thromboxane-a2 and Pre-Eclampsia

Topics: Female; Humans; Magnesium Deficiency; Magnesium Sulfate; Pre-Eclampsia; Pregnancy; Sodium Chloride, Dietary; Thromboxane A2; Zinc

Preeclampsia is a multisystem disorder peculiar to human pregnancy. It occurs in 4-5% of all pregnancies and remains a leading cause of maternal and neonatal mortality and morbidity. The pathophysiology of this syndrome is not fully understood. Two stages of vascular dysfunction seem to be involved. In the early stage suboptimal development of the placenta and a hemodynamic maladaptation to pregnancy exist. At this stage maternal constitutional factors such as genetic and immunological factors and pre-existing vascular diseases may play a role. Due to this defective placentation a factor is released from the placenta, supposedly under the influence of ischemia. This factor then results in the late vascular dysfunction characterised mainly by a generalised endothelial dysfunction, leading to the clinical syndrome of preeclampsia. This review attempts to unravel the mechanisms that may contribute to preeclampsia-associated changes in vascular function and to indicate the research needed to improve our understanding of this disease.

Topics: Adult; Arteries; Atrial Natriuretic Factor; Endothelial Growth Factors; Endothelium, Vascular; Epoprostenol; Female; Genotype; Humans; Lymphokines; Muscle, Smooth, Vascular; Placenta; Pre-Eclampsia; Pregnancy; Thromboxane A2; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vasoconstriction

The disparate results reported in the literature on the effects of low dose aspirin in preventing pre-eclampsia might be caused by non-compliance in the more recent large trials in low-risk patients. All the earlier small trials were done on identified high-risk patients who consider themselves as patients, as do their doctors. Compliance in these patients will be very high. In fact, the only study in healthy subjects in which aspirin intake was controlled for (Hauth et al 1993) showed a marked reduction in the incidence of pre-eclampsia. However, the recent large trials have demonstrated, without any doubt, that low dose aspirin is not a miracle drug. The combined literature points at a 25% reduction in the incidence of pre-eclampsia in association with the use of aspirin (Collins, 1994). The correct indication for the use of low-dose aspirin appears to be the patient that is at very high risk of developing early-onset (less than 32 weeks gestation) pre-eclampsia. Since early-onset pre-eclampsia can begin at any time after 20 weeks gestation, it is necessary to initiate low-dose aspirin therapy early in pregnancy, preferably at 10-14 weeks gestation. The results of the recent large trials emphasize the need for a reliable, sensitive method of predicting or detecting pre-eclampsia at a very early gestational age (Dekker and Sibai, 1991). Valensise et al (1993) recently confirmed earlier studies (McParland et al, 1990) on the useful combination of uteroplacental Doppler flow velocimetry and aspirin in low-risk primigravidae. Results from current large-scale trials, such as the ECPPA, the BLASP, the WHO Jamaica and the second NICHHD studies, will be available in the near future. The results of especially the second NICHHD study on low-dose aspirin, in more than 2000 high-risk women (previous pre-eclampsia/eclampsia, chronic hypertension, class B to F diabetes or multiple gestation), will hopefully give us a more definitive picture on the potential benificial effects of low-dose aspirin in high-risk patients. The effect of aspirin on placental TXA2 deserves further studies. It might be that the optimal level to inhibit placental TXA2 and lipid peroxide production is actually higher than the minimal effective doses of aspirin that are needed to inhibit platelet TXA2 production (Walsh, 1994). Low-dose aspirin appears to be safe for the fetus and neonate. If there is an increased risk of abruptio placentae, this risk appears to be minimal. The final word on the

Topics: Aspirin; Epoprostenol; Female; Humans; Platelet Aggregation Inhibitors; Pre-Eclampsia; Pregnancy; Randomized Controlled Trials as Topic; Thromboxane A2

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

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

Our understanding of the pathophysiology underlying the hypertensive diseases of pregnancy has clearly progressed during the past ten years. The key phenomenon is an early defect of placentation occurring at the end of the first trimester and associated with a more widespread endothelial disorder. This results in early activation of the coagulation cascade and imbalance between prostacyclin and thromboxanes. Hypertension and proteinuria only occur after several weeks or months of placental dysfunction. This explains why antihypertensive treatments are ineffective in improving the prognosis of such pregnancies. In contrast, early preventive treatments, such as antiplatelet therapy, seem to be very promising for these patients. In this respect, early prediction of the risk associated with pregnancy has become a key goal.

Topics: Adult; Antihypertensive Agents; Aspirin; Epoprostenol; Female; Hemostasis; Humans; Hypertension; Kidney Diseases; Placental Insufficiency; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2

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

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

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

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

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

Pre-eclampsia is the most common medical complication of pregnancy. Immunologic maladaptation has been suggested to play a role in the etiology of pre-eclampsia. The putative misalliance of fetal trophoblast with maternal tissue in the uteroplacental vascular bed may give rise to an increase in oxygen free radicals. Oxygen free radicals and lipid peroxides might form the link between the hypothetical immunologic maladaptation and the endothelial cell damage known to occur in pre-eclampsia. Recent studies have demonstrated the existence of increased oxygen free radical production in pre-eclampsia. Oxygen free radicals and lipid peroxides decrease vascular prostacyclin and EDRF release and increase thromboxane A2 and endothelin release. The hypothesis is put forward that in pre-eclampsia a proposed immunologic maladaptation causes an increase in oxygen free radicals by decidual lymphoid cells. A decrease in vasodilatory autocoids, prostacyclin and EDRF may result from the endothelial cell damage induced by oxygen free radicals. Uteroplacental prostacyclin production might be essential as escape mechanism. The adequacy as escape mechanism seems to determine the final clinical outcome.

Topics: Blood Platelets; Embryo Implantation; Endothelium; Epoprostenol; Female; Free Radicals; Humans; Immunity, Cellular; Lipid Peroxidation; Nitric Oxide; Pre-Eclampsia; Pregnancy; Thromboxane A2

The origin of pre-eclampsia lies in uteroplacental ischemia due to an anomaly of the "vascular insertion" of the placenta. Although the cause of this anomaly remains unknown, it would appear to include both a genetic and an immunological origin possibly favourised by special underlying conditions and certain obstetric circumstances. Prostaglandin imbalance (in particular prostacyclins and Thromboxane A2) appears to be one of the chief factors governing these anomalies. One of the consequences of these mechanisms is the onset of hypertension but other disturbances are essential features. In particular, disseminated intravascular coagulation may occur leading to the release of numerous microthrombi which cause placental (leading to chronic fetal distress), renal, hepatic and cerebral lesions.

Topics: Disseminated Intravascular Coagulation; Epoprostenol; Female; Humans; Hypertension; Placenta; Pre-Eclampsia; Pregnancy; Thromboxane A2; Ultrasonography

A severe case of preeclampsia with Hellp Syndrome is reported. Clinical findings, laboratory abnormalities and pathogenesis, were discussed. We concluded that severe preeclampsia and Hellp Syndrome are not different diseases, but the natural course of preeclampsia per se.

Topics: Adult; Anemia, Hemolytic; Anticonvulsants; Antihypertensive Agents; Cesarean Section; Combined Modality Therapy; Epoprostenol; Female; Humans; Incidence; Liver Diseases; Pre-Eclampsia; Pregnancy; Syndrome; Thrombocytopenia; Thromboxane A2; Vasoconstriction

Arachidonic acid is metabolized in endothelial cells to antiaggregatory, vasodilatory prostacyclin (PGI2), and in platelets to aggregatory, vasoconstrictory thromboxane A2 (TxA2). The balance of these two prostanoids is supposed to be involved with thrombogenesis and atherogenesis. Acetylsalicylic acid (ASA) inhibits irreversibly the key enzyme of the synthesis of these prostanoids, i.e. cyclo-oxygenase. Platelets do not synthetize new protein, but endothelial cells do. Because of this, and certain pharmacokinetic characteristics of ASA, it should be possible to shift the balance between PGI2 and TxA2 to the dominance of the former with the proper dose of this drug. Altogether more than 50,000 subjects have volunteered for studies on the effect of ASA in the primary or secondary prevention of myocardial infarction or ischemic stroke. The results show that it is possible to reduce vascular attacks by ASA. Furthermore, ASA has also found to prevent pre-eclampsia. Conclusions on the effect of ASA on the PGI2/TxA2-balance are hampered by uncertainties concerning the measurement PGI2 and TxA2 productions in vivo. It is, however, evident that the doses of ASA used in most trials have been high enough to inhibit partly also the production of PGI2. Whether smaller doses or less frequent administration would be more efficient, remains to be studied.

