thromboxane-a2 and Fetal-Growth-Retardation

Topics: Child, Preschool; Dietary Supplements; Fetal Growth Retardation; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Thromboxane A2

Preeclampsia is characterized by a functional imbalance between vascular prostacyclin and thromboxane A2 production. Studies have demonstrated that the increase in thromboxane A2 can be corrected by administration of low-dose aspirin without causing a further decrease in prostacyclin production. Low-dose aspirin during pregnancy appears to be safe for both mother and child. Furthermore, clinical trials have demonstrated that it is effective in reducing the incidence of preeclampsia and/or intrauterine growth retardation in selected high-risk women. The use of aspirin in the treatment of existing preeclampsia and in the prevention of premature labor is not recommended. With regard to recurrent spontaneous abortion, further studies are warranted to evaluate its efficacy.

Topics: Aspirin; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Obstetric Labor, Premature; Pre-Eclampsia; Pregnancy; Thromboxane A2

Preeclampsia is characterized by a functional imbalance between vascular prostacyclin and thromboxane A2 production. On the basis of the hypothesis that preeclampsia is at least partially caused by an increase in thromboxane A2, some studies attempted to correct this pathologic condition by pharmacologic manipulation with low-dose aspirin. The current literature suggests that the use of low-dose aspirin during pregnancy is safe with regard to congenital anomalies and fetal, neonatal, and maternal cardiovascular physiologic state and hemostasis. Aspirin at least partially corrects the pathologic increase in angiotensin II sensitivity that precedes the clinical development of preeclampsia. In addition, some clinical trials have demonstrated that low-dose aspirin is effective in reducing the incidence of preeclampsia and/or fetal growth retardation in selected high-risk women. Currently, large clinical trials are in progress to evaluate the effectiveness and side effects of the use of low-dose aspirin in preventing preeclampsia and/or fetal growth retardation. Until these studies have been completed, it will remain unclear whether antiplatelet therapy, such as low-dose aspirin, should be adopted for the prevention of either preeclampsia or fetal growth retardation.

Topics: Angiotensin II; Aspirin; Clinical Trials as Topic; Epoprostenol; Female; Fetal Growth Retardation; Humans; Platelet Aggregation Inhibitors; Pre-Eclampsia; Pregnancy; Thromboxane A2

All pregnancy-associated tissues are capable of producing prostaglandins including PGI2 and TXA2. In normal pregnancy there is a dominance of PGI2 over TXA2 which may contribute to the maternal circulatory adaptation to pregnancy. Furthermore, both fetoplacental PGI2 and TXA2 production are important regulators of the fetal blood supply. It has been clearly established that in pre-eclampsia PGI2 production decreases in the fetoplacental tissues and quite probably also in the maternal tissues. The effect of this change may be further exaggerated by the simultaneous stimulation in pre-eclampsia of TXA2 production. The reason for PGI2 deficiency is not known. Other vasoactive agents, such as endothelin, may act in concert with prostaglandins. Relative PGI2 deficiency is likely to exist also in IUGR and lupus anticoagulant syndrome of pregnancy. In the latter, lupus anticoagulant may directly inhibit the synthesis of PGI2. One study suggests PGI2 deficiency also in early pregnancies of women with a history of repeated abortions. Prostaglandin production increases during full-term labour, and similar but smaller changes also occur in preterm labour. A silent bacterial infection may trigger the onset of preterm labour through cytokine-stimulated increase of prostaglandin production. No data were found on prostaglandin production in post-term pregnancies. That oligo-polyhydramnios is possibly prostaglandin mediated is suggested by the control of polyhydramnios by indomethacin treatment. Smoking decreases the production of PGI2 and possibly increases that of TXA2, which may lead to decreased blood flow and IUGR. Which constituent of cigarette smoke exerts this effect is not known. Ethanol consumption causes aberrations in prostaglandin metabolism which cannot be directly connected with fetal alcohol effects.

