[The role played by calcium in neuronal injury following neonatal hypoxia or convulsions]. / Función del calcio en la lesión neuronal tras hipoxia o convulsiones neonatales.

AIM: Calcium plays a complex and pivotal role both in neuronal development and function, and in hypoxia/ ischemia-induced cell death. In this paper, we review current concepts of calcium function emphasizing the neonatal period. DEVELOPMENT: Calcium enters the neuron through glutamate receptors (NMDA and AMPA) located on the neuronal membrane. After hypoxia or seizures, there is a conformational change of the receptors, with increased flow of calcium into the cytoplasm. Cytoplasmatic calcium triggers activation of several free-radical generation pathways, including the nitric oxide pathway, with a deleterious effect upon the neuron. Calcium then enters the neuronal nucleus, through specific receptors on the nuclear membrane. In our experience, hypoxia and neonatal seizures create nuclear membrane dysfunction, increasing the nitric-oxide-dependent flow of calcium into the nucleus. Nuclear calcium increase is critical for genetic transcription, pro-apoptotic gene activation and a cascade of biochemical and molecular events that lead to an increase of caspases and apoptotic neuronal death. CONCLUSIONS: Calcium has a crucial role in neuronal damage after neonatal hypoxia or seizures. A better knowledge of the pathogenic mechanisms that lead to neuronal damage after neonatal hypoxia or seizures will assist in future development of efficacious neuroprotective therapies.

Función del calcio en la lesión neuronal tras hipoxia o convulsiones neonatales / The role played by calcium in neuronal injury following neonatal hypoxia or convulsions

Objetivo. El calcio posee una función importante en eldesarrollo y función neuronales, así como también en los mecanismosde lesión neuronal tras hipoxia o convulsiones. En este trabajose revisarán los conceptos actuales de dicha función, con énfasisen el período neonatal. Desarrollo. El calcio entra en las neuronaspor medio de receptores de glutamato (NMDA y AMPA) localizados en la membrana celular. Tras hipoxia o convulsiones, hay uncambio en la conformación de estos receptores por el que aumentala entrada de calcio al citoplasma de la neurona. El calcio citoplasmáticoactiva varias vías de generación de radicales libres,incluida la del óxido nítrico, con efecto tóxico para la neurona.Posteriormente, el calcio penetra en el núcleo neuronal a través dereceptores específicos en la membrana nuclear. En nuestra experiencia,la hipoxia y las convulsiones neonatales producen una disfunciónde la membrana nuclear que incrementa el flujo del calcioal interior del núcleo, el cual es dependiente del óxido nítrico. Elaumento intranuclear del calcio es crítico para la transcripcióngenética, pues activa genes proapoptóticos y una cascada de fenómenosbioquímicos y moleculares que culminan con el aumento delas caspasas y muerte neuronal por apoptosis. Conclusiones. Elcalcio tiene un papel central en el daño neuronal secundario ahipoxia y convulsiones durante el período neonatal. Un mejorconocimiento de los mecanismos patogénicos que producen lesiónneuronal tras hipoxia o convulsiones neonatales puede favoreceren el futuro el desarrollo de terapias neuroprotectoras eficaces

Aim. Calcium plays a complex and pivotal role both in neuronal development and function, and in hypoxia/ischemia-induced cell death. In this paper, we review current concepts of calcium function emphasizing the neonatal period.Development. Calcium enters the neuron through glutamate receptors (NMDA and AMPA) located on the neuronal membrane.After hypoxia or seizures, there is a conformational change of the receptors, with increased flow of calcium into the cytoplasm.Cytoplasmatic calcium triggers activation of several free-radical generation pathways, including the nitric oxide pathway,with a deleterious effect upon the neuron. Calcium then enters the neuronal nucleus, through specific receptors on the nuclearmembrane. In our experience, hypoxia and neonatal seizures create nuclear membrane dysfunction, increasing the nitricoxide-dependent flow of calcium into the nucleus. Nuclear calcium increase is critical for genetic transcription, pro-apoptoticgene activation and a cascade of biochemical and molecular events that lead to an increase of caspases and apoptoticneuronal death. Conclusions. Calcium has a crucial role in neuronal damage after neonatal hypoxia or seizures. A betterknowledge of the pathogenic mechanisms that lead to neuronal damage after neonatal hypoxia or seizures will assist in futuredevelopment of efficacious neuroprotective therapies

Effect of neuronal nitric oxide synthase inhibition on CA2+/calmodulin kinase kinase and CA2+/calmodulin kinase IV activity during hypoxia in cortical nuclei of newborn piglets.

