Prostacyclin contributes to inhibition of hypoxic pulmonary vasoconstriction by alkalosis

The mechanism by which extracellular alkalosis inhibits hypoxic pulmonary vasoconstriction is unknown. We investigated whether the inhibition was due to intrapulmonary production of a vasodilator prostaglandin such as prostacyclin (PGI2). Hypoxic vasoconstriction in isolated salt-solution-perfused rat lungs was blunted by both hypocapnic and NaHCO3-induced alkalosis (perfusate pH increased from 7.3 to 7.7). The NaHCO3-induced alkalosis was accompanied by a significant increase in the perfusate level of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), an hydrolysis product of PGI2. Meclofenamate, an inhibitor of cyclooxygenase, counteracted both the blunting of hypoxic vasoconstriction and the increased level of 6-keto-PGF1 alpha. In intact anesthetized dogs, hypocapnic alkalosis (blood pH increased from 7.4 to 7.5) blunted hypoxic pulmonary vasoconstriction before but not after administration of meclofenamate. In separate cultures of bovine pulmonary artery endothelial and smooth muscle cells stimulated by bradykinin, the incubation medium levels of 6-keto-PGF1 alpha were increased by both hypocapnic and NaHCO3-induced alkalosis (medium pH increased from 7.4 to 7.7). These results suggest that inhibition of hypoxic pulmonary vasoconstriction by alkalosis is mediated at least partly by PGI2.     

Pulmonary formation of prostacyclin in man

The pulmonary formation of prostacyclin (PGI₂), as reflected by the difference in concentration of pulmonary and systematic arterial radioimmunoassayed 6-keto-PGF_1α, was determined in six healthy waking subjects. The systematic arterial 6-keto-PGF_1α levels were low (50 pg/ml), and no evidence of pulmonary formation and release of the compound was noted. In other experiments systemic arterial 6-keto-PGF_1α levels were determined in patients prior to and during artificial ventilation, as well as during and after occlusion of the pulmonary circulation (extra-corporeal circulation, ECC). The arterial 6-keto-PGF_1α concentration prior to artificial ventillation was 17±4 pg/ml, i.e. within the range observed in the healthy subjects. During artificial ventilation the arterial levels of 6-keto-PGF_1α increased to 191±21 pg/ml, suggesting that pulmonary formation of PGI₂ was stimulated. In the patients subjected to ECC with occluded pulmonary circulation the arterial content of 6-keto-PGF_1α was stabilised at an elevated level (120−170 pg/ml). Following re-establishment of the pulmonary circulation the arterial concentrations of 6-keto-PGF_1α increased markedly, to 284±50 pg/ml. It is suggested that the basal pulmonary formation of PGI₂ in man is low or non-existent, and that enhanced formation of the compound in the lungs is a consequence of intervention with normal pulmonary ventilation or perfusion.     

Prostacyclin induces a surprising long-lasting motility in quiescent uterine strips (indomethacin-treated) isolated from ovariectomized rats

Dose-response curves for several prostaglandins (PGI₂; PGD₂; PGF₂ and PGE₂); BaCl₂ or prostaglandin metabolites (15-keto-PGF_2α; 13, 14-diOH-15-keto-PGF_2α; 6-keto-PGF_1α and 6-keto-PGE₁ in quiescent (indomethacin-treated) uterine strips from ovariectomized rats, were constructed. All PGs tested as well as BaCl₂, triggered at different concentrations, evident phasic contractions. Within the range of concentrations tested the portion of the curves for the metabolites of PGF_2α was shifted to the right of that for PGF_2α itself; the curve for 6-keto-PGF_1α was displaced to the right of the curve for PGI₂ and that for 6-keto-PGE₁ to the left.It was also demonstrated that the uterine motility elicited by 10⁻⁵ M PGF_2α and its metabolites was long lasting (more than 3 hours) and so it was the activity evoked by PGI₂; 6-keto-PGF_1α and BaCl₂, but not the contractions following 6-keto-PGE₁, which disappeared much earlier. The contractile tension after PGF_2α; 15-keto-PGF_2α; 13, 14-diOH-15-keto-PGF_2α and PGI₂, increased as time progressed whilst that evoked by 6-keto-PGF_2α or BaCl₂ fluctuated during the same period around more constant levels.The surprising sustained and gradually increasing contractile activity after a single dose of an unstable prostaglandin such as PGI₂, on the isolated rat uterus rendered quiescent by indomethacin, is discussed in terms of an effect associated to its transformation into more stable metabolites (6-keto-PGF_1α, or another not tested) or as a consequence of a factor which might protects prostacyclin from inactivation.     