Topics: Abortion, Habitual; Alcohol Drinking; Epoprostenol; Female; Fetal Growth Retardation; Humans; Lupus Erythematosus, Systemic; Obstetric Labor, Premature; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Prostaglandins; Smoking; Thromboxane A2; Thromboxane B2

Topics: Aspirin; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Epoprostenol; Female; Fetal Growth Retardation; Humans; Placenta; Placental Insufficiency; Pre-Eclampsia; Pregnancy; Prostaglandin-Endoperoxide Synthases; Thromboxane A2

In a controlled, nonrandomized trial a treatment group of 24 multigravid women with a history of at least two previous pregnancies, all complicated by idiopathic fetal growth retardation and placental infarction, received 1 to 1.6 mg/kg aspirin and 225 mg dipyridamole daily from 16 to 34 weeks' gestation in a total of 30 pregnancies. The end-point measure of the study was birth weight related to gestational age. Results obtained in the treatment group were compared with those in 27 pregnancies of a control group of 24 multigravid women with a similar history of recurrent fetal growth retardation who received comparable antenatal care without low dose aspirin and dipyridamole. Fetal growth retardation occurred in 61% of the control pregnancies and in only 13% of treated pregnancies; severe fetal growth retardation was not observed in treated pregnancies, but it occurred in 27% of the control group. In treated women, platelet cyclo-oxygenase activity was suppressed to 5% to 10% of its pretreatment level, but no effect on vascular prostacyclin production was demonstrated. Treatment did not produce adverse effects in mothers or infants. Low-dose aspirin and dipyridamole direct prostacyclin/thromboxane A2 balance in pregnancy to the dominance of prostacyclin and may thus prevent idiopathic uteroplacental insufficiency and fetal growth retardation in high-risk patients.

Topics: Adult; Aspirin; Birth Weight; Clinical Trials as Topic; Dipyridamole; Epoprostenol; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Pregnancy; Recurrence; Thromboxane A2

Hypertensive disease of pregnancy (HDP) with placental insufficiency is the most common cause of fetal growth restriction (FGR) in the developed world. Despite the known negative consequences of HDP both to the mother and fetus, little is known about the longitudinal placental changes that occur as HDP progresses in pregnancy. This is because longitudinal sampling of human placentae during each gestation is impossible. Therefore, using a mouse model of thromboxane A2-analog infusion to mimic human HDP in the last trimester, we calculated placental efficiencies based on fetal and placental weights; quantified spongiotrophoblast and labyrinth thicknesses and vascular density within these layers; examined whether hypoxia signaling pathway involving vascular endothelial growth factor A (VEGFA) and its receptors (VEGFR1, VEGFR2) and matrix metalloproteinases (MMPs) contributed to vascular change; and examined nutrient transporter abundance including glucose transporters 1 and 3 (GLUT1, GLUT3), neutral amino acid transporters 1, 2, and 4 (SNAT1, SNAT2, and SNAT4), fatty acid transporters 2 and 4 (FATP2, FATP4), and fatty acid translocase (CD36) from embryonic day 15.5 to 19 in a 20-day C57Bl/6J mouse gestation. We conclude that early-to-mid gestation hypertensive placentae show compensatory mechanisms to preserve fetal growth by increasing placental efficiencies and maintaining abundance of important nutrient transporters. As placental vascular network diminishes over late hypertension, placental efficiency diminishes and fetal growth fails. Neither hypoxia signaling pathway nor MMPs mediated the vascular diminution in this model. Hypertensive placentae surprisingly exhibit a sex-differential expression of nutrient transporters in late gestation despite showing fetal growth failure in both sexes.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Amino Acid Transport Systems, Neutral; Animals; Disease Models, Animal; Fatty Acid Transport Proteins; Female; Fetal Growth Retardation; Glucose Transport Proteins, Facilitative; Matrix Metalloproteinases; Mice; Placenta; Placentation; Pregnancy; Signal Transduction; Thromboxane A2; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

