Ronald A. Chez

MATERNAL-FETAL TRANSFER OF MELATONIN IN THE NON-HUMAN PRIMATE

Summary: Melatonin was detected in the circulation of the near-term rhesus monkey (Macaca mulatto) and baboon (Papio papio) fetus. We determined whether the source could be the mother by studying placental transfer of melatonin in the rhesus monkey. When [3H]melatonin was administered i.v. to the mother it promptly appeared in the fetal circulation; the rates of disappearance of [3H]melatonin in the maternal and fetal circulations were parallel. The rapid decrease in circulating [3H]melatonin was associated with a rapid accumulation of [3H]melatonin-metabolites in the maternal and fetal circulations. Although the pattern of appearance of metabolites was similar in both circulations, relatively less [3H]melatonin-metabolites appeared in the fetal circulation.Acute changes in total maternal plasma melatonin, experimentally produced by giving a 20 min infusion of melatonin, were rapidly reflected in the fetus. This suggests that a daily rhythm in maternal melatonin would generate a similar rhythm in the fetus.The fetal monkey pineal was found to have the two enzymes necessary for the conversion of serotonin to melatonin. It is, however, not known whether fetal melatonin synthesis is rhythmic or the extent to which it could contribute to circulating melatonin levels at this or earlier stages of gestation.Speculation: Prompt placental transfer of melatonin could result in a maternally generated dally melatonin rhythm in the fetus. This communication may introduce the developing fetus to a 24-hr chemical periodicity and coordinate certain fetal functions with the prevailing environmental lighting cycles.

Maternal betamethasone and fetal growth and development in the monkey.

Bethamethasone was administered to pregnant rhesus monkeys of 134 to 150 days gestation. At operative delivery, umbilical venous plasma cortisol concentrations were significantly lower in the treated group than in the control group, indicating that the agent crossed the placenta. In the treated group, accelerated differentiation was present in several fetal organs including lung, liver, kidney, and adrenal gland. Brain histologic changes suggestive of neuronal injury were found in some instances. There were no differences in the weights of these fetal organs except for liver. It was markedly increased in steroid-treated fetuses and this was accompanied by a fourfold rise in total hepatic glycogen content. These observations suggest that in the subhuman fetal primate, the differentiation of fetal organs in addition to lung is enhanced by short-term corticosteroid treatment while growth is not affected.

Effect of ritodrine infusion on uterine and umbilical blood flow in pregnant sheep.

The effect of ritodrine upon uterine artery blood flow (UtBF) and umbilical vein blood flow (UmBF) was investigated in near-term chronic sheep preparations. During intravenous ritodrine infusions to the ewe in sequential dose rates from 100 to 800 mug per minute, UtBF fell progressively to 43 per cent below control levels and mean maternal arterial pressure (MMAP) declined 20 per cent. During constant infusions of 100, 400, or 800 mug per minute of ritodrine to the ewe for 120 minutes,, UtBF decreased 10, 37, and 31 per cent, respectively, and MMAP decreased 6, 20 and 25 per cent respectively. Dose-related maternal tachycardia and hyperglycemia occurred. There were no significant changes in UmBF, mean fetal arterial pressure, or fetal heart rate. During all infusions, maternal and fetal arterial pH, PCO2, and PO2 remained within normal physiologic limits. Simultaneous infusion of ritodrine (400 mug per minute) and propranolol (100 mug per minute) blocked the maternal tachycardia, but decreases in UtBF, MMAP, and UmBF were observed. Ritodrine infusions to the fetus (25 mug per minute) resulted in fetal tachycardia and a variable increase in UmBF.

Effects of indomethacin on sheep uteroplacental circulations and sensitivity to angiotensin II

Indomethacin, a prostaglandin synthetase inhibitor, injected simultaneously into the abdominal aorta of the ewe and her fetus at 125 days gestation causes vasoconstriction of both the uterine and umbilical circulations. There is no change in these hemodynamic effects of indomethacin in the presence of phenoxybenzamine, an alpha-adrenergic antagonist. When the indomethacin experiment is repeated seven to 10 days later, a uterine vasoconstriction 10 per cent greater than that found earlier occurs, but there is no change from control umbilical vascular resistance. The mean maternal arterial pressure response (20 mm. Hg) to angiotensin II with and without indomethacin also was examined at the same time in gestation. Indomethacin infusion to the ewe significantly reduces the pressor dose (nanograms per kilogram per minute) by 42 +/- 4 per cent. Thus, in pregnant sheep in the third trimester, endogenous prostaglandins appear to be: (1) partial determinants of basal blood flow in both the uterine and umbilical circulations and (2) modulators of the vasoconstrictive effects of angiotensin II in the ewe.

Effects of prolonged infusion of β-adrenergic agonists on uterine and umbilical blood flow in pregnant sheep

We have extended our evaluation of the effects of three beta-adrenergic agents in near-term pregnant sheep to include a period of infusion three times longer than previously studied. This extension has provided the following information: (1) Initial depression of uterine blood flow and mean arterial pressure associated with administration of ritodrine or salbutamol abate with time despite continued drug infusion; (2) the uterine hyperemia associated with salbutamol and fenoterol are drug-related rather than postinfusion-related phenomena; (3) increased uterine vascular resistance is found with ritodrine, and decreased uterine vascular resistance occurs with salbutamol and fenoterol.