The present study tests the hypothesis that cerebral tissue hypoxia results in increased Ca(2+)/calmodulin (CaM) kinase kinase activity and that the administration of nitric oxide synthase inhibitors (N-nitro-l-arginine [NNLA], or 7-nitroindazole sodium [7-NINA]) prior to the onset of hypoxia will prevent the hypoxia-induced increase in the enzyme activity. To test this hypothesis, CaM kinase kinase and CaM kinase IV activities were determined in normoxic, hypoxic, NNLA-treated hypoxic, and 7-NINA-treated hypoxic piglets. Hypoxia was induced (FiO(2)=0.05-0.08x1 h) and confirmed biochemically by tissue levels of ATP and phosphocreatine. CaM kinase kinase activity was determined in a medium containing protein kinase and phosphatase inhibitors, calmodulin, and a specifically designed CaM kinase kinase target peptide. CaM kinase IV activity was determined by (33)P-incorporation into syntide-2 in a buffer containing protein kinase and phosphatase inhibitors. Compared with normoxic animals, ATP and phosphocreatine levels were significantly lower in all hypoxic piglets whether or not pretreated with nitric oxide synthase inhibitors. There was a significant difference among CaM kinase kinase activity (pmol/mg protein/min) in normoxic (76.84+/-14.1), hypoxic (138.86+/-18.2, P<0.05 vs normoxia), NNLA-pretreated hypoxic (91.34+/-19.3; P=NS vs normoxia, P<0.05 vs hypoxia) and 7-NINA-pretreated hypoxic animals (100.12+/-23.3; P=NS vs normoxia, P<0.05 vs hypoxia). There was a significant difference among CaM kinase IV activity (pmol/mg protein/min) in normoxia (1270.80+/-126.1), hypoxia (2680.80+/-136.7; P<0.05 vs normoxia), NNLA-pretreated hypoxia (1666.00+/-154.8; P<0.05 vs normoxia, P<0.05 vs hypoxia), and 7-NINA-pretreated hypoxic (1712.9+/-231.5; P=NS vs normoxia, P<0.05 vs hypoxia). We conclude that the hypoxia-induced increase in CaM kinase kinase and CaM kinase IV activity is mediated by neuronal NOS-derived NO.

Nitric oxide-mediated activation of extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) during hypoxia in cerebral cortical nuclei of newborn piglets.

Previous studies have shown that mitogen-activated protein kinases, such as extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK), mediate signal transduction from cell surface receptors to the nucleus and phosphorylate anti-apoptotic proteins thereby regulating programmed cell death. The present study tests the hypotheses that hypoxia activates ERK and JNK in neuronal nuclei of newborn piglets and the hypoxia-induced activation of ERK and JNK is mediated by nitric oxide (NO). Activated ERK and JNK were assessed by determining phosphorylated ERK and JNK using immunoblotting in six normoxic (Nx) and 10 hypoxic (Hx) and five N-nitro-L-arginine (a NOS inhibitor, 40 mg/kg,) -pretreated hypoxic (N-nitro-L-arginine [NNLA]-Hx) 3-5 day old piglets. Hypoxia was induced by decreasing inspired oxygen from 21% to 7% for 60 min. Cerebral tissue hypoxia was documented biochemically by determining the tissue levels of ATP and phosphocreatine (PCr). Cortical neuronal nuclei were isolated and the nuclear protein was analyzed for activated ERK and JNK using anti-phosphorylated ERK and JNK antibodies. Protein bands were detected using enhanced chemiluminescence method and analyzed by imaging densitometry. Protein density was expressed as absorbance ODxmm(2). ATP levels were 4.57+/-0.45 micromoles/g brain in the Nx group, 1.29+/-0.23 micromoles/g brain in the Hx group (P<0.05 vs Nx) and 1.50+/-0.14 micromoles/g brain in the NNLA-Hx group (P<0.05 vs Nx). PCr levels were 3.77+/-0.36 micromoles/g brain in the Nx group, 0.77+/-0.13 micromoles/g brain in the hypoxic group (P<0.05) and 1.02+/-0.24 in the NNLA-Hx group (P<0.05 vs Nx). Density of phosphorylated ERK protein was 170.5+/-53.7 ODxmm(2) in the Nx group as compared with 419.6+/-63.9 ODxmm(2) in the hypoxic group (P<0.001 vs Nx) and 270.0+/-28.7 in the NNLA-Hx group (P<0.002 vs Hx). Density of phosphorylated JNK protein was 172.8+/-42.8 ODxmm(2) in the normoxic group as compared with 364.6+/-60.1 ODxmm(2) in the Hx group (P<0.002) and 254.8+/-24.8 in the NNLA-Hx group (P<0.002 vs Hx). The data demonstrate increased phosphorylation of ERK and JNK during hypoxia indicating that hypoxia results in activation of ERK and JNK in neuronal nuclei of newborn piglets. The administration of NNLA, a NOS inhibitor, prevented the hypoxia-induced phosphorylation of ERK and JNK indicating that the hypoxia-induced activation of ERK and JNK in the cerebral cortical nuclei of newborn piglets is NO-mediated

