endothelin-1 and Birth-Weight

The objective of this study was to examine maternal and fetal endothelin-1 (ET-1) in pregnancies complicated with intrauterine growth restriction (IUGR) and to correlate these data with umbilical artery Doppler flow velocity waveforms (FVW). Higher mean maternal (13.8 +/- 6.4 vs 9.2 +/- 3.4 pmol/L, p < 0.05) and fetal (18.5 +/- 9.6 vs 11.7 +/- 6.9 pmol/L, p < 0.05) ET-1 levels were found in pregnancies complicated with IUGR than in controls. Fetal ET-1 level was related to birth weight percentile for gestational week. Maternal and fetal ET-1 concentrations were not related to umbilical artery Doppler flow S/D ratio, PI and RI. Maternal or fetal ET-1 concentrations were also not related to umbilical artery pH, PO2 and PCO2. Pregnancy-induced hypertension was significantly associated with an elevated fetal and maternal ET-1 concentration. In conclusion, increased production and secretion of ET-1 may play a role in the pathophysiology of idiopathic IUGR. Over-production of ET-1 in IUGR is not associated with increased placental resistance as reflected in abnormal umbilical artery Doppler FVW.

Topics: Birth Weight; Endothelin-1; Female; Fetal Growth Retardation; Gestational Age; Humans; Laser-Doppler Flowmetry; Pre-Eclampsia; Pregnancy; Reference Values; Regression Analysis; Ultrasonography; Umbilical Arteries; Vascular Resistance

Topics: Adult; Amniotic Fluid; Birth Weight; Diabetes, Gestational; Endothelin-1; Female; Humans; Infant, Newborn; Pregnancy

In the pathogenesis of neonatal intraventricular hemorrhage (IVH) in preterm infants, an important role is played by changes in venous and arterial cerebral flows. It has been shown that the ability of autoregulation of cerebral flows in response to variations in arterial blood pressure in preterm infants is impaired. This impaired autoregulation causes an increased risk of germinal matrix rupture and IVH occurrence. We examined three polymorphisms of genes, related to regulation of blood flow, for an association with IVH in 100 preterm infants born from singleton pregnancy, before 32 + 0 weeks of gestation, exposed to antenatal steroids therapy, and without congenital abnormalities. These polymorphisms include: eNOS (894G > T and -786T > C) and EDN1 (5665G > T ) gene. We found that infants with genotype GT eNOS 894G > T have 3.4-fold higher risk developing of IVH born before 28 + 6 weeks of gestation. Our investigation did not confirm any significant prevalence for IVH development according to eNOS -786T > C genes polymorphism. Our novel investigations in EDN1 5665G > T polymorphism did not show any link between alleles or genotypes and IVH. Future investigations of polymorphisms in blood-flow associated genes may provide valuable insight into the pathogenetic mechanisms underlying the development of IVH.

Topics: Alleles; Apgar Score; Birth Weight; Blood Pressure; Cerebral Intraventricular Hemorrhage; Endothelin-1; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Male; Nitric Oxide Synthase Type III; Odds Ratio; Polymorphism, Genetic; Severity of Illness Index

Deficiency of vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine whether VD supplementation would reduce the pathophysiology and hypertension associated with the reduced uterine perfusion pressure (RUPP) rat model of PE. Normal pregnant (NP) and RUPP rats were supplemented with VD2 or VD3 (270 IU and 15 IU/day, respectively) on gestation days 14-18 and mean arterial pressures (MAPs) measured on day 19. MAP increased in RUPP to 123 ± 2 mmHg compared with 102 ± 3 mmHg in NP and decreased to 113 ± 3 mmHg with VD2 and 115 ± 3 mmHg with VD3 in RUPP rats. Circulating CD4+ T cells increased in RUPP to 7.90 ± 1.36% lymphocytes compared with 2.04 ± 0.67% in NP but was lowered to 0.90 ± 0.19% with VD2 and 4.26 ± 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 ± 0.4 bpm in RUPPs to 8.3 ± 0.5 bpm with VD2 and to 15.4 ± 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 ± 2.1-fold change from NP) and decreased with both VD2 (3.3 ± 1.1-fold) and VD3 (3.1 ± 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 ± 6.6 pg/ml in VD2-treated and 91.0 ± 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 ± 19.9 pg/ml in RUPP rats. VD treatment reduced CD4+ T cells, AT1-AA, ET-1, sFlt-1, and blood pressure in the RUPP rat model of PE and could be an avenue to improve treatment of hypertension in response to placental ischemia.