Glycogen Regulation in Isolated Perfused Near Term Monkey Liver

Extract: Glycogen metabolism was studied in the isolated perfused liver of the monkey conceptus at 90% of gestation using an in situ recirculating perfusion system. Net uptake of glucose and galactose and the activities of the enzymes, glycogen synthetase and phosphorylase, were studied in response to varied perfusate composition. Synthetase activity was expressed as %1, the percentage of total synthetase activity in the active form. Perfusate glucose concentrations as high as 700 mg/100 ml did not lead to net glucose uptake or to an increase in the baseline %I synthetase (4 ± 1, mean ± SEM). In the presence of 300 mg/100 ml glucose, insulin at 10-7 M increased %I to 8 ± 2, and galactose > 75 mg/100 ml increased %I to 8 ± 1. The combination of galactose, glucose, and insulin increased %I to 40 ± 5. With this latter combination, synthetase activity was proportional to perfusale glucose concentration above 100 mg/100 ml. Phosphorylase activity was diminished by either galactose or insulin, and phosphorylase activity was lowest in the group receiving galactose, glucose, and insulin. Galactose was taken up by all livers, but net glucose uptake was not observed under any condition; net hexose uptake was observed in perfusions with galactose. Glycogen levels did not vary significantly with varied perfusate composition during the 30-min perfusion periods.Speculation: We speculate that galactose may be uniquely important for neonatal liver glycogen synthesis, and that its action is mediated through reciprocal changes in the activities of the enzymes, glycogen synthetase and phosphorylase. If liver glycogen is important for acute neonatal glucose homeostasis, then galactose may also be essential for maintaining circulating glucose concentration by ensuring glycogen synthesis during feeding.

Comparison of phospholipid indicators of fetal lung maturity in the amniotic fluid of the monkey (Macaca mulatta) and baboon (Papio papio)

Abstract The pregnancies of two subhuman primate species, the monkey (Macaca mulatta) and the baboon ( Papio papio ), were examined to determine if either is a model for human fetal lung development as reflected in amniotic fluid studies. From the data, we suggest that the pregnant rhesus monkey is a model for the study of human lung development. The biochemical pathways for surfactant are the same; the concentrations of lecithin in amniotic fluid correspond closely; there is a parallel rise in L/S ratios which correspond, and the lecithin acyl ester structures and their changes during gestation are very similar. The presence of chronic stress is associated with acceleration of maturation of the surfactant systems of the lung. Although there are some analogies in baboon pregnancy, important differences in lecithin pathway timing and lecithin acyl ester structures make extrapolation to the human subject less tenable. Ligation of the monkey fetal trachea in the second trimester results in oligohydramnios without apparent lung distention. At delivery, the normal changes with age in surfactant biochemistry are not found in the amniotic fluid but are present in lung-bronchial tree washes.

Effects of salbutamol and isoxsuprine on uterine and umbilical blood flow in pregnant sheep

The effects of salbutamol and isoxsuprine upon uterine artery blood flow (UtBF) and umbilical vein blood flow (UmBF) were investigated in near-term, nonlaboring chronic sheep preparations. During both intravenous salbutamol and isoxsuprine infusions to the ewe, UtBF and mean maternal arterial pressure decreased significantly. Also, dose-related maternal tachycardia, hyperglycemia, and relative acidemia occurred. There were no significant changes in UmBF, mean fetal arterial pressure, or fetal heart rate (FHR) during salbutamol infusions, but UmBF and FHR increased during isoxsuprine infusions. During the 120 minute postinfusion recovery period, UtBF rose significantly after the salbutamol infusions but not after the isoxsupine infusions. The effects and structure-activity relationship of these two drugs are comparable to those of ritodrine and fenoterol, two other beta-adrenergic agonists.

Lung Lecithin Biosynthesis in the Nonhuman Primate Fetus: Determination of the Primary Pathway in vivo

The two pathways for de novo lecithin (phosphatidylcholine) biosynthesis, choline incorporation (1) and phosphatidylethanolamine methylation (II), were examined simultaneously in lung and other tissues of Rhesus monkey fetuses. Cannulation of interplacental fetal vessels permitted studies on the intrauterine fetus without disruption of fetal-placental-maternal-amniotic fluid anatomic integrity. In contrast to observations with indirect techniques in the same species, direct measurement of the incorporation of isotopic precursors (3H-choline and 14C-ethanolamine) into lecithin indicated that pathway I predominates by 100-fold over PE methylation in pulmonary lecithin synthesis. Fetal liver, brain, and kidney also showed 10--70-gold greater choline incorporation that methylation activity. Measurement of lung phosphatidylcholine production via the two pathways in acidemic fetuses (umbilical venous pH less than 7.20) demonstrated marked inhibition of pathway I, but not II. It is concluded that the choline pathway is the major mechanism of lung lecithin synthesis in fetal primates and that this pathway is pH sensitive in vivo.

Effect of α-Adrenergic Agonist and Antagonist Infusion on the Umbilical and Uterine Circulations of Pregnant Sheep

The effects of the alpha-adrenergic agonists, norepinephrine and methoxamine, and the alpha-antagonist, phenoxybenzamine, on umbilical and uterine blood flows, fetal and maternal heart rates, arterial and venous pressures were examined in near-term chronic sheep preparations. Norepinephrine injection or methoxamine infusion to either fetus or ewe resulted n a respective unilateral fetal or maternal pressur response associated with bradycardial. Uterine blood flow decreased significantly with alpha-agonist administration to either fetus or ewe. Umbilical blood flow did not change with either, but an increase in calculated umbilicalo vascular resistance did occur after fetal administrations of the alpha-agonist. Thus, both the uterine and umbilical vascular beds are responsive to alpha-agonism, but maternal uteroplacental perfusion appears to be more sensitive. alpha-Blockade in either fetus or mother produced no significant changes in umbilical or uterine blood flows or fetal or maternal perfusion pressure suggesting that basal alpha-adrenergic tone is unnecessary for normal maintenance of either fetal or maternal uteroplacental circulation.