressin gene expression and pituitary gland content in neonatal sheep. STUDY DESIGN: Pregnant ewes at 119 +/- 3 days of gestation were water restricted to achieve and maintain plasma hypertonicity (10-20 mOsm/kg above baseline level) until normal term delivery. Newborns were provided maternal nursing ad libitum. Within 24 hours after birth, study neonatal lambs (n = 6) and age-matched control neonatal lambs (n = 5) were killed, and the pituitary gland and hypothalamus were removed and frozen immediately. Pituitary arginine vasopressin content was determined by radioimmunoassay, and hypothalamic arginine vasopressin gene expression was quantified with Northern blot. Differences in pituitary arginine vasopressin content and hypothalamic arginine vasopressin gene expression (arginine vasopressin/ beta-actin ratio) between study and control newborn lambs were analyzed by unpaired t test. RESULTS: In response to maternal water restriction, maternal plasma osmolality increased from 307 +/- 0.9 mOsm/kg to 325 +/- 1.3 mOsm/kg, and plasma sodium increased from 147 +/- 1.3 mEq/L to 156 +/- 1.2 mEq/L. The maternal plasma hyperosmolality and hypernatremia were maintained until normal term delivery. At the time of death, study (in utero dehydrated) lambs had higher plasma sodium (150 +/- 0.4 mEq/L vs 146.5 +/- 1.5 mEq/L; P <.05) and chloride (112.8 +/- 1.0 mEq/L vs 108.5 +/- 1.5 mEq/L; P <.05) levels, and lower potassium (4.5 +/- 0.2 mEq/L vs 5.5 +/- 0.3 mEq/L; P <.05) concentrations than control newborn lambs. Both newborn groups had similar plasma osmolality (320.0 +/- 1.3 mOsm/kg vs 318.0 +/- 3.4 mOsm/kg). Total pituitary arginine vasopressin content was significantly greater in the study than in the control newborn lambs (8.3 +/- 2.8 microg vs 1.6 +/- 1.3 microg; P <.05). Conversely, hypothalamic arginine vasopressin messenger RNA levels were lower in the study newborn lambs than in the control newborn lambs (arginine vasopressin/beta-actin ratio: 0.29 +/- 0.01 vs 0.68 +/- 0.15; P <.05). CONCLUSION: Despite the presence of plasma hypernatremia, prolonged elevation of fetal plasma tonicity increases newborn pituitary arginine vasopressin content yet decreases hypothalamic arginine vasopressin gene expression. The present study suggests that prolonged prenatal exposure to plasma hypertonicity may imprint the hypothalamic-pituitary arginine vasopressin regulatory system.     

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.     

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 absorption of intra-amniotic aldosterone: effects on urine composition.

OBJECTIVES: Amniotic fluid (AF) volume and composition are maintained by a balance of fetal fluid production and resorption. Ovine fetal resorption of peptide hormones (e.g., arginine vasopressin) from the amniotic cavity has been demonstrated, with resultant effects on fetal urine production. The present study was undertaken to determine whether intra-amniotically administered steroid hormones could be absorbed from the amniotic cavity into fetal plasma and whether intra-amniotic aldosterone administration would affect fetal renal sodium and potassium excretion. METHODS: Seven singleton fetuses (132 +/- 2 days) were prepared with bladder, vascular, and amniotic cavity catheters. After a 5-day recovery period, a bolus of aldosterone was injected into the amniotic cavity. Fetuses were monitored for an additional 24 hours during which time maternal, fetal, and AF samples were collected at timed intervals. RESULTS: After intra-amniotic aldosterone injection, AF aldosterone concentrations increased at 30 minutes and remained elevated for 4 hours after the aldosterone bolus. In response to increased AF aldosterone, fetal plasma aldosterone levels significantly increased by 30 minutes, peaked at 1 hour (17 +/- 4 to 758 +/- 160 pg/mL), and remained elevated for a minimum of 4 hours. Fetal urine sodium excretion significantly decreased and potassium excretion increased. Maternal plasma aldosterone levels increased significantly (25 +/- 10 to 401 +/- 56 pg/mL) but to levels below fetal values. Amniotic fluid and fetal and maternal aldosterone concentrations and fetal urine sodium and potassium excretion returned toward basal levels by 24 hours. CONCLUSION: The steroid hormone aldosterone can be absorbed from the amniotic cavity into the fetal circulation and can alter fetal urine electrolyte excretion. These results suggest that the amniotic cavity is a potential route of in utero pharmacologic fetal therapy.     