Acetylcholine induces vasodilation and prostacyclin synthesis in rat lungs

Acetylcholine causes pulmonary vasodilation, but its mechanism of action is unclear. We hypothesized that acetylcholine-induced pulmonary vasodilation might be associated with prostacyclin formation. Therefore, we used isolated rat lungs perfused with a recirculating cell- and plasma-free physiological salt solution to study the effect of acetylcholine infusion on pulmonary perfusion pressure, vascular responsiveness and lung prostacyclin production. Acetylcholine (20 ug infused over 1 minute) caused immediate vasodilation during ongoing hypoxic vasoconstriction and prolonged depression of subsequent hypoxic and angiotensin II-induced vasoconstrictions. Both effects of acetylcholine were abolished by atropine pretreatment. The prolonged acetylcholine effect, but not the immediate response, was blocked by meclofenamate, an inhibitor of cyclooxygenase. The prolonged effect, but not the immediate response, of acetylcholine was associated with an increase in perfusate 6-keto-PGF_1α concentration. The acetylcholine stimulated increase in 6-keto-PGF_1α production was inhibited by meclofenamate and by atropine. Thus, blockade of prostacyclin production corresponded with blockade of the prolonged acetylcholine effect. In conclusion, acetylcholine caused in isolated rat lungs an immediate vasodilation and a prolonged, time-dependent depression of vascular responsiveness. Whereas both acetylcholine effects were under muscarinic receptor control, only the prolonged effect depended on the cyclooxygenase pathway and, presumably, protacyclin synthesis.     

Estrogen increases male rat aortic endothelial cell (RAEC) PGI2 release

Estrogen has been proposed as a negative risk factor for development of peripheral vascular disease yet mechanisms of this protection are not known. This study examines the hypothesis that estrogen stimulates rat aortic endothelial cell (RAEC) release of PGI₂. Male Sprague-Dawley rat abdominal aortic 1-mm rings were placed on 35 mm matrigel plates, and incubated for 1 week. The cells were transferred to a Primaria 60-mm dish and maintained from passage 3 in RAEC complete media and experiments performed between passages 4–10. Cells were incubated with Krebs-Henseleit buffer (pH 7.4) containing carrier or increasing concentrations of β-estradiol or testosterone for 60 min. The effluent was analyzed for eicosanoid release of 6-keto-PGF_1α (6-keto, PGI₂ metabolite), PGE₂ and thromboxane B₂ (TXB₂) by EIA (hormone stimulated — basal). Cells were analyzed for total protein by the Bradford method and for cyclooxygenase-1 (COX-1) and prostacyclin synthase (PS) content by Western blot analysis and densitometry. Testosterone did not alter RAEC 6-keto-PGF_1α release, whereas estrogen increased RAEC 6-keto-PGF_1α release in a dose-related manner. Estrogen preincubation (10 ng/ml) decreased COX-1 and PS content by 40% suggesting that the estrogen-induced increase in male RAEC PGI₂ release was not due to increased synthesis of COX-1 or PS. These data support the hypothesis that estrogen stimulation can increase endogenous male RAEC release of PGI₂.     

Role of prostacyclin on steroidogenesis by frog interrenal gland

The role of prostacyclin (PGI₂) on amphibian adrenal steroidogenesis was studied in perifused interrenal fragments from adult male frogs. Exogenous PGI₂ (3×10⁻⁸ M to 3×10⁻⁵ M) and, in a lesser extent, 6-keto-PGF_1α increased both corticosterone and aldosterone production in a dose-related manner. Short pulses (20 min) of 0.88 μM PGI₂ administered at 90 min intervals within the same experiment did not induce any desensitization phenomenon. A prolonged administration (6 h) of PGI₂ gave rise to an important increase in steroid production followed by a decline of corticosteroidogenesis. Indomethacin (IDM, 5 μM) induced a marked reduction of the spontaneous secretion of corticosteroid which confirmed the involvement of endogenous PGs in the process of corticosteroid biosynthesis. The IDM-induced blockade of corticosterone and aldosterone secretion was totally reversed by administration of exogenous PGI₂ in our model. Angiotensin II (AII) induced a massive release of 6-keto-PGF_1α, the stable metabolite of PGI₂. The increase of 6-keto-PGF_1α preceded the stimulation of corticosterone and aldosterone secretions. In contrast, the administration of ACTH did not modify the release of 6-keto-PGF_1α. These results indicate that PGI₂ might be an important mediator of adrenal steroidogenesis in frog. They confirm that the corticosteroidogenic actions of ACTH and AII are mediated by different mechanisms.     