Topics: Arteriosclerosis; Aspirin; Clinical Trials as Topic; Drug Administration Schedule; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2

The aetiology of pregnancy-induced hypertension (PIH) is at present unknown. Epidemiological data lead us to assume, that two main mechanisms could be responsible for the development of PIH. They are not well understood in their complexity, but result in the same pattern of signs and symptoms: Oedema, proteinuria and hypertension. 1. "Goldblatt-Phenomenon" in the uterus, as a result of a disturbed maternal immune response to the cytotrophoblast, followed by the reduction of uterine blood flow and the liberation of vasoactive substances from the placenta. 2. Renal factors, especially in elderly women, result in a manifestation of nephrotic diseases during pregnancy. No screening methods are at the present time available to diagnose PIH in advance. It is therefore necessary, to look at typical clinical manifestations, i.e. the development of hypertension. It is also important to estimate the weight gain and the occurrence of oedema before rising blood pressure demonstrates a general vasoconstriction in the maternal vascular system. The basic therapeutical concept is to reduce the peripheral vascular resistance, to prevent maternal complications and to reduce the uterine vascular resistance to improve foetal oxygenation. In many cases an improvement of the oxygen supply to the foetus is not possible, since irreversible alterations of the uterine arterial vascular bed have already taken place. For the treatment of PIH, different drugs are available which act on different targets. In cases of special medical history, the early application of magnesium and acetyl salicylic acid (ASA) should be included in the therapeutical concept of prophylaxis.

Topics: Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension; Infant, Newborn; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Renin-Angiotensin System; Thromboxane A2; Uterus; Vascular Resistance

Topics: Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2

The etiology of preeclampsia remains unknown. Because of their widespread and varied effects in the human body, prostaglandins--specifically PGI2, thromboxane A2, PGE, and PGF2 alpha--have come under much investigation as possible etiologic factors. The vasodilating, platelet-disaggregating prostaglandins (PGI2 and PGE) are increased during normal pregnancy and may account for many of the observed hemodynamic changes, which begin as early as the first trimester. In contrast, a relative increase in the vasoconstricting, platelet-aggregating prostaglandins (thromboxane A2 and PGF2 alpha) is seen in preeclampsia. The disruption in the delicate balance between these two opposing pairs of prostaglandins may play an important role in the causation of preeclampsia. The growing body of literature that deals with the relationship between prostaglandins and preeclampsia is discussed.

Topics: Dinoprost; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane A2

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

1. The lack of a general agreement on the definition of PE makes the interpretation of laboratory findings in different series of these patients difficult. 2. Thrombocytopenia is the most common hemostatic abnormality in patients with PE and is caused by platelet consumption. 3. There is little concrete evidence that thrombin mediates the thrombocytopenia in most of these patients. 4. Immune mechanisms or severe vasospasm with resultant endothelial damage may contribute to the thrombocytopenia in some patients.

Topics: Anemia, Hemolytic; Disseminated Intravascular Coagulation; Eclampsia; Epoprostenol; Factor VIII; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Humans; Hypertension; Platelet Count; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Thrombin; Thrombocytopenia; Thromboxane A2

Topics: Adult; Blood Circulation; Blood Coagulation; Blood Platelets; Epoprostenol; Female; Fetus; Homeostasis; Humans; Platelet Adhesiveness; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Prostaglandins; Prostaglandins D; Prostaglandins E; Thromboxane A2

Topics: Contraceptives, Oral; Endometriosis; Epoprostenol; Female; Genital Neoplasms, Female; Humans; Hysterectomy; Placental Insufficiency; Pre-Eclampsia; Pregnancy; Prostaglandins; Thromboxane A2; Time Factors; Uterine Neoplasms; Uterus

Recurrent miscarriage is a major women's health problem. Aspirin and heparin have been shown to have potentially beneficial effects on trophoblast implantation. However, few published data on this issue are available from developing countries.. An open clinical trial was conducted at the Department of Obstetrics and Gynecology at Misurata Teaching Hospital in Libya from January 2009 to December 2010 to investigate the effects of treatment with low dose aspirin (LDA) versus treatment with low-molecular-weight-heparin (LMWH) in combination with LDA on patients with a history of recurrent miscarriages. A total of 150 women were enrolled in the study. Women were eligible for the study if they had a history of three or more consecutive miscarriages. Participants were randomly assigned to receive either LDA (75 mg daily) alone or a combination of LDA and LMWH (75 women per treatment group). The primary outcomes were the rate of miscarriages and live births for each group.. Compared with the group who received LDA alone, the combination group had a significantly lower number of miscarriages (22/75 [29%] vs. 43/75 [47%], P < 0.001) and had a significantly higher number of live births (53/75 [71%] vs. 32/75 [42%], P < 0.001). Two preterm infants in the LDA group and three in the combination group were admitted to the neonatal intensive care unit. There were no significant differences in the mean (SD) birth weights of neonates born in either group (2955.4 ± 560 vs. 3050 ± 540 g for the LDA and combination groups, respectively, P = 0.444). There were no congenital abnormalities detected in either group.. The combination of LDA and LMWH is better than LDA alone for the maintenance of pregnancy in patients with recurrent first trimester miscarriage.. NCT01917799.

Topics: Abortion, Habitual; Adult; Aspirin; Birth Weight; Embryo Implantation; Enoxaparin; Female; Fibrinolytic Agents; Humans; Infant, Newborn; Libya; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Prostaglandins I; Thrombophilia; Thromboxane A2; Trophoblasts; Vasodilation; Young Adult

To study effects of magnesium sulfate (MgSO(4)) on prostacyclin (PGI(2)) and thromboxane A(2) (TXA(2)) levels in women with severe preeclampsia during antepartum and postpartum periods.. Women with severe preeclampsia were randomized into two groups. Patients in Group A were continuously infused with MgSO(4) for 24 hours postpartum. In Group B, MgSO(4) administration was discontinued when urinary output was of > or =100 ml/hr for 2 consecutive hours. Patient demographic data were collected. Venous blood was drawn at time of MgSO(4) administration and 24 hours after delivery. Plasma levels of 6-keto-PGF1alpha and TXB(2), stable metabolites of PGI(2) and TXA(2), were measured by enzyme-linked immunosorbent assay (ELISA). Data are presented as mean +/- SE, and analyzed by paired t-test.. A total of 50 patients were recruited, with 27 in Group A and 23 in Group B. There were no statistical differences for demographic data between the two groups with regards to maternal age; gestational age; systolic and diastolic blood pressures at admission, 12 hours postpartum, and 24 hours postpartum; and mode of delivery. Platelet counts were all within the normal range at the time of enrollment. MgSO(4) was administered for an average of 10 hours postpartum in Group B. Maternal blood pressures returned to normal or close to normal levels in both groups at 24 hours postpartum. 6-keto PGF1alpha levels were significantly decreased 24 hours after delivery compared with the levels at enrollment in both groups, (Group A: 98 +/- 13 vs. 180 +/- 28 pg/mL; Group B: 142 + 17 vs. 194 +/- 31 pg/mL, p < 0.05, respectively). However, there was no difference detected between the two groups. TXB(2) levels were not different between group A and Group B at the time of enrollment, 38 +/- 9 vs. 33 +/- 8 pg/mL, and 24 hours postpartum, 26 +/- 5 vs. 25 +/- 3 pg/mL, respectively.. Administration of MgSO(4) does not affect prostacyclin and thromboxane levels in the maternal circulation in women with preeclampsia during antepartum and postpartum periods. We speculate that a higher level of prostacyclin before delivery may reflect compensatory effects of this vasodilator to offset increased maternal blood pressure during pregnancy.

Topics: Adolescent; Adult; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Female; Humans; Magnesium Sulfate; Postpartum Period; Pre-Eclampsia; Pregnancy; Severity of Illness Index; Thromboxane A2; Tocolytic Agents; Treatment Outcome

A major pathophysiologic change of pre-eclampsia has been attributed to the overproduction of thromboxane A2 (TXA2) mainly from activated platelets. On the other hand, increased biosynthesis of TXA2 has also been reported from preeclamptic placentas. The systemic role of these different sources of TXA2 has not been clarified. The purpose of this study is to define the changes of TXA2 and the antagonizing prostacyclin (PC) in maternal and fetal circulations.. The stable metabolites of TXA2 and PC [Thromboxine B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), respectively] in the cord and maternal blood of nine patients with pre-eclampsia and nine normal parturients were measured by radioimmunoassay.. In normal pregnancy, the cord blood contained much higher TXB2 (1697+/-898 vs. 267+/-128 ng/ml, P < 0.01) and 6-keto-PGF1alpha (266+/-263 vs. 12.5+/-3.9 ng/ml, P < 0.05) levels than the maternal blood. In the preeclamptic state, a marked increase of TXB2 was noted in both maternal and cord blood, reaching levels which were significantly higher than during normal pregnancy (2995+/-1103 vs. 267+/-128 ng/ml in maternal blood, P < 0.0001, and 3197+/-1288 vs. 1697+/-898 ng/ml in cord blood, P < 0.005). A less significant increase in 6-keto-PGF1alpha (134+/-10.8 vs. 12.5+/-3.9 ng/ml, P < 0.05) was also noted in the maternal blood. Moreover, the level of TXB2 correlated with the diastolic blood pressure of preeclamptic patients before and after delivery.. The results suggest an abundant source of eicosanoids in the feto-placental circulation, which does not readily cross the placental barrier. In pregnancy complicated with pre-eclampsia, thromboxane level of both fetal and maternal circulations are markedly increased, which may be responsible for the pathophysiologic changes. The lack of adverse systemic effects on the fetus highlights a placental source of TXA2 of transient bioactivity which is rapidly hydrolyzed to non-active TXB2. Federation of Gynecology and Obstetrics