Intrauterine growth restriction (IUGR) is a pathology of pregnancy that results in failure of the fetus to reach its genetically determined growth potential. In developed nations the most common cause of IUGR is impaired placentation resulting from poor trophoblast function, which reduces blood flow to the fetoplacental unit, promotes hypoxia and enhances production of bioactive lipids (TXA2 and isoprostanes) which act through the thromboxane receptor (TP). TP activation has been implicated as a pathogenic factor in pregnancy complications, including IUGR; however, the role of TP isoforms during pregnancy is poorly defined. We have determined that expression of the human-specific isoform of TP (TPβ) is increased in placentae from IUGR pregnancies, compared to healthy pregnancies. Overexpression of TPα enhanced trophoblast proliferation and syncytialisation. Conversely, TPβ attenuated these functions and inhibited migration. Expression of the TPβ transgene in mice resulted in growth restricted pups and placentae with poor syncytialisation and diminished growth characteristics. Together our data indicate that expression of TPα mediates normal placentation; however, TPβ impairs placentation, and promotes the development of IUGR, and represents an underappreciated pathogenic factor in humans.

Topics: Adult; Animals; Animals, Newborn; Cell Line, Tumor; Female; Fetal Growth Retardation; Humans; Hypoxia; Male; Mice, Inbred C57BL; Mice, Transgenic; Placenta; Pregnancy; Protein Isoforms; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Trophoblasts

Intrauterine growth restriction (IUGR) offspring with rapid catch-up growth are at increased risk for early obesity especially in males. Persistent insulin-like growth factor-1 (IGF-1) reduction is an important risk factor. Using a mouse model of maternal hypertension-induced IUGR, we examined IGF-1 levels, promoter DNA methylation, and histone H3 covalent modifications at birth (D1). We additionally investigated whether prenatal perturbations could reset at preadolescence (D21).. IUGR was induced via maternal thromboxane A2-analog infusion in mice.. IUGR uniformly decreased D1 IGF-1 mRNA and protein levels with reduced promoter 1 (P1) transcription and increased P1 DNA methylation. IUGR males also had increased H3K4ac at exon 5 and 3' distal UTR. At D21, IUGR males continued to have decreased IGF-1 levels, originating from both P1 and P2 with reduced 1A variant. IUGR males also had decreased activation mark of H3K4me3 at P1 compared with sham males. In contrast, D21 IUGR females normalized their IGF-1 levels, in association with an increased activation mark of H3K4me3 at P1 compared with sham females.. IUGR uniformly affected D1 hepatic IGF-1 epigenetic modifications in both sexes. However, at preadolescence, IUGR males are unable to correct for the prenatal reduction possibly due to a more perturbed IGF-1 chromatin structure.

Topics: Animals; Blood Glucose; Body Weight; Chromatin; Chromatin Assembly and Disassembly; DNA Methylation; Exons; Female; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Histones; Insulin; Insulin-Like Growth Factor I; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Promoter Regions, Genetic; Risk Factors; Sex Factors; Thromboxane A2

Fetal growth restriction (FGR) remains a cause of perinatal brain injury, sometimes leading to neurological and intellectual impairment. Although the mechanisms and pathophysiology of CNS injuries have not been elucidated completely, it is possible carbohydrate and energy metabolism may have an important role in the FGR brain. In this study, FGR was induced in rats by administration of synthetic thromboxane A2 (STA2). Pups were delivered by cesarean section. After killing, samples were obtained from the fetuses of both control and FGR rats for evaluation of carbohydrate and energy metabolism in brain tissue. Lactate and pyruvate levels in brain were reduced significantly in the FGR group. Glucose content in brain tissue tended to be increased in the FGR group. In contrast, glycogen content in brain tissue tended to be lower in the FGR group. However, these differences in glucose and glycogen content did not reach statistical significance. Brain high-energy reserves, including ATP, ADP, AMP, and phosphocreatine (P-Cr), were similar in the control and FGR groups. Gluconeogenesis compensated for chronic fetal hypoxia and decreased glycogen storage. Energy metabolism in the FGR brain is likely to be disrupted as a consequence of lower reserves of energy substrates.

