Inhibition of the enzymes of glutathione metabolism by mercuric chloride in the rat kidney: reversal by selenium.

The treatment of rats with 10 mumoles/kg (s.c.) of mercuric chloride (Hg2+) caused time-dependent decreases in the activities of the enzymes of the glutathione (GSH) metabolism pathway in the kidney. Twenty-four hours after administration of Hg2+, the activities of gamma-glutamylcysteine synthetase and glutathione disulfide (GSSG)-reductase in the kidney were decreased by 50-60%, and the activities of the GSH catabolic enzymes, gamma-glutamyl transpeptidase and GSH-peroxidase, were decreased by 25-35%. In the liver, only the activity of GSSG-reductase was decreased at this time. The observed decreases in the enzyme activities were not accompanied by a depression in the cellular protein concentration. The same pattern of enzyme response was noted when rats were given 30 mumoles/kg Hg2+; however, the decreases in the specific activity of the enzymes were accompanied by great losses in the cellular protein concentrations in both the liver and the kidney (35-40%). This dose of Hg2+ also caused significant decreases in the concentration of GSH in both organs. In vitro, Hg2+ only inhibited the activity of GSSG-reductase. When rats were given sodium selenite (Na2SeO3; 5, 10 or 20 mumoles/kg, s.c.) 30 min after Hg2+ treatment (10 mumoles/kg), the Hg2+-related depressions in the activities of the enzymes of GSH metabolism in the liver and the kidney were blocked. Also, in rats treated with 30 mumoles/kg Hg2+, the administration of 10 mumoles/kg selenium significantly decreased the magnitude of depression in the concentration of GSH in the kidney.

Aspartame administration to the infant monkey: hypothalamic morphology and plasma amino acid levels.

Infant monkeys received 2 gm/kg body weight of aspartame (APM) or 2 gm/kg body weight APM plus 1 gm/kg body weight monosodium glutamate (MSG) by gastric tube. Blood samples were obtained at intervals over the ensuing 4 hours and analyzed for amino acid levels. At this time, each infant was perfused with glutaraldehyde. The hypothalamus was embedded in plastic and then serially sectioned at 1 mu. Hypothalamic morphology was normal in all eight infants given 2 gm/kg body weight APM and in the six infants given 2 gm/kg body weight APM plus 1 gm/kg body weight MSG. By light microscopy, no pycnotic nuclei, neuronal degeneration, or dendritic swelling was noted. In both experimental and control brains, localized areas of poor perfusion exhibited abnormal morphology. Elevated plasma levels of aspartate, glutamate, and phenylalanine indicated that the test compounds were administered and absorbed. Variable rates of absorption were evident, probably due to the necessity of administering APM as a slurry, due to its low solubility. On the basis of blood absorption curves, it appears that infant monkeys metabolize aspartate and glutamate and phenylalanine somewhat more rapidly than man. It is concluded that APM given alone or with MSG, in large acute doses, does not result in hypothalamic damage in the newborn monkey.

Calcium-regulating hormones and ions in amniotic fluid.

Concentrations of the hormones and ions involved in calcium homeostasis were analyzed in simultaneous samples of amniotic fluid and maternal blood obtained from normal pregnant women between 14 weeks' gestation and term. Amniotic fluid total calcium, magnesium, and phosphorus levels fell progressively and markedly despite constant or only declining maternal serum levels. Ionized calcium was constant in both amniotic fluid (mean 2.22 mEq/L) and maternal serum (mean 2.33 mEq/L) throughout gestation. Parathyroid hormone levels in amniotic fluid declined after 20 weeks' gestation, despite rising maternal serum levels, consistent with suppressed fetal parathyroid activity secondary to the relative hypercalcemia of late fetal life. Calcitonin levels in both amniotic fluid and maternal serum were unchanged throughout gestation, with amniotic fluid levels being significantly lower than those in maternal serum.

Altered maternal calcium homeostasis in diabetic pregnancy.

Twenty-one diabetic gravidas were studied with serial measurements of serum concentrations of total and ionized calcium, magnesium, phosphorus, albumin, and parathyroid hormone and plasma levels of calcitonin. Pregnant diabetics had significantly lower serum magnesium concentrations throughout pregnancy than did nondiabetics. They also had significantly lower parathyroid hormone levels after midpregnancy, because the progressive increase in parathyroid hormone concentration observed in control subjects did not occur in diabetics. There was no significant difference between pregnant diabetics and nondiabetics in serum concentrations of total calcium, ionized calcium, phosphorus, or albumin or in plasma levels of calcitonin.

Effects of magnesium sulfate treatment on perinatal calcium metabolism. I. Maternal and fetal responses.

