Preeclampsia: an imbalance in placental prostacyclin and thromboxane production

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

A trial of low-dose aspirin therapy in high-risk pregnancy]

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

Endothelium-derived relaxing factor and indomethacin-sensitive contracting factor alter arterial contractile responses to thromboxane during pregnancy.

OBJECTIVES: Pregnancy reduces uterine artery contractile responses to norepinephrine and angiotensin II in many species, including the human and the guinea pig, by release of endothelium-derived relaxing substances. We hypothesized that vascular reactivity to thromboxane during pregnancy would also be reduced by a similar mechanism. STUDY DESIGN: Isolated ring segments of uterine and carotid arteries from nonpregnant and near-term pregnant guinea pigs were suspended in a myograph for the measurement of isometric tension. RESULTS: Uterine but not carotid artery sensitivity to cumulative addition of the thromboxane analog U46619 was decreased during pregnancy. The maximal contractile responses of both vessels were unaltered by pregnancy. N omega-nitro-L-arginine (10(-4) mol/L), an inhibitor of nitric oxide endothelium-derived relaxing factor synthesis, increased the sensitivity of uterine and carotid arteries to U46619 in both pregnant and nonpregnant animals. The maximal contractile response of uterine arteries from pregnant guinea pigs was also increased, but that of nonpregnant ones was not. The maximal U46619 contractile response of the carotid artery was not significantly altered by N omega-nitro-L-arginine. Indomethacin (10(-5) mol/L), a cyclooxygenase inhibitor, reduced both the sensitivity and the maximal response of U46619 in each vessel group. Removal of the endothelium from uterine artery of pregnant animals enhanced both sensitivity and maximal response to U46619. Pretreatment of the denuded segments with indomethacin reduced the sensitivity to U46619. However, indomethacin-treated denuded segments were still more sensitive to U46619 than controls. CONCLUSION: The sensitivity of guinea pig uterine artery but not carotid artery to thromboxane is reduced during pregnancy. Although the precise mechanism remains unclear, both endothelium-derived relaxing factor and an indomethacin-sensitive contracting factor are involved. If indomethacin-sensitive contracting factor is released by humans and disease alters that release, it is possible that any enhanced contractile response to thromboxane resulting from the loss of endothelium-derived relaxing agents such as prostacyclin and endothelium-derived relaxing factor would be offset by the loss of indomethacin-sensitive contracting factor.     

Prevention of recurrent idiopathic fetal growth retardation by low-dose aspirin and dipyridamole

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

On the Brain in Eclampsia

Eclampsia is a syndrome of unknown etiology that is unique to human pregnancy. The pathophysiologic abnormalities of eclampsia have been the subject of extensive investigation and speculation. Reported abnormalities include vasospasm, disturbed hemodynamics, activation of the coagulation system, endothelial cell injury, mitochondria injury, and uteroplacental ischemia (1). Endothelial cell dysfunction or injury plays a central role in its pathogenesis (2). Endothelial cell injury results in altered balance between the release of potent vasoconstricting substances such as endothelin and lack of potent vasodilating substances such as prostacyclin and endothelium-derived relaxing factors. In addition, platelet activation results in abnormal production of vasoconstricting and platelet aggregating agents such as thromboxane A₂ and serotonin. A combination of the above may lead to pathophysiologic ischemic lesions within multiple organ systems including the uteroplacental vascular beds, kidneys, liver, and brain.

The precise etiology of eclamptic convulsions remains an enigma. Reported mechanisms have included vasospasm, hypertensive encephalopathy, cerebral edema, infarction, and hemorrhage (3). Overall, the results of clinical studies and neurodiagnostic findings in eclamptic women suggest that cerebral vasospasm play a central role in the etiology of eclamptic convulsions (4-10).     