Topics: Animals; Brain; Carbohydrate Metabolism; Cesarean Section; Disease Models, Animal; Energy Metabolism; Female; Fetal Growth Retardation; Fetal Hypoxia; Fetal Weight; Gestational Age; Gluconeogenesis; Organ Size; Placental Circulation; Pregnancy; Rats; Rats, Sprague-Dawley; Thromboxane A2

To examine the effect of maternal smoking in pregnancy on the production of two eicosanoids, thromboxane A(2) and prostacyclin I2, and their role in the pathogenesis of intrauterine growth restriction.. Prospective case control study enrolled smoking and non-smoking women at ≤14 weeks gestation. Maternal urine samples were obtained at ≤14, 28 and 36 weeks. High performance liquid chromatography tandem mass spectrometry (LC-MS-MS) was used to quantify 11-dehydrothromboxane B(2) (TX-M) and 2,3 dinor-6-ketoprostaglandin F1α (PG-M), stable urinary metabolites of thromboxane A(2) and prostacyclin I2. Confirmation of the smoking status was performed by quantitation of urinary nicotine metabolites. Data was analysed using SPSS and Stata(®).. Thirty five were enrolled in the smoking group and 32 in the non-smoking group. Smoking resulted higher levels of TX-M at ≤14, 28 and 36 weeks gestation. There was no difference in PG-M at any gestational time point between the two groups. The median customised birthweight centile in the smoking group was 17.0 (0-78) compared to 55.5 (4-100) in the non-smoking group (P<0.001). A causal relationship between elevated TX-M and IUGR could not be established.. Maternal smoking in pregnancy is associated with altered eicosanoid production in favour of the vasoconstrictor thromboxane A(2) which occurs early in the first trimester.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Case-Control Studies; Female; Fetal Growth Retardation; Humans; Pregnancy; Smoking; Thromboxane A2; Thromboxane B2; Young Adult

Fetal growth retardation (FGR) is a critical problem in the neonatal period, because a substantial population of infants born with FGR go on to develop various developmental disorders. In the present study, we produced FGR model rats by continuous administration of a synthetic thromboxane A2 analogue (STA2) to pregnant rats. The FGR pups exhibited a significant delay in postnatal neurological development. Moreover, behavioral analyses revealed the presence of a learning disability in juvenile FGR male rats. To investigate the mechanism underlying the neurological disorders, histological and biochemical analyses of the brain of FGR rats were performed. The density of neurons in the cortical plate of an FGR brain was low compared with the brains of a similarly aged, healthy rat. Consistent with this finding, the density of TUNEL-positive cells was higher in the cortical plate of FGR brains. Western blot analyses showed that the levels of three brain-specific chondroitin sulfate proteoglycans (CSPGs), neurocan, phosphacan, and neuroglycan C, were all significantly reduced in the brain of neonatal FGR rats compared with those of the control. The reduction of CSPG-levels and morphological changes in the brain may be relevant to neurological dysfunction in FGR.

Topics: Animals; Animals, Newborn; Brain; Cell Count; Cerebral Cortex; Chondroitin Sulfate Proteoglycans; Developmental Disabilities; Disease Models, Animal; Female; Fetal Growth Retardation; Growth Inhibitors; Humans; Infant, Newborn; Learning Disabilities; Male; Membrane Proteins; Neurocan; Pregnancy; Proteoglycans; Rats; Rats, Sprague-Dawley; Receptor-Like Protein Tyrosine Phosphatases, Class 5; Thromboxane A2

Intrauterine growth retardation (IUGR) is an important cause of prenatal and neonatal morbidity, and neurologic abnormalities. Although several animal models of IUGR have been developed for scientific investigation, few models approximate the pathophysiology in human fetal growth failure resulting from pregnancy-induced hypertension and preeclampsia. We developed an animal model of IUGR in which fetal growth restriction was induced by administering a synthetic thromboxane A(2) analogue (STA(2)) to the mother.. Timed pregnant Sprague-Dawley rats were used in this study. STA(2) was delivered into the peritoneal cavity of the pregnant female at a rate of 20 ng/h from day 13 of pregnancy. The effectiveness of this model was evaluated by monitoring the overall growth of the fetuses and neonates and measuring the weight and biochemical composition of individual organs.. Fetuses and neonates from the STA(2) group showed a highly significant weight reduction throughout the observation period from day 19 of gestation to postnatal day 7. Weight reduction near and at term exceeded 10% and became more pronounced during the first week after birth. Fetuses on the 20th gestational day exhibited a pattern of growth retardation characteristic of asymmetrical IUGR in which the weight reduction was prominent in the liver with relative sparing of the brain. However, the decrease in brain weight was more than 10%. The protein, DNA, and RNA contents of the liver were lower in the STA(2) group. The protein content of the forebrain and brainstem also decreased significantly in the STA(2) group compared with the control; however, the DNA content of the forebrain was higher in the STA(2) group.. This animal model may mimic human IUGR more closely than previous models because the growth restriction is induced in a truly chronic manner.