Blunted response of maternal ovine placental lactogen levels to arginine stimulation after single umbilical artery ligation in pregnant sheep

Ovine placental lactogen levels in the maternal circulation are significantly reduced after single umbilical artery ligation in pregnant sheep. We report the ovine placental lactogen response to high-dose amino acid stimulation in four ewes with fetuses that underwent single umbilical artery ligation and six control ewes with fetuses that underwent sham operation. After maternal infusion with 50 gm of arginine in 350 ml of distilled water, mean ovine placental lactogen levels in ewes with fetuses that underwent single umbilical artery ligation increased by 170%, while mean levels in control ewes increased by 294%. Maternal infusions with hypertonic saline solution of osmolality and volume equal to those of the arginine solutions failed to increase maternal ovine placental lactogen levels. Fetal well-being, both during and after the maternal arginine infusions, was confirmed by unchanged fetal arterial blood gases and catecholamines. The ovine placental lactogen levels in the fetal circulation were not altered by maternal arginine infusion. These data suggest that the correlation between maternal ovine placental lactogen levels and functioning placental mass may be enhanced by arginine stimulation. The possible use of this provocation of placental lactogen levels as a test of placental function in clinical practice is discussed.     

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.     

Indomethacin-induced urinary flow rate reduction in the ovine fetus is associated with reduced free water clearance and elevated plasma arginine vasopressin levels.

OBJECTIVE: The purpose of our study was to explore the urinary responses of the ovine fetus to indomethacin levels comparable with those used therapeutically in the human fetus. STUDY DESIGN: After a 1-hour control period, chronically catheterized ovine fetuses between 125 and 139 days of gestation were given an intravenous bolus of indomethacin (0.05 mg/kg estimated fetal weight) followed by a 0.0025 mg/kg/min continuous infusion for 5 hours. The experimental group (n = 9) was compared with a vehicle-only infusion group (n = 10). RESULTS: There was a sustained 55.7% +/- 9.5% (mean +/- SEM) decrease in urinary output by 2 hours of indomethacin infusion (p < 0.00001, analysis of variance). Urinary osmolality, potassium, and chloride concentrations underwent sustained increases during the infusion period (p < 0.005). Free water clearance decreased by 67.5% +/- 12.0% (p < 0.001). Fetal arterial pressure increased only transiently (p < 0.05), and increases in venous pressure (p = 0.013) and heart rate (p < 0.0001) were sustained. Fetal plasma arginine vasopressin concentration increased during indomethacin infusion (p < 0.05) and was correlated with the fall in urinary flow rate and free water clearance (p = 0.002). During vehicle infusion no significant changes were observed in any of the variables. CONCLUSIONS: Our data indicate that the fetus undergoes antidiuresis when exposed to low levels of indomethacin and that the observed antidiuresis is mediated by a decrease in free water clearance. The reduction in free water clearance may be mediated by increases in plasma arginine vasopressin concentrations.     

Pharmacokinetics of betamethasone after maternal or fetal intramuscular administration

OBJECTIVE: The purpose of this study was to determine the pharmacokinetics of betamethasone in maternal and fetal circulations after maternal or fetal intramuscular administration. STUDY DESIGN: Ewes that bore single fetuses underwent surgery at approximately 96 days of pregnancy for the implantation of fetal and maternal vascular catheters. At approximately 103 days, five ewes were injected intramuscularly with betamethasone (0.5 mg/kg body weight) or five fetuses received ultrasound-guided intramuscular injections of betamethasone (0.5 mg/kg estimated fetal weight). Maternal and fetal blood samples were collected serially for the measurement of plasma betamethasone concentrations. RESULTS: Fetal injection caused higher peak fetal betamethasone concentrations (341.2+/-23.7 nmol/L) than maternal injection (37.6+/-3.7 nmol/L; P<.001) and greater cumulative betamethasone exposure. The half-life of betamethasone in the fetal circulation was shorter after fetal injection (1.1+/-0.3 hours) than after maternal injection (8.5+/-2.0 hours; P=.006). CONCLUSION: The duration of fetal and maternal exposure to betamethasone can be minimized by direct fetal intramuscular administration that, in sheep, affords lung maturation without adverse effects on fetal growth.     

Oxytocin in maternal and fetal blood.