Immunoreactive prostacyclin and thromboxane metabolites in normal pregnancy and the puerperium

Prostacyclin and thromboxane have been implicated in the pathophysiology of several disorders of pregnancy, but there is little information on concentrations of these prostaglandins in normal pregnancy. The aim of our study was to determine the range of values throughout normal pregnancy and the puerperium and to compare this with concentrations in normal non-pregnant women. Measurement was by radioimmunoassay of prostacyclin and thromboxane metabolites. We observed a significant difference in prostacyclin metabolites in the first trimester, (mean 19.9, SEM 0.96 pg/ml) compared with the normal non-pregnant group (mean 15.9, SEM 0.68 pg/ml). There were no significant differences between values in the normal non-pregnant group and those in the second and third trimester or postnatally. The increase in prostacyclin in the first trimester may be associated with placentation and physiological vasodilation, and insensitivity to angiotensin II seen in early pregnancy. We noted a significant reduction in thromboxane metabolites in the second (mean 133, SEM 14.9 pg/ml) and third (mean 123, SEM 10.7 pg/ml) trimesters and the puerperium (mean 119, SEM 6.3 pg/ml) compared with the values in the normal non-pregnant group (mean 142, SEM 4.9 pg/ml). This may be due to increased platelet stability or decreased thromboxane synthesis.     

Low-dose aspirin: treatment for the imbalance of increased thromboxane and decreased prostacyclin in preeclampsia

The discovery of the imbalance of increased thromboxane and decreased prostacyclin production in preeclamptic women has explained the cause of the major clinical symptoms of this disorder and has formed the basis and rationale for clinical studies with low-dose aspirin to treat preeclampsia. Low doses of aspirin (60 to 81 mg/day) have a remarkable ability to inhibit thromboxane production selectively without significantly inhibiting prostacyclin production. Therefore the actions of thromboxane to increase vasoconstriction, stimulate platelet aggregation, increase uterine contractility, and decrease uteroplacental blood flow are attenuated, and the ratio of thromboxane to prostacyclin is altered in favor of prostacyclin. Prostacyclin promotes vasodilation, inhibits platelet aggregation, decreases uterine contractility, and increases uteroplacental blood flow. The initial clinical studies with low doses of aspirin are very encouraging with respect to the treatment and prevention of preeclampsia. Substantial evidence already indicates that low-dose aspirin therapy decreases the incidence of preeclampsia; it decreases the maternal systemic arterial pressor response to angiotensin II; and it does not seem to be harmful to the fetus. Treatment of preeclampsia with prostacyclin appears to be contraindicated because prostacyclin is a potent systemic vasodilator and the clinical outcome of preeclamptic women infused with prostacyclin has been poor. The mechanism whereby low-dose aspirin preferentially inhibits thromboxane synthesis is not known.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of plasma on the platelet antiaggregatory action of prostacyclin in pregnancy

Platelet-poor plasma from 13 nonpregnant, 33 normally pregnant, and eight preeclamptic women was incubated with prostacyclin. The ability of platelet-poor plasma to diminish the antiaggregatory effect of prostacyclin was assessed by measuring this effect on arachidonic acid-induced platelet aggregation. Platelet aggregation greater than 95% in response to arachidonic acid was observed when incubated plasma without exogenous prostacyclin was assayed. When prostacyclin and platelet-poor plasma were preincubated together, subsequent arachidonic acid-induced platelet aggregation measured 9.6% in samples from nonpregnant patients, 40.3% in samples from normally pregnant patients, and 78.2% in samples from patients with preeclampsia. The ability of exogenous prostacyclin to inhibit arachidonic acid-induced platelet aggregation was significantly different in the presence of plasma from nonpregnant, normally pregnant, and preeclamptic women. These observations suggest that a plasma factor may affect the action of prostacyclin during pregnancy.     

Ritodrine infusion during late pregnancy: effects on fetal and placental blood flow, prostacyclin, and thromboxane

To study the effects of ritodrine on fetal and placental blood flow and maternal prostacyclin and thromboxane A2, 14 women with premature uterine contractions between the thirty-first and thirty-sixth weeks of pregnancy were treated with intravenous infusions of ritodrine, with incremental doses up to 200 micrograms per minute. The intervillous and the umbilical vein blood flows were measured before and after 1 hour of infusion of ritodrine, with the xenon 133 method and with a combination of real-time and Doppler ultrasonic equipment, respectively. Ritodrine decreased maternal diastolic and mean arterial pressures, as well as placental vascular resistance, but caused no significant changes in intervillous and umbilical vein blood flows. Ritodrine stimulated the synthesis of vasodilatory prostacyclin, as seen from a rise in maternal plasma 6-keto-prostaglandin F1 alpha, but inhibited the platelets' capacity to generate the vasoconstrictor thromboxane A2. Thus, apart from maternal hemodynamic changes, the intervillous and umbilical circulations are maintained during short-term administration of ritodrine in normotensive pregnancies.     

