endothelin-1 and Fetal-Hypoxia

To investigate the levels of endothelial constricting and dilating mediators in preterm infants with hypoxic-ischaemic encephalopathy and prospectively evaluate the association between levels measured during the perinatal period and the diagnosis of neurodevelopmental disorders at 3 years of age.. This regional observational cohort study was conducted at the Azerbaijan Medical University, Baku, Azerbaijan, from November 2011 to January 2013, and comprised very-low-birth-weight infants admitted to the intensive care unit during the perinatal period. Blood concentrations of nitric oxide, endothelin-1 and endothelial nitric oxide synthase were measured on days 1-3 and 5-7 of the neonatal period. Concentrations of neuron-specific enolase and antibodies against N-methyl-D-aspartate glutamate receptors were measured in peripheral blood samples for detection of brain damage in the early neonatal period of life. The infants were divided in 3 different groups: those diagnosed with moderate-to-severe neurodevelopmental disorders or cerebral palsy were included in the first group; those with mild neurologic changes were in the second group; and children without evidence of neurological impairment were in the third group. The fourth group comprised controls. SPSS 20 was used for data analysis.. Of the 62 participants, there were 8(12.9%) in the first group, 20(32.3%) in second, 14(22.6%) in third and 20(32.3%) in the control group. The activity of endothelial nitric oxide synthase was reduced and nitric oxide concentrations were increased in the first group compared to those in the third group (p<0.05). Deep endothelial nitric oxide synthase depression and insufficient endothelin-1 synthesis were associated with diagnosis in the first group (p<0.05). No differences in concentrations of neuron-specific enolase and NR2 antibodies were identified among infants with and without a subsequent diagnosis of neurodevelopmental disorders (p>0.05).. The association between depressed endothelial nitric oxide synthase activation and insufficient endothelin-1 synthesis in the early days of life of very-low-birth-weight infants might be one of the causes of more serious and irreversible injury of brain tissue.

Topics: Azerbaijan; Cerebral Palsy; Developmental Disabilities; Endothelin-1; Female; Fetal Hypoxia; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Nitric Oxide; Nitric Oxide Synthase Type III

Blood oxygen level dependent (BOLD) contrast was used to monitor hypoxia induced by cloprostenol, a prostaglandin F(2alpha) (PGF(2alpha)) analog, in the rat embryo-placental unit (EPU). It is shown that administration of cloprostenol (0.025 mg/rat) at mid-gestation (day 16) reduced EPU oxygenation, as detected by BOLD contrast MRI, in correlation with induction of vascular endothelial growth factor (VEGF) gene (Vegfa) expression in the corresponding placenta (r = 0.56, p = 0.03). Elevated VEGF mRNA expression in response to cloprostenol treatment was also observed at early gestation (day 9) in the forming placenta (p = 0.04) and uterus (p = 0.03). Cloprostenol increased the expression levels of endothelin-1 (ET-1) gene (Edn1) (p = 0.03) and its corresponding peptide (p = 0.02) in the forming placenta, as well as the expression of the endothelin receptor type A (ETA) gene (Ednra) in both the forming placenta (p = 0.009) and the uterus (p = 0.01). The levels of the endothelin receptor type B (ETB) gene (Ednrb) were not affected in response to cloprostenol, but a significant elevation in the expression level of this receptor was observed in the uterus at mid- and late gestation (day 22) (p = 0.04 and 0.01 respectively), suggesting a role for ETB in the vasodilatory status of the pregnant uterus. It is suggested that PGF(2alpha) induces uteroplacental vasoconstriction in the rat, and that ET-1 may take part in mediating this effect, probably via activation of ETA receptor. The uteroplacental vasoconstriction induces hypoxia, as manifested by significant changes in BOLD MRI and by upregulation of VEGF.

Topics: Animals; Blotting, Western; Cell Hypoxia; Cloprostenol; Dinoprost; Endothelin-1; Endothelium, Vascular; Estrous Cycle; Female; Fetal Hypoxia; Gene Expression Regulation; Gestational Age; Hemoglobins; Magnetic Resonance Imaging; Oxygen; Placenta; Placentation; Pregnancy; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uterus; Vascular Endothelial Growth Factor A; Vasodilation

In response to reduced oxygen or nutrient supply, the fetus may redistribute cardiac output to conserve brain and heart growth, at the expense of the peripheral tissues; however, it is not known whether alterations in vascular function are maintained after birth or whether reduced fetal oxygen versus nutrient supply produces distinct effects. Using a pressure myograph, we examined isolated carotid and femoral artery responses to phenylephrine and endothelin-1 in neonatal rats, after either reduced maternal oxygen or global nutrient restriction during late gestation. Timed-pregnant Sprague-Dawley rats were randomly assigned to control (n = 10), hypoxia (12% O2, n = 9), or nutrient restriction (NR, 40% of control diet, n = 7) protocol and treated from day 15-21 of pregnancy. Pups were collected 3-12 h after birth. Neonatal weights (P < 0.001) and relative liver weights (P < 0.001) were lower in hypoxia and nutrient restriction treatments compared with control, while relative heart weights were greater in the hypoxia than in the control or nutrient restriction groups (P < 0.01). Constriction to phenylephrine was reduced in carotid arteries from the hypoxia and nutrient restriction groups compared with control (P < 0.001), while the femoral artery response was greater in hypoxia-treated neonates compared with control or nutrient-restricted neonates (P < 0.01). Only the hypoxia reduced carotid responses to endothelin-1, while no differences were observed in the endothelin-1 responses in femoral arteries. Maternal hypoxia and maternal nutrient restriction produced distinct effects on heart growth and neonatal vascular function, suggesting that regional changes in cardiovascular function after poor fetal growth are dependent on the nature of the insult in utero.