Nitration as a mechanism of Na+, K+-ATPase modification during hypoxia in the cerebral cortex of the guinea pig fetus.

Previous studies have shown that hypoxia induces nitric oxide synthase-mediated generation of nitric oxide free radicals leading to peroxynitrite production. The present study tests the hypothesis that hypoxia results in NO-mediated modification of Na+, K+-ATPase in the fetal brain. Studies were conducted in guinea pig fetuses of 58-days gestation. The mothers were exposed to FiO2 of 0.07% for 1 hour. Brain tissue hypoxia in the fetus was confirmed biochemically by decreased ATP and phosphocreatine levels. P2 membrane fractions were prepared from normoxic and hypoxic fetuses and divided into untreated and treated groups. The membranes were treated with 0.5 mM peroxynitrite at pH 7.6. The Na+, K+-ATPase activity was determined at 37 degrees C for five minutes in a medium containing 100 mM NaCl, 20 mM KCl, 6.0 mM MgCl2, 50 mM Tris HCl buffer pH 7.4, 3.0 mM ATP with or without 10 mM ouabain. Ouabain sensitive activity was referred to as Na+, K+-ATPase activity. Following peroxynitrite exposure, the activity of Na+, K+-ATPase in guinea pig brain was reduced by 36% in normoxic membranes and further 29% in hypoxic membranes. Enzyme kinetics was determined at varying concentrations of ATP (0.5 mM-2.0 mM). The results indicate that peroxynitrite treatment alters the affinity of the active site of Na+, K+-ATPase for ATP and decreases the Vmax by 35% in hypoxic membranes. When compared to untreated normoxic membranes Vmax decreases by 35.6% in treated normoxic membranes and further to 52% in treated hypoxic membranes. The data show that peroxynitrite treatment induces modification of Na+, K+-ATPase. The results demonstrate that peroxynitrite decreased activity of Na+, K+-ATPase enzyme by altering the active sites as well as the microenvironment of the enzyme. We propose that nitric oxide synthase-mediated formation of peroxynitrite during hypoxia is a potential mechanism of hypoxia-induced decrease in Na+, K+-ATPase activity.

Effect of gestational age and hypoxia on activity of ribonucleic acid polymerase in fetal guinea pig brain.

