thromboxane-b2 and Pre-Eclampsia

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

The gynecologic and obstetric implications of the smooth muscle-relaxing, antiaggregatory prostacyclin and its endogenous antagonist, thromboxane A2, are reviewed. In addition to the vascular wall and circulating platelets, which are primary sources for prostacyclin and thromboxane A2, respectively, reproductive tissues produce great amounts of these prostanoids, evidently for the regulation of the vascular tone and/or vascular platelet interaction. Several gynecologic and obstetric disorders are characterized by abnormalities in prostacyclin and/or thromboxane A2. In primary menorrhagia the uterine release of prostacyclin is increased, and consequently menstrual blood loss can be reduced with various prostaglandin synthesis inhibitors. Prostacyclin relaxes the nonpregnant myometrium in vitro and may also do so in vivo, although intravenous infusion of prostacyclin has no effect upon the uterine contractility in nonpregnant or pregnant subjects. Patients with pelvic endometriosis may have increased levels of prostacyclin and thromboxane A2 metabolites in the peritoneal fluid. The prostacyclin/thromboxane A2 balance shifts to thromboxane A2 dominance in patients with gynecologic cancer. During pregnancy the production of prostacyclin and thromboxane A2 increases in the mother and fetoplacental tissue. Preeclampsia and other chronic placental insufficiency syndromes are accompanied by prostacyclin deficiency in the mother and in fetomaternal tissues and by an overproduction of thromboxane A2, at least in the placenta. These changes may account for the vasoconstriction and platelet hyperactivity, which are pathognomonic for hypertensive pregnancies. By directing the prostacyclin/thromboxane A2 balance to prostacyclin dominance (by dietary manipulation, administration of prostacyclin and/or its analogues, drugs with prostacyclin-stimulating and/or thromboxane A2-inhibiting action), it may be possible to prevent and/or treat hypertensive pregnancy complications in the future.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Ascitic Fluid; Endometriosis; Epoprostenol; Estrogens; Female; Genital Diseases, Female; Genital Neoplasms, Female; Humans; Hypertension; Menorrhagia; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Complications, Cardiovascular; Progestins; Thromboxane A2; Thromboxane B2; Thromboxanes; Uterine Contraction; Vasoconstriction

Preeclampsia is a unique disease of pregnancy. Delivery via caesarean section is the most important way of terminating the pregnancy and treating preeclampsia. Perioperative fluid therapy is performed to maintain the circulatory volume and reduce tissue edema. This study evaluated the effects of hypertonic sodium chloride hydroxyethyl starch 40 (HSH40) as perioperative fluid therapy for preeclampsia patients.. Forty preeclamptic women were randomly divided into two groups: the Ringer's solution group and the HSH40 group. Their ECG, HR, MAP, and SPO2 were monitored. Their MVP and HR were recorded at five, eight, and ten minutes after anesthesia induction and at the end of the caesarean section. The corresponding volume of infusion, blood loss, and urine output during the operation were also recorded. Venous samples were collected before HSH40 infusion and 30 min after infusion to measure the plasma concentrations of ET, TXB2, 6-keto-PGF1α, and ANP via a radioimmunoassay.. HSH40 infusion significantly decreased the plasma ET levels (p < 0.01), significantly changed the plasma ANP and TXB2 levels (p < 0.05), and significantly increased the plasma 6-keto-PGF1α levels (p < 0.01) in the experimental group compared with those before infusion. The plasma levels of ET, ANP, TXB2, and 6-keto-PGF1α did not significantly change in the control group. Compared with T1, MAP decreased significantly at T2, T3, T4, and T5 within groups (p < 0.05) and between the two groups. MAP significantly changed at T2, T3, T4, and T5 (p < 0.05). HR did not significant change at T1, T2, T3, T4, and T5 within or between groups. Volume of infusion and urine volume significantly differed between groups (p < 0.05).. Low-dose HSH40 lowers the plasma levels of vasoconstrictor substances (ET and TXB2) and increases the levels of vasodilator substances (6-keto-PGF1α and ANP) during preeclampsia. It effectively maintains and stabilizes the circulating blood volume, increasing renal blood flow, which improves renal function and increases urine output.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Atrial Natriuretic Factor; Cesarean Section; Female; Fluid Therapy; Humans; Hydroxyethyl Starch Derivatives; Isotonic Solutions; Perioperative Care; Plasma Substitutes; Pre-Eclampsia; Pregnancy; Ringer's Solution; Saline Solution, Hypertonic; Therapeutics; Thromboxane B2

To determine the effect of low doses of linoleic acid and calcium on prostaglandin (PG) levels and the efficacy of this treatment in the prevention of preeclampsia.. In a randomized, double-blind, placebo-controlled study we treated 86 primigravidas with risk factors for preeclampsia (high biopsychosocial risk [above 3 points], positive roll-over test, and high mean blood pressure [above 85 mmHg)] with daily doses of either 450 mg linoleic acid and 600 mg calcium (n=43) or 450 mg starch and 600 mg lactose placebo (n=43) during the third trimester of pregnancy.. Four women in the experimental group (9.3%) developed preeclampsia compared with 16 (37.2%) controls (relative risk 0.25, 95% confidence interval 0.09, 0.69, P < .001). The median serum levels of PGE2 after 4 weeks of treatment increased by 106% in the experimental group (P=.03) and decreased by 33% in the control group (P=.02). The median ratio between thromboxane B2 and PGE2 decreased by 40% in the experimental group (P=.02) and increased by 18% in the control group (P=.14). No significant differences were observed in the median ratio between thromboxane B2 and 6-keto PGF1alpha in either group. No serious maternal or neonatal side effects of treatment occurred in either group.. The administration of low daily doses of linoleic acid and calcium during the third trimester of pregnancy reduced the incidence of preeclampsia significantly in women at high risk, possibly by correcting the PGE2 levels.

Topics: Calcium; Dietary Supplements; Dinoprostone; Double-Blind Method; Female; Humans; Linoleic Acid; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Prostaglandins; Socioeconomic Factors; Thromboxane B2

To examine the fetal effects of a novel controlled-release, low dose aspirin preparation in normal and hypertensive pregnancies.. Random double-blind study. Participants assigned to receive conventional formulation aspirin (75 mg), controlled-release low dose aspirin (75 mg), or a matching placebo.. National Maternity Hospital, Dublin.. Eighteen women with an uncomplicated pregnancy and 18 women with preeclampsia.. Urine was analysed for metabolites of thromboxane and prostacyclin by gas chromatography, mass spectrometry. Serum thromboxane B2 was determined in maternal and cord blood.. Both aspirin preparations reduced maternal serum thromboxane B2 by 95% and induced similar reductions in the urinary 11-dehydro-thromboxane B2, a major metabolite of thromboxane A2 in vivo. In contrast, neither preparation altered urinary 2,3-dinor-6-keto PGF1alpha, the major metabolite of prostacyclin. Despite their similar effects in the mothers, the two aspirin preparations differed in their effects on the fetus. While both suppressed cord fetal thromboxane B2, this was significantly (P < 0.005) less for the controlled-release preparation (210+/-42 ng/ml for placebo vs 109+/-22 ng/ml for controlled-release aspirin and 44+/-9 ng/ml for regular oral aspirin).. At equivalent maternal suppression of serum thromboxane B2, a controlled aspirin release preparation results in lower fetal exposure than regular oral aspirin.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Cyclooxygenase Inhibitors; Delayed-Action Preparations; Double-Blind Method; Eicosanoids; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Thromboxane B2

To study the effects of oral low-dose magnesium gluconate in prevention of pregnancy induced hypertension (PIH) and its mechanism.. A prospective randomized double-blind study was carried out in 51 pregnant women as treatment group (including 22 cases as treatment group 1 and 29 cases as treatment group 2) and 51 pregnant women as controls (including 28 cases as controls group 1 and 23 cases as control group 2). Low-dose magnesium gluconate (3 g/day) or placebo was given from the 28th week of gestation to delivery consecutively.. 4% of the pregnant women developed PIH after magnesium gluconate treatment, which was substantially lower than that in the control group (16%) (P < 0.05). In the treatment group 2, women showed higher concentration of 6-keto-prostaglandin F1 alpha (PGF1a) and 6-keto-/thromboxane B2(TXB2) (P/T) ratio than that of the control group 2. Moreover, TXB2 level was lower than that in the control group 2. In the treatment group 1 women showed higher ratio of P/T than that of the control group 1. There were no significant differences of serum magnesium concentration among all groups.. Low-dose magnesium gluconate may efficiently prevent PIH in high risk women. The mechanism of action of magnesium gluconate probably involves to keep the balance of PGI2 and TXA2, but not associates with serum magnesium level.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Double-Blind Method; Female; Gluconates; Humans; Pre-Eclampsia; Pregnancy; Prospective Studies; Thromboxane B2

Our purpose was to determine whether in a low-dose aspirin trial a longitudinal decrease in maternal serum thromboxane B2 is associated with improvement in pregnancy outcomes.. A total of 606 healthy nulliparous women with singleton gestations were randomized at 24 weeks to either 60 mg of aspirin or a placebo. Maternal serum thromboxane B2 was measured at randomization, at 29 to 31 weeks, at 34 to 36 weeks, and at delivery. After delivery, and without knowledge of patient outcome or group assignment, patients were categorized as having had either a longitudinal twofold or greater (> or = 50%) or less than twofold reduction (< 50%) in thromboxane B2 from baseline levels at randomization.. Of 606 entrants, 92% had sufficient thromboxane B2 determinations to allow categorization. Whether patients were assigned to aspirin or placebo, birth weight was significantly greater in women who had a twofold or greater reduction in maternal serum thromboxane B2 levels. When the aspirin and placebo groups were combined, women with a twofold or greater reduction in thromboxane B2 levels had less preeclampsia, 1.9% (6/314) versus 5.7% (14/244) (p = 0.016), less preterm delivery (5.7% vs 10.7%, p = 0.032), fewer small-for-gestational-age newborns, 9 of 314 (2.95) versus 17 of 244 (7%) (p = 0.023), and a higher mean birth weight, 3314 gm versus 3121 gm (p = 0.0001).. Women with a twofold or greater longitudinal reduction in maternal serum thromboxane B2 had less preeclampsia and prematurity, fewer small-for-gestational-age newborns, and higher birth weights than women with less than a twofold reduction.

Topics: Aspirin; Birth Weight; Double-Blind Method; Embryonic and Fetal Development; Female; Humans; Obstetric Labor, Premature; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Thromboxane B2

Concern has been expressed about possible neonatal side effects after the use of maternal anti-platelet agents in pregnancy, particularly low dose aspirin treatment. We have studied neonatal platelet behaviour using whole blood techniques, and assessed the neonatal effect of the maternal ingestion of 60 mg aspirin daily.. Cross sectional and randomised, double-blind, placebo-controlled.. University hospital.. 1. Eight normal women, studied before conception, and their infants. 2. Twenty-four infants whose mothers had been randomised to receive either 60 mg aspirin daily, or placebo, in double-blind fashion.. The Clay Adams Ultra Flo 100 whole blood single platelet counter was employed to measure platelet aggregation in response to various agonists. The platelet release reaction was also measured in whole blood, and serum thromboxane B2 (TxB2) production was measured by radio-immunoassay. Umbilical cord blood samples were obtained at delivery.. 1. Neonatal platelet aggregation induced by adrenaline, ADP and platelet activating factor was reduced in comparison with their mothers (P < 0.01), whereas the neonatal platelet release reaction was reduced when stimulated by collagen and U46619 (a thromboxane mimetic) (P < 0.01). Serum TxB2 production was similar in mothers and babies. 2. Neonatal platelet aggregation, release reaction and serum TxB2 production were not significantly reduced in infants exposed to maternal aspirin in comparison with those neonates exposed to maternal placebo. This is in contrast to the effect on maternal platelets.. Although only a small number of patients were studied, we interpret this as a relative sparing of neonatal platelet reactivity due to the presystemic action of low dose aspirin.

Topics: Adult; Aspirin; Double-Blind Method; Female; Fetal Blood; Humans; Hypertension; In Vitro Techniques; Infant, Newborn; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

We compared pill counts with a biochemical measure of compliance in 283 women who participated in a randomized double-blind trial that evaluated the efficacy of low-dose aspirin in the prevention of preeclampsia. Subjects whose pill counts indicated a usage > 100% were less compliant than women with lower pill counts.

Topics: Aspirin; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Patient Compliance; Pre-Eclampsia; Pregnancy; Thromboxane B2

Our aim was to test the hypothesis that acetylsalicylate (aspirin) treatment reduces the incidence or severity of pregnancy-associated hypertension.. Patients were nulliparous, healthy, and with a singleton gestation at between 20 and 22 weeks' gestation. A sample size of 600 patients was calculated on the basis of p < or = 0.05 and 90% power of observation. A 2-week placebo-controlled "run-in" was used to select compliant patients. Randomization occurred at 24 weeks, with 60 mg of aspirin or placebo treatment from randomization to delivery.. Follow-up was maintained on 99% of the patients. The randomized patients had a 94% pill compliance index. At randomization, serum thromboxane medians were similar in both groups. Thromboxane B2 levels in the aspirin group decreased significantly from baseline at 29 to 31 weeks, 34 to 36 weeks, and at delivery as compared with an overall increase in the placebo group. Preeclampsia developed in five of 302 women (1.7%) who received aspirin versus 17 of 302 (5.6%) who received the placebo (p = 0.009). Preeclampsia was severe in one aspirin and in six placebo recipients (p = 0.06).. Daily ingestion of 60 mg of aspirin beginning at 24 weeks' gestation significantly reduced the occurrence of preeclampsia.