Topics: Animals; Disease Models, Animal; Female; Fetal Development; Fetal Growth Retardation; Infusions, Parenteral; Pregnancy; Rats; Rats, Sprague-Dawley; Thromboxane A2

Prostanoids influence differentiation in diverse cell types. Altered expression of cyclooxygenase and prostaglandins has been implicated in the pathophysiology of placental dysfunction, which results in preeclampsia and fetal growth restriction. We hypothesized that prostanoids modulate differentiation and apoptosis in cultured human trophoblasts. Villous cytotrophoblasts were isolated from term human placentas and cultured in serum-free medium. The level of human chorionic gonadotropin was used as a marker of biochemical differentiation of primary trophoblasts, and syncytia formation was used as a marker of morphologic differentiation. Of the prostanoids tested, we found exposure to thromboxane A(2) hindered both biochemical and morphologic differentiation of cultured trophoblasts. As expected, human chorionic gonadotropin levels in the media were elevated in a concentration-dependent manner in the presence of the thromboxane synthase inhibitor, sodium furegrelate, or the thromboxane A(2) receptor blocker SQ 29,548. Furthermore, thromboxane A(2) enhanced trophoblast apoptosis, determined using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, cell morphology, and a concentration-dependent increase in p53 expression. We conclude that thromboxane A(2) hinders differentiation and enhances apoptosis in cultured trophoblasts from term human placenta. We speculate that thromboxane may contribute to placental dysfunction by restricting differentiation and enhancing apoptosis in human trophoblasts.

Topics: Apoptosis; Cell Differentiation; Cells, Cultured; Chorionic Gonadotropin; Female; Fetal Growth Retardation; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2; Trophoblasts; Tumor Suppressor Protein p53

Thromboxane (Tx) A2 is a platelet agonist, smooth muscle cell constrictor, and mitogen. Urinary Tx metabolite (Tx-M) excretion is increased in syndromes of platelet activation and early in both normal pregnancies and in pregnancy-induced hypertension. A further increment occurs in patients presenting with severe preeclampsia, in whom Tx-M correlates with other indices of disease severity. TxA2 exerts its effects through a membrane receptor (TP), of which two isoforms (alpha and beta; refs. 5,6) have been cloned. Overexpression of TP in the vasculature under the control of the pre-proendothelin-1 promoter results in a murine model of intrauterine growth retardation (IUGR), which is rescued by timed suppression of Tx synthesis with indomethacin. IUGR is commonly associated with maternal diabetes or cigarette smoking, both conditions associated with increased TxA2 biosynthesis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Vessels; Disease Models, Animal; Female; Fetal Growth Retardation; Humans; Male; Mice; Receptors, Thromboxane; Thromboxane A2

Many reports have associated intrauterine growth retardation (IUGR) with adverse neurological outcome, but the underlying pathology is imperfectly understood. We have developed a new rat model of IUGR using maternal administration of synthetic thromboxane A(2) (STA(2)). In the present study, the effect of this insult on neuronal migration in the rat cerebral cortex was examined. Bromodeoxyuridine (BrdU), a time-specific cell marker was administered intraperitoneally to the mothers on embryonic day (E) 19. At postnatal day (P) 3, P4, P5, and P6, pups were terminally anesthetized and brains were removed. BrdU-labeled cells were detected immunohistochemically and counted in cerebrum, which was divided into the cortical plate (CP), the intermediate zone, and the subventricular/ventricular zone (SVZ+VZ). Numbers of labeled cells in the three areas over time were compared between IUGR and control animals. Numbers of labeled cells in SVZ+VZ were significantly greater in IUGR than in controls at P3, 5, and 6 (P<0.05). In contrast, labeled cells in the CP were significantly less abundant in IUGR animals than in controls at P3, 4, and 6 (P<0.05). We concluded that neuronal migration was delayed in IUGR rats.