OBJECTIVE: The aim of this study was to determine the effect of gestational age and hypoxia on the activity of ribonucleic acid polymerase in fetal guinea pig brain. STUDY DESIGN: Fetal cerebral cortical neuronal nuclei were isolated at 40, 50, and 60 days (term) of gestation to determine the effect of gestational age on the activity of ribonucleic acid polymerase I, II, and III. Pregnant guinea pigs at 60 days' gestation were randomly assigned to a normoxic or hypoxic group to determine the effect of hypoxia on ribonucleic acid polymerase activity. The fetal neuronal nuclei were pooled from 6 pregnant animals in each group. In the normoxic group the pregnant guinea pigs were exposed to room air before delivery. In the hypoxic group delivery occurred after the pregnant guinea pig had been exposed to 7% oxygen for 60 minutes. The fetuses were delivered by cesarean, and the fetal cerebral cortical neuronal nuclei were isolated immediately. Ribonucleic acid polymerase activity was determined with nuclei suspended in a buffer containing adenosine triphosphate, guanosine triphosphate, cytidine triphosphate, and tritiated uridine triphosphate. Dactinomycin (actinomycin D) and polydeoxyadenylic-thymidylic acid were used to determine the activity of bound and free ribonucleic acid polymerase. alpha-Amanitin was used to determine the activity of ribonucleic acid polymerase II. RESULTS: The activity of total (bound and free) ribonucleic acid polymerase I and III increased from 85.4 +/- 9.4 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour at 40 days' gestation to 233.3 +/- 82.1 fmol at 50 days and to 343.4 +/- 231.6 fmol at 60 days (P =.02). Total ribonucleic acid polymerase II activity increased from 19.9 +/- 6.0 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour at 40 days to 123.8 +/- 53.0 fmol at 50 days and to 200.9 +/- 77.8 fmol at 60 days (P <.01). In the term fetal guinea pig brain the activity of bound ribonucleic acid polymerase I and III decreased from 116.8 +/- 107.2 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour under normoxic conditions to 92.8 +/- 76.0 fmol in hypoxic fetal brain, a decrease of 20.5%. Free ribonucleic acid polymerase I and III activity decreased from 199.2 +/- 115.2 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour in normoxic fetal brain to 132.0 +/- 66.4 fmol in hypoxic fetal brain, a decrease of 33.8%. Free ribonucleic acid polymerase II activity decreased from 62.4 +/- 70.4 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour in normoxic fetuses to 13.6 +/- 9.6 fmol in hypoxic fetal brain, a decrease of 78.2%. In contrast, however, in term fetal guinea pig brain, bound ribonucleic acid polymerase II activity increased from 8.0 +/- 10.4 fmol of tritiated uridine triphosphate incorporated per milligram of protein per hour under normoxic conditions to 35.2 +/- 8.8 fmol in hypoxic fetal brain, an increase of 340% (P <.01). CONCLUSION: The activity of ribonucleic acid polymerases I, II, and III increases throughout the latter half of gestation, from 40 to 60 days, in the fetal guinea pig brain. Hypoxia in utero is associated with a decrease in ribonucleic acid polymerase I and III activity. Although hypoxia is associated with a decrease in free ribonucleic acid polymerase II activity, we observed a marked increase in bound ribonucleic acid polymerase II activity, which may represent a hypoxia-induced alteration of gene expression.

Spermine dependent activation of the N-methyl-D-aspartate receptor and the effect of nitric oxide synthase inhibition during hypoxia in the cerebral cortex of newborn piglets.

This study tests the hypothesis that brain tissue hypoxia results in modification of spermine-dependent activation of the cerebral N-methyl-D-aspartate (NMDA) receptor ion-channel in newborn piglet brains and that pretreatment with N(omega)-nitro-L-arginine (NNLA), an inhibitor of nitric oxide synthase, will reduce the hypoxia-induced modification of the spermine-dependent activation of the receptor. Piglets were assigned to one of four groups; normoxia or hypoxia with or without NNLA. The infusion of NNLA or vehicle lasted for 60 min while the animals were ventilated under either hypoxic or normoxic conditions. Cerebral tissue hypoxia was confirmed by measuring ATP and phosphocreatine (PCr) levels. P2 membranes were isolated and 3H-MK-801 binding was measured in the presence of spermine. Steady state 3H-MK-801 binding in the presence of spermine, showed an increase in receptor affinity in both normoxic (47% of control) and hypoxic (42% of control) animals without change in receptor density. During hypoxia, the spermine-dependent increase in the maximal response of the 3H-MK-801 binding correlated inversely with the ATP concentrations. NNLA pretreatment prior to hypoxia, resulted in a decrease in the slope of the regression line describing the relationship between cellular energy state (ATP) and percent change in maximal response to spermine compared with vehicle treated animals indicating attenuation of the response to hypoxia. We conclude that the spermine-dependent modification of the affinity of the NMDA receptor ion-channel as assessed by 3H-MK-801 binding is similar in hypoxic and normoxic cortical tissue. NNLA administration reduces the hypoxia-induced spermine-dependent activation of the receptor indicating that nitric oxide mediates modification of the spermine site activation of the NMDA receptor ion-channel complex.