Topics: Animals; Arterial Pressure; Birth Weight; CD4-Positive T-Lymphocytes; Dietary Supplements; Endothelin-1; Female; Ischemia; Kidney; Lymphocyte Count; Pre-Eclampsia; Pregnancy; Rats; Receptor, Angiotensin, Type 1; Regional Blood Flow; Uterus; Vascular Endothelial Growth Factor Receptor-1; Vitamin D; Vitamins

Renal failure is common in the NICU; Acute Kidney Injury (AKI) occurs in 8-24% of admissions. Although AKI is preventable with early diagnosis, no reliable AKI biomarkers exist. Endothelin-1 (ET-1) has been implicated in renal pathogenesis, and elevated urinary ET-1 (uET-1) levels may correlate with progression of renal dysfunction. The study objectives were to determine whether uET-1 levels correlate with renal function parameters and/or fetal growth restriction, and if uET-1 is a potential neonatal AKI biomarker.. Sixty-three neonates were enrolled and divided into gestational age (GA) groups by weeks: 1) (24-30 6/7; n = 24); 2) (31-36 6/7; n = 26); and 3) (37-42; n = 13). Additional preterm subgroups for fetal growth restriction analysis included: 1) Appropriate for GA (AGA; n = 40), and 2) Small for GA (SGA; n = 10). ET-1 levels, measured using enzyme linked immunosorbent assay, were collected at birth (cord blood) and 24 h ( ± 4) of life (blood/urine).. No correlation was found between uET-1 and blood plasma levels at birth (r = 0.15; p > 0.05) or 24 h (r = 0.17; p > 0.05). uET-1 negatively correlated with GA (r = -0.44; p < 0.001) and GFR (r = -0.34; p < 0.01). uET-1 levels did not correlate with creatinine (r = 0.13; p > 0.05), BUN (r = 0.19; p > 0.05), BUN/Cr ratio (r = 0.15; p > 0.05), or urinary output (r = 0.12; p > 0.05). In fetal growth restriction subgroup analyses: uET-1 levels negatively correlated with GFR in the PT-AGA subgroup (r = -0.38; p = 0.017), but not with PT-SGA (r = 0.01; p > 0.05).. Plasma and uET-1 levels did not correlate; therefore, renal ET-1 excretion may reflect renal ET-1 production. uET-1 levels correlated negatively with GA and GFR. uET-1 may be a marker of impaired neonatal circulatory regulation and consequent renal injury.

Topics: Acute Kidney Injury; Biomarkers; Birth Weight; Creatinine; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Male; Pilot Projects; Predictive Value of Tests; Pregnancy; Prospective Studies; United States

Kernel machine learning methods, such as the SNP-set kernel association test (SKAT), have been widely used to test associations between traits and genetic polymorphisms. In contrast to traditional single-SNP analysis methods, these methods are designed to examine the joint effect of a set of related SNPs (such as a group of SNPs within a gene or a pathway) and are able to identify sets of SNPs that are associated with the trait of interest. However, as with many multi-SNP testing approaches, kernel machine testing can draw conclusion only at the SNP-set level, and does not directly inform on which one(s) of the identified SNP set is actually driving the associations. A recently proposed procedure, KerNel Iterative Feature Extraction (KNIFE), provides a general framework for incorporating variable selection into kernel machine methods. In this article, we focus on quantitative traits and relatively common SNPs, and adapt the KNIFE procedure to genetic association studies and propose an approach to identify driver SNPs after the application of SKAT to gene set analysis. Our approach accommodates several kernels that are widely used in SNP analysis, such as the linear kernel and the Identity by State (IBS) kernel. The proposed approach provides practically useful utilities to prioritize SNPs, and fills the gap between SNP set analysis and biological functional studies. Both simulation studies and real data application are used to demonstrate the proposed approach.