Comparison of umbilical vein models for measurement of relative prostacyclin and thromboxane production

There is growing evidence that blood vessels generate TXA₂ in addition to PGI₂. We examined effluents from continously perfused human umbilical vein and supernatants from umbilical vein rings for TXB₂ and 6-keto-PGF_1α measurements (stable metabolites of TXA₂ and PGI₂, respectively). TXB₂ and 6-keto-PGF_1α were identified in all samples. 6-keto-PGF_1α to TXB₂ ratio was higher in intact vein effluents than in the venous ring supernatants (112:1 and 28:1, respectively, P<0.01). Arachidonate stimulation increased 6-keto-PGF_1α and TXB₂ levels similarly in the intact vein effluent. In contrast, stimulation of the venous rings resulted in a relatively larger increase in TXB₂ than in 6-keto-PGF_1α. This caused 6-keto-PGF_1α to TXB₂ ratio to decline (p<0.01). The identity of TXB₂ was confirmed in several different ways. These data suggest that 1) human umbilical veins produce TXA₂ in addition to PGI₂, 2) TXA₂ release is more by venous rings than by the intact vein probably reflecting contribution from non-endothelial layers, and 3) arachidonate stimulation causes relatively greater release of TXA₂ than of PGI₂ from the venous rings, whereas release of PGI₂ and TXA₂ is similar from the intact vein.     

Cross-Reactivity of Δ17-6-Keto-PGF1α with 6-Keto-PGF1α antibodies

The cross-reactivity of the PGI₃ metabolite, Δ17-6-keto-PGF_1α, with antibodies against 6-keto-PGF_1α for radioimmunoassays (RIA) has been investigated. Δ17-6-keto-PGF_1α was obtained either from commercial sources or after its purification from endothelial cells. In the latter case, primary cultured bovine aortic endothelial cells were incubated for 20 min at 37°C with 10 μM eicosapentaenoic acid (EPA) in the presence of 2 μM 13-hydroperoxy-octadecadienoic acid, an activator of the EPA cyclooxygenation, and the 6-keto-PGF_1α and Δ17-6keto-PGF_1α produced were separated by RP-HPLC. Then, cross-reactivities of the commercial and purified Δ17-6-keto-PGF_1α with 6-keto-PGF_1α antibodies were determined and found not to exceed 10%. In addition, the amounts of prostacyclin-related compounds detected by direct measurements in media of cells loaded with EPA were compared with those obtained after purification of 6-keto-PGF_1α. In accordance with the cross-reactivity data, we found that RIA in media mainly measured 6-keto-PGF_1α, the Δ17-6-keto-PGF_1α formed being undetected at 90%. It is concluded that 6-keto-PGF_1α antibodies generally used for RIA of 6-keto-PGF_1α are highly specific since they can discriminate a metabolite bearing an additional double bond such as the PGI₃ metabolite Δ17-6-keto-PGF_1α.     

Histamine releases PGI2 from human pulmonary artery

Histamine caused a triphasic response of human pulmonary artery strips in vitro, consisting of a small initial contraction followed by pronounced relaxation preceding a second contractile response. These characteristics were not seen with other contractile stimuli including 5-hdyroxytryptamine, leukotriene D₄, and KC1. The relaxant component of this response was ablated by removal of endothelium from the vascular strips or by pretreatment of the tissues with 1μM indomethacin. Measurement of the PGI₂ degradation product 6-keto-PGF_1α in supernatants from histamine-challenged tissues confirmed the synthesis of PGI₂. Supernatants from unstimulated or leukotriene-challenged tissues contained no detectable amounts of 6-keto-PGF_1α. The histamine H₁ antagonist diphenhydramine inhibited both the contractile and relaxant responses to histamine whereas the H₂ antagonist cimetidine affected neither component. The released PGI₂ significantly altered the dose-respons curve to histamine without inhibiting the maximal contractile responses. We conclude that histamine induces PGI₂ formation from pulmonary arterial endothelium via an H₁ receptor.     

Thromboxane and pulmonary hypertension following E. coli endotoxin infusion in sheep: Effect of an imidazole derivative

We assessed the effect of a specific thromboxane synthetase inhibitor (an imidazole derivative) on pulmonary hemodynamics and the concentrations of TxB₂ (TxA₂), 6-keto-PGF_1α (PGI₂), and PGF_2α in pulmonary lymph and transpulmonary blood samples following intravenous administration of E. coli endotoxin (1 μg/kg) in sheep. In control animals the rise in pulmonary artery pressure correlated with increases in plasma and lymph TxB₂ concentrations and large transpulmonary concentration gradients of this metabolite were measured. In imidazle treated animals both pulmonary hypertension as well as increases in plasma and lymph TxB₂ concentrations were substantially reduced. In contrast, peak concentrations of 6-keto-PGF_1α (PGI₂) and PGF_2α were severalfold higher than those measured in control animals. This suggests a shunting of endoperoxide metabolism towards prostacyclin and primary prostaglandins and documents the specificity of the thromboxane synthetase inhibitor. Out study provides evidence that endotoxin-induced pulmonary hypertension is mediated by pulmonary synthesis of TxA₂.     