Serial maternal and cord blood determinations of the ions and hormones involved in calcium homeostasis were made in pre-eclamptic women treated with intravenous magnesium sulfate. A 4 gm loading dose followed by 1 to 2 gm/hr caused maternal serum magnesium concentrations to rise 150%, to levels of 3.3 to 4.5 mEq/L, and ionized calcium levels to fall 16%, to 1.89 mEq/L. The hypocalcemia etly altering calcitonin. Changes in total calcium paralleled those of ionized calcium; phosphorus levels were not affected by magnesium infusion. At the time of delivery the offspring of these women were hypermagnesemic and relatively hypocalcemic, although less so than their mothers. Fetal ionized calcium levels, although lower with magnesium treatment than in control subjects, were within the lower limits of the normal range, which perhaps explains why the fetus did not respond with increased PTH or decreased calcitonin output. These results indicate that the principal maternal response to magnesium-induced hypocalcemia involves increased parathyroid hormone secretion which tends to preserve maternal calcium homeostasis, while the fetus is partially protected from hypermagnesemia and hypocalcemia by the placenta.

Calcium metabolism in normal pregnancy: a longitudinal study.

Total and ionic calcium, magnesium, phosphorus, albumin, and immunoreactive parathyroid hormone (iPTH) and calcitonin (iCT) were measured in serum or plasma from 30 women throughout pregnancy (beginning before 12 weeks' gestation) and the puerperium. Total calcium levels declined during gestation, paralleling a progressive fall in albumin concentration, whereas ionic calcium values declined only very slightly. Although iPTH levels in early pregnancy were lower than postpartum values (suggesting that iPTH may decline initially following conception), the major portion of gestation was characterized by progressively increasing concentrations which at term averaged 53% above early pregnancy levels and 33% above puerperal values. Thus, the principal adjustment during pregnancy is "physiologic hyperparathyroidism" which acts to preserve maternal homeostasis by maintaining the concentration of calcium ions in extracellular fluid in the presence of expanding fluid volume, increased renal function, and placental transfer. iCT levels were not affected consistently by pregnancy and exhibited highly variable patterns; half of the subjects demonstrated an increase during the first and second trimesters and then a decline in the third trimester and the remaining half was equally divided between those with no change and those with progressively falling levels.

Hypothalamic morphology following ingestion of aspartame or MSG in the neonatal rodent and primate: a preliminary report.

Neonatal mice received oral doses of monosodium glutamate (MSG) at levels of 0.25, 0.5m 1.0, 2.0, and 4.0 g/kg or aspartame at levels of 0.5, 1.0, 1.5, and 2.0 g/kg. Hypothalamic lesions were encountered at dose levels equal to or exceeding 0.5 g/kg (MSG) and 1.0 g/kg (aspartame). Aspartame administration resulted in a much smaller hypothalamic lesion than did equal dosages of MSG. Infant monkeys received MSG (1-4 g/kg) or aspartame (2 g/kg) by stomach tube. Hypothalamic morphology remained normal at both the microscopic and ultrastructural level. Thus, in contrast to the neonatal rodent, the neonatal primate is able to cope either metabolically or at the level of the blood-brain barrier with excessive amino acid loads.

Calcitonin effects in primate pregnancy.

The acute effects of calcitonin (CT), a hypocalcemic hormone to act by inhibiting bone resorption, were studied in rhesus monkeys in late pregnancy. Salmon CT was injected intravenously into either mother or fetus and the concentration of total calcium and inorganic phosphorus in maternal plasma, fetal plasma, and amniotic fluid measured. Maternal CT administration produced a gradual fall in maternal plasma calcium levels and, to a lesser extent, in maternal plasma phosphorus levels. Both depth and duration of maternal hypocalcemia were related to dose. In addition, the dbree of hypocalcemic response was greater in pregnant than in nonpregnant animals at equivalent dosage levels. Hypocalcemia induced in the mother by CT injection was not reflected in fetal hypocalcemia. Fetal CT administration produced a triphasic response in fetal plasma calcium, consisting of a prompt initial drop followed by a return to or above the baselineand then a more gradual decline. Bth the initial and the secondary hypocalcemic responses in the fetus were dose-related in terms of depth and duration. These observations suggest that CT MAY BE AN IMPORTANT HORMONE IN BOTH MATERNAL AND FETAL PHYSIOLOGY.

Monosodium glutamate: absence of hypothalamic lesions after ingestion by newborn primates.

After receiving monosodium glutamate by stomach tube, the brains of infant macaques were perfused for examination by light and electron microscopy. No morphological differences were observed in the hypothalamic regions of treated and control monkeys. However, inadequately fixed tissue had the same appearance as that of the previously reported brain lesion in a newborn monkey.