Topics: Adult; Aspirin; Eclampsia; Female; Humans; Hypertension; Parity; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Prospective Studies; Thromboxane B2

A prospective randomized double-blind study was carried out in pregnant women with risk of pregnancy induced hypertension (PIH). Low dose Aspirin (50 mg/day) or placebo was given consecutively from the 28th weeks of gestation. The results have shown that 8% of the pregnant women in the aspirin treatment group had developed PIH, which was substantially lower than that in the control group (24%) (P less than 0.05). The ratio of TXB2/6-keto-PGF1 alpha increased significantly in the control group while it remained unchanged in treatment group. Increasing plasma fibronectin (Fn) and decreasing AT-III level were seen in the control group but no changes of these parameters in the treatment group. It was presumed that low dose aspirin may have prophylactic effect on PIH. The mechanism of aspirin may be the inhibition of TXA2 and Fn synthesis and decreased consumption of AT-III.

Topics: 6-Ketoprostaglandin F1 alpha; Aspirin; Double-Blind Method; Female; Fibronectins; Humans; Pre-Eclampsia; Pregnancy; Prospective Studies; Thromboxane B2

Preeclampsia is a pregnancy-specific disorder, leading to maternal and infant morbidity and mortality. Abnormal placentation has been reported in preeclampsia. Nutrients like vitamin D and long-chain polyunsaturated fatty acids (LCPUFA) are known to play a role in placental development. In an animal model, we have previously demonstrated that maternal vitamin D deficiency increases the thromboxane/prostacyclin ratio and contributes to inflammation and vasoconstriction. We hypothesize that maternal vitamin D status influences placental LCPUFA metabolism through alterations in one carbon metabolism in women with preeclampsia. To test this hypothesis, we recruited 69 normotensive control (NC) women and 50 women with preeclampsia. Women with preeclampsia had lower placental protein and mRNA levels of cystathionine-β-synthase (CBS), higher plasma malondialdehyde (MDA) levels and higher levels of arachidonic acid (AA) and total omega-6 fatty acids in the placenta. Women with preeclampsia also demonstrated higher placental mRNA levels of cyclooxygenase-2 (COX-2) as compared to NC women. Maternal 25(OH)D levels were negatively associated with maternal plasma MDA levels. Placental vitamin D receptor (VDR) levels were positively associated with CBS while maternal MDA levels were positively associated with serum levels of thromboxane-B2 (TXB2) levels. Our findings indicate that vitamin D deficiency increases oxidative stress through alterations in one carbon metabolism to influence pro-inflammatory omega-6 metabolic pathway in the placenta. This study demonstrates a possible mechanism through which vitamin D deficiency can result in an imbalance in the LCPUFA metabolites and contribute to placental inflammation and endothelial dysfunction in preeclampsia.

Topics: Adolescent; Adult; Cross-Sectional Studies; Fatty Acids; Fatty Acids, Unsaturated; Female; Humans; Infant, Newborn; Malondialdehyde; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Receptors, Calcitriol; Thromboxane B2; Vitamin D; Vitamin D Deficiency; Young Adult

The content of vasoactive compounds and arachidonic acid in the placenta and amniotic fluid was studied in full-term (39-40 weeks) physiological pregnancy and preeclampsia (PE). The content of metabolites of nitric oxide (NOx), endothelin-1, thromboxane B2 (TxB2), prostacycline (PGI2) and arachidonic acid was estimated using spectrophotometric, immunoenzyme methods and gas-liquid chromatography. It was found that in PE the content of vasoconstrictors, of endothelin and TxB2, increased in the placenta and amniotic fluid, while the content of vasodilators, PGI2 and NOx decreased. Despite the same directionality of changes in both studied objects, the degree of changes differed and was more pronounced in the placenta. A direct or inverse correlative relationship was found between various vasoactive components (depending on their effect on vascular tone). In the case of arachidonic acid changes in its content in PE correlated with the level of vasoactive compounds, the source of which it is. The revealed differences in the ratio of vasoactive components obviously play a pathogenetic role in the development of PE and its subsequent complications.. Izucheno soderzhanie vazoaktivnykh soedineniĭ i arakhidonovoĭ kisloty v platsente i okoloplodnykh vodakh pri donoshennoĭ (39-40 nedel') fiziologicheskoĭ beremennosti i preéklampsii (PÉ). S pomoshch'iu spektrofotometricheskikh, immunofermentnykh metodov i gazozhidkostnoĭ khromatografii otsenivali soderzhanie metabolitov oksida azota (NOx), éndotelina-1 (ÉT-1), tromboksana B2 (TxB2), prostatsiklina (PGI2) i arakhidonovoĭ kisloty. Ustanovleno, chto pri PÉ kolichestvo vazokonstriktorov ÉT-1 i TxB2 vozrastaet v platsente i okoloplodnykh vodakh, a vazodilatatorov – NOx i PGI2 snizhaetsia. Na fone odinakovoĭ napravlennosti izmeneniĭ v oboikh issledovannykh ob"ektakh stepen' izmeneniia razlichna i bolee vyrazhena v platsente. Mezhdu razlichnymi vazoaktivnymi komponentami obnaruzhena priamaia ili obratnaia korreliatsionnaia vzaimosviaz' (v zavisimosti ot ikh vliianiia na sosudistyĭ tonus). Izmenenie soderzhaniia arakhidonovoĭ kisloty pri PÉ korrelirovalo s urovnem vazoaktivnykh soedineniĭ, istochnikom kotorykh ona iavliaetsia. Vyiavlennye otlichiia v sootnoshenii vazoaktivnykh komponentov, ochevidno, igraiut patogeneticheskuiu rol' v razvitii PÉ i ee posleduiushchikh oslozhneniĭ.

Topics: Amniotic Fluid; Arachidonic Acid; Endothelin-1; Female; Humans; Nitric Oxide; Placenta; Pre-Eclampsia; Pregnancy; Prostaglandins I; Thromboxane B2

Verify that resistance to aspirin may have an impact on pregnancy and neonatal outcome.. We enrolled 43 pregnant women, aged 30.7 ± 4.0 years regularly taking 75 mg of aspirin daily and 32 (aged 30.8 ± 4 years) pregnant women not receiving aspirin who served as control group. Laboratory tests were performed at 18 to 22 weeks of gestation, 28 to 32 weeks of gestation and 16 to 32 weeks after delivery. Resistance to aspirin was defined as urinary 11-dehydrothromboxane B2 (u11-dTXB2) concentrations in the highest quartile and additionally, as the resistance index (RI) calculated for each woman, defined as the difference between u11-dTXB2 concentration of each woman treated with aspirin and the median value at the same time point measured in the control group.. Women taking aspirin in the highest quartile of u11-dTXB2 delivered prematurely (35.8±3.4 vs 38.1±1.7 weeks, p=0.02). Delivery of small for gestational age (SGA) newborns (p=0.003) as well as fetal distress (p=0.014) and preeclampsia (p=0.003) occured more frequently in aspirin-resistant women. Resistance to aspirin based on the RI value was also associated with higher prevalence of preeclampsia (p=0.02) and SGA newborns delivery (p=0.01). The two groups resistant to ASA designed on the basis of both (RI and u11-dTXB2 urine levels) methods compared with ASA sensitive group differed in frequency of SLE prevalence.. Aspirin resistance may be associated with increased risk of adverse pregnancy outcomes including preeclampsia, premature delivery and delivery of SGA newborns.

Topics: Adult; Aspirin; Cesarean Section; Drug Resistance; Female; Fetal Distress; Humans; Infant, Newborn; Infant, Small for Gestational Age; Lupus Erythematosus, Systemic; Obstetric Labor, Premature; Parity; Platelet Aggregation Inhibitors; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Thromboxane B2; Young Adult

To investigate apical and basal releases of thromboxane (TX) and prostacyclin (PGI2) by trophoblasts (TCs) from normal and preeclamptic (PE) placentas.. TCs isolated from normal and PE placentas were incubated in cell culture inserts for 48h. Medium from the upper (apical) and the lower (basal) chambers were then collected separately and measured for TX and PGI2 by their stable metabolites of TXB2 and 6-keto PGF1alpha by ELISA. Apical and basal releases of TX and PGI were also examined with apical exposure of TCs to arachidonic acid (AA)+/-aspirin at different concentrations. Villous tissue expressions for PGI synthase, TX synthase and TX (TP) receptor were examined by immunohistochemistry.. (1) TXB2, but not 6-keto PGF1alpha, concentrations were significantly higher in the lower than in the upper chambers with both normal and PE TCs (p<0.01); (2) apical exposure of TCs to AA resulted in a significant increase in TX release towards both the upper and the lower chambers in normal TCs (p<0.01), but only a significant increase in the upper chamber in PE TCs (p<0.01); (3) aspirin could attenuate AA-induced TX release both in the upper and the lower chambers in normal, but not in PE, TCs (p<0.01), respectively; (4) there were no differences in 6-keto PGF1alpha productions both in normal and PE TCs treated with AA+/-aspirin; (5) intense staining of TX synthase and TP receptor was seen in syncytiotrophoblast layer, villous core vessels and stromal cells in preeclamptic placental tissue sections.. Predominant basal release of TX together with intense staining of TX synthase and TP receptor in trophoblasts, stromal cells and villous core vessels are found in placentas from PE. We speculate if predominant basal release of TX by TCs occurs in vivo as we found in our in vitro culture condition, basal released TX may play a significant role in increased placental vasoconstriction such as in PE.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Aspirin; Epoprostenol; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Receptors, Thromboxane; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Trophoblasts; Vasoconstriction

In this study we determined whether hypoxia could promote vasoactivator thromboxane (TX) and prostacyclin (PGI2) as well as phospholipase A2 (PLA2) production by placental trophoblast cells (TCs) from normal and preeclamptic (PE) pregnancies. Placentas were obtained immediately after delivery from normal (n=9) and preeclamptic (n=9) pregnancies. TCs were isolated by dispase digestion of villous tissue and purified by Percoll gradient centrifugation. TCs (5x10(6) cells/well) were cultured with Dulbecco's Modified Eagles Medium (DMEM) under hypoxia condition (2% O2/5% CO2/93% N2) for 48 h. TCs cultured under normoxia condition (5% CO2/air) were used as control. Culture medium was collected at the end of incubation. Productions for TX, PGI2 and PLA2 were measured by ACE competitive enzyme immunoassay (EIA). Comparisons were made using the Mann-Whitney U test or paired t-test and the data are expressed as mean+/-SE (pg/microg cellular protein). Significance was set at a p-value of <0.05. We found: (1) PE-TCs produced more TXB2 and PLA2 than normal-TCs under normoxia conditions, TXB2: 4.33+/-1.03 vs. 1.84+/-0.29 pg/microg protein, p<0.05; PLA2: 0.38+/-0.08 vs. 0.21+/-0.03 pg/microg protein, p<0.05, respectively. (2) Hypoxia promoted both PE- and normal-TCs to generate more TXB2 and PLA2, TXB2: 6.36+/-1.72 vs. 3.05+/-0.45 pg/microg; PLA2: 0.52+/-0.10 vs. 0.30+/-0.04 pg/microg, respectively. (3) No change in 6-keto PGF1alpha production was observed for normal-TCs or PE-TCs when compared under normoxia vs. hypoxia condition, normal-TCs: 0.20+/-0.05 vs. 0.21+/-0.05 pg/microg; PE-TCs: 0.38+/-0.05 vs. 0.36+/-0.04 pg/microg, respectively. We concluded that hypoxia promotes both PLA2 and TX, but not PGI2, production by placental trophoblast cells cultured under hypoxia condition. These results suggest that increased PLA2 release may alter the arachidonic acid cascade and promote TX synthesis. Relative hypoxia could contribute to the increase in TX production and result in vasoconstriction in placental vasculature in preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cell Hypoxia; Cells, Cultured; Epoprostenol; Female; Humans; Kinetics; Phospholipases A; Phospholipases A2; Pre-Eclampsia; Pregnancy; Thromboxane B2; Thromboxanes; Trophoblasts

Preeclampsia is associated with oxidative stress, elevated plasma levels of linoleic acid (LA), and increased vascular smooth muscle expression of the inflammatory chemokine, interleukin-8 (IL-8). We hypothesized that increased levels of LA under conditions of oxidative stress would increased production of IL-8 by vascular smooth muscle cells because LA is the dietary precursor to arachidonic acid (AA) and its metabolites that mediate inflammation. We also hypothesized that oleic acid (OA), which is not metabolized to AA metabolites, would not increase IL-8 under conditions of oxidative stress.. To test this hypothesis, we cultured placental arterial smooth muscle (PASM) cells with an oxidizing solution enriched with LA (OxLA) or OA (OxOA). Media concentrations were analyzed for IL-8 and AA metabolites. Inhibitors were used to block the lipoxygenase and cyclooxygenase pathways.. Exposure of cells to OxLA, but not to OxOA, significantly increased production of IL-8. OxLA also significantly increased production of AA metabolites. Nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway, blocked IL-8 and leukotriene B4 (LTB4) production induced by OxLA, whereas indomethacin, an inhibitor of the cyclooxygenase pathway, blocked IL-8, prostaglandin E2 (PGE2), and thromboxane B2 (TXB2) production. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated gene expression in PASM cells for representative lipoxygenase (LTB4) and cyclooxygenase (thromboxane) metabolite receptors.. PASM cells produced IL-8 in response to LA, but not OA, under conditions of oxidative stress. The IL-8 response was mediated by AA metabolites.