Topics: Birth Weight; Data Interpretation, Statistical; Endothelin-1; Genetic Association Studies; Genetic Markers; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Models, Genetic; Phenotype; Polymorphism, Single Nucleotide; Selection, Genetic; Wounds and Injuries

To explore the role of endothelin-1 (ET-1) and leptin in intrauterine growth restriction (IUGR) among preeclamptic and non-pre-eclamptic women.. Forty three patients with a pregnancy complicated by IUGR, 23 cases with severe pre-eclampsia and 20 cases of non-pre-eclamptic were enrolled. Control group comprised 15 cases with uncomplicated pregnancy. Blood samples from umbilical artery and maternal venous blood were collected at the time of delivery for analysis of ET-1 and leptin levels. Mode of delivery, birth weight and Apgar score were also recorded.. The mean maternal and fetal ET-1 level was significantly higher in pregnancies complicated by IUGR than in control group. The mean maternal leptin level was significantly higher in pre-eclamptic patients when compared to non-preeclamptic and control groups. Mean fetal leptin level was significantly lower in patients compared to control; however, when fetal leptin corrected to fetal weight, it was insignificantly different in the both groups. E-mail: m. alhaggar@yahoo.co.uk.. Maternal plasma ET-1 and leptin correlate with the degree of fetal growth restriction originating from deterioration of placental function. Maternal plasma leptin and ET-1 levels may reflect deterioration in fetal growth.

Topics: Adult; Analysis of Variance; Biomarkers; Birth Weight; Case-Control Studies; Chi-Square Distribution; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Linear Models; Maternal Age; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Outcome; Prenatal Care; Probability; Reference Values; Sensitivity and Specificity; Severity of Illness Index; Ultrasonography, Prenatal; Young Adult

Reduced uteroplacental blood flow is hypothesized to play a key role in altitude-associated fetal growth restriction. It is unknown whether reduced blood flow is a cause or consequence of reduced fetal size. We asked whether determinants of uteroplacental blood flow were altered prior to reduced fetal growth and whether vasoactive and/or angiogenic factors were involved. Women residing at low (LA; 1,600 m, n = 18) or high altitude (HA; 3,100 m, n = 25) were studied during pregnancy (20, 30, and 36 wk) and 4 mo postpartum (PP) using Doppler ultrasound. In each study, endothelin (ET-1), nitric oxide metabolites (NO(x)), soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PlGF) levels were quantified. At HA, birth weights were lower (P < 0.01) and small-for-gestational age was more common (P < 0.05) compared with LA. HA was associated with lower uterine artery (UA) diameter (P < 0.01) and blood flow (P < 0.05). Altitude did not affect ET-1, sFlt-1 or PlGF; however, ET-1/NO(x) was greater and NO(x) lower during pregnancy and PP at HA vs. LA. ET-1/NO(x) was negatively associated with birth weight (20 wk, P < 0.01; 36 wk, P = 0.05) at LA and HA combined. At HA, UA blood flow (30 wk) was positively associated with birth weight (dagger). UA blood flow and ET-1/NO(x) levels accounted for 45% (20 wk) and 32% (30 wk) of birth weight variation at LA and HA combined, primarily attributed to effects at HA. We concluded that elevated ET-1/NO(x) and altered determinants of uteroplacental blood flow occur prior to altitude-associated reductions in fetal growth, and therefore, they are likely a cause rather than a consequence of smaller fetal size.

Topics: Adult; Altitude; Birth Weight; Colorado; Endothelin-1; Female; Femur; Fetal Growth Retardation; Head; Humans; Infant, Newborn; Infant, Small for Gestational Age; Nitric Oxide; Oxygen; Pregnancy; Regression Analysis; Uterus

Reductions in uterine perfusion pressure (RUPP) in pregnant rats is associated with increased tumor necrosis factor-alpha (TNF-alpha). This study was designed to determine the role of endogenous TNF-alpha in mediating changes in arterial pressure and endothelin-1 (ET-1) in RUPP rats. To achieve this goal we examined the effect of RUPP in the presence and absence of a TNF-alpha-soluble receptor, etanerecept (0.4 mg/kg). Mean arterial pressure increased from 102+/-1 mm Hg in normal pregnant (NP) rats to 134+/-3 mm Hg (P<0.05) in RUPP rats. Serum TNF-alpha increased to 40+/-7.6 pg/mL in RUPP rats (n=24) versus 14.8+/-3.3 pg/mL (n=16; P<0.05) in NP rats. Administration of etanerecept decreased TNF-alpha in RUPP rats (n=20) to 17.2+/-3 pg/mL and mean arterial pressure to 118+/-2 mm Hg (P<0.05). Tissue ET-1 decreased in etanerecept-treated RUPP rats compared with control RUPP rats. The direct effect of TNF-alpha blockade on endothelial activation in response to placental ischemia was examined in human umbilical vein endothelial cells. ET-1 secreted from human umbilical vein endothelial cells treated with RUPP serum was 59.2+16 pg/mg and decreased when etanerecept was added to the medium with RUPP serum (7.60+/-0.77 pg/mg), as well as in response to serum from etanerecept-treated RUPP rats (7.30+/-0.55 pg/mg; P<0.001). ET-1 secreted from human umbilical vein endothelial cells was 15.6+/-2 pg/mg when treated with NP serum. These data support the hypothesis that endogenous TNF-alpha is an important stimulus for ET-1 in response to placental ischemia and is important in mediating endothelial cell activation and hypertension during pregnancy.