Topics: Animals; Animals, Newborn; Brain; Cell Movement; Disease Models, Animal; Female; Fetal Growth Retardation; Neurons; Pregnancy; Rats; Rats, Sprague-Dawley; Thromboxane A2

Intrauterine growth retardation (IUGR) often results in clinical neurodevelopmental disorders. To clarify the influence of uteroplacental insufficiency on central nervous system development, we have created a model of IUGR in rats using maternal administration of synthetic thromboxane A(2). We investigated expression patterns of neural cell adhesion molecule (NCAM) and reelin in this model by semiquantitative competitive polymerase chain reactions. On postnatal day 2, NCAM expression was decreased in rat cerebral cortex, and reelin expression was decreased in hippocampus from levels in controls without maternal thromboxane exposure. No significant differences in NCAM expression were seen in hippocampus, nor did reelin expression differ in cerebral cortex between control and IUGR groups. We also examined expression of two neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). In cerebral cortex the IUGR group showed less BDNF and NT-3 expression than controls. Delay of neuronal migration and histological changes observed in our IUGR rats may be related to altered expression of these molecules.

Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Cerebral Cortex; Female; Fetal Growth Retardation; Gene Expression; Hippocampus; Nerve Growth Factors; Neural Cell Adhesion Molecules; Neurotrophin 3; Pregnancy; Rats; Rats, Sprague-Dawley; Reelin Protein; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thromboxane A2

IUGR was induced by maternal administration of synthetic thromboxane A2 (STA2) from the 13th day of gestation. Fetuses and neonates showed a markedly significant weight reduction. In E16 IUGR brain, no pathological abnormalities were found, but morphological changes appeared in the cortical plate of E18 IUGR brain. In E20 IUGR brain, ectopic clusters of differentiating cells cytologically mimicking neuroblasts were found in the neuroepithelial layer, but these abnormal clusters of cells in IUGR brain of late gestation were never observed in PN7. Morphometric analysis of coronal-sectional areas of the brain and cortical plate demonstrated that there were no differences between IUGR rats and controls in E16 and E18. These areas were, however, significantly reduced in E20 and PN7 growth-retarded rats compared with the control. Because the period of STA2 administration coincides with the neuro-developmental stage of cell migration and differentiation, reduction of the uteroplacental blood supply might cause a transient abnormal cytoarchitecture of the cerebral cortex resulting in brain growth retardation.

Topics: Animals; Animals, Newborn; Body Weight; Brain; Brain Diseases; Disease Models, Animal; Embryonic and Fetal Development; Female; Fetal Growth Retardation; Pregnancy; Rats; Rats, Sprague-Dawley; Thromboxane A2

This study on the human umbilical artery was undertaken in order to elucidate possible correlations between changes in response to vasoactive substances in vitro and abnormal umbilical artery flow velocity waveforms in vivo associated with preeclampsia and intrauterine growth retardation. The vascular reactivity to endothelin-1, noradrenalin, serotonin, the thromboxane A2 analogue U46619, substance P and prostacyclin was determined in umbilical artery segments from 13 normal pregnancies and 29 pregnancies complicated with preeclampsia and/or intrauterine growth retardation with normal or abnormal umbilical flow velocity waveforms. The contractile effect in vitro of endothelin-1 and noradrenalin was reduced in segments from pregnancies complicated by abnormal umbilical flow velocity waveforms in vivo. No differences were detected in the contractile effect of serotonin and U46619, or in the relaxatory effect of substance P and prostacyclin. In conclusion, endothelin-1- and noradrenalin-related mechanisms could be involved in the abnormal umbilical flow velocity waveforms associated with preeclampsia and intrauterine growth retardation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Blood Flow Velocity; Dose-Response Relationship, Drug; Endothelins; Epoprostenol; Female; Fetal Growth Retardation; Hemodynamics; Humans; Muscle, Smooth, Vascular; Norepinephrine; Pre-Eclampsia; Pregnancy; Prostaglandin Endoperoxides, Synthetic; Regional Blood Flow; Serotonin; Substance P; Thromboxane A2; Ultrasonography, Doppler; Umbilical Arteries; Vasoconstriction; Vasoconstrictor Agents