Effect of nicotine on fetal prostacyclin and thromboxane in humans

To study the effect of nicotine on fetal prostacyclin and thromboxane A2, specimens from the umbilical arteries of infants born to healthy nonsmoking mothers were superfused in the absence or presence of nicotine (50 to 10,000 micrograms/mL), and the releases of 6-keto-prostaglandin F1alpha (a break-down product of prostacyclin) and thromboxane B2 (a metabolite of thromboxane A2) were measured. The baseline production of 6-keto-prostaglandin F1alpha (63.9 +/- 8.8 ng/minute per gram of dry weight tissue, mean +/- SE, N = 10) or that of thromboxane B2 (1.3 +/- 0.2 ng/minute per gram, N = 10) were unaffected by nicotine. To study the effect of nicotine on thromboxane A2 synthesis by the fetal platelets, thrombin-induced platelet aggregation and consequent thromboxane A2 synthesis were allowed to occur in the whole cord blood in the absence or presence of nicotine (10 to 500 micrograms/mL). Nicotine inhibited concentration dependently platelet thromboxane A2 synthesis from the baseline level (107.3 +/- 7.1 ng/mL) by 15 to 93%. This inhibition was also seen in thromboxane A2 synthesis starting from exogenous arachidonic acid, suggesting that nicotine inhibits either cyclooxygenase and/or thromboxane A2 synthetase in the fetal platelets. Thus, nicotine is hardly responsible for maternal smoking-induced changes in fetal prostacyclin formation.     

Nonpregnant women with a history of habitual abortion have normal and luteal function independent production of prostacyclin and thromboxane A2.

OBJECTIVE: To see if changes in prostacyclin and thromboxane A2 (TXA2) production during early pregnancy in women with habitual abortion is a pregnancy-induced change, we compared the production of these prostanoids in habitual aborters and in healthy controls in nonpregnant state and related it to luteal function. DESIGN: Comparison between patients (n = 16) with a history of at least three consecutive miscarriages and healthy controls without a history of abortions (n = 11). SETTING: Departments I and II of Obstetrics and Gynecology, University Central Hospital of Helsinki, Helsinki, Finland. RESULTS: Habitual aborters and control women exhibited no change in the urinary output of the stable degradation products of prostacyclin and TXA2 when studied between 0 and 2 and 5 and 8 days after the luteinizing hormone peak. Habitual aborters as a whole, or when subgrouped to those with normal (10 cycles) or defective luteal function (12 cycles) did not differ from the control series with regard to prostacyclin and TXA2 production. CONCLUSIONS: Productions of prostacyclin and TXA2 are not relative to the luteal function and are normal in nonpregnant women with a history of habitual abortion.     

Effect of calcitonin gene-related peptide on the uterine vasculature of the nonpregnant ewe.

OBJECTIVES: The current study was designed to evaluate the uterine vascular effects of calcitonin gene-related peptide on the uterine vasculature of nonpregnant sheep and compare them with the effects of prostacyclin. STUDY DESIGN: Five nonpregnant oophorectomized ewes were instrumented with uterine and pulmonary artery flow probes and catheters. Dose-response curves were constructed according to increasing doses of calcitonin gene-related peptide (0.01, 0.03, 0.1, 0.3, 1, and 3, micrograms/min) and prostacyclin (0.03, 0.1, 0.3, 1, 3, and 10 micrograms/min) via 10-minute uterine artery infusions. RESULTS: Both calcitonin gene-related peptide and prostacyclin produced a significant increase in uterine blood flow and a decrease in uterine vascular resistance. Calcitonin gene-related peptide was found to be approximately 17 times more potent than prostacyclin as a vasodilator. Local uterine artery infusions of calcitonin gene-related peptide led to significant increases in heart rate but did not alter blood pressure, cardiac output, or total peripheral resistance at the doses tested. In contrast, at doses of prostacyclin that produced similar uterine vasodilatation, prostacyclin led to significant decreases in systemic arterial blood pressure and total peripheral resistance and increases in heart rate and cardiac output. CONCLUSION: These data strongly suggest that calcitonin gene-related peptide, an endogenously occurring vasoactive peptide, could play an important role in regulating uterine and systemic hemodynamics.     