Topics: Animals; Animals, Newborn; Carotid Arteries; Diet; Endothelin-1; Female; Femoral Artery; Fetal Hypoxia; Hypoxia; Malnutrition; Phenylephrine; Pregnancy; Pregnancy Complications; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Normal placental function is dependent on maintenance of uteroplacental perfusion. Endothelin, a potent vasoconstrictor, is produced in and is active in the uteroplacental vasculature. The purpose of this study was to determine the role of endothelin in the regulation of uteroplacental perfusion under normal conditions, and in hypoxia-induced fetal growth restriction.. Timed-pregnant Sprague-Dawley rats, outfitted with arterial catheters, were maintained in either a normoxic or a normobaric hypoxic (12% oxygen) atmosphere from day 18 to 21 of gestation. During this time, the endothelin receptor A antagonist, A-127722, or its vehicle was administered. Regional blood flow was determined on gestational day 21 using 57Co-labeled microspheres. Data were analyzed by analysis of variance with statistical significance accepted at P<.05.. Both placental and uterine placental bed perfusion were significantly decreased by hypoxia and returned to normal values with the endothelin antagonist (P<.01 and P<.05, respectively). Fetal weights were significantly lower in the hypoxic group (P<.001) and restored to control levels by the antagonist.. In the rat, endothelin contributes little to the regulation of uteroplacental perfusion under normal conditions. Hypoxia results in a decrease in perfusion of the uteroplacental bed and of the placenta, and perfusion in both of these beds is normalized by endothelin A receptor antagonism. We conclude that endothelin plays a primary role in the pathophysiology of hypoxia-induced fetal growth restriction by reducing uteroplacental perfusion.

Topics: Animals; Atrasentan; Blood Flow Velocity; Blood Pressure; Cobalt Radioisotopes; Endothelin A Receptor Antagonists; Endothelin-1; Female; Fetal Growth Retardation; Fetal Hypoxia; Fetus; Gestational Age; Kidney; Microspheres; Oxygen; Placenta; Pregnancy; Pyrrolidines; Rats; Rats, Sprague-Dawley; Uterus

Endothelin-1 (ET-1), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) are regulators of feto-placental hemodynamics. In this study we explore the inter-regulatory pathways that modulate the levels of these vasoactive agents in control and neonatal streptozotocin-induced (n-stz) diabetic rat placenta. ET-1 levels are increased in diabetic placenta when compared to controls (P<0.001), and are strongly reduced by an NO synthase inhibitor (P<0.001). PGE(2) production is increased in diabetic placenta when compared to controls (P<0.01), but these levels are not modulated by ET-1. NO levels, similar in control and in diabetic placenta, are not influenced by PGE(2), but they are negatively modulated by ET-1 in both control (P<0.05) and diabetic (P<0.01) placenta. We conclude that rat placental ET-1 inhibits NO levels but does not modify PGE(2) concentrations. The elevated levels of ET-1 and PGE(2) in diabetic placenta, potent vasoconstrictors of placental vasculature, are probably related to the induction of placental insufficiency and fetal hypoxia in this pathology.

Topics: Animals; Animals, Newborn; Diabetes Mellitus, Experimental; Dinoprostone; Endothelin-1; Female; Fetal Hypoxia; Nitric Oxide; Placenta; Placental Insufficiency; Pregnancy; Rats; Rats, Wistar; Vasoconstriction

We have examined whether endothelin-1 (ET-1) and erythropoietin (EPO) in amniotic fluid, and EPO in fetal serum obtained by cordocentesis from fetuses with signs of intrauterine growth retardation (IUGR), were correlated to fetal growth and/or chronic fetal hypoxia.. Amniotic fluid and fetal serum were obtained by cordocentesis from 28 fetuses suspected to have IUGR and subsequently analyzed for EPO and ET-1 by ELISA. These data were correlated to blood gas results and fetal/maternal parameters at delivery.. A novel finding was that ET-1 correlated to PO2 in amniotic fluid. The average level of ET-1 in amniotic fluid was 48.3+/-4.7 pmol/L. The results also showed a correlation between EPO levels in amniotic fluid and EPO in fetal serum. Furthermore, EPO correlated weakly to birth weight at delivery. Children with the lowest birth weights had the highest EPO levels. High EPO values, similarly to ET-1, correlated to low pO2 values. The level of EPO in amniotic fluid was 8.0+/-1.6 mIU/ml and in cord blood 29.5+/-9.6 mIU/ml.. The results indicate that ET-1 levels may be a marker for short-term hypoxia, but not for fetal growth, since ET-1 in amniotic fluid was correlated to PO2 at the time of cordocentesis, but not to birth weight. The results also indicate that EPO levels in amniotic fluid and in fetal cord serum are highly correlated, and thus both can be used as markers for fetal growth and chronic hypoxia before the onset of labor.