Topics: Adult; Biomarkers; Female; Fetal Blood; Humans; Immunohistochemistry; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Prostaglandins F; Reference Values; Sensitivity and Specificity; Thromboxane A2

To study the effect of daily treatment with 50 mg of aspirin (ASA) on the hypertensive pregnancy complications and on the production prostacyclin (PGI2) and thromboxane A2 (TxA2) in high risk pregnant women and their infants.. Placebo controlled prospective study.. Departments of Obstetrics and Gynaecology, University of Helsinki, University of Oulu and Central Hospital of Middle Finland, Finland.. Two hundred and eight pregnant women with pre-existing hypertension or a history of severe preeclampsia in their previous pregnancy. Prostanoids were studied in a subgroup of 18 women.. The women were randomised to receive ASA (50 mg/day, n = 103) or placebo (n = 105) from the mean of 15 weeks gestational age to delivery. The exacerbation of pre-existing hypertension or the appearance of hypertension in previously normotensive women, the appearance of proteinuria and fetal growth were the main end points, but some other clinical characteristics were also recorded. Urinary excretion of PGI2 and TxA2 metabolites by mothers and infants and their production in umbilical arteries in vitro were also studied.. Two women (one in both groups) had miscarriages, and one pregnancy was terminated for fetal anencephaly (ASA group). In addition, seven women discontinued the treatment due to urticaria (two women in ASA group), increased activity of aspartate amino transferase in serum (one woman in both groups), or increased bleeding time (one woman in ASA group, two women in placebo group), and one woman in the placebo group was lost from follow-up. Thus the end points could be assessed in 97 women taking ASA and 100 women taking placebo. ASA did not diminish the rate of the rise of blood pressure without (12 vs 14, respectively) or with proteinuria (9 vs 11), but fetal haemodynamic disturbances as assessed by Doppler equipment (1/44 vs 6/45 women studied, P = 0.05) and need for treatment in neonatal intensive care unit (10 vs 21, P = 0.04) were more rare in ASA group. ASA tended to increase the birthweight of the newborn (3348 +/- 707 g vs 3170 +/- 665 g, mean +/- SD, P = 0.07), but two perinatal deaths occurred in ASA group. ASA prolonged the bleeding time of the mother (435 s, 210-998 s (geometric mean, range) vs 349 s, 210-690 s, P = 0.02), but caused no extra blood loss during delivery, nor affected neonatal hemostasis. In a subgroup of mothers (ASA, n = 10; placebo, n = 8), ASA inhibited more than 90% of platelet TxA2-production, and caused a 65 to 80% decrease in the urinary excretion of TxA2 metabolites, but no decrease in the urinary excretion of PGI2 metabolites.. ASA did not prevent the rise of maternal hypertension, but improved fetal haemodynamic performance and reduced the need of intensive neonatal care. It inhibited strongly maternal thromboxane A2 but not PGI2 production and thus shifted the balance between PGI2/TxA2 to the dominance of the vasodilatory, anti-aggregatory side.

Topics: Adult; Aspirin; Drug Administration Schedule; Epoprostenol; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Prospective Studies; Thromboxane A2; Time Factors

To study whether balance between antiaggregatory, vasodilatory prostacyclin (PGI2) and proaggregatory, vasoconstrictory thromboxane A2 (TXA2) could be affected by dietary manipulation, 18 pre-eclamptic women were treated in randomized order between 31 and 36 weeks of gestation either with primrose oil (n = 7), with fish oil (n = 5), or with placebo (n = 6). Urinary excretions of the degradation products of PGI2 (6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha) and TXA2 (TXB2, 2,3-dinor-TXB2) were measured in 24 h urines before and serially during the supplementation. Fatty acid supplementation did not affect urinary prostanoid excretions or clinical signs of pre-eclampsia.

Topics: Epoprostenol; Fatty Acids, Essential; Female; Fish Oils; gamma-Linolenic Acid; Humans; Linoleic Acids; Oenothera biennis; Plant Oils; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Thromboxane A2

The hypothesis that an enhanced vasopressor response to angiotensin II in pregnancy may be corrected by suppressing production of platelet thromboxane A2 with low-dose aspirin was tested in a randomized, placebo-controlled, double-blind trial. We studied 36 normotensive primigravid women with an elevated blood pressure response to intravenously infused angiotensin II at 28 weeks' gestation; 18 women received 60 mg of aspirin daily and the same number received matched placebo until 34 weeks' gestation, when angiotensin-sensitivity was again determined. In women taking aspirin, values of thrombin-induced platelet malondialdehyde production were approximately 10% of those determined in the placebo group, indicating marked suppression of thromboxane A2 synthesis. In the aspirin group vascular refractoriness to angiotensin II was restored in 14 of 17 treated women, by comparison with 5 of 15 women in the placebo group who had remained normotensive. These results support the hypothesis that prostacyclin/thromboxane imbalance is an important pathophysiologic factor in the development of the enhanced angiotensin-sensitivity associated with pregnancy-induced hypertensive disorders.

Topics: Administration, Oral; Adolescent; Adult; Angiotensin II; Aspirin; Blood Pressure; Double-Blind Method; Drug Antagonism; Female; Heart Rate; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Thromboxane A2; Vasoconstriction

We carried out a prospective, randomized, double-blind, placebo-controlled study to investigate the capacity of aspirin to prevent pregnancy-induced hypertension and to alter prostaglandin metabolism. A total of 791 pregnant women with various risk factors for pre-eclamptic toxemia were screened with use of the rollover test (a comparison of blood pressure before and after the woman rolls from her left side to her back) during week 28 or 29 of gestation. Of 69 women with abnormal results (an increase in blood pressure during the rollover test), 65 entered the study and were treated with a daily dose of either aspirin (100 mg; 34 women) or placebo (31 women) during the third trimester of pregnancy. The number of women in whom pregnancy-induced hypertension developed was significantly lower among the aspirin-treated than among the placebo-treated women (4 [11.8 percent] vs. 11 [35.5 percent]; P = 0.024); the same was true for the incidence of preeclamptic toxemia (1 [2.9 percent] vs 7 [22.6 percent]; P = 0.019). The mean ratio of serum levels of thromboxane A2 to serum levels of prostacyclin metabolites after three weeks of treatment decreased by 34.7 percent in the aspirin-treated group but increased by 51.2 percent in the placebo-treated group. No serious maternal or neonatal side effects of treatment occurred in either group. We conclude that low daily doses of aspirin taken during the third trimester of pregnancy significantly reduce the incidence of pregnancy-induced hypertension and pre-eclamptic toxemia in women at high risk for these disorders, possibly through the correction of an imbalance between levels of thromboxane and prostacyclin.

Topics: Adult; Aspirin; Clinical Trials as Topic; Double-Blind Method; Epoprostenol; Female; Humans; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Prospective Studies; Random Allocation; Thromboxane A2

Clinical trials and meta-analyses have demonstrated that low-dose aspirin can reduce the risk of preeclampsia and fetal growth restriction in high-risk pregnant women. Current obstetric guidelines recommend that the administration of low-dose aspirin to prevent preeclampsia be initiated after 12 weeks' gestation. This starting time was chosen to minimize possible risks of maternal bleeding and fetal anomalies. However, evidence from reproductive medicine, where low-dose aspirin is commonly recommended to use before and in early pregnancy, as well as existing literature, does not support these concerns. On the other hand, defective placentation resulting in a subsequent ischemic placenta is considered as the starting point of preeclampsia. Low-dose aspirin initiated in early pregnancy can balance the levels of thromboxane A

Topics: Anti-Inflammatory Agents; Aspirin; Endothelium, Vascular; Epoprostenol; Female; Humans; Obstetrics; Placenta; Placentation; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Risk; Thromboxane A2

To observe the effect of magnesium sulfate, Nifedipine Tablet (NT) combined Salvia Injection (SI) on endothelin-1 (ET-1), nitric oxide (NO), thromboxane A2(TXA2), prostacyclin I2(PG2), and hemorheology of preeclampsia patients.. Totally 704 preeclampsia patients were randomly assigned to the treatment group and the control group, 352 cases in each group. All patients were treated with magnesium sulfate combined NT (on the first day: slow intravenous injection of magnesium sulfate 5 g + intravenous dripping of magnesium sulfate injection 10 g + oral administration of NT 30 mg; on the second and third day, intravenous dripping of magnesium sulfate injection 10 g + oral administration of NT 30 mg), while those in the treatment group were dripped with SI additionally at 20 mL per day for 3 consecutive days. Before and after treatment plasma levels of endothelin-1 (ET-1), nitric oxide (NO), TXA2, PGi2, and hemorheology indicators [such as high blood viscosity (HBV), low blood viscosity (LBV), plasma viscosity (PV), erythrocyte rigidity index (ERI), fibrinogen (FIB)] of two groups were detected.. Compared with the same group before treatment, serum levels of ET-1, TXA2, HBV, LBV, PV, ERI, and FIB decreased in the two groups after treatment (P <0. 05), but levels of NO and PG2 increased (P <0. 05). Compared with the control group in the same period, levels of ET-1, TXA2, HBV, LBV, PV, ERI, and FIB decreased in the treatment group after treatment (P <0. 05), but levels of NO and PGI2 increased (P <0. 05).. Magnesium sulfate, NT combined SI could effectively regulate the balance of ET-1/NO and TXA2/PGI2, and improve hemorheology of preeclampsia patients.