Topics: Arachidonic Acid; Cells, Cultured; Female; Gene Expression; Humans; Interleukin-8; Leukotriene B4; Linoleic Acid; Lipoxygenase; Muscle, Smooth, Vascular; Oleic Acid; Oxidative Stress; Pre-Eclampsia; Pregnancy; Prostaglandin-Endoperoxide Synthases; Reverse Transcriptase Polymerase Chain Reaction; Thromboxane B2; Up-Regulation

The purpose of this study was to examine 6-keto-prostaglandin F(1)(alpha) and thromboxane B(2) plasma levels throughout normotensive and preeclamptic pregnancies and to analyze the predictive values of these quantifications for the detection of preeclampsia during the second trimester of pregnancy.. Blood samples were collected from 30 healthy, nonpregnant women and at 4-week intervals from a cohort of nulliparous women who were recruited before 16 weeks of gestation. Preeclampsia developed in 26 patients; 52 normotensive control subjects were matched from the same cohort. The 6-keto-prostaglandin F(1)(alpha) and thromboxane B(2) were assayed by radioimmunoassay. Trends were compared between pregnancy groups and with the nonpregnant women. Predictive values were determined with the second-trimester assessments.. The 6-keto-prostaglandin F(1)(alpha)/thromboxane B(2) ratio decreased throughout pregnancy in women with preeclampsia; there were no significant changes in normotensive women. We found higher thromboxane B(2) levels within the group with preeclampsia during the first gestational trimester (preeclampsia, 188 +/- 17 pg/mL; control, 119 +/- 4.8 pg/mL [mean +/- SEM]; P =.001). During the third trimester, patients with preeclampsia had lower 6-keto-prostaglandin F(1)(alpha) levels than did control subjects (preeclampsia, 191 +/- 9.8 pg/mL; control, 288 +/- 10 pg/mL; P =.001). The 6-keto-prostaglandin F(1)(alpha)/thromboxane B(2) ratio was suitable to calculate predictive values; the best cutoff point and time interval were 3.0 and 22 to 26 weeks of gestation, respectively. Sensitivity, specificity, and positive and negative predictive values were 88%, 97%, 69%, and 99%, respectively; the odds ratio was 14.6 (95% CI, 6.9-30.4).. The prostacyclin/thromboxane ratio favored vasoconstriction early in gestation in women in whom preeclampsia developed. A 6-keto-prostaglandin F(1)(alpha)/thromboxane B(2) ratio of

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Biomarkers; Case-Control Studies; Cohort Studies; Female; Humans; Longitudinal Studies; Odds Ratio; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Reference Values; Sensitivity and Specificity; Thromboxane B2

The activities of placental superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), but not catalase, are lower than normal in preeclampsia, which could contribute to the uncontrolled placental production of lipid peroxides and thromboxane (TX). Oxidative stress, hyperlipidemia and increased iron levels in the maternal compartment in preeclampsia could be responsible for these placental changes by causing oxidative stress in the placenta.. We tested this possibility in vitro by exposing a trophoblast-like cell line, ED27, to a combination of linoleic acid (LA, 90 microM) and an oxidizing solution composed of hypoxanthine, xanthine oxidase and ferrous sulfate (OxLA) for 6 days. For these studies, the cells were treated with dexamethasone (10-8 M) for the first 72 hr. This was done to differentiate the cells into a phenotype more like syncytiotrophoblast cells as evidenced by production of beta-human chorionic gonadotropin (beta-hCG).. After 6 days of exposure to OxLA, the activities of SOD and GSH-Px were significantly decreased as compared to exposure to LA alone. In contrast, catalase activity was increased by OxLA. The OxLA-induced decreases in SOD and GSH-Px activities were attenuated by deferoxamine, an iron chelator, suggesting a role for Fe2+ in the decreased activities. Compared to LA, OxLA significantly increased TX secretion and lipid peroxidation in cells and media at 2, 4 and 6 days. Deferoxamine inhibited the OxLA-induced increase in lipid peroxidation, but not the increase in TX. Isolation of trophoblast cells and villous core tissue from term placentas verified that antioxidant enzyme activity was localized primarily to the trophoblast cell compartment lending validity to the in vitro findings.. These data mimic the changes in placental SOD, GSH-Px, catalase, TX and lipid peroxidation that occur in preeclampsia suggesting that maternal hyperlipidemia and increased iron levels may be responsible for placental oxidative stress and abnormalities in antioxidants and thromboxane.

Topics: Adult; Analysis of Variance; Catalase; Cell Line; Chorionic Gonadotropin; Deferoxamine; Female; Ferrous Compounds; Glutathione Peroxidase; Humans; Iron Chelating Agents; Linoleic Acid; Lipid Peroxidation; Oxidative Stress; Pre-Eclampsia; Pregnancy; Superoxide Dismutase; Thromboxane B2; Trophoblasts; Xanthine Oxidase

To analyse whether pregnancies resulting in a small for gestational age neonate are preceded by a prostacyclin deficiency or an imbalance between thromboxane and prostacyclin.. At five fixed time points during pregnancy, 24-h urine samples were collected for the measurement of thromboxane and prostacyclin metabolites thromboxane-B(2) (TXB(2)) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)). In order to study trend differences between pregnancies with appropriate (AGA; n=26) and small for gestational age neonates (SGA; n=17), trend analysis with simple contrasts were accomplished for TXB(2), 6-keto-PGF(1alpha) and the TXB(2)/6-keto-PGF(1alpha) ratio.. Trend analysis showed higher TXB(2) levels and higher TXB(2)/6-keto-PGF(1alpha) ratios in patients with SGA versus AGA newborns. No statistically significant difference in 6-keto-PGF(1alpha) excretion between patients with SGA and AGA newborns was detected.. The birth of an SGA neonate is not preceded by prostacyclin deficiency. With ongoing pregnancy an imbalance between thromboxane and prostacyclin becomes more obvious in pregnancies with SGA newborns.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Birth Weight; Female; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Pre-Eclampsia; Pregnancy; Thromboxane B2

To study the effect of plasma from women with preeclampsia on endothelial cell activators in vitro and determine whether factor(s) in the plasma of women with preeclampsia induces activation of vascular endothelial cells.. Twenty women with preeclampsia and 15 normal ones at late trimester of pregnancy were studied, from whom maternal venous blood samples were collected. Plasma 6-keto-PGF1 alpha, the end products of prostacyclin (PGI2) and TXB2, the end products of thromboxane A2(TXA2), were measured by radioimmunoassay. Plasma from women with preeclampsia or from normal women at late trimester was added to the bovine pulmonary microvessel endothelial cells in vitro. Twenty-four hours later, levels of 6-keto-PGF1 alpha produced by cultured endothelial cells were measured.. The mean values of 6-keto-PGF1 alpha in matrnal venous plasma were (94.49 +/- 25.23) ng/L in preeclamptic group and (248.81 +/- 51.99) ng/L in normal pregnant group. Plasma TXB2 values were (104.61 +/- 13.12) ng/L in preeclamptic group and (66.26 +/- 38.80) ng/L in normal pregnant group. TXB2/6-keto-PGF1 alpha ratios were (1.11 +/- 0.03) in preeclamptic group and (0.28 +/- 0.02) in normal pregnant group. Maternal plasma values of 6-keto-PGF1 alpha were lower in peeclamptic group than those of normal pregnant group (P < 0.01). On the other hand, plasma TXB2 values were higher in preeclamptic group than in normal pregnant group (P < 0.01). TXB2/6-keto-PGF1 alpha ratios, however, were significantly different between the two groups (P < 0.01). The values of 6-keto-PGF1 alpha produced by cultured endothelial cells exposed to 2% plasma were (1,363.00 +/- 99.16) ng/L in preeclamptic group and (819.49 +/- 96.62) ng/L in normal pregnant group (P < 0.01).. PGI2 and TXA2 may play an important role in preeclampsia. Plasma from women with preeclampsia could stimulate the production of prostacyclin in cultured endothelial cells in vitro.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Endothelium, Vascular; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2; Thromboxane B2

An imbalance in vasodilating (prostacyclin [PGI2]) and vasoconstricting (thromboxane A2 [TxA2]) eicosanoids may be important in preeclampsia, but prospective data from large studies needed to resolve this issue are lacking. Because most trials using aspirin to reduce TxA2 production have failed to prevent preeclampsia, it is critical to determine whether eicosanoid changes occur before the onset of clinical disease or are secondary to clinical manifestations of preeclampsia.. To determine whether PGI2 or TxA2 changes occur before onset of clinical signs of preeclampsia.. Multicenter prospective study from 1992 to 1995 of subjects from the placebo arm of the Calcium for Preeclampsia Prevention Trial. Women who developed preeclampsia (n = 134) were compared with matched normotensive control women (n = 139).. Excretion of urinary metabolites of PGI2 (PGI-M) and TxA2 (Tx-M) as measured from timed urine collections obtained prospectively before 22 weeks', between 26 and 29 weeks', and at 36 weeks' gestation.. Women who developed preeclampsia had significantly lower PGI-M levels throughout pregnancy, even at 13 to 16 weeks' gestation (long before the onset of clinical disease); their gestational age-adjusted levels were 17% lower than those of controls (95% confidence interval [CI], 6%-27%; P=.005). The Tx-M levels of preeclamptic women were not significantly higher overall (9% higher than those of controls; 95% CI, -3% to 23%; P=.14). The ratio of Tx-M to PGI-M, used to express relative vasoconstricting vs vasodilating effects, was 24% higher (95% CI, 6%-45%) in preeclamptic women throughout pregnancy (P=.007).. Our results show that reduced PGI2 production, but not increased TxA2 production, occurs many months before clinical onset of preeclampsia. Aspirin trials may have failed because an increase in thromboxane production is not the initial anomaly. Future interventions should make correcting prostacyclin deficiency a major part of the strategy to balance the abnormal vasoconstrictor-vasodilator ratio present in preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Biomarkers; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Prospective Studies; Randomized Controlled Trials as Topic; Thromboxane A2; Thromboxane B2

A disturbance of prostacyclin (PGI2) and thromboxane A2 (TXA2) balance has been reported in preeclampsia. However, little is known about the concentrations of these prostanoids in neonates born to preeclamptic pregnant women. The purpose of this study is to determine whether the PGI2 and TXA2 concentrations are altered and whether the prostanoid balance correlates to the cerebral blood flow in neonates born to preeclampsia.. Spontaneously voided urine samples were collected from 20 neonates of normotensive and 16 neonates of preeclamptic women during the first 24 h after birth. We measured by radioimmunoassay the concentrations of urinary 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) and 11-dehydro-thromboxane B2 (11-dehydro-TXB2), respectively. Blood flow velocity in the middle cerebral artery was studied by pulsed Doppler ultrasonography in the neonates between 17 and 38 h after birth.. There was no significant difference between the urinary 6-keto-PGF1alpha in the neonates of mothers with and without preeclampsia (median, 5.3 vs. 3.6 ng/mg of creatinine). In contrast, the urinary 11-dehydro-TXB2 and the ratio of 11-dehydro-TXB2 to 6-keto-PGF1alpha in the neonates of mothers with preeclampsia were significantly lower as compared with the neonates without preeclampsia, respectively (13.7 vs. 20.6 ng/mg of creatinine and 3.0 vs. 5.2, median). The resistance index in the middle cerebral artery was significantly reduced in the neonates with preeclampsia than without preeclampsia (0.67 +/- 0.01 vs. 0.74 +/- 0.02, mean +/- SEM).. There was an association between maternal preeclampsia and the imbalance in the neonatal urinary excretion of PGI2 and TXA2 metabolites. This imbalance may contribute to the regulation of cerebral blood flow.

Topics: 6-Ketoprostaglandin F1 alpha; Cerebrovascular Circulation; Female; Humans; Infant, Newborn; Pre-Eclampsia; Pregnancy; Thromboxane B2

The aims of this study were to describe levels of thromboxane secretion by decidual endothelial cells from normal pregnancies and to determine whether decidual endothelial cell secretion of thromboxane, implicated in the causation of the hypertension and vasoconstriction of preeclampsia, is increased in this disorder.. We measured thromboxane generation by cultured decidual endothelial cells from 13 normal pregnancies (NDEC) and 13 pregnancies complicated by preeclampsia (PEDEC), compared with a control population of 6 normal human umbilical vein endothelial cells (HUVEC). Responses to stimulation by bacterial lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) were examined.. Thromboxane B2 levels in supernatants of cultured endothelial cells.. The level of secretion over 24 h in culture by NDEC [14 (7-26) pg/10(6) cells] was approximately 25% that of HUVEC [63 (49-70) pg/10(6) cells]. Levels achieved in response to all stimuli examined were consistently lower in NDEC than in HUVEC (p < 0.01). Proportional stimulation by LPS and TNF-alpha was comparable in HUVEC and NDEC, whereas NDEC displayed a greater increase (25-fold) than HUVEC (10-fold) in response to IL-1 beta (p < 0.01). There were no significant differences between decidual endothelial cells from normotensive and preeclamptic women in basal secretion of thromboxane or in responses to the stimuli examined.. In vitro thromboxane secretion by decidual endothelial cells is lower than that of HUVEC, and responsiveness to specific stimuli may be quantitatively different. These findings emphasize the importance of examining endothelial cells from the involved maternal vascular bed if intrauterine vascular pathophysiological events are to be clarified. No significant differences were noted in decidual endothelial cell thromboxane secretion between normal and preeclamptic subjects.