Lipid free radical generation and brain cell membrane alteration following nitric oxide synthase inhibition during cerebral hypoxia in the newborn piglet.

Nitric oxide (NO) is reported to cause neuronal damage through various mechanisms. The present study tests the hypothesis that NO synthase inhibition by N(omega)-nitro-L-arginine (NNLA) will result in decreased oxygen-derived free radical production leading to the preservation of cell membrane structure and function during cerebral hypoxia. Ten newborn piglets were pretreated with NNLA (40 mg/kg); five were subjected to hypoxia, whereas the other five were maintained with normoxia. An additional 10 piglets without NNLA treatment underwent the same conditions. Hypoxia was induced with a lowered FiO2 and documented biochemically by decreased cerebral ATP and phosphocreatine levels. Free radicals were detected by using electron spin resonance spectroscopy with a spin trapping technique. Results demonstrated that free radicals, corresponding to alkoxyl radicals, were induced by hypoxia but were inhibited by pretreatment with NNLA before inducing hypoxia. NNLA also inhibited hypoxia-induced generation of conjugated dienes, products of lipid peroxidation. Na+,K+-ATPase activity, an index of cellular membrane function, decreased following hypoxia but was preserved by pretreatment with NNLA. These data demonstrate that during hypoxia NO generates free radicals via peroxynitrite production, presumably causing lipid peroxidation and membrane dysfunction. These results suggest that NO is a potentially limiting factor in the peroxynitrite-mediated lipid peroxidation resulting in membrane injury.

Neonatal intestinal perforation caused by intestinal muscularis defect associated with vascular ectasia.

We describe a rare case of a viable preterm infant who developed a spontaneous localized perforation of the small bowel caused by a segmental absence of the intestinal musculature and associated with vascular ectasia. The findings may support a causal relationship between absence of the intestinal muscle coat and a vascular network disorder which may be responsible for the gastroenteric defect.

Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group.

There are few blood pressure (BP) data reported for premature and term newborn infants after 24 hours of age. To determine BP levels and BP trends in a representative population of infants admitted to neonatal intensive care units (NICUs), this study was conducted in 14 NICUs in the greater Philadelphia area. All infants admitted to the 14 NICUs during a 3-month period were entered into the study. BP data, along with data on clinical conditions and therapeutic interventions (independent variables), were prospectively collected by a uniform protocol. Systolic BP (SBP) and diastolic BP (DBP) were measured indirectly by oscillometry and recorded every 8 hours. Data from 608 infants followed up for 1 to 99 days after delivery generated 9911 infant-day records and 24,052 individual BP measurements. On day 1, birth weight and gestational age were strong correlates of SBP (r = 0.68, p < 0.0001 and r = 0.66, p < 0.0001, respectively) and DBP (r = 0.48, p < 0.0001 and r = 0.47, p < 0.001, respectively). During the first 5 days of life there was a progressive rise in SBP (2.23 to 2.67 mm Hg/day) and DBP (1.58 to 2.02 mm Hg/day) regardless of gestational age or weight at birth. After day 5 there was a more gradual increment in the daily SBP (0.24 to 0.27 mm Hg/day) and DBP (0 to 0.15 mm Hg/day). Stepwise linear multiple regressions were used to examine the multiple correlations among the independent variables and to build a regression model for BP. Gestational age and day of life emerged in the first two steps of the multiple regression analysis (multiple R = 0.463 and 0.655, respectively; p < 0.0001 for both). The multiple R values for day of life and gestational age were virtually identical to that for postconceptional age (day of life + gestational age at birth). Although other common diagnosis and treatment variables contributed a small amount to the total variance in BP, postconceptional age was the primary determinant of BP in this population of infants.

Limb gangrene secondary to thromboembolic disease of the newborn.

Thromboembolic disease of the newborn is a well-known entity to neonatologists. When severe arterial compromise threatens limb survival, the orthopaedic surgeon may be called on to assist in the management of this disorder. A case of spontaneous postnatal ischemic gangrene of an upper extremity that resulted in amputation in a premature infant is presented; management options are discussed. Newborns are prone to thromboembolism due to a fibrinolytic capability that is significantly different from that of adults.