Topics: Drug Therapy, Combination; Drugs, Chinese Herbal; Endothelin-1; Epoprostenol; Female; Hemorheology; Humans; Injections; Magnesium Sulfate; Nifedipine; Nitric Oxide; Pre-Eclampsia; Pregnancy; Salvia; Tablets; Thromboxane A2

Preeclampsia is a complex obstetrical syndrome characterized by hypertension and proteinuria. This syndrome is associated with oxidative stress, antioxidant imbalance and impaired production of vasoactive eicosanoids such as thromboxane A(2) (TXA(2)), a potent vasoconstrictor, and prostacyclin (PGI(2)), a well-known vasodilator. We hypothesized that there was a relationship between antioxidant vitamins, such as vitamin E and coenzyme Q(10) (CoQ(10)), and the production of vasoactive eicosanoids- PGI(2) and TXA(2)-potentially regulated by pro-oxidants and antioxidants in preeclampsia.. Therefore, the plasma levels of vitamin E, CoQ(10), TXA(2) and PGI(2) in normotensive (n = 30) and preeclamptic (n = 29) pregnancies were evaluated. Reduced and oxidized forms of vitamin E and CoQ(10) in blood were measured using a HPLC coupled to electrochemical detection. The levels of TXB(2) and 6-keto-PGF(1alpha), stable metabolites of TXA(2) and PGI(2) respectively, were measured by ELISA.. The CoQ(10) oxidized/reduced ratio was significantly higher in preeclamptic compared to normotensive pregnancies (p = 0.04). A strong correlation between plasma levels of reduced vitamin E and CoQ(10), corrected for apolipoprotein B, was observed only in preeclampsia (r = 0.69, p < 0.0001). The 6-keto-PGF(1alpha)/TXB(2) ratio was higher in preeclampsia than in controls (p = 0.02), and this ratio was correlated to the oxidized/reduced ratio of both, vitamin E and CoQ(10) in all pregnancies (p <0.023).. The data indicated that CoQ(10) is a sensitive marker of oxidative stress in preeclampsia. The correlation between vitamin E and CoQ(10) suggested a coordinated defense mechanism against oxidation. Furthermore, the higher 6-keto-PGF(1alpha)/TXB(2) ratio that strongly correlated with oxidative stress markers, suggests a mechanism developed by the maternal cardiovascular system to counteract hypertension during preeclampsia.

Topics: Adult; Chromatography, High Pressure Liquid; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Fatty Acids; Female; Humans; Hypertension; Oxidative Stress; Patient Selection; Pre-Eclampsia; Pregnancy; Thromboxane A2; Ubiquinone; Vitamin E

To evaluate whether impaired endothelial function and endothelial inflammatory response occur in parallel in the women with preeclampsia.. Venous blood was drawn from normal (n=40) and severe preeclamptic (sPE) (n=40) pregnant women when they were admitted to the L&D Unit and 24 hrs after delivery. Plasma and serum samples were extracted and measured for 6-keto PGF1α and TXB(2) (stable metabolites of PGI2 and TXA2), and intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) by ELISA. Data are analyzed by Mann-Whitney test and paired t-test. The statistical significance is set as P<0.05. Results  Plasma 6-keto PGF1α levels were significantly reduced at admission and 24hr after delivery in sPE compared to normal pregnant controls, P<0.01. The ratio of 6-keto PGF1α and TXB(2) was significant less in sPE than that in normal pregnant controls before delivery. There was no significant difference for ICAM and VCAM levels between normal and patients with sPE before and after delivery.. Maternal 6-keto PGF1α levels and the ratio of 6-keto PGF1α and TXB(2) were decreased in patients with sPE compared to normal pregnant controls. In contrast, maternal ICAM and VCAM levels were not different between the two groups. These data suggest that serum ICAM and VCAM levels may not be sensitive inflammatory biomarkers for preeclampsia.

Topics: Adolescent; Adult; Biomarkers; Endothelium; Epoprostenol; Female; Gene Expression Regulation; Humans; Inflammation; Intercellular Adhesion Molecule-1; Pre-Eclampsia; Pregnancy; Thromboxane A2; Vascular Cell Adhesion Molecule-1

Platelet activation is a hallmark of severe preeclampsia, and platelet PGH synthase 1-derived (PGHS1-derived) thromboxane A(2) (TxA(2)) has been implicated in its pathogenesis. However, genetic disruption of PGHS1 delays parturition. We created hypomorphic PGHS1 (PGHS1(Neo/Neo)) mice, in which the substantial but tissue-dependent variability in the inhibition of PGHS1-derived eicosanoids achieved by low-dose aspirin treatment is mimicked, to assess the relative impact of this strategy on hemostatic and reproductive function. Depression of platelet TxA(2) by 98% in PGHS1(Neo/Neo) mice decreased platelet aggregation and prevented thrombosis. Similarly, depression of macrophage PGE(2) by 75% was associated with selectively impaired inflammatory responses. PGF(2alpha) at 8% WT levels was sufficient to induce coordinated temporal oxytocin receptor (OTR) expression in uterus and normal ovarian luteolysis in PGHS1(Neo/Neo) mice at late gestation, while absence of PGHS1 expression in null mice delayed OTR induction and the programmed decrease of serum progesterone during parturition. Thus, extensive but tissue-dependent variability in PG suppression, as occurs with low-dose aspirin treatment, prevents thrombosis and impairs the inflammatory response but sustains parturition. PGHS1(Neo/Neo) mice provide a model of low-dose aspirin therapy that elucidates how prevention or delay of preeclampsia might be achieved without compromising reproductive function.

Topics: Animals; Arachidonic Acid; Aspirin; Blood Platelets; Cyclooxygenase 1; Edema; Estradiol; Female; Humans; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovary; Parturition; Pre-Eclampsia; Pregnancy; Progesterone; Prostaglandin-Endoperoxide Synthases; Receptors, Oxytocin; Thromboxane A2; Uterus

We studied the effects of hydralazine, nicardipine, nitroglycerin, and fenoldopam (a dopamine D1-agonist) on isolated human umbilical arteries (HUA) from patients classified as normotensive and with pregnancy-induced hypertension (PIH). Umbilical artery rings were contracted with the thromboxane A(2) analog (U46619; 10(-8) M) and then exposed to cumulative concentrations of fenoldopam, hydralazine, nicardipine, and nitroglycerin. Second, rings were preexposed to prazosin (10(-5) M), phenoxybenzamine (10(-5) M), or none, and the constriction responses to increasing doses of fenoldopam or dopamine were recorded. Nitroglycerin, hydralazine, and nicardipine produced concentration-dependent relaxation of U46619-preconstricted HUA segments from normotensive and PIH patients. Fenoldopam and dopamine induced umbilical artery constriction in both normal and PIH rings at concentrations > or = 10(-5) M and > or = 10(-3) M, respectively. Phenoxybenzamine, but not prazosin, pretreatment irreversibly abolished fenoldopam-induced contraction. In this in vitro study, nitroglycerin was the most potent vasodilator of the HUA constricted with U46619, followed by nicardipine and hydralazine. However, fenoldopam constricted HUA rings only at supratherapeutic concentrations. No significant differences of vascular responses to fenoldopam (P = 0.3534), nitroglycerin (P = 0.7416), nicardipine (P = 0.0615), and hydralazine (P = 0.5514) between rings from normotensive or hypertensive pregnant patients were shown.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Dopamine; Dose-Response Relationship, Drug; Female; Fenoldopam; Humans; Hydralazine; In Vitro Techniques; Muscle Contraction; Nicardipine; Nitroglycerin; Potassium Chloride; Pre-Eclampsia; Pregnancy; Receptors, Adrenergic, alpha; Thromboxane A2; Umbilical Arteries; Vasoconstrictor Agents; Vasodilator Agents