Radioimmunoassayable plasma oxytocin (OT) has been measured in maternal and fetal blood. Simultaneous samples were obtained in maternal forearm venous blood and in umbilical venous and arterial blood in 29 patients at term delivery. In addition, maternal forearm venous blood samples were also obtained 10 minutes prior to delivery. Mean OT level in maternal plasma at delivery was 82 +/- 12 muU/ml, and at 10 minutes prior to delivery the mean OT level was 90 +/- 11 muU/ml. The umbilical arterial plasma OT showed 95 +/- 12 muU/ml and the umbilical vein plasma OT was 60 +/- 10 muU/ml. Oxytocin levels higher in maternal blood than in fetal blood were found with the following incidence: In 51% of samples there was more OT in maternal venous blood than in umbilical arterial blood, and in 84% of samples there was more OT in maternal blood than umbilical vein blood. During the postpartum period, the mean maternal plasma OT was 66 +/- 8 muU/ml for the first day, and 50 +/- 9 muU/ml and 54 +/- 9 muU/ml for the second and third days, respectively. This study indicates that both the fetus and the mother are active producers of oxytocin.     

Sex-determining region Y levels in maternal plasma: Evaluation in abnormal pregnancy

AIM: A number of studies for the measurement of cell-free fetal DNA in maternal blood have been reported; however, their clinical significance has remained unclear. We proposed to clarify the relationship between fetal DNA levels and obstetrical disorders. METHODS: One hundred and eighty-five cases of normal pregnancy, ranging from 8 to 40 weeks' gestation, and 70 cases of abnormal pregnancy were included. SRY levels in maternal plasma were quantified with a real-time quantitative polymerase chain reaction. RESULTS: Sex-determining region Y (SRY) levels and the number of patients with positive levels peaked at 33-36 weeks in normal pregnancy. The SRY levels in threatened abortion (11.6 +/- 4.8 copies/mL to 0 +/- 0, P < 0.05) and threatened preterm labor (44.6 +/- 16.1 copies/mL to 15.9 +/- 6.2, P < 0.01) were significantly higher than those of the normal group. In pre-eclamptic patients, SRY levels were markedly higher than those of the normal group (173.2 +/- 94.8 copies/mL to 22.4 +/- 8.9, P < 0.05). Patients with premature separation of the placenta (266.8 +/- 137.1 copies/mL to 4.9 +/- 3.7, P < 0.05) and placenta previa (167.7 +/- 32.4 copies/mL to 37.0 +/- 17.3, p <0.01) also showed elevated SRY levels. CONCLUSION: Sex-determining region Y levels in maternal plasma were elevated in patients with an abnormal pregnancy, particularly those with placental injury of damage. These results suggested that increased SRY levels are consistently caused by the leak of fetal components, and thus the measurement of SRY levels in maternal plasma is useful for the evaluation of placental injuries.     

Effect of maternal hyperketonemia in hyperglycemic pregnant ewes and their fetuses

The fetus of the pregnant diabetic woman is exposed to hyperglycemia frequently accompanied by ketoacidosis. Previous studies have demonstrated that beta-hydroxybutyrate, a major ketone body, crosses the ovine placenta in significant amounts, leading to significant reductions in fetal PaO2 and increased fetal heart rate. In the present study the pregnant ewe was used to evaluate the maternal and fetal cardiovascular and metabolic responses to hyperketonemia in the presence of hyperglycemia and to determine if the combined diabetic insults were more detrimental to the fetus than hyperketonemia alone. A glucose priming dose of 25 gm was administered in the maternal femoral vein followed by a continuous glucose infusion of 200 mg/min to achieve steady maternal plasma glucose levels of 180 mg/dl. Once glucose levels were stable, beta-hydroxybutyrate was infused for 2 hours at a rate of 0.39 mmol/100 ml of uterine blood flow into both left and right uterine arteries. Infusion of glucose alone did not significantly alter fetal cardiovascular and blood gas parameters but did increase the fetal glucose level from 17 +/- 4 to 58 +/- 8 mg/dl. The simultaneous infusion of beta-hydroxybutyrate and glucose produced significant decreases in fetal PaO2 and oxygen content as were reported for hyperketonemia alone and significant time-related increases in fetal lactate levels and fetal heart rate. These data suggest that hyperketonemia in the pregnant ewe leads to quantitatively similar changes in oxygenation in both normoglycemic and hyperglycemic fetuses. These observations may in part help explain the increased perinatal mortality in the pregnant woman with uncontrolled diabetes.     

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.     