Topics: Cells, Cultured; Decidua; Endothelium; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane B2

The objectives of this study were to evaluate the possible mechanisms involved in prolongation of bleeding time in pre-eclamptic patients receiving a magnesium sulfate infusion to prevent convulsions. Eighteen pre-eclamptic patients near term or at term (4 cases 33 to 35 weeks; the remainder > 36 weeks) were studied. Fifteen of them received magnesium sulfate infusion; 3 did not and served as controls. Bleeding time (modified Ivy method with Surgicutt), platelet count, platelet aggregation pattern, as well as serum arachidonic acid metabolites [thromboxane B2 (TxB2) and 6-Keto-prostaglandin F1 alpha (6-Keto-PGF1 alpha)] werde done on admission to the labor floor (before magnesium infusion) and repeated at discontinuation of the infusion, 12-24 hours postpartum; the controls received the second test 24 hours postpartum. Thirteen of 15 patients receiving magnesium sulfate had an increase in bleeding time from an average of 6 minutes 31 seconds to 11 minutes 56 seconds, an 82% rise (p < 0.004). In 2 there was a decrease. Among the 3 controls the averages were 6 minutes 38 seconds and 6 minutes 3 seconds. The total magnesium given ranged from 52.5 to 145 grams. Platelet counts averaged 251,000/mm3 (range 145,000-519,000). Platelet aggregation pattern done in 11 patients and was normal and unchanged after magnesium in 10 of the patients with increased bleeding time and one control. TxB2 and 6-Keto-PGF1 alpha levels did not change significantly either after magnesium administration (688 and 135 pgm/ml, to 654 and 117) or in controls (695 and 230 pgm/ml, to 445 and 225). Likewise, the ratio of these 2 substances did not change in either group (6.3 to 6.6, and 4.2 to 2.2). There was no correlation between duration of infusion or total magnesium given and directions of small changes observed. This study confirms a prior preliminary observation that magnesium sulfate infusion, as currently used to prevent eclamptic convulsions, induces a significant prolongation of bleeding time. This effect is mediated neither by changes in platelets count or aggregation pattern, nor by changing the level or ratios of serum arachidonic acid metabolites (TxB2 and 6-Keto-PGF1 alpha). Further studies are needed to clarify the mechanism of this clinically important observation of increased bleeding following magnesium sulfate infusion.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Bleeding Time; Female; Gestational Age; Humans; Magnesium Sulfate; Platelet Aggregation; Platelet Count; Postpartum Hemorrhage; Pre-Eclampsia; Pregnancy; Seizures; Thromboxane B2

The objective of this study was to evaluate the extent to which endothelin and the eicosanoids prostacyclin and thromboxane A2 are involved in the pathophysiology of gestational hypertension and preeclampsia.. In a longitudinal design, venous blood samples and 24-hour urine specimens were collected from 396 women in each trimester of pregnancy. After delivery of all patients, venous plasma endothelin was assessed in 20 subjects with identified preeclampsia, 48 subjects with gestational hypertension, and 59 normotensive subjects. Urinary excretions of the thromboxane A2 and of the prostacyclin metabolites thromboxane B2 and 6-keto-prostaglandin F1 alpha were assessed in 16 subjects with preeclampsia, 35 subjects with gestational hypertension, and 31 normotensive subjects.. Endothelin levels showed a second-trimester drop in all groups. In all 3 gestational trimesters a high correlation was found between the excretion of thromboxane B2 and that of 6-keto-prostaglandin F1 alpha (P <.001). The overall thromboxane B2 and 6-keto-prostaglandin F1 alpha urinary excretions increased throughout pregnancy and the overall thromboxane B2 /6-keto-prostaglandin F1 alpha ratio decreased. No significant differences in endothelin, thromboxane B2, and 6-keto-prostaglandin F1 alpha excretion levels or in thromboxane B2 /6-keto-prostaglandin F1 alpha ratios were found between women with preeclampsia, gestational hypertension, and normotension. Only in a small group of patients with severe preeclampsia (n = 2) and severe gestational hypertension (n = 2) were increased second-trimester endothelin values and increased thromboxane B2 /6-keto-prostaglandin F1 alpha ratios found.. In this longitudinal study we found no evidence for prostacyclin deficiency or increased endothelin levels in preeclampsia. Only women with severe preeclampsia and severe gestational hypertension expressed increased endothelin levels and thromboxane dominance over prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Eicosanoids; Endothelins; Female; Humans; Hypertension; Longitudinal Studies; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values; Thromboxane A2; Thromboxane B2

We hypothesized that aspirin Mg++, and dihydralazine affect the release of vasoactive agents from cultured human placental trophoblast.. Cytotrophoblasts isolated from placentas of preterm or term deliveries of 14 healthy control women and 15 preeclamptic women were cultured in Dulbecco's modified Eagle's medium for 5 days in the presence or absence of either 0.1 mmol/L aspirin, 3 mmol/L magnesium chloride, or 136 ng/ ml dihydralazine. Vasoactive substances were quantitated by radioimmunoassay with mean +/- SEM percentage of untreated cells (= 100%) compared by the Mann-Whitney U test and analysis of variance.. Aspirin inhibited (p < 0.01) both thromboxane and prostacyclin on days 1 and 2 in culture but not on days 3 to 5 unless the Dulbecco's modified Eagle's medium was supplemented with arachidonic acid. Aspirin inhibition was greater (p < 0.01) for thromboxane in cells cultured 24 hours after preeclamptic pregnancy (preterm 29.9% +/- 6.8%, term 20.1% +/- 5.9%) compared with normal controls (preterm 66.3% +/- 10.6%, term 68.9% +/- 11.6%). Aspirin reduced (p < 0.01) the ratio of thromboxane to prostacyclin in media of cells from preeclampsia (untreated 27.8 +/- 7.2, aspirin 13.3 +/- 4.4), but aspirin had no effect on this ratio in cultures from control normal pregnancies (untreated 6.8 +/- 2.9, aspirin 4.8 +/- 1.1). Neither magnesium chloride nor dihydralazine affected trophoblast prostanoid production, and no drug altered the media levels of angiotensin II, endothelin-1, or leukotriene B4.. Aspirin selectively inhibits trophoblast prostanoid production. This inhibition depends on the availability of arachidonic acid and the presence or absence of preeclampsia. Magnesium and dihydralazine effects in pregnancy are not related to altered release of trophoblast vasoactive compounds.

Topics: Angiotensin II; Antihypertensive Agents; Aspirin; Cells, Cultured; Cyclooxygenase Inhibitors; Dihydralazine; Endothelin-1; Epoprostenol; Female; Humans; Leukotriene B4; Magnesium Chloride; Pre-Eclampsia; Pregnancy; Thromboxane B2; Trophoblasts

Platelet activation occurs in early pregnancy in women at risk of developing pre-eclampsia. Cytokines have been implicated in the pathogenesis of pre-eclampsia, so we determined the effects of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) on the in vitro aggregation of human platelets. IL-1beta increased aggregation of platelets from non-pregnant and pre-eclamptic women, and inhibited the aggregation of platelets from normal pregnant women. This latter effect was linked to a diminished P-selectin expression on ADP-stimulated whole blood platelets in normal pregnant women (p = 0.011). Platelet aggregation in response to ADP was found to be inhibited after preincubation with TNF-alpha in non-pregnant (38%, p = 0.01) and in normal pregnant women (54%, p = 0.001) and not affected in pre-eclamptic women. The inhibitory effects of TNF-alpha were mediated through the P75 receptor for TNF-alpha.

Topics: Adenosine Diphosphate; Adult; Blood Platelets; Cyclic AMP; Cyclic GMP; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Middle Aged; Nitric Oxide; P-Selectin; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Recombinant Proteins; Second Messenger Systems; Sialoglycoproteins; Thromboxane B2; Tumor Necrosis Factor-alpha

The aim of the study was to investigate whether pre-eclampsia is associated with an altered release of vasoactive substances from trophoblastic cells in vitro. Trophoblastic cells from 15 uncomplicated control pregnancies and 18 pre-eclamptic pregnancies at preterm (weeks 31-36; n = 12) and term (weeks 37-40; n = 21) were cultured for 5 days. The concentrations of angiotensin II (AII), endothelin-1,2 (ET-1,2), thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene B4 (LTB4) were measured daily in culture media for 5 days by radioimmunoassay. In pre-eclampsia, concentrations of ET-1,2 were decreased (P < 0.01) at both preterm and term, TXB2 concentrations were increased (P < 0.05) only at preterm and the TXB2-6-keto-PGF1 alpha ratio was increased at both preterm and term (P < 0.01) as compared with the controls. Concentrations of AII, 6-keto-PGF1 alpha and LTB4 were similar to the controls. The data suggest that pre-eclampsia is associated with a decreased release of ET-1 and an increased release of TXB2 from trophoblastic cells in vitro.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cell Survival; Cells, Cultured; Endothelins; Epoprostenol; Female; Humans; Immunohistochemistry; Leukotriene B4; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Thromboxane A2; Thromboxane B2; Trophoblasts; Vasodilator Agents

Little is known about the pathophysiological processes leading to superimposed preeclampsia. We present an animal model where the uteroplacental blood flow in spontaneously hypertensive rats (SHR) was reduced by a silver clip. Thus, a superimposed preeclampsia-like syndrome could be studied under defined conditions. Urinary excretion of 2,3-dinor-6-keto PGF1 alpha and 11-dehydro-TxB2 were measured by enzyme immunoassays at day 16 and 20 of pregnancy. In gravid, sham-operated animals excretion of 2,3-dinor-6-keto-PGF1 alpha was largely elevated compared to non gravid control animals (day 16: 1259 vs. 258 ng/kg 24h; day 20: 471 vs. 269 ng/kg.24h). However, in the gravid rats with reduced uteroplacental blood flow urinary excretion of 2,3-dinor-6-keto-PGF1 alpha decreased to non gravid levels (day 16: 335 ng/kg.24h; day 20: 238 ng/kg.24h). By antihypertensive therapy with dihydralazin this effect was largely abolished. Only minor alterations were found in the excretion of 11-dehydro-TxB2. Our findings suggest, that a reduction of uteroplacental blood flow in the spontaneously hypertensive rat decreases the systemic prostacyclin synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Dihydralazine; Disease Models, Animal; Female; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Inbred SHR; Thromboxane B2

1. Platelet behaviour in vitro in relation to cyclic AMP was studied longitudinally during pregnancy and in the same women when they were not pregnant. Subjects comprised a group of healthy primigravidae and a group of women deemed at risk of pre-eclampsia, on the basis of a previous history of the condition. 2. There was a progressive decline during pregnancy in sensitivity of platelets to inhibition of the arachidonic acid-induced release reaction by agents which act via cyclic AMP. This effect was maximum at 36 weeks' gestation. 3. Basal platelet cyclic AMP levels, and those in the presence of a phosphodiesterase inhibitor, did not change throughout the period of the study. 4. By contrast, platelet cyclic AMP accumulation in response to a variety of adenylate cyclase stimulators was reduced from early pregnancy, throughout the gestational period, compared with post-natally. This effect was noted when platelets were incubated with prostaglandins acting via different surface receptors or with forskolin and was most marked on co-incubation with a phosphodiesterase inhibitor. 5. Compared with healthy women, platelets from women with a previous history of pre-eclampsia tended to accumulate less cyclic AMP in response to adenylate cyclase stimulators. This was the case both during pregnancy and post-natally. Further investigation of adenylate cyclase activity in platelets in relation to pre-eclampsia is required.

Topics: Adenylyl Cyclases; Adult; Arachidonic Acid; Blood Platelets; Cyclic AMP; Female; Humans; Iloprost; Longitudinal Studies; Pre-Eclampsia; Pregnancy; Pregnancy, High-Risk; Prospective Studies; Prostaglandin D2; Risk Factors; Serotonin; Thromboxane B2

Placentas obtained from women with preeclampsia produce more lipid peroxides and more thromboxane, but less prostacyclin, than normal. The tissue compartments within the placenta that are responsible for this are not known. The placenta is a heterogeneous tissue compartmentalized into trophoblast cells and villous core tissue that is comprised of stromal and vascular tissue. In this study we determined the placental compartments responsible for increased production of lipid peroxides and thromboxane in preeclampsia. Placentas were obtained from six normally pregnant women and seven women with preeclampsia. Trophoblast cells and villous core tissues were isolated and incubated in Dulbecco's Modified Eagle's Medium for 48 h. Samples were collected at 0, 2, 6, 16, 28, and 48 h of incubation and analyzed spectrophotometrically for lipid peroxides by a peroxide equivalent assay and for thromboxane and prostacyclin by RIA of their stable metabolites, thromboxane-B2 and 6-keto-prostaglandin-F1 alpha. Trophoblast cells isolated from preeclamptic placentas produced significantly more lipid peroxides (1972 +/- 502 vs. 1102 +/- 335 pmol/micrograms protein after 48 h of incubation), more thromboxane (328 +/- 57 vs. 153 +/- 53 pg/microgram at 48 h), and more prostacyclin (50 +/- 11 vs. 13 +/- 3 pg/microgram at 48 h, respectively) than trophoblast cells isolated from normal placentas. Villous core tissue isolated from preeclamptic placentas produced significantly more lipid peroxides (455 +/- 107 vs. 241 +/- 34 pmol/microgram) and more thromboxane (148 +/- 51 vs. 76 +/- 14 pg/microgram) than normal villous core tissue, but there was no difference in prostacyclin production (36 +/- 11 vs. 40 +/- 9 pg/microgram). Because of the increase in thromboxane production, the ratio of thromboxane to prostacyclin was higher in preeclamptic than normal villous core tissue (6.29 vs. 2.17). Comparison of production by different compartments within the placenta demonstrated that lipid peroxides and thromboxane were primarily produced by the trophoblast cells and stromal tissue, whereas prostacyclin was primarily produced by the vascular tissue. We conclude that increased placental production of lipid peroxides and thromboxane in preeclampsia originates from both the trophoblast cell and the villous core compartments. As the placenta secretes lipid peroxides, the trophoblast cells could be a source of increased lipid peroxides in the maternal circulation of women with preeclampsia. The