To investigate whether decidual endothelial cells (DEC) contribute to the pathogenesis of preeclampsia through abnormal nitric oxide production. Decidual endothelial cells from normal (NDEC) and preeclamptic (PEDEC) pregnancies, and also human umbilical vein endothelial cells (HUVEC), were examined.. HUVEC, NDEC, and PEDEC were incubated for 45 min in serum-free media with the addition of potential stimulators [calcium ionophore (A23187), sepiapterin, and a combination of cytokines (TNF-alpha, gamma-IFN and LPS)], and the competitive inhibitor, NG-monomethyl-L-arginine (L-NMMA). These were added alone or in combination. Supernatants were measured for nitrate/nitrite (NOx) levels and the cells acid-extracted for measurement of cyclic guanosine monophosphate (cGMP). The effect of 30 min of shear stress (approximately 20 dynes/cm2) on NO and cGMP production by NDEC and PEDEC and on production of prostacyclin and thromboxane A2, was assessed.. PEDEC and HUVEC both produced more NO than NDEC under all conditions examined. Cell-associated cGMP levels, however, were not different among the cell groups but were increased by A23187 and inhibited by L-NMMA. In control conditions, shear stress stimulated cGMP levels 5-fold (p<0.01) in both NDEC and PEDEC, and PGI2 production 2-fold (p<0.05).. DEC from preeclamptic women do not have reduced NO production and respond normally to shear stress by increasing cGMP and PGI2 production. Our results are consistent with other reports of equal or higher NO levels in preeclampsia and indicate that reduced NO production by endothelial cells is not the explanation for the vasoconstriction of uterine vessels.

Topics: Adult; Calcimycin; Case-Control Studies; Cells, Cultured; Cyclic GMP; Cytokines; Decidua; Endothelium, Vascular; Epoprostenol; Female; Humans; Nitric Oxide; omega-N-Methylarginine; Pre-Eclampsia; Pregnancy; Pteridines; Pterins; Thromboxane A2; Umbilical Veins

The major pathophysiologic changes observed in preeclampsia suggest that endothelial cell dysfunction plays an important role in this disorder. The pathway mediating endothelial cell layer dysfunction is unknown. The concentration of endothelin-1 (ET-1), a potent mammalian vasoconstrictor peptide produced by the vascular endothelium, has been observed to be significantly increased in preeclampsia. In this study, we determined the in vitro effect of endothelin-1 on glutathione and lipid peroxide levels and on the secretion of vasoactive substances by human umbilical vein endothelial cells (HUVECs).. Human umbilical vein endothelial cells were incubated for 24 h in the presence of different concentrations of ET-1 (0-1000 pmol L(-1)), which were shown in an earlier experiment to have no effects on vitality and proliferation rate of HUVECs. The levels of glutathione (GSH) and lipid peroxides (LPO) were measured in endothelial cell lysates. For the measurement of vasoactive substances, levels of nitric oxide (NO), prostacyclin (PGI2) and thromboxane A2 (TXA2) were measured in endothelial cell supernatants.. At lower concentrations (5-50 pmol L(-1)), ET-1 increases the intracellular content of LPO, stimulates the secretion of TXA2, but inhibits the secretion of PGI2 in endothelial cells compared with control cells. At higher concentrations (100-1000 pmol L(-1)), ET-1 increases the intracellular content of GSH, but results in a decrease of LPO, and increase of PGI2, back to control levels. ET-1 has no effect on NO secretion.. These findings demonstrate that at concentrations corresponding to values in plasma from preeclamptic women, ET-1 induces oxidative stress and results in altered secretion of vasoactive substances in human endothelial cells. We conclude that ET-1 may participate in the pathway leading to endothelial cell dysfunction seen in preeclampsia.

Topics: Cells, Cultured; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; Glutathione; Humans; Intracellular Fluid; Lipid Peroxides; Nitric Oxide; Pre-Eclampsia; Pregnancy; Thromboxane A2; Umbilical Veins

The purpose of this study was to determine the role of thromboxane A2 (TXA2) in a conscious, chronically instrumented rat model of pregnancy-induced hypertension (PIH) produced by chronic reductions in uterine perfusion pressure (RUPP).. Mean arterial pressure (MAP), glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and 24-h urinary excretion of TXB2 (metabolite of TXA2) were determined in normal pregnant rats and RUPP pregnant rats.. At day 20 of pregnancy, RUPP rats showed a significantly (P < .05) higher MAP (125 +/- 3 mm Hg v 100 +/- 2 mm Hg) as compared with normal pregnant controls. The elevation in arterial pressure in RUPP group was associated with a marked increase (P < .05) in the urinary concentration of TXB2 compared with normal pregnant group (3663 +/- 488 v 2646 +/- 257 pg/24 h). Baseline GFR (1.74 +/- 0.13 v 2.40 +/- 0.20 mL/min, respectively, P < .05) and ERPF (5.13 +/- 0.44 v 6.44 +/- 0.58 mL/min, respectively) were decreased in RUPP rats relative to pregnant controls. Infusion of a TX receptor antagonist, SQ 29,548 (2 mg/kg bolus plus 2 mg/kg per h infusion) had no significant effect on increased MAP in RUPP pregnant rats. Similarly, ERPF and GFR did not change during acute blockade of TXA2 receptors in this group.. These findings suggest that enhanced production of TXA2 does not play a major role in mediating the hypertension and renal vasoconstriction produced by chronic RUPP in pregnant rats.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Fatty Acids, Unsaturated; Female; Hydrazines; Hypertension; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Renal Circulation; Thromboxane A2; Uterus

There is substantial evidence of increased platelet reactivity in vivo and in vitro during pregnancy, with the risk of developing pre-eclampsia. In this study, platelet function was studied during 28-40 weeks of gestation in a group of women who remained normotensive and in a group of nonpregnant female controls. Platelet aggregation stimulated by thrombin and adenosine diphosphate was markedly enhanced in washed platelets from pregnant subjects. Thrombin (0.04 U/ml)-evoked increases in intracellular Ca+2 mobilization of Fura 2-AM-loaded platelets were also enhanced in pregnant subjects. The binding of fluorescein isothiocyanate (FITC)-triflavin (2 microg/ml) to the glycoprotein IIb/IIIa complex in thrombin-activated platelets did not differ significantly between the nonpregnant and pregnant groups. Thromboxane A2 (TXA2) formation in both resting and thrombin-activated platelets from pregnant subjects was significantly greater than from nonpregnant subjects. Levels of cyclic adenosine monophosphate (cAMP) in both resting and prostaglandin E1-treated platelets (10 micromol/l) from pregnant subjects were significantly lower than those from nonpregnant subjects. There were no significant differences between nonpregnant and pregnant subjects in platelet cAMP levels in the presence of imidazole (600 micromol/l) and indomethacin (500 micromol/l). Intracellular pH values in platelets were measured spectrofluorometrically using the fluorescent probe, BCECF-AM. The increase in intracellular pH stimulated by thrombin (0.04 U/ml) in pregnant subjects was markedly greater than that in observed nonpregnant subjects. We conclude that the agonist-induced hyperaggregability of platelets in normal pregnancy may be due, at least partly, to stimulation of the Na+/H+ exchanger and subsequently to elevated intracellular Ca+2 mobilization, and then to increased TXA2 formation and a lowered level of cAMP, which leads to further increases in intracellular Ca+2 mobilization, and finally to enhanced platelet aggregation.

Topics: Adult; Alprostadil; Calcium Signaling; Cyclic AMP; Disease Susceptibility; Female; Humans; Hydrogen-Ion Concentration; Imidazoles; Indomethacin; Intracellular Fluid; Peptides; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Second Messenger Systems; Sodium-Hydrogen Exchangers; Thrombin; Thrombophilia; Thromboxane A2

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

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

1. In pre-eclampsia, a functional change occurs in the role played by endothelium-derived nitric oxide (NO) in the regulation of smooth muscle contraction in resistance arteries. We investigated the underlying mechanism in human omental resistance arteries from normotensive pregnant and pre-eclamptic women in the presence of diclofenac (an inhibitor of cyclo-oxygenase). 2. In endothelium-intact strips, the sensitivity to 9,11-epithio-11,12-methano-thromboxane A2 (STA2) was significantly higher in pre-eclampsia, and this was not modified by either NG-nitro-L-arginine (L-NNA, an inhibitor of NO synthase) or removal of the endothelium. 3. Bradykinin and substance P each produced an endothelium-dependent relaxation of the STA2-induced contraction in both groups, although the relaxation was significantly smaller for pre-eclampsia. L-NNA markedly attenuated the endothelium-dependent relaxation in the normotensive pregnant group but not in the pre-eclamptic group. 4. In the presence of L-NNA, the relaxation induced by sodium nitroprusside (SNP) on the STA2 contraction was significantly smaller for pre-eclamptic than for normotensive pregnant women. 5. In endothelium-denuded strips, the relaxation induced by 8-para-chlorophenyl thio-guanosine-3', 5'-cyclic monophosphate (8-pCPT-cGMP) on the STA2 contraction was significantly less for pre-eclampsia. 6. In beta-escin-skinned strips from both groups of women, 8-pCPT-cGMP (1-10 microM) concentration-dependently attenuated the contraction induced by 0.5 microM Ca2+. However, its relaxing action was significantly weaker in pre-eclampsia. 7. It is suggested that the weaker responsivene to NO seen in strips from pre-eclamptic women may be partly due to a reduced smooth muscle responsiveness to cyclic GMP.