Pulse oximetry in sick premature infants and the effects of phototherapy and radiant warmers on the oxygen saturation readout.

Forty-five arterial blood samples for oxygen saturation on 15 sick premature infants were significantly correlated with pulse oximeter determinations (r = 0.87, p less than 0.0001) giving a regression equation of y = 1.19X - 18.15. Chronologic age in the first 2 weeks of life did not alter the accuracy of the pulse oximeter. Four groups (in isolette with phototherapy off, in isolette with phototherapy on, on radiant warmer with phototherapy off, and on radiant warm with phototherapy on) were observed to see if environmental light and energy would affect pulse oximetry oxygen saturation values; no effect was observed. Therefore the pulse oximeter is an accurate machine to assess sick premature infant oxygen saturation. The measurements are not altered by environmental light.

Plasma vasopressin, renin and catecholamines during nitroprusside-induced hypotension in the newborn lamb.

The circulating levels of vasopressin, catecholamines and renin activity before, during and following a 10-20% fall in mean arterial blood pressure induced by sodium nitroprusside were measured in six chronically catheterized lambs during the first week of life. No significant changes in pHa, PaO2, PaCO2, Plasma sodium or osmolality were observed during or following the infusion of sodium nitroprusside at an average of 12 g.kg-1.min-1 (table I). However, the fall in blood pressure at the end of 60 minutes infusion, was associated with significant increases in the plasma levels of vasopressin from a control value of 2.4 +/- 0.57 to a maximum of 35.1 +/- 16.3 pg/ml (p = .002), renin activity from 6.7 +/- 1.56 to 27.4 +/- 11.44 ng.ml-1.hr-1 (p = .003), and catecholamines from 189.3 +/- 42.15 to 543.3 +/- 100.52 pg.ml-1 (p = .0001). The increase in vasopressin is lower, while that of PRA was higher and catecholamines similar to those found in the ewe. Plasma renin activity (PRA) and catecholamine levels remained elevated for at least 30 minutes following the end of the infusion while the mean blood pressure rose significantly above control levels and remained elevated for twenty minutes. We speculate that the persistent elevated levels of vasoactive mediators are responsible for the prolonged rebound hypertension following the cessation of the nitroprusside infusion and is the result of an immaturity of either a feedback process or metabolism of the vasoactive mediators or a combination of both mechanisms. This rebound hypertension could have adverse effects particularly in the very immature neonate.

Lesion mistaken for hemorrhage in a premature infant: lipoma of corpus callosum.

An infant, 26 weeks gestation, had a stormy neonatal course; at 10 hours of age, initial cranial ultrasound apparently demonstrated a left subependymal hemorrhage placed somewhat medially with possible extension into the lateral ventricle. These ultrasound findings were present up to and including a study on the seventeenth day of life. At 7 months of age, repeat ultrasound once again demonstrated supposed hemorrhage which involved both choroid plexuses and the third ventricle or basilar cisterns. Computed tomography revealed a lipoma of the corpus callosum with calcifications. This patient is one of the youngest reported in the literature with this tumor.

Plasma vasopressin, renin, and catecholamines during nitroprusside-induced maternal and fetal hypotension in sheep.