Immunoreactive prostacyclin and thromboxane metabolites in normal pregnancy and the puerperium

Summary. Prostacyclin and thromboxane have been implicated in the pathophysiology of several disorders of pregnancy, but there is little information on concentrations of these prostaglandins in normal pregnancy. The aim of our study was to determine the range of values throughout normal pregnancy and the puerperium and to compare this with concentrations in normal non-pregnant women. Measurement was by radioimmunoassay of prostacyclin and thromboxane metabolites. We observed a significant difference in prostacyclin metabolites in the first trimester. (mean 19·9, SEM 0·96 pg/ml) compared with the normal non-pregnant group (mean 15·9. SEM 0·68 pghl). There were no significant differences between values in the normal non-pregnant group and those in the second and third trimester or postnatally. The increase in prostacyclin in the first trimester may be associated with placentation and physiological vasodilation, and insencitivity to angiotensin It seen in early pregnancy. We noted a significant redaction in thromboxane metabolites in the second (mean 133, SEM 14·9 pg/ml) and third (mean 123, SEM 30·7 pg/ml) trimesters and the puerperium (mean 119, SEM 6·3 pg/ml) compared with the values in the normal non-pregnant group (mean 142, SEM 4·9 pg/ml). This may be due to increased platelet stability or decreased thromboxane synthesis.     

Effect of endothelin-1 on the uterine vasculature of the pregnant and estrogen-treated nonpregnant sheep.

OBJECTIVE: This study was designed to evaluate the uterine vascular responses to endothelin-1 in pregnant and estrogen-treated nonpregnant sheep. STUDY DESIGN: Seven pregnant and five nonpregnant oophorectomized ewes received local uterine artery infusions of endothelin-1, norepinephrine, and phenylephrine. Arterial blood pressure, heart rate, and uterine blood flow were recorded. RESULTS: Endothelin-1 (0.01 to 3.0 micrograms/min), norepinephrine (0.1 to 3 micrograms/min), and phenylephrine (0.1 to 10 micrograms) produced significant dose-related decreases in uterine blood flow and increases in uterine vascular resistance. On a nanomoles infused per minute basis, endothelin-1 was much more potent than norepinephrine and phenylephrine as a uterine artery vasoconstrictor in both pregnant and nonpregnant sheep. The uterine vascular responses to norepinephrine and phenylephrine were similar in pregnant and nonpregnant ewes, whereas response to endothelin-1 was blunted in pregnancy. CONCLUSION: Endothelin-1 is an extremely potent uterine vasoconstrictor in both pregnant and nonpregnant ewes, but the uterine vascular responsiveness to endothelin-1 is decreased in pregnancy.     

Systemic and uterine hemodynamic responses to dopamine in pregnant and nonpregnant sheep

The systemic and uterine hemodynamic effects of dopamine were studied in nonpregnant and near-term pregnant, unanesthetized, chronically instrumented sheep. Dopamine was administered by constant intravenous infusion in doses ranging from 2 to 40 microgram per kilogram per minute. A hypertensive effect was consistently observed when doses greater than 5 microgram per kilogram per minute were given. The rise in pressure was accompanied by a rise in the systemic vascular resistance and an increase in the cardiac output; the increment in the latter was greater in the pregnant than in the nonpregnant animals. Uterine blood flow increased consistently despite some rise in uterine vascular resistance; uterine fraction of cardiac output either remained unchanged or increased slightly. Venomotor construction, reflected by a rise in central venous pressure, occurred at all dose levels. These hemodynamic properties of dopamine may be explained partly on the basis of its combined beta- and alpha-mimetic action, as well as through redistributions of flows and resistances among various regional vascular beds.     