Topics: 6-Ketoprostaglandin F1 alpha; Arteries; Epoprostenol; Female; Humans; Kinetics; Lipid Peroxides; Placenta; Pre-Eclampsia; Pregnancy; Thromboxane B2; Trophoblasts

By combining serial measurements of the circulating concentrations of thromboxane A2 and prostacyclin with measurements of venous distensibility (taken during the pregnancies of both normal women and those with pregnancy induced hypertension or pre-eclampsia), to test the following hypotheses: 1. that changes in the venous plasma ratio of thromboxane (TXB2) and 6-keto-PGF1 alpha would correlate with changes in the blood pressure of women developing and recovering from pregnancy induced hypertension or pre-eclampsia and 2. that changes in venous distensibility would correlate with changes in arterial blood pressure in pregnancy induced hypertension or pre-eclampsia.. Prospective, longitudinal cohort study.. John Hunter Hospital clinic, Newcastle, Australia.. One hundred and sixty primiparous women, recruited when presenting for their first routine antenatal visit, were investigated at, or close to, 19, 28 and 37 weeks of gestation; a subgroup was also studied in the postnatal period. The measurements of the patients who developed pregnancy induced hypertension or pre-eclampsia were compared with those of controls selected from the cohort.. Serial measurements of the circulating concentrations of the stable metabolites of thromboxane A2 and prostacyclin (TXB2 and 6-keto-PGF1 alpha, respectively), venous distensibility and immediate (no rest) and resting (for at least 30 min) blood pressures.. There was no significant difference between the subject and control groups at any time during or after the pregnancy in the concentrations of prostaglandin metabolites, their ratio or venous distensibility. In contrast, there was a significant difference between the groups at 19 weeks for immediate and resting readings of diastolic pressure (6 mmHg (95% CI 1.5 to 10.5) and 4 mmHg (95% CI 0.1 to 7.9), respectively). These differences increased through the pregnancy but mean postnatal readings for the groups were almost identical suggesting that the subjects were not intrinsically hypertensive compared with controls. Blood pressures for the subject group, both immediate and resting, were significantly different from the 19 week readings at 28 weeks (diastolic) and at 37 weeks (systolic and diastolic). The only significant change from first readings among controls was in postnatal systolic pressure which was significantly higher than 19 week values, probably reflecting the vasodilatation, with accompanying hypotension, of early, normal pregnancy. This difference was not observed in those who subsequently developed pregnancy induced hypertension or pre-eclampsia.. Our study was unable to demonstrate differences in circulating metabolites or venous distensibility between normotensive women and those with pregnancy induced hypertension or pre-eclampsia. If pregnancy induced hypertension or pre-eclampsia in humans represents not so much the presence of abnormal constrictor influences as a process initiated by failure of normal vasodilatation in early pregnancy, studies carried out later may detect mainly adaptive and secondary changes.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Pressure; Cohort Studies; Elasticity; Female; Hand; Humans; Hypertension; Longitudinal Studies; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, First; Pregnancy Trimester, Second; Prospective Studies; Thromboxane A2; Thromboxane B2; Veins

The aim of the present study was to assess whether changes in prostacyclin (PGI2) and thromboxane (TXA2) generation precede the manifestation of pregnancy-induced hypertension (PH). The metabolites 6-oxo-PGF1 alpha and TXB2 were measured in the urine of 69 randomly selected pregnant women from 16-20 weeks of gestation (wg) until delivery and more than 6 weeks postpartum. Between 16-20 and 21-24 wg 6-oxo-PGF1 alpha excretion did not change in patients who later developed PIH (n = 6) but increased significantly in the control group (n = 63). In contrast, a marked rise in TXB2 excretion was found in the PIH group but not in controls. Thereafter significant differences between both groups persisted from 25 wg until delivery. The 6-oxo-PGF1 alpha/TXB2 ratio was below the 10th percentile from 21-24 wg until delivery in patients with developing PIH. The excretion of both metabolites was substantially lower in the non-pregnant state without any difference between patient groups. These results show an altered urinary excretion of both 6-oxo-PGF1 alpha and TXB2 preceding the onset of the disease. A pathophysiological role of PGI2 deficiency and increased TXA2 formation in PIH appears substantiated.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Postpartum Period; Pre-Eclampsia; Pregnancy; Prospective Studies; Thromboxane B2

Pregnancy-induced hypertension is no uniform disease with one cause and one pathophysiologic course. On the contrary it seems to be a multifactorial event with a very different symptomatology and a variable damage of various organs. Because of the heterogeneity of the disease and the difficulty of differentiation these various kinds of courses clinical studies, mostly retrospectively done, have to be criticized. The aim of this study is to examine vasoactive regulation systems by means of a standardized animal model, using wistar rats. A systemic hypertension could be achieved only in pregnant animals with aid a infrarenal aortic stenosis. Non pregnant and simulated operated pregnant animals are the control group. In the normotensive pregnant rats there was an elevation of all renal prostanoids: PGI2, TxB2 and PGE2. On the contrary hypertensive pregnant rats showed a decrease of all eicosanoids, prononcigated of PGE2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Disease Models, Animal; Epoprostenol; Female; Gestational Age; Homeostasis; Hypertension; Kidney; Pre-Eclampsia; Pregnancy; Prostaglandins; Rats; Rats, Wistar; Thromboxane B2

Hypertensive diseases represent the most frequent disorders among medical complications of pregnancy. Numerous studies have proven the central role of prostaglandins in these complex diseases. Thus, determination of urinary prostaglandins may lead to a better understanding of the pathomechanismus and may be a basis for therapeutic approaches. Our study included 59 patients with pregnancy-induced hypertension. From these 18 women had a proteinuria > 300 mg/l and were classified as pre-eclamptic. As controls 53 normotensive pregnancies were investigated. Quantification of 6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha, TxB2, 11-Dehydro-TxB2 and PGE2 was performed with radio or enzyme immunoassays after purification with solid phase extraction and partly HPLC. In the third trimester of pregnancy following alterations were found in urine concentrations of prostaglandins in preeclamptic women compared to controls: 6-keto-PGF1 alpha - 54%, 2,3-dinor-6-keto-PGF1 alpha - 29%, PGE beta 2-41%, TxB2-29% and 11-Dehydro-TxB2 + 21%. Thus, our results show a disturbed balance between vasodilatory and vasoconstrictive prostaglandins in PIH patients. This imbalance correlated to the severity of the disease and was more pronounced in preeclamptic patients. The decrease of PGI2- and PGE2-production was more distinct than the increase of thromboxane production. We conclude that the endothelial damage, rather than an overproduction of TxA2 predominantly is responsible for some pathophysiological events in PIH.

Topics: Adult; Epoprostenol; Female; Gestational Age; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Prostaglandins; Reference Values; Thromboxane B2; Vascular Resistance

The aim of the present study was to investigate the occurrence of changes in the plasma levels of vasoactive prostanoids and inhibitors of blood coagulation in normal pregnancy and in cases of pregnancy induced hypertension. Levels of the coagulation inhibitors antithrombin III, protein C, Protein S as well as the prostaglandin metabolites thromboxane B2 and 6-oxo-prostaglandin F1 alpha were measured between 13 and 37 weeks gestation in 36 primigravidae. In 8 of the examined patients persistently raised blood pressure values of 140/90 and above were measured after 20 weeks of gestation. Our results indicated that an imbalance of vasoactive prostanoids may precede the appearance of clinical symptoms of PIH. The determination of coagulation factors before blood pressure is elevated has no predictive value regarding the later development of PIH. The reduced levels of protein C associated with our PIH group are considered to be the result of an activated coagulation followed by consumption of clotting factors. Reduced measured levels of protein S in normotensive as well as hypertensive pregnancies offer an explanation for the increased risk of thromboembolic disease. This increased susceptibility to thromboembolic disorders is further enhanced by the altered balance between the platelet aggregator and vasoconstrictor thromboxane A2 and its antagonist prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Antithrombin III; Antithrombins; Epoprostenol; Female; Humans; Hypertension; Infant, Newborn; Longitudinal Studies; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Prostaglandins; Protein C; Protein S; Thromboxane A2; Thromboxane B2; Vascular Resistance

This study examined plasma and urinary endothelin 1 and urinary metabolites of prostacyclin and thromboxane, in women with pre-eclampsia and age and gestation matched controls. To determine if changes in endothelin 1 and urinary prostanoids in pre-eclampsia were due to hypertension per se, a comparison was made to a group of age and gestation matched pregnant uncomplicated essential hypertensive women. Measurements were taken prior to delivery, and at 6 weeks and 6 months post-partum, and were compared to a group of age matched non-pregnant controls. Plasma endothelin 1 was significantly elevated and the urinary metabolite of prostacyclin (2,3-dinor-6-keto-PGF1 alpha) was significantly suppressed in pre-eclamptic pregnancy, compared to normal pregnancy and essential hypertensive pregnancy. As the level of blood pressure was similar in the pre-eclamptic and essential hypertensive groups, these changes are not due to an increase in blood pressure per se. Urinary endothelin 1 was not different in the 3 pregnant groups prior to delivery but fell significantly after delivery. Urinary endothelin 1 was significantly lower in the essential hypertensive group at 6 weeks post-partum compared to pregnant controls with a similar trend at 6 months. Urinary 11-dehydro-TXB2 was elevated in pregnancy, but no further elevation was seen in women with pre-eclampsia. Platelet counts were lower, and circulating neutrophil counts higher in pre-eclampsia prior to delivery. A combination of increased plasma endothelin 1 and reduced tissue prostacyclin synthesis may contribute to hypertension, placental insufficiency, foetal growth retardation and renal dysfunction in pre-eclampsia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Platelets; Blood Pressure; Endothelins; Epoprostenol; Female; Heart Rate; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Reference Values; Thromboxane B2

The etiology of pregnancy induced hypertension (PIH) is still unknown. The pathophysiology must be clarified. In this paper we present an animal model where hypertension in pregnant and non-pregnant rats was induced by an experimental reduction of uteroplacental blood flow. Thus, a preeclampsia-like syndrome could be studied under defined conditions. The eicosanoid system was investigated for pathophysiological alterations of the kidney by measuring urinary excretion of 6-keto-PGF1 alpha, TxB2 and PGE2 with radioimmunoassay at day 18 of pregnancy. First, in gravid control animals concentrations of all three prostaglandins were significantly elevated compared to non-gravid controls. However, in hypertensive gravid rats urinary concentrations of these prostaglandins fell even below the levels of non-gravid controls. The observed decrease was more pronounced for the vasodilatory 6-keto-PGF1 alpha and PGE2 than for the vasoconstrictive TxB2. Our results demonstrate that an experimental reduction of uteroplacental blood flow in the rat culminates in symptoms which clinically (hypertension, proteinuria) and pathophysiologically (eicosanoid system) resemble to preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Disease Models, Animal; Female; Pre-Eclampsia; Pregnancy; Rats; Rats, Wistar; Thromboxane B2

Topics: Female; Fetal Growth Retardation; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Thromboxane B2

In recent years an increasing amount of evidence supports the concept that preeclampsia is an endothelial disease. The purpose of our study was to evaluate the extent to which endothelial cell dysfunction is involved in pathophysiology of preeclampsia.. We studied the urinary excretion of thromboxane B2 and 6-keto-prostaglandin F1 alpha and the venous plasma endothelin levels in 23 preeclamptic patients and in control subjects. In six of these patients and in six controls arterial plasma endothelin levels were also measured. In addition, plasma levels of calcitonin gene-related peptide and plasma fibronectin levels were measured. Results were analyzed by Wilcoxon's rank-sum test or signed-rank test.. In preeclampsia the urinary thromboxane B2/6-keto-prostaglandin F1 alpha ratio (p < 0.001), venous plasma endothelin levels (p < 0.001), and plasma fibronectin levels (p < 0.001) were significantly elevated compared with normotensive pregnancy. Arterial plasma endothelin levels were significantly higher than venous plasma endothelin levels in normotensive and hypertensive patients (p < 0.05). Calcitonin gene-related peptide levels showed a wide range in normotensive pregnancy and in preeclampsia, but the difference was not significant.. These results confirm the extensive involvement of the endothelium in the pathophysiology of preeclampsia. Preeclamptic vasoconstriction seems to be mediated by an increase in the vasoconstrictor autocoids thromboxane A2 and endothelin. Production of prostacyclin by the vessel wall and endovascular trophoblast might be just a pivotal escape mechanism of the uteroplacental circulation. Calcitonin gene-related peptide appears not to be involved in the pathophysiology of preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteries; Calcitonin Gene-Related Peptide; Endothelins; Endothelium, Vascular; Female; Fibronectins; Humans; Pre-Eclampsia; Pregnancy; Thromboxane B2; Veins

Because pregnant women with diabetes have an increased risk of preeclampsia, we tested the hypothesis that urinary excretion of thromboxane metabolites is increased in diabetic pregnancies without evidence of preeclampsia at the time of testing.. Urinary excretion of thromboxane A2 metabolites (either 2,3-dinor-thromboxane B2 or 11-dehydro-thromboxane B2) was measured in 24 type I pregnant diabetic individuals and in 20 women with normal pregnancies between 28 and 32 weeks' gestation.. The amount of 2,3-dinor-thromboxane B2 and 11-dehydro-thromboxane B2 in the urine of pregnant women with diabetes (1727 +/- 415 and 827 +/- 276 pg/mg creatinine) was significantly higher than in women with normal pregnancies (638 +/- 218 and 178 +/- 145 pg/mg creatinine) (p < 0.002 and p < 0.001).. Our findings support a role for thromboxane in the pathogenesis of preeclampsia.