Topics: Animals; Birth Weight; Blood Pressure; Cells, Cultured; Endothelial Cells; Endothelin-1; Etanercept; Female; Humans; Hypertension, Pregnancy-Induced; Immunoglobulin G; Immunologic Factors; Ischemia; Kidney; Organ Size; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Tumor Necrosis Factor; RNA, Messenger; Tumor Necrosis Factor-alpha; Umbilical Veins; Uterus

The aim of this study was to determine if there is any correlation between the hypoxia induced deterioration of renal functions and urinary excretions of endothelin (ET). Therefore using a sensitive and specific radioimmunoassay, we have investigated plasma ET-1 concentrations and urine ET-1 excretions in healthy and asphyxiated newborns. Sixteen newborns (10 boys, 6 girls) with perinatal asphyxia or hypoxia of variable seriousness which were followed at Newborn Intensive Care Unit in Eskisehir Osmangazi University Faculty of Medicine were enrolled. Simultaneously, gestation and weight matched 10 newborns (6 boys, 4 girls) with no asphyxia (first minute Apgar score >7) were enrolled as controls. Plasma ET-1 concentrations of the asphyxiated infants (61.8+/-79.3 pg/ml, between 23.4-125.2 pg/ml) were higher than in the control group (29.3+/-22.1 pg/ml, between 12.3 and 50.8 pg/ml, p<0.05). However creatinine clearance values were not different between the two groups (p>0.05), mean fractional excretion of sodium levels (FeNa%) were higher in the study group than the controls (p<0.01). Urinary ET-1 concentrations in the asphyxiated infants were 144.6+/-63.4 pg/ml versus 70.1+/-27.7 pg/ml in the control group (p<0.001). The ET clearance were more elevated in the asphyxiated newborns than in the healthy infants (p<0.05). Urinary ET-1/Cr ratio in the hypoxic infants were significantly elevated in the first day of life when compared with those of healthy infants (p<0.05). Total ET excretion was negatively correlated with FeNa (%) (r=-0.603, p<0.05). Plasma ET-1 concentrations of the asphyxiated infants reduced at 48 hours of age (p<0.001). Fifth minute Apgar score was negatively correlated with urinary ET-1 levels (r=-0.615, p<0.01), urinary Na excretion (r=-0.583, p<0.01), FeNa (%) (r=-0.597, p<0.01) and total ET excretion (r=-0.560, p<0.01) and positively correlated with ET clearance (r=0.559, p<0.05). Urinary ET-1 levels were negatively correlated with umbilical artery BE levels (r=-0.612, p<0.05). To our study, elevated urinary ET-1 levels were observed during perinatal asphyxia and urinary ET-1 levels were negatively correlated with 5th minute Apgar score and cord blood base excess levels. For this reason urinary ET-1 levels could be a marker of perinatal asphyxia as cord blood ET-1 levels. With investigations showing renal production is independent from plasma and increased urinary ET-1/Cr levels in newborn with perinatal asphyxia and also negative correlat

Topics: Apgar Score; Asphyxia Neonatorum; Birth Weight; Case-Control Studies; Endothelin-1; Female; Humans; Infant, Newborn; Male; Prospective Studies; Sodium