Topics: Adult; Benzimidazoles; Bradykinin; Calcium; Calcium Channel Agonists; Cyclic GMP; Cyclooxygenase Inhibitors; Endothelium, Vascular; Female; Humans; In Vitro Techniques; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Omentum; Potassium; Pre-Eclampsia; Pregnancy; Substance P; Thromboxane A2; Vasodilation

Changes in the effect of histamine on the smooth muscle of resistance arteries in pre-eclampsia were investigated by measuring isometric contractions in endothelium-denuded strips of omental resistance arteries from pre-eclamptic and normotensive pregnant women (pregnancy-term matched). Histamine (0.03 -1 microM) caused concentration-dependent relaxation of the contraction induced by 9, 11-epithio-11,12-methano-thromboxane A(2) (STA(2)) in strips from both groups. Sensitivity (for pre-eclampsia: pD(2)=6.66+/-0.04, n=5 and for normotensive pregnant women: pD(2)=7.07+/-0.03, n=10, P<0.001) was lower and the maximum response (90.6+/-0.6% vs 95.5+/-1.1%, P<0.05) was smaller in strips from pre-eclamptic women. Although 8-bromoadenosine-3', 5'-cyclic monophosphorothioate (Sp-isomer: Sp-8-Br-cAMPS, 0.1 - 0.3 mM), a phosphodiesterase (PDE)-resistant activator of adenosine-3',5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase, concentration-dependently attenuated the contraction induced by STA(2) in strips from both groups, the sensitivity (for pre-eclampsia: pD(2)=3.68+/-0.04, n=5 and for normotensive pregnant women: 3.94+/-0.09, n=7, P:=0.02) was lower and the maximum response (64.2+/-2.4% vs 74.9+/-4.4%, P:<0.05) was smaller in pre-eclampsia. In beta-escin-skinned strips, the pD(2) value for the contraction-inducing effect of Ca(2+) did not differ significantly between the two groups (for pre-eclampsia, n=6; for normotensive pregnant women, n=6). Thus, omental resistance arteries from human subjects with pre-eclampsia showed (i) a weaker H(2)-receptor-mediated relaxation to histamine and (ii) a weaker cyclic AMP-analogue-induced relaxation, suggesting that the reduced action of histamine may be partly due to a decreased effect of cyclic AMP.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Calcium; Cyclic AMP; Dose-Response Relationship, Drug; Female; Histamine; Humans; In Vitro Techniques; Muscle, Smooth, Vascular; Omentum; Pre-Eclampsia; Pregnancy; Thromboxane A2; Vascular Resistance; Vasoconstriction

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

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

Our purpose was to compare the responsiveness of omental resistance arteries from nonpregnant women and from normotensive and preeclamptic pregnant women to selected contractile agonists.. Omental artery rings with intact endothelium from normotensive premenopausal nonpregnant women and from normal and preeclamptic pregnant women were mounted in Krebs-bicarbonate solution in organ baths for isometric tension recording. After the presence of endothelium was confirmed, cumulative concentrations of norepinephrine, serotonin, U46619, and endothelin-1 were added. Concentration-response curves were constructed and expressed as percentage of a reference 60 mmol/L potassium chloride contraction. Data analysis was by repeated-measures analysis of variance. Newman-Keuls test, and paired or unpaired Student t test, as appropriate. Statistical significance was by two-tailed p<0.05.. Endothelin-1 and U46619 increased tension similarly in all three groups. Norepinephrine increased tension in nonpregnant vessels to a greater extent than in either preeclamptic or pregnant vessels (nonpregnant 114.3 +/- 5.42% vs pregnant 65.2 +/- 10.5%, p<0.05). Nonpregnant omental artery developed significantly greater tension than did pregnant tissue at three concentrations of norepinephrine (10(-5) mol/L, 3 x 10(-5) mol/L, 10(-4) mol/L), and preeclamptic vessels developed more tension than that from normal pregnant vessels at 3 x 10(-6) mol/L (p=0.06) and 10(-5) mol/L (p<0.05). There was a negligible change in tension with increasing concentrations of serotonin in the vessels from nonpregnant women; serotonin-induced contraction in the omental arteries from normotensive pregnant women and preeclamptic patients was <6% of the potassium chloride reference contraction, but this was significantly (p<0.05) different from that of the nonpregnant women.. Omental artery segments from nonpregnant, normotensive pregnant and preeclamptic women contract similarly to endothelin-1 and U46619 but exhibit variable responses to norepinephrine and serotonin.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Arteries; Endothelins; Female; Humans; In Vitro Techniques; Isometric Contraction; Norepinephrine; Omentum; Pre-Eclampsia; Pregnancy; Premenopause; Prostaglandin Endoperoxides, Synthetic; Serotonin; Thromboxane A2; Vasoconstrictor Agents

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

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

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

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 clinical efficiency and mechanism of traditional Chinese medicinal herb Salvia Miltiorrhizae Bge (SMB) and Ligustrazine (L) on pregnancy induced hypertension (PIH) were studied in 30 patients. Before and after the administration of SMB and L, the following parameters: mean arterial pressure (MAP), proteinuria, levels of Thromboxane A2 (TXA2) and Prostacyclin (PGI2) were observed. TXA2 and PGI2 were measured by their stable hydration products Thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by an established radioimmunoassay. The results of treatment were compared with the base line values and showed as follows: MAP and proteinuria decreased significantly (P < 0.05); no marked difference existed in TXB2; the level of 6-keto-PGF1 alpha increased significantly (P < 0.05); the rate of TXB2/6-keto-PGF1 alpha decreased significantly (P < 0.05). The results suggested that SMB and L can invigorate blood circulation by decreasing vasoconstriction.

Topics: Adult; Drugs, Chinese Herbal; Epoprostenol; Female; Humans; Plant Extracts; Pre-Eclampsia; Pregnancy; Pyrazines; Salvia miltiorrhiza; Thromboxane A2

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

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

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

Preeclampsia is a disease of late pregnancy characterized by hypertension, edema, and proteinuria, in which vasoconstriction, platelet aggregation, and reduced uteroplacental blood flow contribute to preterm delivery, perinatal morbidity, and mortality. Increased thromboxane-A2 (TXA2) and/or decreased prostacyclin (PGI2) have been implicated as causative factors of this disease. The present studies investigated the expression of TXA2 synthase gene along with those of TXA2 receptors, PGI2 synthase, cyclooxygenase-1 (COX-1), and COX-2 in placental and decidual tissue from preeclamptic and normal pregnancies. In situ hybridization and immunocytochemistry showed that primarily trophoblast layer and decidual cells express TXA2 synthase, COX-1, and COX-2 enzymes. Immunocytochemistry for PGI2 synthase and in situ hybridization for TXA2 receptors showed similar results. Trophoblast layer and decidua from preeclamptic pregnancies contained a greater abundance of mRNA and protein of TXA2 synthase than the matched normal pregnancies. In summary, our findings suggest that an increased local expression of TXA2 synthase could be responsible for local and/or peripheral vascular changes in preeclampsia.