Topics: Diabetes Mellitus, Type 1; Female; Gestational Age; Humans; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Thromboxane B2

The short term effect of anisodamine, an alkaloid isolated from the chinese herb anisodas tonguticus, on blood flow of uterine and umbilical arteries in 16 pregnant women with pregnancy-induced hypertension (PIH) was investigated by means of pulsed doppler ultrasound technique Results have shown that anisodamine could decrease the A/B ratio, resistant index (RI), and pulsative index (PI) of blood velocity in these arteries with statistical significant difference. Its mechanism of action might be the improving of the rheology in PIH and adjusting the imbalance of TXA2/PGI2. It was suggested that the resistance in uteroplacental circulation was decreased and its perfusion improved, so that favors the fetal growth and development.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Viscosity; Female; Humans; Microcirculation; Placenta; Pre-Eclampsia; Pregnancy; Regional Blood Flow; Solanaceous Alkaloids; Thromboxane B2; Umbilical Arteries; Uterus; Vascular Resistance

There is an imbalance of increased thromboxane and decreased prostacyclin in placentas of women with preeclampsia, but this may not be the only imbalance. There is also an abnormal increase in serum lipid peroxides in preeclamptic women. Lipid peroxides are toxic compounds that damage cells and inhibit prostacyclin synthesis. The following study examined lipid peroxides to determine if they were also increased in placentas of preeclamptic women.. Placental tissue for nine normal and eight preeclamptic women were frozen in liquid nitrogen immediately after delivery. Frozen tissue samples (1 gm) were homogenized and analyzed for lipid peroxides by malondialdehyde and hydrogen peroxide equivalents and for thromboxane and prostacyclin by radioimmunoassay of their stable metabolites, thromboxane B2 and 6-keto prostaglandin F1 alpha.. Lipid peroxides were significantly higher in preeclamptic placentas than in normal placentas by both analytic methods (49 +/- 5 vs 31 +/- 1 nmol/gm for malondialdehyde and 5.3 +/- 0.3 vs. 3.2 +/- 0.3 mumol/gm for hydrogen peroxide equivalent; mean +/- SE; p < 0.01, respectively). Thromboxane was significantly higher and prostacyclin significantly lower in preeclamptic placentas than in normal placentas (213 +/- 23 vs 158 +/- 14 ng/gm for thromboxane and 24 +/- 3 vs 53 +/- 7 ng/gm for prostacyclin, p < 0.05). The thromboxane/prostacyclin and lipid peroxides/prostacyclin ratios were threefold higher in preeclamptic placentas than in normal placentas.. Placental levels of both lipid peroxides and thromboxane are increased and prostacyclin decreased in preeclampsia. We speculate that abnormally increased levels of lipid peroxides in preeclamptic placentas may be a cause of decreased prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Female; Humans; Lipid Peroxides; Malondialdehyde; Placenta; Pre-Eclampsia; Pregnancy; Reference Values; Thromboxane B2

Intra-uterine growth retardation, intra-uterine fetal death and pre-eclampsia have common abnormalities: A reduction of uteroplacental perfusion, lack of vasodilation of spiral arteries and subsequent thrombosis. These physiological processes have been explained by an imbalance between prostacyclin and thromboxane A2 production. Many studies have suggested that treatment with low-dose aspirin and steroids is effective in preventing pregnancy loss or pre-eclampsia, but the mechanism has not been established. We evaluated the effectiveness of these therapies in patients at risk for pregnancy loss with the aspect of intracellular ionized calcium mobilization. Low-dose aspirin directs the prostacyclin/thromboxane A2 balance to the dominance of prostacyclin and steroids suppress the activities of lupus anticoagulant or antiphospholipid antibodies. The intracellular ionized calcium concentration in platelets is decreased significantly after these therapies. Concerning the pathological examination of placenta, there were deposits of fibrin in only 2 out of 8 cases and there were no abnormal findings in the other 6 cases. These data show that the aggregation of platelets is suppressed in microvascular circulations. These therapies do not cause any adverse effect on the mother or fetus. It is concluded that low-dose aspirin therapy with steroids is useful for patients with a poor obstetrical history.

Topics: 6-Ketoprostaglandin F1 alpha; Aspirin; Calcium; Female; Fetal Death; Fetal Growth Retardation; Humans; Lupus Coagulation Inhibitor; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Thromboxane B2; Treatment Outcome

In normal pregnancy, increased production of platelet thromboxane A2(TXA2) parallels increased biosynthesis of vascular prostacyclin (PGI2). An imbalance in the formation of these prostaglandins is believed to be associated with the pathogenesis of pregnancy-induced hypertension (PIH). Recent evidence suggested that aspirin in low doses was effective in reducing the incidence of PIH, by selective inhibition of platelet-derived TXA2 biosynthesis. In this communication, we determined the urinary 11-dehydro TXB2 and 6-keto-PGF1 alpha, which are major metabolites of TXA2 and PGI2, respectively, from early to late pregnancy of normal pregnant women and of women complicated with PIH. The ratio of 11-dehydro TXB2 to 6-keto-PGF1 alpha decreased significantly from as early as 10wks of gestation when compared with that in non-pregnant controls (1.43 +/- 0.15 vs 1.99 +/- 0.13: Mean +/- SEM, p less than 0.05), and increased in later pregnancy to the control values at term. No significant difference was found in the excretion of 11-dehydro TXB2 between normal pregnant women and women with PIH. In contrast, urinary excretion of 6-keto-PGF1 alpha decreased in women with PIH. The ratio of 11-dehydro TXB2 to 6-keto-PGF1 alpha increased significantly as compared with that of pregnant controls. These results demonstrated that disturbed production of vascular PGI2 may be the primary cause of PIH, and affect the vascular responsiveness to pressor inducers such as angiotensin II.

Topics: 6-Ketoprostaglandin F1 alpha; Endothelium, Vascular; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2; Thromboxane B2

The activity of Na-Li countertransport (CT), a marker of the risk of essential hypertension, was determined in 55 primigravid women during pregnancy, together with urinary 11-dehydro-thromboxane B2 (11-dehydro-TXB2) as a marker of thromboxane A2 synthesis. The mean Na-Li CT (mean +/- SEM) value was increased significantly at 20 weeks gestation and thereafter, and reached higher levels in late pregnancy than in non-pregnant controls (0.31 +/- 0.02 vs. 0.21 +/- 0.01mmol per hr per liter RBC, p less than 0.05). Fifty five primigravid women could be divided into two groups, depending upon Na-Li CT activity either higher or lower than the value of 0.25mmol per hr per liter RBC at any time in the pregnancy up to term. At 20 weeks gestation all but one of 13 women in the lower-activity group had Na-Li CT activity less than 0.20 mmol per hr per liter RBC, and none developed PIH, whereas out of 42 women in the higher-activity group, all but one had Na-Li CT activity more than this value, and 8 developed PIH. Urinary 11-dehydro-TXB2 increased as pregnancy progressed, maximum levels being attained in women at term, about 3 times higher than in controls (4.19 +/- 0.35 vs. 1.36 +/- 0.10 ng per mg creatinine, p less than 0.05). Although the formation of thromboxane A2 was reported to be higher in pregnancy complicated by hypertension, no significant difference existed in the levels of 11-dehydro-TXB2 between women with PIH and women with uncomplicated pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biological Transport; Creatinine; Erythrocytes; Female; Humans; Lithium; Pre-Eclampsia; Pregnancy; Sodium; Thromboxane B2

Eleven preterm patients with severe preeclampsia underwent Doppler velocimetry prior to cesarean section. Maternal venous blood and umbilical arterial and venous samples were collected for prostacyclin and thromboxane determination by radioimmunoassay. Umbilical artery pulsatility index correlated positively with umbilical artery thromboxane B2 levels (r = 0.76; P less than 0.05) and maternal thromboxane levels (r = 0.78; P less than 0.05). We conclude that the vasoactive action of thromboxane A2 may alter placental resistance.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Flow Velocity; Female; Humans; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Thromboxane B2; Umbilical Arteries; Uterus

1. Platelet activation in vivo occurs in healthy pregnant women and is more marked in women with preeclampsia. During pregnancy platelets have also been shown in vitro to be less susceptible to the inhibitory effects of prostacyclin. The cyclic nucleotide cyclic AMP has a key role as an inhibitory second messenger in platelets and mediates the inhibitory effects of prostacyclin. 2. We have studied cyclic AMP in relation to platelet behaviour in healthy pregnant women in the third trimester and in women with pregnancy-induced hypertension and pre-eclampsia. Non-pregnant young women were used as controls. 3. Pharmacological agents which increase levels of cyclic AMP were significantly less effective as inhibitors of platelet activation during pregnancy, but there was no difference between the healthy and hypertensive pregnant subjects. 4. Basal platelet cyclic AMP levels were the same in all three groups. However, the production of cyclic AMP in response to a range of adenylate cyclase stimulators was reduced during pregnancy, but again there was no difference between healthy and hypertensive pregnant subjects. 5. The reduction in platelet cyclic AMP levels in pregnancy occurred not only with those adenylate cyclase stimulators which operate via surface receptors, but also on direct stimulation of the enzyme with forskolin. 6. The most likely explanation of these observations is a reduction in the ability of the platelet adenylate cyclase enzyme to respond to stimulation of the third trimester of pregnancy. The consequent reduction in formation of the inhibitory second messenger cyclic AMP may in part be responsible for platelet activation in vivo during pregnancy. There does not appear to be a further difference in platelet cyclic AMP production in hypertensive pregnant women.

Topics: Adenylyl Cyclases; Adult; Arachidonic Acids; Blood Platelets; Cross-Sectional Studies; Cyclic AMP; Female; Humans; Iloprost; Platelet Activation; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Thromboxane B2

Preeclampsia is associated with an imbalance between thromboxane and prostacyclin. The cause of the imbalance is unknown. Preeclampsia sera contain cytotoxic factors that can damage endothelial cells. Lipid peroxides can damage cell membranes, so elevated levels in the mother's blood could be related to endothelial cell injury and decreased prostacyclin in preeclampsia. This study determined maternal plasma levels of thromboxane and prostacyclin and serum levels of lipid peroxides and vitamin E in women with normal pregnancy (n = 12), mild preeclampsia (n = 16), and severe preeclampsia (n = 19) between 36 and 40 weeks' gestation. In normal pregnancy the ratio of thromboxane to prostacyclin (0.63) favored prostacyclin, and the ratio of lipid peroxides to vitamin E (0.43) favored vitamin E. Prostacyclin was significantly decreased in both mild and severe preeclampsia. Thromboxane was not increased in mild preeclampsia but was significantly increased in severe preeclampsia. The ratio of thromboxane to prostacyclin was increased in mild preeclampsia (0.77) and greatly increased in severe preeclampsia (1.94). Lipid peroxides were significantly increased in mild preeclampsia and increased further in severe preelcampsia. Vitamin E levels were unaltered in mild preeclampsia but significantly decreased in severe preeclampsia. The ratio of lipid peroxides to vitamin E was increased in mild (0.52) and greatly increased in severe (1.09) preeclampsia. We concluded the following: (1) Maternal plasma prostacyclin is decreased in both mild and severe preeclampsia, but thromboxane is increased only in severe cases. (2) Lipid peroxides are significantly increased in both mild and severe preeclampsia and vitamin E is significantly decreased in severe preeclampsia. We speculate that this imbalance could result in endothelial and platelet cell damage and in decreased prostacyclin and increased thromboxane synthesis. (3) Preeclampsia is associated with an imbalance not only between thromboxane and prostacyclin but also between lipid peroxides and vitamin E in maternal blood. The imbalances progressively favor thromboxane and lipid peroxides with the increasing severity of preeclampsia, which is consistent with the clinical symptoms of this disorder.

Topics: 6-Ketoprostaglandin F1 alpha; Female; Humans; Lipid Peroxides; Pre-Eclampsia; Pregnancy; Thromboxane B2; Vitamin E

To determine the nature and extent of changes in platelet reactivity in gestational hypertension and pre-eclampsia (using whole blood techniques which may be more physiological than those previously employed).. Cross-sectional observational study.. 8 normal primigravidae, 16 women with gestational hypertension and 12 women with pre-eclampsia, studied at around 36 weeks gestation.. Platelet reactivity (aggregation and release reaction) induced by stimulation with adrenaline was decreased in the pre-eclamptic group. Serum thromboxane B2 production was unchanged in both hypertensive groups compared with the control group.. In the context of evidence of platelet activation in pre-eclampsia, our findings are interpreted as reflecting platelet exhaustion.