The aim of this study was to evaluate the effect of the traditional Chinese medicine tetrandrine (Tet) and to determine its possible mechanism on expression of endothelin-1 (ET-1) and epidermal growth factor (EGF) in the lung of a rat model of nitrofen-induced congenital diaphragmatic hernia (CDH).. A single oral dose (115 mg/kg) of nitrofen on day 9.5 of pregnancy was maternally administered to induce CDH. Pregnant rats were divided into 4 groups on day 18.5: control (n = 5), CDH (n = 5), CDH+dexamethasone (Dex) (n = 5), and CDH+Tet (n = 5). All fetuses were delivered by cesarean delivery on day 21.5. Accordingly, there were 4 groups of fetuses: control (n = 38), CDH (n = 25), CDH+Dex (n = 21), and CDH+Tet (n = 22). Lung tissue weight (LW) and body weight (BW) of each fetus were recorded, lung histologic evaluations and ET-1 and EGF immunohistochemistry staining were performed, and image analysis was performed after lung processing.. Five female rats in the control group produced 38 fetuses without CDH. CDH was observed in 68 of the 128 rat fetuses (53.1%) among the other 3 groups. The LW/BW ratio of the CDH group was significantly lower than those of the Dex and EGF groups (P < .05). The lungs of fetuses with CDH showed marked abnormal structure such as pulmonary hypoplasia and vascular remodeling, in contrast to improved pulmonary structure in lungs of fetuses in the CDH+Dex and CDH+Tet groups. Statistical differences in morphologic parameters (radial alveolar counts, percentage of alveoli, percentage of medial wall thickness, and vascular volume) were found (P < .05). The immunoreactivity of EGF and ET-1 in the CDH group was markedly stronger than that in the control, CDH+Dex, and CDH+Tet groups (P < .01). In addition, EGF and ET-1 expression in the CDH+Dex and CDH+Tet groups was stronger than that in the control group (P < .05). There was no difference in lung EGF and ET-1 immunoreactivity between CDH+Dex and CDH+Tet groups (P > .05).. Antenatal treatment with Tet may improve lung growth and vascular remodeling, and its mechanism seems to be involved in decreasing EGF and ET-1 expression. Tet administered maternally may be a hopeful new therapeutic option in the treatment of CDH and may be effective in helping to avoid the side effects of Dex.

Topics: Abnormalities, Drug-Induced; Alkaloids; Animals; Benzylisoquinolines; Birth Weight; Dexamethasone; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Endothelin-1; Epidermal Growth Factor; Female; Fetal Organ Maturity; Hernia, Diaphragmatic; Lung; Organ Size; Phenyl Ethers; Pregnancy; Pulmonary Artery; Random Allocation; Rats; Rats, Sprague-Dawley

The mechanism of pre-eclampsia is still an enigma. There is now some evidence that amniotic concentrations of endothelin is elevated in pregnancies associated with pre-eclampsia. The aim of this prospective observational study was to record the concentration of amniotic fluid endothelin and compare this in women who develop pre-eclampsia and women who do not develop pre-eclampsia. Amniotic fluid concentration of endothelin is elevated by the second trimester in women who later develop pre-eclampsia.

Topics: Adult; Amniotic Fluid; Birth Weight; Endothelin-1; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second

To evaluate the relationship of endothelin 1 (ET-1) and leptin concentrations in women and newborns following a pregnancy complicated with intrauterine growth restriction (IUGR).. Twenty-five women with a pregnancy complicated with IUGR at 19 different gestational ages were matched with women with uncomplicated pregnancies. Blood samples from the umbilical artery and maternal peripheral venous circulation were collected at delivery, and ET-1 and leptin levels were determined from the blood samples. Data relating to obstetric complications (e.g., pregnancy-induced hypertension), delivery (e.g. mode, birth weight, signs of intrapartum fetal distress, and Apgar scores) were also recorded.. Mean maternal ET-1 (13.4+/-6.2-9.9+/-2.9 pmol/l) and mean fetal ET-1 (14.5+/-4.2-11.7+/-3.1 pmol/l) concentrations were significantly higher when women had experienced pregnancies complicated with IUGR than when they had had normal pregnancies. Mean fetal leptin concentration was significantly lower in the study group (6.8+/-2.2 ng/ml) than in the control group (10.6+/-3.6 ng/ml (P<0.05). However, fetal leptin per kilogram of fetal weight was not significantly different in the study group (3.16+/-1.18 ng/ml) than in the control group (3.23+/-0.96 ng/ml) (P>0.05, paired t-test). However, a statistically significant correlation was observed between fetal leptin concentrations per kilogram of fetal weight and fetal endothelin concentrations in pregnancies complicated with IUGR (r=0.546; P<0.05).. These results suggest the intertwined roles of ET-1 and leptin in the pathophysiology of IUGR. Further studies concerning interaction between these peptides in different pregnancy conditions may provide important information about the actions of ET-1 and leptin on fetal growth.