Maternal thromboxane, prostacyclin, and umbilical blood flow in humans

The stable hydration products of the vasoconstrictory and proaggregatory thromboxane A2 and vasodilatory and antiaggregatory prostacyclin, ie, thromboxane B2 and 6-keto-prostaglandin F1a, respectively, were measured with radioimmunoassays from 67 women with normal pregnancy, preeclampsia, or other pregnancy complications with the determination of the blood flow in the umbilical vein with the ultrasound method. In addition, the maternal platelets' capacity to release thromboxane B2 was studied. No relation was seen between these prostanoids and the umbilical blood flow and/or pregnancy complications. Moreover, the concentrations of the prostanoids were similar in women with high (161.1 +/- 6.8 mL/minutes/kg of fetal weight, mean +/- SE, N = 33) and low (50.5 +/- 2.1 mL/minutes/kg, N = 34) umbilical flow. If thromboxane A2 and prostacyclin regulate the umbilical circulation in the human, they exert this effect locally in the fetoplacental unit, and the changes are not reflected by the levels of their metabolites in the maternal peripheral circulation.     

The responses of isolated uterine arteries from pregnant sows to vasoconstrictive agents

Isometric contractions of isolated uterine arteries, mesenteric arteries and the thoracic aortae of nonpregnant and pregnant sows were measured in a modified Krebs-Henseleit solution in order to investigate the characteristics of the uterine artery responsiveness to vasopressor substances during pregnancy. Contractile response (delta T) of the uterine artery from pregnant sow to angiotensin II(A II) was significantly smaller than that from nonpregnant animal. On the other hand, delta T of uterine artery from pregnant sow to norepinephrine (NE) was greater than that from nonpregnant animal. NE-induced delta T of preparations from both pregnant and nonpregnant sow were suppressed nearly to the same level following the treatment of phentolamine, or verapamil in the incubation medium of 2.5mM Ca2+. In the Ca2+-free (EDTA 1mM) incubation medium, the responses decreased to the minimum degree. These results imply that conspicuous refractoriness of the uterine artery to A II during pregnancy is due to the changes in the characteristics of the uterine vascular wall, and the enhanced responsiveness to NE of the uterine artery may be due to the increased sensitivity in alpha-adrenergic receptor on the vasculature with the increase in Ca ion influx.     

Urinary prostacyclin and thromboxane metabolites in drinking pregnant women and in their infants: relations to the fetal alcohol effects

To study the effect of maternal ethanol consumption on the production of prostacyclin and thromboxane, we measured urinary 6-keto-prostaglandin F1 alpha (a hydration product of prostacyclin), 2,3-dinor-6-keto-prostaglandin F1 alpha (generated from 6-keto-prostaglandin F1 alpha through beta oxidation), and thromboxane B2 (a hydration product of thromboxane A2) using consequent high-performance liquid chromatography and radioimmunoassays in 39 drinking women and 16 abstinent controls, and in their infants. Thirty-one drinkers and two control women smoked. Maternal ethanol consumption was accompanied by increased output of prostacyclin and thromboxane metabolites in the mothers, but no relationship was apparent between the increased metabolites and development of fetal alcohol effects in 22 mothers. There were no differences between smoking and nonsmoking drinkers in the excretion of these prostanoids. All the infants born to the drinkers had increased thromboxane B2 excretion, but the excretion of prostacyclin metabolites was increased only in infants with fetal alcohol effects. The ratio between prostacyclin and thromboxane was reduced in infants with fetal alcohol effects. Thus, maternal ethanol consumption is associated with enhanced prostacyclin and thromboxane synthesis, perhaps in the kidneys and/or systemic circulation and vascular bed. Similar changes may also occur in the fetus and/or newborn with fetal alcohol effects.     

Platelet sensitivity to prostacyclin in pregnancy and uterine cancer

Platelet sensitivity to prostacyclin was investigated in platelet-rich plasma obtained from 12 pregnant women, 5 patients with cancer of the uterine cervix and 5 normal female controls.ADP-, collagen- and arachidonic acid-induced aggregation, as well as spontaneous platelet aggregation, were estimated. It was shown that platelets from pregnant women and, above all, from women with uterine cancer, are less sensitive to the inhibiting effect of prostacyclin on platelet aggregation. Thus, decreased sensitivity to prostacyclin seems to be another aspect of altered platelet function found in pregnancy and malignancy.