The release of vasopressin, renin, and catecholamines by the fetus during either maternal or fetal hypotension was examined in chronically catheterized fetal lambs. Nitroprusside was infused intravenously for 1 h into seven pregnant ewes (maternal hypotension) or nine fetal lambs (fetal hypotension); the rates were adjusted to achieve a 15 to 30% decrease in mean blood pressure. During maternal hypotension, mean +/- SE vasopressin in maternal plasma increased from 1.2 +/- 0.2 pg.ml-1 to 208 +/- 153 pg.ml-1 and plasma renin activity increased from 1.5 +/- 0.3 ng.ml-1.h-1 to 6.6 +/- 1.6 ng.ml-1.h-1. Fetal vasopressin and plasma renin activity also increased during the same interval from 1.1 +/- 0.3 to 16.9 +/- 7.5 pg.ml-1 and 3.7 +/- 1.1 to 10.5 +/- 2.85 ng.ml-1.h-1, respectively; but no changes were observed in fetal blood pressure, heart rate, or acid base status. During fetal hypotension, mean vasopressin in fetal plasma increased from 4.3 +/- 3.4 pg.ml-1 to 1054 +/- 772 pg.ml-1, plasma renin activity increased from 5.7 +/- 2.2 ng.ml-1 to 22.2 +/- 7.1 ng.ml-1.h-1, and total catecholamines from 174 +/- 58 pg.ml-1 to 810 +/- 416 pg.ml-1. There was no change in fetal heart rate, acid base status, osmolality, or sodium concentration. The fetus became and remained hypertensive for at least 1 h after the end of infusion. This prolonged hypertension was associated with elevated levels of vasopressin and plasma renin activity. Peak vasopressin levels were proportional to the total nitroprusside dose in both the ewe and fetus (maternal r = 0.796, fetus r = 0.870).(ABSTRACT TRUNCATED AT 250 WORDS)

Vasopressin concentration in amniotic fluid as an index of fetal hypoxia: mechanism of release in sheep.

Hypoxia is a potent stimulus to the release of vasopressin in fetal sheep, and plasma concentrations of the hormone correlate inversely with fetal oxygenation. Since the fetal kidney contributes to vasopressin clearance, we propose that measurement of increased amounts of vasopressin in amniotic fluid would be indicative of fetal hypoxia. Therefore, we measured concentrations of vasopressin in amniotic fluid under resting conditions, during and after fetal hypoxia, and with intravenous and intra-amniotic administration of vasopressin in 15 chronically instrumented fetal lambs between 111 and 141 days gestation. In the resting state, mean (+/- SE) vasopressin concentrations in amniotic fluid (1.6 +/- 0.3 pg ml-1) did not differ from those in maternal (1.4 +/- 0.4 pg ml-1) or fetal (1.8 +/- 0.2 pg ml-1) plasma. Following exposure of the ewe to 10% O2 or partial occlusion of the umbilical cord, vasopressin concentrations in fetal plasma increased significantly (P less than 0.001) to 200 +/- 59 pg ml-1 with a delayed increase in amniotic fluid concentrations (P less than 0.03) to 15.8 +/- 4.5 pg ml-1. This rise in concentration of vasopressin in amniotic fluid was sustained for at least 24 h and levels at that time were highly correlated with peak plasma concentrations (r = 0.83; P less than 0.001). Intravenous infusion of vasopressin into the fetus was accompanied by an equally significant (P less than 0.02) and sustained increase of vasopressin in amniotic fluid. Following intra-amniotic injection of vasopressin, levels remained increased for at least 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasopressin concentration in amniotic fluid as an index of fetal hypoxia: mechanism of release in sheep.

Hypoxia is a potent stimulus to the release of vasopressin in fetal sheep and, in turn, plasma concentrations of the hormone correlate inversely with fetal oxygenation. Because the fetal kidney contributes to vasopressin clearance, we propose that measurement of increased amounts of vasopressin in amniotic fluid would be indicative of fetal hypoxia. We therefore measured concentrations of vasopressin in amniotic fluid under resting conditions, during and after fetal hypoxia, and with intravenous and intra-amniotic administration of vasopressin in 15 chronically instrumented fetal lambs 111-141 d gestation. In the resting state mean (+/- SE) vasopressin concentrations in amniotic fluid (1.6 +/- 0.3 pg . ml-1) did not differ from those in maternal (1.4 +/- 0.4 pg . ml-1) or fetal (1.8 +/- 0.2 pg . ml-1) plasma. After exposure of the ewe to 10% O2 or partial occlusion of the umbilical cord, vasopressin concentrations in fetal plasma increased significantly (P less than 0.001) to 200 +/- 59 pg . ml-1 with a delayed increase in amniotic fluid concentrations (P less than 0.03) to 15.8 +/- 4.5 pg . ml-1. This rise in concentration of vasopressin in amniotic fluid was sustained for at least 24 h and levels at that time were highly correlated with peak plasma concentrations (r = 0.83, P less than 0.001). Intravenous infusion of vasopressin into the fetus was accompanied by an equally significant (P less than 0.02) and sustained increase of vasopressin in amniotic fluid. After intraamniotic injection of vasopressin, levels remained increased for at least 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of hypoxia on vasopressin concentrations in cerebrospinal fluid and plasma of sheep.