Topics: Adult; Birth Weight; Body Mass Index; Case-Control Studies; Endothelin-1; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Pre-Eclampsia; Pregnancy; Regression Analysis

To determine the changes in plasma nitrite/nitrate (NOx) and endothelin-1 (ET-1) concentrations during neonatal sepsis.. In a prospective study, 60 consecutive newborns meeting the criteria for sepsis and without receiving exogenous nitric oxide (25 haemoculture-positive [HC+] and 35 haemoculture-negative [HC-]) were compared with 68 healthy newborns (46 full-term and 22 preterm). NOx and ET-1 concentrations were measured in each newborn within 48 h of diagnosis of sepsis and then every third day up to three determinations. SNAP-II and SNAPPE-II severity scores were performed at the moment of highest clinical severity.. At the beginning of the sepsis period, controls and septicaemic newborns had similar NOx and ET-1 levels, with the exception of infants with severe HC+ sepsis. Throughout the sepsis period, NOx increased in moderate HC+ sepsis and decreased in HC--sepsis, reaching a significant difference at the end of the study period (59.9 +/- 72.7 vs 33.9 15.3 micromol/L; p = 0.036). Meanwhile, ET-1 in newborns with severe HC+ sepsis remained higher than that in the moderate HC+ sepsis group and HC--group, reaching significant differences in all the periods. The highest ET-1 value was positively correlated with SNAP-II and SNAPPE-II scores.. NOx concentrations increased throughout the neonatal HC+ sepsis period, reaching significant differences after 7-9 d. The highest ET-1 levels in neonatal HC+ sepsis emerged before the NOx peak, at 3-5 d, and later decreased. Only newborns with severe HC+ sepsis presented a significant increase in ET-1 concentrations from the beginning of the septicaemic process.

Topics: Birth Weight; Endothelin-1; Female; Gestational Age; Humans; Infant, Newborn; Male; Nitrates; Nitrites; Prospective Studies; Sepsis; Severity of Illness Index; Time Factors

We have examined the cellular localization and human amniotic fluid content of endothelin-1 (ET-1) and macrophage colony-stimulating factor (M-CSF). The study material consisted of amniotic fluid from 20 patients referred for amniocentesis, and placental samples from normal deliveries. ET-1 and M-CSF were analysed by radioimmunoassay and enzyme-linked immunosorbent assay respectively. The cellular localization of ET-1 and M-CSF in the amnion membranes was analysed by double-labelling immunocytochemistry using fluorescein isothiocyanate- and Cy3-labelled secondary antibodies. Release of ET-1 and M-CSF was studied in cultured amniocytes. We found that the mean +/- SD concentrations of ET-1 and M-CSF in fetal amniotic fluid were 45.6 +/- 17.3 pmol/l (range 16.8-85.5) and 7323 +/- 3415 ng/l (range 2640-12 110) respectively. Double-labelling immunocytochemistry showed that both M-CSF and ET-1 were co-localized in the same cells to a high extent. Further analysis revealed that levels of M-CSF, but not ET-1, were significantly correlated with pregnancy length. Both M-CSF and ET-1 were released from cultured amniocytes in response to interleukin-1. These findings show that ET-1 and M-CSF are partly co-localized to specific cells in the human amniotic membrane. As both M-CSF and ET-1 were released from cultured amniocytes in vitro, this suggests that they both may be secreted into fetal amniotic fluid in vivo as well.

Topics: Adolescent; Adult; Amnion; Amniotic Fluid; Birth Weight; Embryonic and Fetal Development; Endothelin-1; Female; Humans; Macrophage Colony-Stimulating Factor; Pregnancy; Pregnancy Trimesters