Simulation of a probable biologic action of decidual prolactin on fetal membranes

As evidence continues to accumulate supporting a specific effect of prolactin on the permeability of reflected fetal membranes to tritiated water, no information on the role of decidual prolactin in this process is available. Simulation of in vivo events was conducted with the use of isolated membrane preparations of human amnion or chorioamnion with adherent decidua. In the presence of ovine prolactin in equal concentrations on both sides of human amnion, membrane permeability (cm X 10(-4) X sec-1) was reduced from 1.52 +/- 0.16 to 1.18 +/- 0.07 (mean +/- SEM) from the fetal to the maternal surface. Permeability in the opposite direction was significantly increased from 1.15 +/- 0.10 to 1.39 +/- 0.08. No osmotic effect of ovine prolactin was noted. With the use of chorioamnion with adherent decidua, permeability was significantly reduced from the maternal to the fetal surfaces only when ovine prolactin bathed the maternal surface. These in vitro results may suggest that the accumulation of decidual prolactin at the choriodecidual interface in vivo supports bulk water flow across fetal membrane from the amniotic to the maternal compartments.     

Evaluation of maternal fluid dynamics during tocolytic therapy with ritodrine hydrochloride and magnesium sulfate.

OBJECTIVE: The purpose of the study was to observe and compare the effects of ritodrine hydrochloride and magnesium sulfate on maternal fluid dynamics. STUDY DESIGN: Fourteen women in preterm labor were prospectively studied during tocolytic therapy with either ritodrine hydrochloride or magnesium sulfate. The cardiovascular and renal effects of a pretreatment crystalloid infusion were compared with those observed during tocolytic therapy. Profile analysis and repeated measures of variance were used to analyze the data. RESULTS: Ritodrine hydrochloride was associated with decreased colloid osmotic pressure, hematocrit, and serum proteins and increased maternal and fetal heart rates. Arginine vasopressin levels increased during the first 2 hours of therapy, then returned to baseline. Sodium excretion was reduced and there was marked fluid retention. Intravenous magnesium sulfate also resulted in a reduction of colloid osmotic pressure, but hematocrit, serum protein concentration, arginine vasopressin, maternal and fetal heart rates, and mean arterial pressure were minimally affected. Sodium excretion increased to a maximum at 6 to 8 hours of treatment, then returned to baseline. A positive fluid balance was also noted in magnesium sulfate-treated patients but to a lesser degree than with ritodrine. CONCLUSIONS: Sodium retention appears to be the primary cause of plasma volume expansion in ritodrine-treated patients, whereas volume expansion during magnesium sulfate therapy is probably related to intravenous overhydration. In the absence of risk factors for pulmonary capillary membrane injury, available evidence supports volume overload as the principal mechanism for pulmonary edema during tocolytic therapy.     

The role of arginine vasopressin in human labour: functional studies, fetal production and localisation of V1a receptor mRNA

Objective To investigate labour-associated changes in: 1. the myometrial contractile response to arginine vasopressin compared with oxytocin in vitro 2. fetal production of arginine vasopressin and 3. myometrial vasopressin  V_1a  receptor mRNA.
Design The contractile response to vasopressin (compared with oxytocin) was investigated in paired myometrial strips in vitro . Blood was taken from the umbilical artery and vein at delivery and arginine vasopressin measured by radio-immunoassay.  V_1a  receptor mRNA was determined by in situ hybridisation.
Results Myometrium was more sensitive to arginine vasopressin than oxytocin (   P <0.05 for frequency, amplitude and activity integral in paired strips  ) after, but not before labour. There was a marked umbilical arteriovenous difference in arginine vasopressin concentration at delivery suggesting fetal production which was not influenced by labour. Myometrial vasopressin  V_1a  receptor mRNA was not increased after the onset of labour.
Conclusions The human uterus is extremely sensitive to arginine vasopressin in vitro . Arginine vasopressin is produced by the fetus but fetal formation is not increased during labour.     

Vasopressin levels during pregnancy and labor

Baseline plasma vasopressin concentrations were measured in 10 healthy women during a normal menstrual cycle, 97 normal women during pregnancy and 43 pregnant women hospitalized during the third trimester because of pregnancy-induced hypertension (PIH). Plasma vasopressin levels were also measured in 44 normal pregnant women in early labor and in 30 parturients at delivery. The random plasma vasopressin concentrations did not vary significantly between the nonpregnant women during the follicular phase (2.3 +/- 0.2 microU/ml) and luteal phase (2.2 +/- 0.3 microU/ml) or during the third trimester in normal pregnant women (2.0 +/- 0.2 microU/ml) or those with PIH (2.0 +/- 0.1 microU/ml). There was a significant reduction (p less than 0.01) in plasma vasopressin levels in the pregnant women during the first trimester (1.5 +/- 0.1 microU/ml) and second trimester (1.5 +/- 0.1 microU/ml) as compared to levels in nonpregnant and pregnant women in the third trimester. The mean plasma vasopressin levels in the pregnant women complaining of nausea were similar to those in the pregnant women without nausea. Plasma vasopressin levels in women during labor did not increase significantly over third-trimester-pregnancy concentrations during the first stage of labor (1.9 +/- 0.1 microU/ml) or at delivery (1.8 +/- 0.1 microU/ml). These cross-sectional measurements of maternal plasma vasopressin levels do not support a role for vasopressin in the development of PIH or in the initiation or maintenance of labor.     