The relationship between concentrations of vasopressin in plasma and cerebrospinal fluid (CSF) was examined under basal and hypoxic conditions in unanesthetized and unrestrained adult female sheep. Under basal conditions mean (+/- SE) concentration of vasopressin (4.1 +/- 0.3 pg/ml) in CSF was significantly (p less than 0.001) higher than the concentration in arterial plasma (2.4 +/- 0.2 pg/ml). There was a significant positive correlation between CSF and plasma vasopressin concentrations (r = 0.66, p less than 0.01). The introduction of severe hypoxia by exposure of the sheep to an inspired gas mixture of 5% O2 in N2, a known stimulus to systemic release of vasopressin, was associated with an increase in the concentration of vasopressin in plasma to 339 +/- 65 pg/ml and CSF to 19 +/- 3.9 pg/ml. This increase of vasopressin in CSF was delayed in time with respect to the increases in the plasma and of a lesser magnitude. With moderate hypoxia (10% O2 in N2 exposure) no increase in CSF or plasma vasopressin concentration was observed, suggesting a threshold response. Intravenous infusion of vasopressin to achieve plasma values comparable to those seen with hypoxia was not accompanied by a significant increase in CSF vasopressin concentration. Thus, severe hypoxia is a potent stimulus for release of vasopressin into both CSF and plasma. Furthermore, data suggest that vasopressin may be released into CSF via a separate route from that released into plasma.

Disseminated Kaposi's sarcoma in pregnancy: a manifestation of acquired immune deficiency syndrome.

The first case of acquired immune deficiency syndrome (AIDS) in pregnancy is reported. The patient, a drug addict, presented with lymphadenopathy, pulmonary infiltrates, and skin lesions of Kaposi's sarcoma, a tumor rarely found in young women in this country. The helper T-lymphocyte to suppressor T-lymphocyte ratio showed the profound inversion characteristic of this cell-mediated immune deficiency disease. Chemotherapy, a combination of doxorubicin, bleomycin, and vinblastine, was initiated during pregnancy. A growth-retarded infant was delivered vaginally. At four months of life, the infant had no apparent evidence of immune deficiency. Transplacental transmission of AIDS has not, as yet, been demonstrated. The social factors, clinical and laboratory features, and the controversies surrounding this new disease are discussed.

Factors in the release of vasopressin by the hypoxic fetus.

The relative effects of 3 stimuli in the release of vasopressin (VP) by the fetus were examined in 19 chronically instrumented fetal lambs, 118-135 days gestational age. The fetus was exposed to: 1) 30-min administration of 10% O2 to the pregnant ewe, 2) 20 min of partial occlusion of the umbilical cord, or 3) 2 min of complete occlusion of the umbilical cord. Twelve studies were conducted for each of these experimental protocols. The rises (mean +/- SE) in plasma VP in the 3 groups were 29.9 +/- 8.9, 48.9 +/- 11.5, and 157.8 +/- 12.5 pg/ml, respectively; the corresponding falls in PaO2 were 9.2 +/- 0.7, 7.7 +/- 0.9, and 12.7 +/- 1.2 mm Hg. pHa did not change in the group receiving 10% O2, fell by 0.11 +/- 0.02 and 0.14 +/- 0.01 after partial and complete occlusion of the umbilical cord. The rises in mean arterial pressure were 6 +/- 2.2, 10 +/- 1.9, and 23 +/- 3.1 mm Hg, respectively, at the end of the 3 procedures. The rise in plasma osmolality ranged from 2-8 mosmol/kg in all 3 groups. Linear regression analyses showed that log VP was negatively correlated with PaO2 (r = -0.827; P less than 0.01) and pHa (r = -0.706; P less than 0.01) and positively correlated to mean arterial pressure (r = 0.607; P = 0.01), but was not significantly correlated to plasma osmolality. Our present findings suggest that hypoxemia and acidemia are associated with and may both be potent stimuli for VP release in the hypoxic fetus. Increased release together with decreased rate of metabolism by the placenta offer an explanation for the very high VP levels found in the neonate after labor and delivery.