The aim of this study was to investigate the possible association between Doppler velocimetry and synthesis of prostacyclin (PGI2) and thromboxane A2 (TxA2) in umbilical cord vessels. The hypothesis was that an altered balance between PGI2 and TxA2 production is associated with a change of artery flow resistance.. 17 cases with a suspicion of intrauterine growth retardation and 21 normal pregnancies were studied. The umbilical artery pulsatility index (PI) and venous mean velocity were recorded in vivo by Doppler velocimetry. Cord vessel prostanoid synthesis was determined in vitro. The Mann-Whitney U test and simple linear regression were used for statistical analyses.. The umbilical vessel synthesis of both PGI2 and TxA2 was in general lower in small-for-gestational age (SGA) cases (n = 10) compared to appropriate-for-gestational age (AGA) (n = 28). In the vein, the PGI2/TxA2 ratio was significantly lower in SGA cases. No certain correlations were found between umbilical artery PI and venous velocity, respectively, and PGI2 or TxA2, or their ratio.. The prostanoid synthesis was in general lower in SGA cases, resulting in a significantly lower PGI2/TxA2 ratio in the umbilical vein. This indicates that fetal growth retardation might be associated with a disturbed endothelial function in this vessel. The synthesis of PGI2 and TxA2 in the juxtaplacental umbilical cord vessels was not correlated to the umbilical artery PI or venous flow velocity. It is possible that an altered release of prostanoids in the placental vasculature and tissue accounts for the rise of umbilical artery flow resistance instead.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Flow Velocity; Case-Control Studies; Endothelium, Vascular; Epoprostenol; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Pregnancy; Pulsatile Flow; Reproducibility of Results; Rheology; Thromboxane A2; Thromboxane B2; Ultrasonography, Doppler, Pulsed; Ultrasonography, Prenatal; Umbilical Arteries; Umbilical Veins

Through systematic experimental and clinical studies, the physiological regulation of utero-placental circulation and the relation of the disturbance in this acirculation to pathogenic mechanisms of high risk pregnancies-Intrauterine Growth Retardation (IUGR) and Pregnancy-induced hypertension (PIH) were explored. The pharmacological effects and mechanism of a Chinese herbal medicine-Qingxintong in improving, the utero-placental circulation and the therapeutic efficacy in treatment of IUGR and PIH, both accompanied by disturbance of utero-placental circulation, were investigated as well.

Topics: Acetophenones; Drugs, Chinese Herbal; Epoprostenol; Female; Fetal Growth Retardation; Humans; Placental Circulation; Platelet Aggregation Inhibitors; Pre-Eclampsia; Pregnancy; Pregnancy, High-Risk; Thromboxane A2

High-dose supplements of fish oil reduce thromboxane synthesis in nonpregnant human subjects and were therefore proposed as a means of preventing various small-vessel disorders, including preeclampsia. The effect of fish oil on thromboxane metabolism in pregnancy was investigated in our study.. Sixteen normal pregnant women in the third trimester of pregnancy were treated with a daily ingestion of 6 gm fish oil capsules containing 1.6 gm of n-3 fatty acid. In five patients the treatment was stopped because of severe-flavored reflux and hiccups. Eleven patients completed 3 weeks of treatment. Twenty-four-hour urinary 11-dehydro-thromboxane B2 was measured by means of radioimmunoassay before and after completion of the study protocol in these 11 patients and in seven control pregnant women who did not receive the oil treatment.. A decrease ranging from 32% to 71%, in 24-hour urinary 11-dehydro-thromboxane B2 excretion (mean reduction from 1606 pg/mg creatinine to 779 pg/mg creatinine, p < 0.001) was found among the 11 fish oil-treated women. No change in excretion was found among the control women. No maternal, fetal, or neonatal bleeding disturbances occurred, and no laboratory changes in coagulation markers were observed.. High-dose n-3 fatty acid intake in pregnancy significantly reduces maternal thromboxane A2 synthesis. These results may provide a basis for a possible role of fish oil in managing patients at risk for preeclampsia.