Maternal cocaine abuse is associated with fetal and neonatal neurological abnormalities. Prolonged exposure to cocaine can induce blood flow disorders, growth restriction, and hypoxia in the newborn. We investigated the impact of chronic fetal cocaine exposure on cerebral microvascular reactivity and autonomic function in the piglets. Pregnant pigs received cocaine (1 mg/kg i.v.; twice weekly) or saline throughout the last trimester. Prenatal exposure to cocaine did not have any significant effect on the birth weight of the piglets as compared to the control. Following delivery, effects of recurrent prenatal cocaine exposure on cerebral microvascular functions were examined in piglets (3-6 days old). Pial arteriolar responses to applications of 5-hydroxytryptamine (5-HT), endothelin-1 (ET-1), and clonidine were examined using closed cranial windows. Functional effects of prenatal cocaine exposure on changes in mean arterial pressure (MAP) and pial arteriolar diameter induced by intracisternal injection (i.c.) of clonidine (1 microg/kg) were also determined. Topical applications of 5-HT, ET-1, and clonidine dose-dependently decreased pial arteriolar diameter in the control and these constrictions were significantly enhanced in the in utero cocaine-exposed piglets. Prenatal cocaine exposure did not have any significant effects on the resting MAP and heart rate as there were no differences between the groups. IC clonidine caused sustained decrease in MAP in both groups but the decrease was more pronounced in the cocaine than the control group. IC clonidine causes cerebral microvascular dilation coincident with the development of hypotension. Such dilation was severely attenuated in the cocaine group, even though the hypotension was much more pronounced than in the control. In conclusion, prenatal cocaine exposure resulted in attenuated autoregulatory vasodilation and potentiated responses to vasoconstrictor agents. The mechanisms behind the effects of in utero cocaine exposure on alteration of newborn cerebral functions need further investigation. Such actions may be important in development of cerebral pathologies associated with recurrent prenatal cocaine exposure.

Topics: Animals; Animals, Newborn; Arterioles; Autonomic Nervous System; Birth Weight; Blood Pressure; Cerebrovascular Circulation; Clonidine; Cocaine; Dose-Response Relationship, Drug; Endothelin-1; Female; Fetus; Heart Rate; Male; Pia Mater; Pregnancy; Prenatal Exposure Delayed Effects; Serotonin; Swine; Sympatholytics; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Endothelin-1 (ET-1) is a novel and potent endothelium-derived vasoconstriction peptide present in human plasma. In this study, plasma ET-1 concentrations were determined and their physiological significance was evaluated in Taiwanese neonates with respiratory distress.. Sixty newborn infants consisting of 22 with respiratory distress syndrome (RDS), 13 with transient tachypnea of newborn (TTNB), 4 with meconium aspiration syndrome, 10 healthy preterm and 11 healthy full-term infants were included for plasma ET-1 determination. Plasma ET-1 levels were measured by enzyme immunoassay at the of age of 1 day. For those who were diagnosed with RDS, plasma ET-1 concentrations were scheduled for evaluation at the ages of 1, 2, 3, 7, 14, 28, and 35 days as long as oxygen was being used.. On the first day of life, there was no significant difference in plasma ET-1 concentrations between healthy preterm and term infants (3.92 +/- 0.88 vs. 3.56 +/- 1.98 pg/mL, p = 0.606). However, plasma ET-1 concentrations of infants with RDS were significantly higher than those with TTNB (6.46 +/- 0.58 vs. 3.77 +/- 1.29 pg/mL, p < 0.001). In RDS infants, plasma ET-1 concentrations showed no significant difference between those who developed bronchopulmonary dysplasia (BPD, N = 4) and those who recovered (non-BPD, n = 18) (7.84 +/- 1.85 vs. 5.81 +/- 2.76 pg/mL, p = 0.242).. Plasma ET-1 concentrations were similar in preterm and term infants. ET-1 concentrations were higher in infants with RDS than in infants with TTNB, which suggests that plasma ET-1 levels can be useful in the differential diagnosis. However, the plasma ET-1 concentrations can not be a predictor for BPD.

Topics: Birth Weight; Bronchopulmonary Dysplasia; Endothelin-1; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Meconium Aspiration Syndrome; Respiratory Distress Syndrome, Newborn

The aim of this study was to investigate the relationship between plasma endothelin 1 (ET-1) levels and T helper (Th)-1:Th2 cell immunity in women with preeclampsia. The percentage of Th1 and Th2 cells and the Th1:Th2 cell ratios in peripheral blood from 11 normal pregnant women and 11 patients with preeclampsia at 29-34 weeks of gestation were calculated using flow cytometry. The plasma ET-1 level was also determined using a modified radioimmunoassay. The plasma ET-1 concentrations and the Th1:Th2 cell ratios in normal pregnancies were significantly lower than those in patients with preeclampsia. Negative correlations were found between plasma ET-1 levels and Th2 cells in both the preeclamptic pregnancy groups and in the normal pregnant women. Our results indicate that elevated ET-1 levels are associated with a Th1:Th2 imbalance in preeclampsia.