Topics: Decidua; Eicosanoids; Epoprostenol; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Thromboxane A2; Thromboxane-A Synthase

Plasma concentrations of 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin, and TxB2 were measured in 160 women during pregnancy (n = 106), delivery (n = 40), and in the postpartum period (n = 14). Fifty nine patients had normal blood pressure, 10 had mild and 9 severe preeclampsia while 38 patients were hypotensive. Normotensive patients were grouped according to their gestational age: 22-26 weeks (n = 22), 27-31 weeks (n = 22), and 32-38 weeks (n = 15). 20 patients were in early first stage of delivery (cervical dilatation < or = 5 cm), 20 patients in late first stage (cervical dilatation > or = 6 cm). The concentration (mean value +/- SEM) of the PGI2 metabolite tended to increase during pregnancy without reaching significance (218 +/- 11; 225 +/- 10; 250 +/- 15 pg/ml). At the same time, TxB2 showed a decrease, which was most pronounced at 27-31 weeks (65 +/- 15; 40 +/- 2; 48 +/- 4 pg/ml; p < 0.001). The ratio of PGI2/TxA2 increased in parallel (4.9 +/- 0.4; 6 +/- 0.4; 4 +/- 0.5). There was no difference in plasma concentrations of PGI2 (figure 4) and TxA2 in patients with normal blood pressure, mild preeclampsia and hypotension, whereas in severe preeclampsia, the plasma concentration of PGI2 was significantly lower (p < 0.001) and of TxA2 significantly higher (p < 0.001). The ratio of PGI2/TxA2 shifted significantly to vasoconstriction in patients with severe preeclampsia (p < 0.0001) and to vasodilatation in those with hypotension (p < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Epoprostenol; Female; Humans; Hypotension; Labor, Obstetric; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Thromboxane A2

Although the changes in prostacyclin and thromboxane A2 levels in preeclampsia have been well studied, little work has previously been done on mononuclear cells, and the cause of the changes in unclear. We determined the prostacyclin and thromboxane A2 production in mononuclear cells and investigated the effect of preeclamptic serum on this production.. The production of prostacyclin and thromboxane A2 was measured by enzyme immunoassay in 16 normal pregnant women, nine preeclamptic women with proteinuria, and six preeclamptic women without proteinuria. Sera from these three groups of women were investigated to see whether the sera have any effect on prostaglandin production.. The levels of thromboxane A2 in preeclamptic patients were found to be much higher than those of normal pregnancy, whereas the levels of prostacyclin tended to be lower. Such changes lead to a markedly increased ratio of thromboxane A2 to prostacyclin in preeclamptic patients. There was no difference in the levels of prostacyclin and thromboxane A2 between the preeclamptic patients with and without proteinuria. Serum from preeclamptic patients with proteinuria slightly reduced prostacyclin synthesis in normal pregnancy but significantly increased increased thromboxane A2 production, resulting in a ratio of thromboxane A2 to prostacyclin similar to that of preeclampsia. However, serum from preeclamptic patients without proteinuria failed to exert such effects.. The imbalance between prostacyclin and thromboxane A2 occurs in mononuclear cells from preeclamptic women, and there is a factor(s) in proteinuric-preeclamptic serum to contribute, in part, to these changes. Our findings also suggested that the cause of abnormal prostaglandin production in preeclampsia was complicated and multifactorial.

Topics: 6-Ketoprostaglandin F1 alpha; Cells, Cultured; Epoprostenol; Female; Humans; Monocytes; Osmolar Concentration; Pre-Eclampsia; Pregnancy; Proteinuria; Reference Values; Thromboxane A2

Pregnancy induced hypertension (PIH) is associated with a variety of disturbances in the hemostatic system including alterations in platelet function, thrombocytopenia, and an increase in platelet turnover. The density of platelet Thromboxane A2 (TXA2)/Prostaglandin H2 (PGH2) receptors was determined in patients with PIH and normal pregnant women, using [125I]-PTA-OH, a TXA2/PGH2 receptor antagonist. The number of platelet TXA2/PGH2 receptors significantly increased (p < 0.008) from 1734 +/- 370 sites/platelet (n = 8) in normal pregnant women to 3703 +/- 846 sites/platelet (n = 9) in patients with severe PIH. The sensitivity of platelets to the TXA2 mimetic U46619 was significantly (p < 0.0005) increased in platelets obtained from severe PIH patients (EC50 = 150 +/- 10nM, n = 3) compared to controls (EC50 = 290 +/- 60 nM, n = 5). These results indicate that an increased number of TXA2/PGH2 receptors as well as increased sensitivity to TXA2/PGH2 mimetics occurs in PIH. Collectively, these results provide further support for the notion that TXA2 and its receptor may play an important role in the pathophysiology of PIH.

Topics: Blood Platelets; Female; Humans; Platelet Aggregation; Platelet Count; Pre-Eclampsia; Pregnancy; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Severity of Illness Index; Thromboxane A2

The formation of thromboxane A2 (TXA2) in maternal and foetal cord serum was measured at birth in eight control patients and in 13 patients taking 100 mg of a slow-release formulation of acetylsalicylic acid. The serum concentrations of TXB2 (a stable end product of TXA2 hydrolysis) in both maternal and cord serum from patients who ingested the acetylsalicylic acid formulation were significantly lower (P < 0.01) than those in control subjects. Acetylsalicylic acid was not detected (< 30 ng ml-1) in maternal plasma from six mothers and in cord plasma from seven foetuses in the acetylsalicylic acid-treated group. The mean cord to maternal plasma concentration ratios for detectable acetylsalicylic acid and salicylate were 0.62 +/- 0.19 (s.d.) (n = 6) and 0.84 +/- 0.16 (n = 13), respectively. We conclude that low doses of acetylsalicylic acid given in a slow-release form to mothers during pregnancy cause depression of TXA2 formation in the foetal blood.

Topics: Adult; Aspirin; Delayed-Action Preparations; Female; Fetal Blood; Humans; Indicators and Reagents; Infant, Newborn; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Risk; Salicylates; Salicylic Acid; Thromboxane A2

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

Topics: Aspirin; Blood Platelets; Endothelium, Vascular; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Thromboxane A2

To clarify the possible role of elevated atrial natriuretic peptide (ANP) in the pathophysiology of preeclampsia, we measured ANP, renin activity (PRA), angiotensin II (Ang II), TXB2 (a stable metabolite of TXA2) and 6-keto-PGF1 alpha (a stable end product of PGI2) concentrations in the plasma of 19 normal pregnant women and 35 severe preeclamptic patients at term. Plasma ANP levels in the preeclamptic patients (n = 35, 71.5 +/- 3.8 pg/ml, mean +/- S.E.) and also umbilical plasma ANP (n = 35, 83.0 +/- 4.2 pg/ml) were significantly (p less than 0.01) higher than those of normal pregnant women plasma (n = 19, 58.7 +/- 3.7 pg/ml) and umbilical plasma (n = 19, 47.6 +/- 4.7 pg/ml). There was a significant (p less than 0.01) positive correlation between maternal ANP levels and fetal ANP levels (n = 54, r = 0.44). Plasma PRA and 6-keto-PGF1 alpha levels in preeclampsia were significantly (p less than 0.05) lower than those of normal pregnancy. The ratio of 6-keto-PGF1 alpha/TXB2 in preeclampsia was significantly (p less than 0.01) lower than that of normal pregnancy as we reported previously. There was no significant correlation between plasma ANP level and plasma PRA, Ang II, plasma TXB2 and 6-keto-PGF1 alpha concentrations. Moreover there was no significant correlation between plasma ANP level and the severity of preeclampsia. These data suggest the possibility of a transplacental crossing of ANP secreted by feto-placental unit, which might be, at least in part, responsible for the high ANP levels observed in preeclampsia. The ANP in preeclampsia is not related directly to hypertension, but it may play a substantial role in the regulation or normalization of blood volume and vascular reactivity.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Angiotensin II; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Epoprostenol; Female; Fetus; Humans; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Renin; Thromboxane A2

Enzymes involved in prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) synthesis were studied in maternal and fetal platelets and venous endothelium from normotensive pregnant controls (n = 70), women with mild preeclampsia (MP, n = 45), and severe preeclampsia (SP, n = 34). Activities of phospholipase A2 (PHA2), cyclooxygenase (PGHS), and PGI2 synthetase (PGIS) or TXA2 synthetase (TXAS) were determined in platelets and in endothelial cells. The PGHS enzyme was studied further by immunoblot methodology. In maternal platelets: Vmax (per 10(-10) mol/mg protein) and Michaelis-Menten constant (Km) (10(-7) mol, mean +/- SEM) of PHA2 were 3.0 +/- 0.8, 3.0 +/- 0.7, and 31.7 +/- 10.9* maximum velocity (Vmax) and 1.8 +/- 0.3, 2.0 +/- 0.8, and 0.8 +/- 0.2 (Km) in normal control (NC), mild preeclampsia (MP), and severe preeclampsia (SP), respectively (*P less than 0.05 against NC). The apparent overall PGHS plus TXAS activity was 10.2 +/- 1.8, 23.8 +/- 7.1, and 68.8 +/- 18.8* (Vmax) and 3.2 +/- 1.3, 5.4 +/- 1.4, and 6.9 +/- 1.2* (Km, *P less than 0.05 against NC). TXA synthesis in fetal platelets demonstrated PHA2 activity of 6.4 +/- 1.4, 12.0 +/- 1.3, and 17.2 +/- 3.2* (Vmax) and 3.5 +/- 0.9, 2.2 +/- 1.5, and 0.7 +/- 0.3* (Km, *P less than 0.05 against NC), respectively, whereas an apparent overall PGHS plus TXAS activity was 18.5 +/- 2.8, 87.5 +/- 12.5*, and 3.6 +/- 0.1* (Vmax) and 4.8 +/- 1.0, 8.8 +/- 1.2, and 0.8 +/- 0.3* (Km, *P less than 0.05 against NC).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Platelets; Cytochrome P-450 Enzyme System; Endothelium, Vascular; Epoprostenol; Female; Humans; Intramolecular Oxidoreductases; Isomerases; Phospholipases A; Phospholipases A2; Pre-Eclampsia; Pregnancy; Prostaglandin-Endoperoxide Synthases; Thromboxane A2; Thromboxane-A Synthase; Umbilical Veins

Plasma renin activity, plasma concentrations of angiotensin II (AngII), stable metabolites (6-keto-prostaglandin F1 alpha: 6-keto-PGF1 alpha) of prostacyclin (PGI2) and a metabolite (thromboxane B2: TXB2) of thromboxane A2 (TXA2) were measured with radioimmunoassay(RIA) in 107 normal pregnancy (control) and 139 preeclamptic patients in 28-41 gestational weeks. PRA and 6-keto-PGF1 alpha were significantly higher and AngII was slightly higher in preeclampsia than in control, and TXB2 was significantly lower in preeclampsia in control. The ratio of 6-keto-PGF1 alpha/TXB2 was significantly lower in preeclampsia than in control. These data suggest that the changes in the renin-angiotensin system may not be primary alterations in preeclampsia. It can be speculated that in preeclampsia the changes in absolute concentrations of 6-keto-PGF1 alpha and TXB2 are less important than the decrease in the ratio of the 6-keto-PGF1 alpha/TXB2.