Topics: Adult; Creatinine; Fatty Acids, Omega-3; Female; Fetal Growth Retardation; Fish Oils; Humans; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Third; Thromboxane A2; Thromboxane B2; Urea

To explore the mechanisms underlying the reduced maternal plasma volume associated with idiopathic fetal growth retardation (FGR).. In 30 normotensive women with growth-retarded fetuses and 26 with normal-size fetuses, plasma volume was measured with a modified Evan's blue method. Plasma levels of atrial natriuretic peptide, plasma renin activity, aldosterone, estradiol, and progesterone, and urinary excretion of kallikrein, prostacyclin, and thromboxane A2 were measured at 34-40 weeks' gestation.. Compared with controls, gravidas with growth-retarded fetuses had a reduced plasma volume expansion (P < .01), similar atrial natriuretic peptide and plasma renin activity levels, and lower serum aldosterone (P < .001) and placental steroids (P < .03). These women also had decreased urinary kallikrein activity and prostaglandin excretion (P < .05). When both groups were combined, maternal plasma volume correlated significantly with birth weight (r = 0.53) and placental weight (r = 0.66).. Normotensive women with idiopathic FGR have reduced plasma volume expansion. Although the exact mechanisms of this change are unknown, we postulate that the lower maternal aldosterone levels and reduced levels of vasodilator substances, such as prostacyclin and kallikrein, may have a causal role.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Epoprostenol; Estradiol; Female; Fetal Growth Retardation; Hormones; Humans; Kallikreins; Plasma Volume; Pregnancy; Progesterone; Renin; Thromboxane A2

Pregnancy-induced hypertension (PIH) and preeclampsia develop when an imbalance occurs between prostacyclin (PGI2) and thromboxane A2 (TXA2) production. PGI2 promotes vasodilation and decreases platelet adhesiveness, while TXA2 acts as a vasoconstrictor and enhances platelet aggregation and adhesion to vascular walls. The PGI2/TXA2 ratio appears to be important in pregnancy and the development of the functioning uteroplacental unit. Recently, antiplatelet treatment such as low-dose aspirin therapy has been effective in preventing the development of PIH and preeclampsia. TXA2 breaks down spontaneously into a stable substance, TXB2, which is inactive. Another stable, inactive metabolite, malondialdehyde (MDA), is formed via the same pathway. TXB2 and MDA are produced in approximately equimolar quantities. We studied the effects of a low-dose aspirin prescription. Production of MDA was remarkably suppressed during the low-dose aspirin therapy. Furthermore, pulsed doppler ultrasound assessment of blood flow was performed in the fetal descending aorta, umbilical artery and uterine artery of the low-dose aspirin therapy patients. Doppler abnormalities were improved during the therapy. It is concluded that low-dose aspirin improves the uteroplacental blood flow assessed by pulse doppler waveform and that determination of MDA is useful as an indicator of platelet thromboxane synthesis.

Topics: Adult; Aspirin; Epoprostenol; Female; Fetal Growth Retardation; Humans; Malondialdehyde; Middle Aged; Placenta; Pre-Eclampsia; Pregnancy; Regional Blood Flow; Thromboxane A2; Uterus

The reactivity of the platelet thromboxane pathway was investigated by means of measurement of thrombin-induced formation of malondialdehyde in platelets obtained from 26 women in the third trimester of uncomplicated pregnancies, 27 patients with normotensive pregnancies who were delivered of small--for--gestational age infants, 27 patients with pregnancy-induced hypertension and infants with normal birth weights, and 20 patients with pregnancy-induced hypertension and small--for--gestational age infants. Platelet life span and distribution of platelet volumes were also determined. In normotensive and hypertensive pregnant women with small--for--gestational age infants, platelet malondialdehyde formation was significantly increased, and platelet life span was reduced as compared with the other groups. The enhanced reactivity of the platelet thromboxane pathway may be expected to contribute to the increased in vivo platelet activation and consumption which occur in pregnancies with chronic placental insufficiency. Deficient production of placental vascular prostacyclin might be the underlying cause.

Topics: Blood Platelets; Cell Survival; Female; Fetal Growth Retardation; Humans; Malondialdehyde; Platelet Count; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Third; Thromboxane A2; Thromboxanes