Topics: Adult; Blood Platelets; Cross-Sectional Studies; Female; Humans; Hypertension; Platelet Activation; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

The increased TXA2 and decreased PGI2 seen in the toxemic pregnancies suggest the imbalance of arachidonic metabolism. Thromboxane (TX) B2 was thought to be a suitable parameter of TXA2 production in vivo. However, recently it has come to be recognized that a large amount of TXB2 is readily produced and decomposed to 11-dehydro TXB2 during blood sampling. In this study, a new RIA method was established, capable of measuring the urinary 11-dehydro TXB2 level. (1) The samples were measured with a 125I-labeled RIA kit for 11-dehydro TXB2 (Amersham, U.K.). In this assay system a highly specific antibody to 11-dehydro TXB2 was used. (2) The values for urinary 11-dehydro TXB2 measured by the RIA correlated closely with those measured by gas chromatography-mass spectrometry (r = 0.95). (3) The mean 11-dehydro TXB2 value in non pregnant was 2.62 +/- 1.71ng/mg Cr, The mean values in the first, second and third trimesters of pregnancy were 4.57 +/- 2.45ng/mg Cr, 5.75 +/- 2.81ng/mg Cr, 6.33 +/- 2.60ng/mg Cr, respectively. (4) The mean 11-dehydro TXB2 value in toxemic pregnancy was 4.13 +/- 1.86ng/mg Cr, which was significantly lower than that in normal pregnancies. (5) There was a significant negative correlation (p less than 0.0001) between the urinary 11-dehydro TXB2 concentration and the blood pressure.

Topics: Birth Weight; Female; Humans; Organ Size; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Reagent Kits, Diagnostic; Thromboxane B2

Plasma 6-keto-prostaglandin F 1 alpha and thromboxane B2, the metabolites of prostacyclin and thromboxane A2 respectively, were measured in 12 women with pregnancy-induced hypertension, 12 age-matched normotensive pregnant women and 8 non-pregnant women as controls. Pregnancy was divided into 3 stages, namely: 22-27, 28-32 and 33-39 weeks. The concentrations of thromboxane B2 in the plasma of women with pregnancy-induced hypertension was 1.4-1.7 times greater than normotensive pregnant subjects at the same gestational stage, and 2 times higher than controls. Plasma levels of 6-keto-prostaglandin F 1 alpha in normotensive pregnant women was 1.8 times greater than in those with pregnancy-induced hypertension at 28-32 and 33-39 weeks, and was significantly higher than control. The ratio of thromboxane B2 to 6-keto-prostaglandin F 1 alpha was markedly increased in the group of patients with pregnancy-induced hypertension at 28-32 and 33-39 weeks gestation. The ratio of the two metabolites in normotensive patients at each stage of gestation was similar to the control group. The ratio of circulating aggregated platelets in subjects with pregnancy-induced hypertension was significantly lower than in normotensive pregnant subjects at 33-39 weeks, implying increased turnover of platelets in pregnancy-induced hypertension. There was no significant difference in count of platelets, adenosine diphosphate threshold concentration and variables of platelet aggregation induced by adenosine diphosphate among the 3 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Longitudinal Studies; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Thromboxane B2

Topics: Adult; Aspirin; Blood Platelets; Female; Humans; Platelet Activating Factor; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Thromboxane B2

Urinary levels of 11-keto-thromboxane B2 (11-keto-TXB2), were elevated at all gestational ages (12-41 weeks) compared with non-pregnant levels. 11-keto-TXB2 levels exceeded those of TXB2 throughout pregnancy, which suggested that 11-keto-TXB2 may be the major urinary metabolite of TXA2 in normotensive pregnancy, as in the non-pregnant state. This was reversed in women with mild pregnancy-induced hypertension (P.I.H.), such that urinary levels of TXB2 were higher (p less than 0.01) than those of 11-keto-TXB2. Since the 11-thromboxane dehydrogenase enzyme is found in the placenta, the low levels of 11-keto-TXB2 may be the result of placental damage decreasing the activity of the enzyme. The relationship between these findings and the aetiology of P.I.H. is not clear, but changes in urinary 11-keto-TXB2 may be of use in identifying those women at risk of developing P.I.H.

Topics: Adult; Female; Humans; Hypertension; Platelet Activation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

Topics: Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane B2

Prostaglandin E2 (PGE2), Prostaglandin F2 alpha (PGF2 alpha),6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2) were measured with radioimmunoassay in placentae of 18 normotensive and 22 moderate or severe PIH gravidae. The content of PGE2 and PGF2 alpha did not change significantly in placentae of PIH patients suggesting that PGE2 and PGF2 alpha in placenta were not important in causing PIH. The content of placental 6-keto-PGF1 alpha also showed no significant difference, while TXB2 levels were significantly higher in PIH patients. The 6-keto-PGF1 alpha/TXB2 in PIH patients was remarkably lower than in normotensive women. These results indicate that an increase in TXB2 level and thus a decrease in the ratio of 6-keto-PGF1 alpha to TXB2 of placenta may be a pathogenetic factor in PIH.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dinoprost; Dinoprostone; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Angina Pectoris; Animals; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Pre-Eclampsia; Pregnancy; Rabbits; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Female; Humans; Lipid Peroxidation; Pre-Eclampsia; Pregnancy; Thromboxane B2

Arterial blood pressure, serum fibrin/fibrinogen degratory products, plasma thromboxane B2, in vitro platelet aggregation, and platelet ultrastructure were studied in ten gravid ewes during fast-triggered ovine pregnancy-induced hypertension and subsequent administration of the thromboxane synthetase inhibitors CGS13080 and CGS12970. During the hypertensive period, blood pressure (p less than 0.005) and plasma thromboxane B2 levels (p less than 0.005) were significantly altered. Collagen-induced in vitro platelet aggregation lag times increased (p less than 0.01), and percent aggregation (p less than 0.05), primary (p less than 0.01), and secondary (p less than 0.005) aggregatory slopes decreased. Collagen also failed to induce aggregation in some ewes. Primary slopes of ADP-induced in vitro platelet aggregation decreased (p less than 0.01) during hypertension. Degranulation and open canalicular tubule system swelling were observed in platelets which produced abnormal or no aggregation response. However, these ultrastructural abnormalities did not necessarily correspond to hypertensive periods. Thromboxane synthetase inhibitor administration lowered blood pressure (p less than 0.005) and plasma thromboxane B2 levels (p less than 0.005). Abnormalities in collagen and ADP-induced platelet aggregation curves were also corrected, and ultrastructural abnormalities were not detected. Marked elevations in plasma thromboxane levels during ovine pregnancy-induced hypertension may have had an "exhaustive" effect on thrombocytes which was reversed by thromboxane synthetase inhibition.

Topics: Animals; Blood Platelets; Blood Pressure; Female; Fibrin Fibrinogen Degradation Products; Microscopy, Electron; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Sheep; Thromboxane B2; Thromboxane-A Synthase

Topics: 6-Ketoprostaglandin F1 alpha; Chorionic Villi; Female; Humans; Microcirculation; Placenta; Pre-Eclampsia; Pregnancy; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane B2

The role of prostaglandin (PG) system in preeclampsia (pre-E) was investigated. Urinary excretion of PGE2,6-keto PGF1 alpha,2,3 dinor 6-keto PGF1 alpha, TxB2 and 2,3-dinor-TxB2 and kallikrein were determined in 10 normotensive pregnant women and 14 with pre-E. 6-keto PGF1 alpha and 2,3-dinor 6-keto PGF1 alpha (the main renal and extrarenal metabolites of vasodilator PGI2) and PGE2 excretion was lower in pre-E. TxB2 metabolites in urine were similar in the two groups of women. Our data are consistent with the hypothesis of an imbalance between vasodilator and vasoconstrictor PGs in pre-E.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Dinoprostone; Epoprostenol; Female; Humans; Kidney; Pre-Eclampsia; Pregnancy; Prostaglandins; Prostaglandins E; Thromboxane A2; Thromboxane B2; Vasodilator Agents

In order to characterize the prostacyclin and thromboxane system during gestosis the stable degradation products 6-keto-prostaglandin F1 alpha (6-keto-PG F1 alpha) and thromboxane B2 (TX B2) have been determined by radioimmunoassay in amniotic fluid and maternal venous plasma from 16 normotensive pregnant women and 14 patients with preeclampsia. At preeclampsia as well in amniotic fluid as in plasma a tendency towards lowered levels of 6-keto-PG F1 alpha and at the same time increased levels of TX B2 may be visualized. In the plasma generally significant higher levels of both 6-keto-PG F1 alpha and TX B2 than in amniotic fluid have been established. The imbalance between anti-aggregatory and vasodilatatory prostacyclin and proaggregatory and vasoconstrictory thromboxane in preeclampsia is indicated by an increase of the ratio TX B2/6-keto-PG F1 alpha from 1.38 to 2.44 in amniotic fluid and from 1.88 to 2.81 in plasma.

Topics: 6-Ketoprostaglandin F1 alpha; Amniotic Fluid; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Thromboxane B2

Platelet function and coagulation activity were followed prospectively throughout normal pregnancy and in puerperium in 17 healthy women. Plasma beta-thromboglobulin reflecting platelet activation increased progressively during pregnancy. This was not accompanied by any changes in platelet count or lifespan nor in serum or plasma thromboxane B2 levels. The levels of both factor VIII:C and factor VIIIR:Ag increased, the former less than the latter resulting in a rise of the FVIIIR:Ag/FVIII:C ratio. Antithrombin III (AT III), however remained unaltered. FVIIIR:Ag/FVIII:C ratio was increased both in mild (n = 7) and severe (n = 9) preeclampsia, whereas beta-thromboglobulin was increased and AT III was decreased only in severe preeclampsia. Platelet count and lifespan, plasma and serum thromboxane B2 as well as FVIII:C were normal in severe preeclampsia.

Topics: Adult; beta-Thromboglobulin; Blood Coagulation; Blood Platelets; Factor VIII; Female; Humans; Platelet Count; Postpartum Period; Pre-Eclampsia; Pregnancy; Reference Values; Thromboxane B2

Topics: Adult; Aged; Animals; Coronary Disease; Diabetes Mellitus; Endotoxins; Escherichia coli; Female; Humans; Male; Middle Aged; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane B2; Toxemia

Renal synthesis of the antiaggregatory and vasodilatory prostacyclin and its endogenous antagonist thromboxane A2 may be disturbed in patients with preeclampsia. We tested this hypothesis by measuring 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha; a hydration product of prostacyclin), 2,3-dinor-6-keto-PGF1 alpha (generated from 6-keto-PGF1 alpha through beta-oxidation) and thromboxane B2 (a hydration product of thromboxane A2) in the urine of healthy pregnant and preeclamptic women. Urinary excretion of 6-keto-PGF1 alpha [19.8 +/- 10.5 pmol/mmol creatinine, (mean +/- SD)] and 2,3-dinor-6-keto-PGF1 alpha (19.2 +/- 7.5 pmol/mmol creatinine) increased during normal pregnancy, reaching a maximum (about 5-fold rise) during the last month of pregnancy. No significant changes occurred in the urinary excretion of thromboxane B2. In women with severe preeclampsia (n = 17), the excretion of both 6-keto-PGF1 alpha (37.7 +/- 29.5 pmol/mmol creatinine) and 2,3-dinor-6-keto-PGF1 alpha (54.5 +/- 56.2 pmol/mmol creatinine) was lower (P less than 0.001) than in the normotensive women during the last trimester of pregnancy (80.6 +/- 43.7 and 98.7 +/- 42.9 pmol/mmol creatinine, respectively). The neonates excreted 6-25 times more 6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha and thromboxane B2 than did the nonpregnant women. In contrast to the adults, neonatal 6-keto-PGF1 alpha excretion was 2-3 times greater than that of 2,3-dinor-6-keto-PGF1 alpha suggesting reduced beta-oxidation in the newborns. Infants born to preeclamptic women had reduced output of 6-keto-PGF1 alpha and 2,3-dinor-6-keto-PGF1 alpha on the first day of life. Thus, renal prostacyclin synthesis is diminished in women with severe preeclampsia and their infants.

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Female; Humans; Infant, Newborn; Kidney; Postpartum Period; Pre-Eclampsia; Pregnancy; Thromboxane A2; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Reference Values; Thromboxane A2; Thromboxane B2; Umbilical Arteries

Plasma 6-keto prostaglandin F1 alpha, 13,14-dihydro-15-keto prostaglandin F, and thromboxane B2 levels were measured in normotensive and preeclamptic patients during pregnancy and the postpartum period. From 30 to 40 weeks of gestation, 6-keto prostaglandin F1 alpha levels of preeclamptic patients were significantly lower than those of normotensive women; 13,14-dihydro-15-keto prostaglandin F and thromboxane B2 concentrations in preeclamptic patients did not significantly differ from those of the normotensive group. At delivery, 6-keto prostaglandin F1 alpha levels of maternal and umbilical venous plasma of preeclamptic women were also significantly lower than those of normotensive women. In the postpartum period these three prostanoids were not significantly different in normotensive women compared to preeclamptic women, with clinical preeclamptic symptoms soon disappearing in most of our patients. From the results, it seems that prostacyclin plays an important role in preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Dinoprost; Female; Fetal Blood; Humans; Labor, Obstetric; Postpartum Period; Pre-Eclampsia; Pregnancy; Prostaglandins F; Radioimmunoassay; Thromboxane B2; Thromboxanes