Topics: Adult; Angiotensin II; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Regression Analysis; Renin; Thromboxane A2

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

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

Topics: Aspirin; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Thromboxane A2; Thromboxanes

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

Topics: Aspirin; Blood Platelets; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Thromboxane A2

In the present study, metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), 6-oxoprostaglandin F1 alpha (PGF1 alpha) and thromboxane B2 (TxB2) in the umbilical circulation were determined. Also the baseline and substrate stimulated synthesis and release of these compounds in the umbilical vessels were measured. Umbilical serum 6-oxo-PGF1 alpha levels were significantly higher while no consistent pattern was found for TxB2. The 6-oxo-PGF1 alpha levels in the umbilical artery (UA) were revealed to be significantly lower in preeclamptic patients (PRC) while TxB2 levels were higher. These levels in the umbilical veins (UV) showed no difference. The base line release of 6-oxo-PGF1 alpha and TxB2 from UA and UV showed no statistical difference. With a saturating dose of sodium arachidonate (A . A), both UA and UV tissue showed marked enhancement in the release of the two, in which 6-oxo-PGF1 alpha from UV was significantly higher than that from UA while TxB2 was without statistical difference. Between normal subjects and PRC, there was no difference in the base line release of 6-oxo-PGF1 alpha from UA, while TxB2 was higher in PRC. Substrate A . A did not enhance the release of 6-oxo-PGF1 alpha in the PRC, but the mean TxB2 release tended to increase both in the control and PRC. Present data indicate that the impaired metabolism, especially that of TxA2, and an imbalance between PGI2 and TxA2 may be involved in the development of PRC.

Topics: Adult; Epoprostenol; Female; Fetal Blood; Humans; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Thromboxane A2

The fetal and maternal morbidity and mortality from the hypertensive disease states of pregnancy is a major problem. While much is known about the syndrome, the cause has been elusive. The ewe was chosen to test a hypothesis that depletion of magnesium may be involved. Twelve Finnish ewes were subjected to low magnesium diets with half given magnesium in the water. Tests included measurement of blood pressure in the waking state and by noninvasive technique. Magnesium levels were measured by atomic absorption spectrophotometry in the plasma and tissue of the ear tips. Findings included significant elevation of arterial blood pressure, reduction in fetal weight with pathologic confirmation of placental and renal lesions which were similar to those seen in the human condition. Significant lowering of both plasma and tissue of magnesium was noted. The hypothesis was supported and extended to include possible interaction with prostacyclin and thromboxane as intermediaries in a hypomagnesic coagulative angiopathy. This entity would also explain the association of migraine in the eclamptic and preeclamptic syndrome reported by previous authors. The success of parenteral magnesium in the treatment of these human conditions is therefore more than purely empiric.

Topics: Animals; Blood Pressure; Body Weight; Epoprostenol; Female; Fetus; Hypertension; Kidney; Magnesium; Magnesium Deficiency; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Sheep; Thromboxane A2

The effect of intravenously administered labetalol (1 mg/kg) on placental and fetal blood flow was studied in 13 pre-eclamptic women. Although the maternal blood pressure decreased, no changes occurred in the blood flows in the intervillous space, the umbilical vein or the fetal descending aorta, nor did the indices of peripheral vascular resistance in the fetal aorta change, but the placental vascular resistance did decrease. Labetalol had no effect on prostacyclin or thromboxane A2 as measured by urinary 6-keto-prostaglandin F1 alpha and serum thromboxane B2 respectively. These findings are clinically relevant since they suggest that labetalol reduces maternal blood pressure without interfering with the placental or fetal blood flow.

Topics: Blood Pressure; Epoprostenol; Female; Fetus; Heart Rate; Hemodynamics; Humans; Labetalol; Placenta; Pre-Eclampsia; Pregnancy; Regional Blood Flow; Thromboxane A2

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

The hemodynamic effects of intravenously infused dihydralazine (incremental doses up to 125 micrograms per minute during 60 minutes) were studied in ten women with acute or superimposed severe preeclampsia. The intervillous and umbilical vein blood flow were measured before and during dihydralazine infusion with 133Xenon method and with a combination of real-time and Doppler ultrasonic equipment, respectively. Maternal blood pressure decreased and pulse rate increased during the infusion. Dihydralazine did not change the intervillous blood flow but it increased the blood flow in umbilical vein. No effect on the 6-ketoprostaglandin F1 alpha in maternal plasma and urine or thromboxane B2 in maternal serum was observed. The results indicate that dihydralazine affects the placental and fetal circulations differently.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Pressure; Dihydralazine; Female; Fetal Heart; Humans; Hydralazine; Hypertension; Infusions, Parenteral; Placenta; Pre-Eclampsia; Pregnancy; Pulse; Regional Blood Flow; Thromboxane A2; Umbilical Veins

Topics: Angiotensin II; Blood Platelets; Blood Vessels; Disseminated Intravascular Coagulation; Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia; Thromboxane A2

The production of vasodilatory, antiaggregatory prostacyclin (PGI2) and vasoconstrictory, proaggregatory thromboxane A2 (TxA2) by the placenta was studied in the cases of hypertensive pregnancy complications by superfusing pieces from maternal and fetal sides of placentae of 9 pre-eclamptic, 6 hypertensive and 11 healthy women in vitro and measuring the release of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), the breakdown products of PGI2 and TxA2 respectively, from the superfusate. Both sides of the placentae from the controls produced 6-keto-PGF1 alpha (maternal side 0.5 +/- 0.1 ng/g/min dry weight of tissue, mean +/- SEM; fetal side 0.7 +/- 0.2 ng/g/min) and TxB2 (maternal side 2.5 +/- 0.4 ng/g/min; fetal side 2.7 +/- 0.5 ng/g/min) with no correlation between the two. The 6-keto-PGF1 alpha production was normal in hypertensive complications whereas the TxB2 production was increased on the fetal side of the placentae obtained from the pre-eclamptic (3.7 +/- 0.3 ng/g/min: p less than 0.05) and hypertensive women (4.1 +/- 0.4 ng/g/min; p less than 0.025). This may explain the occurrence of microthrombi and infarctions in placentae of hypertensive women.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Humans; Hypertension; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboxane A2; Thromboxanes

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

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

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

Topics: Epoprostenol; Female; Humans; Pre-Eclampsia; Pregnancy; Prostaglandins; Purpura, Thrombotic Thrombocytopenic; Thromboxane A2; Uremia

Prostacyclin is a very unstable prostaglandin, which is continuously synthetized and released by blood vessels. It fulfills 2 main functions, namely strong inhibition of platelet aggregation and vasodilation. Thus it acts as an important defense mechanism of the vascular wall, which is directed against overwhelming platelet aggregation and against the development of atherosclerosis. Besides endogenous prostacyclin is an important antihypertensive factor. In several diseases, as diabetes mellitus, obliterative arteriopathy and haemolytic-uraemic syndrome, the reduced prostacyclin-synthesis is thought to be a key mechanism for the development of vascular lesions. On the other hand the haemorrhagic diathesis of uraemics is seen in connection with an increased vascular prostacyclin release. Synthetic prostacyclin is now under trial for therapy in peripheral obliterative arteriopathy and extracorporeal circulation, as haemodialysis and cardiopulmonary bypass.

Topics: Arteriosclerosis; Diabetic Angiopathies; Epoprostenol; Female; Hemolytic-Uremic Syndrome; Humans; Intermittent Claudication; Muscle, Smooth, Vascular; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Prostaglandins; Purpura, Thrombotic Thrombocytopenic; Thromboxane A2; Vasodilation