Topics: Adult; Birth Weight; Endothelin-1; Female; Flow Cytometry; Gestational Age; Humans; Infant, Newborn; Lymphocyte Count; Pre-Eclampsia; Pregnancy; Th1 Cells; Th2 Cells

Preeclampsia is a mainly vascular disease of pregnancy, probably caused by an imbalance between vasodilator and vasoconstrictor agents that results in generalized vasospasm and poor perfusion in many organs. Among these factors, endothelin-1 (ET-1), a potent vasoconstrictor, is highly increased in preeclamptic women, while nitric oxide (NO), a vasodilator of human utero-placental arteries, is reduced in the same patients. The present study was designed to investigate the interactions between ET-1 and the NO system in the feto-placental unit; to this purpose we also examined the messenger ribonucleic acid (mRNA) expression of ET-1, inducible NO synthase (iNOS), and endothelial NOS (eNOS) in human cultured placental trophoblastic cells obtained from preeclamptic (PE) and normotensive (NT) pregnancies. We also studied whether exogenous ET-1 may affect the expression of iNOS and eNOS in human placental trophoblastic cells. Interestingly, by Northern blot analysis we observed an increased ET-1 mRNA expression level in PE trophoblastic cells compared to NT trophoblastic cells. Furthermore, exogenous ET-1 (10(-7) mol/L) was able to up-regulate its own mRNA expression in both NT and PE trophoblastic cells. iNOS and eNOS mRNA expression was then detected, by semiquantitative PCR, in both NT and PE trophoblastic cells. PE trophoblastic cells expressed lower iNOS mRNA levels compared with NT pregnancies. On the contrary, eNOS mRNA expression was higher in PE trophoblastic cells than in NT cells. Moreover, in the presence of ET-1 we observed a decrease in iNOS and an increase in eNOS mRNA expression levels in both NT and PE trophoblastic cells compared with the respective untreated cells. In conclusion, we demonstrate that ET-1 expression is increased in PE cells, whereas iNOS, which represents the main source of NO synthesis, is decreased; conversely, eNOS expression is increased. Finally, ET-1 is able to influence its own as well as NOS isoform expression in normal and PE trophoblastic cultured cells. These findings suggest the existence of a functional relationships between ET(s) and NOS isoforms that could constitute the biological mechanism leading to the reduced placental blood flow and increased resistance to flow in the feto-maternal circulation, which are characteristic of the pathophysiology of preeclampsia.

Topics: Adult; Birth Weight; Endothelin-1; Female; Gestational Age; Humans; Infant, Newborn; Isoenzymes; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription, Genetic

To study the concentrations of endothelin-1 (ET-1) and its precursor, big ET-1, in samples of amniotic fluid, fetal urine, umbilical arterial and venous blood, retroplacental blood and maternal uterine and brachial venous blood obtained from normal and preeclamptic women. Samples were collected from 31 healthy pregnant women (16 in labor and 15 undergoing elective cesarean section) and 35 preeclamptic women (9 in labor and 26 undergoing cesarean section). Big ET-1 and ET-1 were measured by radioimmunoassay and the ET-1 to big ET-1 ratios were calculated. In preeclamptic women there was a significant elevation of ET-1 in the maternal brachial and uterine veins and of big-ET-1 in the brachial vein. The ET-1 concentrations and the ET-1/big ET ratios were significantly higher on the fetal side (i.e., in the umbilical vein and amniotic fluid) than in maternal blood, but in these sampling locations there was no difference between the normal pregnancy and preeclampsia group. A significant negative correlation (r = -0.67, P < 0.01) was found between plasma ET-1 in the umbilical vein and birth weight in the preeclamptic group. ET-1 was significantly higher in amniotic fluid than in the first neonatal urine of corresponding pregnancies (15.0 +/- 2.0 vs. 3.0 +/- 2.9 pmol/l, P < 0.05). The ET-1 and big ET-1 concentrations are significantly higher in fetal plasma and amniotic fluid than in maternal plasma, indicating increased endothelin converting enzyme activity and increased ET-1 production in utero. The elevated ET-1 concentration in maternal blood in preeclamptic compared with normal pregnant women and the negative correlation between ET-1 in the umbilical vein and birth weight suggest that ET-1 plays a pathophysiological role in preeclampsia and other conditions with intrauterine growth restriction.

Topics: Adult; Amniotic Fluid; Birth Weight; Endothelin-1; Endothelins; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Protein Precursors; Statistics as Topic