Preeclampsia is characterized by increased vasoconstriction frequently associated with increased platelet aggregation, reduced uteroplacental blood flow, and premature delivery. Because prostacyclin antagonizes the vasoconstrictor, platelet-aggregating, and uterine-activating actions of thromboxane, we considered the hypothesis that placental production of thromboxane was increased coincident with decreased production of prostacyclin in preeclampsia. Fresh human term placentas were obtained immediately after delivery from 11 normal and 10 preeclamptic pregnancies (blood pressure greater than or equal to 140/90 mm Hg, urinary protein greater than 0.3 gm/24 hr). Tissues (350 mg) were incubated sterilely in 6 ml of Dulbecco's Modified Eagle's Medium for 48 hours at 37 degrees C with 95% oxygen and 5% carbon dioxide in a metabolic shaker. Samples were collected at 8, 20, 32, and 48 hours and analyzed for thromboxane by radioimmunoassay of its stable metabolite, thromboxane B2, and for prostacyclin by radioimmunoassay of its stable metabolite, 6-keto prostaglandin F1 alpha. The production of thromboxane was significantly increased in preeclamptic versus normal placental tissue (22.9 +/- 4.7 versus 6.3 +/- 1.5 pg/mg/hr, mean +/- SE, p less than 0.01), whereas the production of prostacyclin was significantly decreased (3.0 +/- 0.3 versus 6.7 +/- 0.5 pg/mg/hr, p less than 0.001). In both normal and preeclamptic placentas, the production rates of thromboxane and prostacyclin were inhibited by indomethacin (5 mumol/L) and not affected (p greater than 0.50) by arachidonic acid (100 mumol/L). Therefore, during normal pregnancy, the placenta produces equivalent amounts of thromboxane and prostacyclin, so that their biologic actions on vascular tone, platelet aggregation, and uterine activity will be balanced. In preeclamptic pregnancy, however, the placenta produces seven times more thromboxane than prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Arachidonic Acids; Culture Media; Epoprostenol; Female; Humans; Indomethacin; Infant, Newborn; Placenta; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Thromboxane B2; Thromboxanes

A prospective study was performed on 26 preeclamptic patients and 17 pregnant control subjects relating the platelet count to in vivo platelet function as assessed by the bleeding time and in vitro platelet function as assessed by collagen-stimulated thromboxane B2 biosynthesis. The results of these tests were normal in all control subjects. Nine of the 26 preeclamptic patients (34%) showed thrombocytopenia, and five of these patients had a prolonged bleeding time. Four of the 16 nonthrombocytopenic patients also had a prolonged bleeding time. Eleven patients had impaired thromboxane B2 biosynthesis, and seven of these had a prolonged bleeding time. In all patients, the bleeding time returned to normal, and in most the platelet count returned to normal within five days or after delivery. A significant proportion of patients with preeclampsia develop an acquired defect of platelet function that could contribute to bleeding.

Topics: Bleeding Time; Blood Platelets; Female; Humans; Platelet Count; Platelet Function Tests; Pre-Eclampsia; Pregnancy; Prospective Studies; Thrombocytopenia; Thromboxane B2

Production of the antiaggregatory and vasodilatory prostacyclin (prostaglandin I2) and the proaggregatory and vasoconstrictory thromboxane A2 during human labor was studied by measuring serial concentrations of the stable metabolites of these prostanoids, 6-keto-prostaglandin F1 alpha and thromboxane B2, respectively, in the amniotic fluid of 43 parturients whose labor was induced by amniotomy. The concentration of 6-keto-prostaglandin F1 alpha at amniotomy in 28 healthy parturients (92.7 +/- 12.1 pg/ml, mean +/- SE) was higher (p less than 0.02) than that in 15 preeclamptic women (48.6 +/- 5.5 pg/ml). The concentration of thromboxane B2 at amniotomy was 292.4 +/- 56.1 pg/ml, with no difference between the healthy and preeclamptic parturients. Both prostanoid levels rose consistently during labor, reaching peak levels when the cervix was fully dilated, but this rise started only after the established uterine contractility. Epidural anesthesia and paracervical blockade had no effect on 6-keto-prostaglandin F1 alpha and thromboxane B2 in the amniotic fluid, whereas oxytocin infusion was accompanied by reduced levels of thromboxane B2. The rise in amniotic fluid 6-keto-prostaglandin F1 alpha was reduced at every stage of labor in the preeclamptic women (n = 15), and its maximal increase (112.4 +/- 28.3 pg/ml) was smaller (p less than 0.005) than in the healthy women (n = 28, 240.8 +/- 21.4 pg/ml). The ratio of 6-keto-prostaglandin F1 alpha to thromboxane B2 also shifted to thromboxane B2 dominance in the preeclamptic parturients. It is concluded that a relative prostacyclin deficiency deteriorates in preeclamptic women during labor.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Amniotic Fluid; Epoprostenol; Female; Humans; Labor Stage, First; Labor, Obstetric; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Thromboxane A2; Thromboxane B2; Thromboxanes; Uterine Contraction

Amniotic fluid from 19 patients with preeclampsia was compared with samples from normotensive control subjects with respect to the levels of prostaglandin 6-keto prostaglandin F1 alpha, thromboxane B2, and the ratio of 6-keto prostaglandin F1 alpha to thromboxane B2. The study found no significant differences in the levels of these prostanoids or the ratio of 6-keto prostaglandin F1 alpha to thromboxane B2 (study patients, 2.7 +/- 2.1; control patients, 2.8 +/- 1.9) between groups.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Amniotic Fluid; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane B2; Thromboxanes

Umbilical blood-flow (UBF) was measured by ultrasonography in 28 pregnant women. A superfusion preparation was used to investigate the production of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), a breakdown product of prostacyclin (PGI2) and thromboxane B2 (TxB2), a breakdown product of TxA2, by specimens from the umbilical arteries of the infants born to these 28 mothers and those born to 36 other women in whom UBF had not been measured. UBF was significantly related to 6-keto-PGF1 alpha production. 6-keto-PGF1 alpha production was lower in infants of the 8 pre-eclamptic mothers (14.5 ng min-1 g-1) than in those of 45 healthy mothers (26.9 ng min-1 g-1). Generation of TxA2 by the umbilical artery was 15-25 times less than that of 6-keto-PGF1 alpha, and TxA2 concentrations were unrelated to UBF or the type of pregnancy. These data provide the first evidence for a direct association between blood-flow and PGI2 generation in human vasculature.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Circulation; Epoprostenol; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2; Thromboxane B2; Thromboxanes; Umbilical Arteries; Umbilicus

This study evaluated the role of platelets in the pathogenesis of toxemia. The findings were: (1) Thrombocytopenia and macrothrombocytosis are characteristic of toxemia. (2) ADP induced platelet aggregation increases during pregnancy, but decreases in severe toxemia significantly. (3) beta-thromboglobulin levels in both plasma and urine rise during pregnancy, and are significantly high in toxemia, especially in a severe type. (4) The plasma TxB2/6-keto-PGF1 alpha ratio markedly increase in severe toxemia due to the increase in the amount of TxB2. And in the IInd trimester, the ratio in the toxemia onset group in which toxemic pregnancy occurred in the IIIrd trimester showed a significantly higher value than the control group. These findings suggest that, in toxemic patients, platelets are in a hyperactive state and there is rapid turnover caused by selective consumption in organs such as the kidneys and placenta, and that platelet aggregation decreases due to the relative increase in the number of exhausted platelets as the toxemic state is impending. Furthermore, the TxA2/PGI2 balance shifts to TxA2 dominant and measurement of the plasma TxB2/6-keto-PGF1 alpha ratio was considered to help prediction of toxemia in the latter term of pregnancy.

Topics: 6-Ketoprostaglandin F1 alpha; beta-Thromboglobulin; Blood Platelets; Female; Humans; Platelet Aggregation; Platelet Count; Pre-Eclampsia; Pregnancy; Thromboxane B2

The implications of the antiaggregatory and vasodilatory prostacyclin (PGI2) and proaggregatory and vasoconstrictory thromboxane A2 (TxA2) during human pregnancy in vivo are briefly reviewed. The level of circulating PGI2 in maternal plasma, as measured by its metabolite (= 6-keto-PGF1a) levels, rises during parturition, but there is no conclusive evidence that the PGI2 production increases already during pregnancy. In pre-eclampsia, PGI2 production can decrease, at least in amniotic fluid, but it is not known whether this PGI2 deficiency is a primary or secondary change in the pre-eclamptic state. TxA2 production in the maternal blood, as measured by the plasma and serum levels of TxB2, is increased during pregnancy, but the effect of pregnancy complication on its production is not known. In amniotic fluid, however, the TxB2 levels did not differ between normal and pre-eclamptic pregnancies. Further in vivo studies are needed to prove or reject the theory that a shift in the PGI2/TxA2 balance to a TxA2 predominance could be of etiological significance in preeclampsia or other pregnancy complications.

Topics: 6-Ketoprostaglandin F1 alpha; Amniotic Fluid; Epoprostenol; Female; Fetal Blood; Humans; Pre-Eclampsia; Pregnancy; Prostaglandins; Thromboxane A2; Thromboxane B2; Thromboxanes

To determine the significance of EPH-gestosis, the author measured the blood levels of lipid peroxides, vitamin E, thromboxane B2, and 6-Keto-prostaglandin F1 alpha. The basis for this was presence of lipid metabolism abnormalities in this disease. 1. The serum lipid peroxides level. In severe cases of EPH-gestosis, a significant increase was observed compared with normal pregnant women in the 10th month of gestation. 2. The serum V-E level. In severe cases of EPH-gestosis, there was a tendency to decrease compared with the values for the late stage of pregnancy. 3. The serum TXB2 level. In severe cases of EPH-gestosis, a significant increase was observed compared with normal pregnant women in the 10th month of gestation. 4. The serum 6-Keto-PGF1 alpha level. In severe cases of EPH-gestosis, a significant decrease was observed compared with normal pregnant women in the 10th month of gestation. 5. Relationship to the gestosis index (G-I). a. Elevation of the lipid peroxide level was noted in cases with a G.I. of 5 or higher. b. The V-E level tended to drop in cases with a G.I. of 4 or higher. c. There was a significant difference between the TXB2 levels at G.I.-3 and G.I.-4. d. The level of 6-Keto-PGF1 alpha dropped as the G.I. increased in cases with a G.I. of 4 or higher.

Topics: 6-Ketoprostaglandin F1 alpha; Female; Humans; Lipid Peroxides; Pre-Eclampsia; Pregnancy; Thromboxane B2; Thromboxanes; Vitamin E

To study the involvement of the antiaggregatory and vasodilator prostacyclin (PGI2) and proaggregatory and vasoconstrictor thromboxane A2 (TxA2) in complicated pregnancies, we measured by radioimmunoassay the stable metabolites of PGI2 and TxA2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), respectively, in samples of amniotic fluid collected at amniocentesis from 88 women between 30 and 40 weeks' normal or complicated pregnancy. The concentrations (mean +/- SE) of 6-keto-PGF1 alpha were 171.8 +/- 9.0 pg/ml in normal pregnancies (N = 27), 134.4 +/- 9.3 pg/ml in severe preeclampsia (N = 13) (0.001 less than p less than 0.005 in comparison with normal pregnancy), 175.6 +/- 13.9 pg/ml in mild preeclampsia (N = 14) (0.01 less than p less than 0.05 in comparison with severe preeclampsia), 168.5 +/- 16.9 pg/ml in diabetic pregnancies (N = 14), 158.7 +/- 5.9 pg/ml in rhesus-immunized pregnancies (N = 10), and 178.7 +/- 13.7 pg/ml in pregnancies with intrauterine fetal growth retardation (N = 10). The corresponding TxB2 concentrations were, respectively, 35.0 +/- 5.7 pg/ml, 29.1 +/- 4.6 pg/ml, 31.3 +/- 3.1 pg/ml, 35.3 +/- 4.0 pg/ml, 31.4 +/- 5.9 pg/ml, and 39.2 +/- 3.2 pg/ml, and these levels did not differ from each other. The level of 6-keto-PGF1 alpha in amniotic fluid correlated with the pregnancy week in normal and preeclamptic pregnancies, and the levels of TxB2 in amniotic fluid in normal, preeclamptic, and rhesus-immunized pregnancies. Furthermore, these two prostanoids correlated with each other in normal pregnancy and in all complications except rhesus-immunized pregnancies. Thus, it is evident that the release of PGI2 into the amniotic fluid is decreased in severe preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Amniotic Fluid; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Thromboxane B2; Thromboxanes

The concentrations of prostaglandins E (PGE) and F (PGF), 13, 14-dihydro-15-oxo-prostaglandin F (PGFM) and thromboxane B2 (TXB2) were measured by specific radioimmunoassays in tissues obtained from women with and without pre-eclampsia. The concentrations of PGE in the amnion, chorion, decidua and placenta obtained from subjects with pre-eclampsia were significantly lower than those from subjects without pre-eclampsia. The concentration of PGE in these tissues increased significantly with gestational age and correlated with urinary oestrogen excretion. PGF concentrations were lower in the amnion and placenta of the pre-eclamptics compared to those without pre-eclampsia. The concentrations of PGFM in the amnion, decidua, and myometrium were lower in the pre-eclamptics. No significant difference in the TXB2 concentrations between the two groups of subjects were found. It is suggested that the altered tissue concentrations of prostaglandins in pre-eclamptics are due to the effects of gestational age and oestrogens and may or may not be involved in the pathogenesis of pre-eclampsia.

Topics: Adolescent; Adult; Amnion; Chorion; Decidua; Dinoprost; Female; Humans; Myometrium; Placenta; Pre-Eclampsia; Pregnancy; Prostaglandins E; Prostaglandins F; Thromboxane B2; Thromboxanes

The concentration of thromboxane B2 has been measured in the plasma of women during late pregnancy, during term and pre-term labour, in women with pre-eclampsia and in umbilical cord arterial and venous plasma. In addition, the rates of production of thromboxane B2 in vitro were determined for placental tissues obtained after spontaneous vaginal delivery or elective Caesarean section. The results obtained indicate significant differences during parturition between the sources and controlling mechanisms of thromboxane and prostaglandin production.

Topics: Female; Humans; In Vitro Techniques; Labor, Obstetric; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Thromboxane B2; Thromboxanes