Topics: Adult; Amniotic Fluid; Biomarkers; Blood Gas Analysis; Embryonic and Fetal Development; Endothelin-1; Erythropoietin; Female; Fetal Growth Retardation; Fetal Hypoxia; Humans; Pregnancy

To compare plasma endothelin-1 (ET-1) concentrations in preterm neonates from pre-eclamptic and normal mothers; and to evaluate whether ET-1 has a role in altered arterial blood flow velocity.. Umbilical arterial blood and neonatal arterial blood were sampled on days 1 and 3 for gas analysis and measurement of plasma ET-1. Doppler ultrasonography of the middle cerebral, renal, and superior mesenteric arteries (SMA) was performed.. Neonates in the pre-eclampsia (n = 18) and control (n = 18) groups had mean (SD) gestational ages of 31.1 (2.5) weeks and 30.4 (2.1) weeks; their birth-weights were 1432 (SD 676) g and 1692 (SD 500) g, respectively. In the pre-eclampsia group mean umbilical arterial PO2 was lower--1.88 (0.75) kPa compared with 3.27 (1.41) kPa (p < 0.01)--and mean plasma ET-1 concentration was higher in the umbilical artery--40.6 (SD 15.0) compared with 30.5 (SD 13.8) pg/ml (p = 0.04) and day 1 blood--54.9 (35.0) pg/ml compared with 33.6 (14.6) pg/ml (p = 0.03). Middle cerebral artery peak systolic velocity was higher and SMA time averaged, peak systolic, and mean peak velocities were lower in the pre-eclampsia group. SMA time averaged velocity was inversely related to plasma ET-1 concentration.. The association between increased production of ET-1 and reduction in SMA time averaged velocity suggests a possible mechanism for hypoperfusion of the intestinal wall in neonates.

Topics: Blood Flow Velocity; Cerebral Arteries; Endothelin-1; Female; Fetal Hypoxia; Humans; Infant, Newborn; Infant, Premature; Mesenteric Artery, Superior; Oxygen; Pre-Eclampsia; Pregnancy; Prospective Studies; Ultrasonography, Doppler

To investigate the relationship between endothelin-1 (ET-1) concentration in amniotic fluid (AF) and perinatal hypoxia.. 161 cases were measured for amniotic fluid(AF) ET-1 levels by radioimmunoassay. 110 cases of normal pregnancy were included in control group among which 30 term pregnancies were simultaneously measured for maternal and umbilical plasma ET-1. 51 cases of intrauterine hypoxia were the study group.. (1) The AF ET-1 levels showed increasing trend after 14 weeks (P < 0.01). (2) Fetal plasma ET-1 levels were significantly higher than that of maternal plasma ET-1 levels, but lower than those of AF ET-1 (P < 0.01). The ET-1 levels of umbilical plasma had positive correlation with those of AF ET-1 (r = 0.952, P < 0.01), but there is no correlation with levels of maternal plasma ET-1 (r = 0.338, P < 0.05). (3) In study group, the level of AF ET-1 was elevated with severity of hypoxia, the average level of AF ET-1 in cases of intrauterine hypoxia was (30.654 +/- 5.832) ng/L. In cases of severe neonatal asphyxia it was (960.650 +/- 236.698) ng/L.. The ET-1 exists in AF and gradually increases while pregnancy advanced. AF ET-1 levels can be served as a marker to predict perinatal hypoxia.

Topics: Adult; Amniotic Fluid; Asphyxia Neonatorum; Biomarkers; Endothelin-1; Female; Fetal Blood; Fetal Hypoxia; Humans; Infant, Newborn; Pregnancy

The changes in fetal carotid arterial plasma levels of endothelin-1, catecholamines, PO2, PCO2 and pH were measured after intermittent repetitive umbilical cord occlusion in late gestation pregnant goats (n = 9). Endothelin-1 levels increased to 3.58 +/- 0.28 pg/ml immediately after the onset of fetal hypoxia, a level significantly higher than the respective values in the control period (p < 0.05). The elevation of fetal plasma endothelin-1 levels correlated inversely with carotid arterial PO2 (r = -0.41, p < 0.05) and pH (r = - 0.43, p < 0.05). The results suggest that increased endothelin-1 levels may contribute to the maintenance of the fetal circulation during fetal asphyxia.

Topics: Animals; Catecholamines; Endothelin-1; Female; Fetal Hypoxia; Goats; Heart Rate, Fetal; Oxygen; Pregnancy