Vasopressin-induced bradycardia in fetal and adult sheep is not dependent on an increase in blood pressure

Other investigators have reported that intravenous infusion of synthetic arginine vasopressin into fetal lambs increases mean arterial pressure and decreases heart rate. To determine if the bradycardia produced by arginine vasopressin is a reflex response to the increase in blood pressure, we studied the effect of arginine vasopressin infusion on heart rate with and without blocking the increase in blood pressure. We performed 34 experiments in 12 chronically cannulated fetal lambs between 103 and 137 days' gestation. All animals had normal blood gas and pH values. Infusion of arginine vasopressin increased mean arterial pressure 10.1 +/- 1.1 mm Hg and decreased heart rate 50 +/- 8 bpm. Fetal heart rate decreased similarly when arginine vasopressin was infused and the hypertensive response was blocked with nitroprusside or a selective vasoconstrictor antagonist. [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid) 2-(O-methyl)tyrosine] arginine vasopressin. For comparison we also studied five adult nonpregnant ewes. Bradycardia was observed in the adults after infusion of arginine vasopressin alone and when the hypertensive response was blocked with the vasoconstrictor antagonist. We conclude that arginine vasopressin infusion causes a fall in heart rate independent of any increase in blood pressure in both the fetal lamb and the adult sheep.     

Asymmetric dimethylarginine,an endogenous inhibitor of nitric oxide synthase,in maternal and fetal circulation

Pronounced dilation of the maternal vasculature occurs during normal pregnancy. Likewise, low resistance characterizes the fetoplacental circulation. Nitric oxide released by endothelial cells is a potent vasodilator known to be a key modulator of both maternal and fetal vascular tone. However, the mechanisms underlying the maternal circulatory adaptations and the low resistance of the fetal circulation remain unknown. The aim of the present study was to compare levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in the maternal and fetal circulations.High performance liquid chromatography was used to measure asymmetric ADMA in the maternal and umbilical venous plasma.Plasma ADMA levels during the first trimester were 0.29 +/- 0.05, the third trimester before term 0.29 +/- 0.05, and at term 0.32 +/- 0.05 nmol/mL, which were significantly (P <.05) lower than the levels measured in nonpregnant women (0.41 +/- 0.06 nmol/mL). By contrast, ADMA levels in umbilical venous plasma averaged 1.02 +/- 0.18 nmol/mL, significantly (P <.005) higher than maternal levels. Unlike ADMA, levels of plasma L-arginine, the nitric oxide precursor, did not significantly differ among nonpregnant and pregnant women and the fetus.During pregnancy, maternal hemodynamics are modulated, at least in part, by a reduction in ADMA. Conversely, the low resistance to umbilical blood flow is maintained despite substantially higher fetal ADMA levels. Thus, the predominant mechanisms regulating the maternal and fetal circulation apparently differ.     

Human maternal and fetal plasma glyceryl trinitrate concentrations

OBJECTIVE: This study was undertaken to determine the maternal and fetal steady-state concentrations of glyceryl trinitrate (GTN) and its dinitrate metabolites during transdermal administration, at the time of fetal blood sampling for obstetric indications. STUDY DESIGN: Transdermal GTN (0.4 mg/h) was applied approximately 2 hours before investigative fetal blood sampling to maintain uterine quiescence. Serial maternal venous (MV) and a single fetal venous (FV) plasma samples were collected and assayed for GTN and its metabolites, 1,2- and 1,3-glyceryl dinitrate. RESULTS: The steady-state MV plasma concentration was 4.3+/-0.84 nmol/L (mean+/-SEM, n=7), and the dinitrate metabolites were detectable in the MV but not quantifiable. GTN was detectable in the FV (n=7) but was not quantifiable as the levels were less than the lower limit of sensitivity of the assay (<1 nmol/L). CONCLUSION: During transdermal GTN administration, the steady-state FV/MV concentration ratio is less than 0.23 at the time of fetal blood sampling.