Decreased pulmonary vascular responsiveness in rats raised on an essential fatty acid deficient diet

Leukotriene C₄ is produced during hypoxic pulmonary vasoconstriction and leukotriene inhibitors preferentially inhibit the hypoxic pressor response in rats. If lipoxygenase products are important in hypoxic vasoconstriction, then an animal deficient in arachidonic acid should have a blunted hypoxic pressor response. We investigated if vascular responsiveness was decreased in vascular rings and isolated perfused lungs from rats raised on an essential fatty acid deficient diet (EFAD) compared to rats raised on a normal diet. Rats raised on the EFAD diet had decreased esterified plasma arachidonic acid and increased 5-, 8-, 11- eicosatrieonic acid compared to rats raised on the normal diet (control). Compared to the time matched responses in control isolated perfused lungs the pressor responses to angiotensin II and alveolar hypoxia were blunted in lungs from the arachidonate deficient rats. This decreased pulmonary vascular responsiveness was not affected by the addition of indomethacin or arachidonic acid to the lung perfusate. Similarly, the pulmonary artery rings from arichidonate deficient rats demonstrated decreased reactivity to norepinephrine compared to rings from control rats. In contrast, the tension increases to norepinephrine were greater in aortic rings from the arachidonate deficient rats compared to control. Stimulated lung tissue from the arachidonate deficient animals produced less slow reacting substance and platelet activating factor like material but the same amount of 6-keto-PGF_1α and TXB₂ compared to control lungs. Thus there is an associated between altered vascular responsiveness and impairment of stimulated production of slow reacting substance and platelet activating factor like materiali rat raised on an EFAD diet.     

Dose-dependent effects of a pyridoquinazoline thromboxane synthetase inhibitor on arachidonic acid metabolites and hemodynamics during E. Coli endotoxemia in anesthetized sheep

We investigated the effects of a new pyridoquinazoline thromboxane synthetase inhibitor infused before administering endotoxin into 18 anesthetized sheep with lung lymph fistulas. In normal sheep increasing plasma Ro 23-3423 concentrations were associated with increased plasma levels of 6-keto-PGF_1α, a reduced systemic vascular resistance (SVR, r = −0.80) and systemic arterial pressure (SAP, r = −0.92), the mean SAP falling from 80 to 50 mm Hg at the 20 and 30 mg/kg doses. Endotoxin infused into normal sheep caused transient pulmonary vasoconstriction associated with increased TxB₂ and 6-keto-PGF_1α levels while vasoconstriction and TxB₂ increase were significantly inhibited by pretreatment with Ro 23-3423 in a dose-dependent manner. When compared to controls, plasma and lymph levels of 6-keto-PGF_1α, PGF_2α and PGE₂ after endotoxin infusion were increased several-fold by administering Ro 23-3423 up to plasma levels of 10 μg/ml. Doses over 30 mg/kg with blood levels above 10 μg/ml reduced plasma and lymph levels of 6-keto-PGF_1α, PGF_2α and PGE₂, suggesting cyclooxygenase blockade at this dose. The peak 6-keto-PGF_1α levels at 60 min after endotoxin infusion in sheep with Ro-23-3423 levels below 10 μg/ml were associated with the greatest systemic hypotension due to a reduced SVR (r = −0.86). After endotoxin infusion the leukotrienes B₄, C₄, D₄ and E₄ in lung lymph were assayed by radioimmunoassay and high pressure liquid chromatography and remained at baseline values.     

Studies of the mechanisms involved in the fate of prostacyclin (PGI2) and 06-keto-PGF1α in the pulmonary circulation

We have investigated the metabolism of [3]H-prostaglandin (PG)I₂ and its non-enzymatic breakdown product [3]H-6-keto-PGF_1α by rat pulmonary tissue and their possible uptake and metabolism upon passage through the isolated perfused rat lung. When incubated with rat lung homogenate in the presence of β-NAD, [3]H-PGI₂ was extensively degraded into at least one metabolite, while [3]H-6-keto-PGF_1α was only minimally metabolized. However, on passage through isolated perfused rat lungs, neither [3]H-PGI₂ nor [3]H-6-keto-PGF_1α were removed from the circulation into the lung or degraded. This demonstration that PGI₂ is not a substrate for the transport system for the removal of PGs from the circulation into the lung further illustrates that this system is a critical determinant for the pulmonary inactivation of circulating prostaglandins. The experimental findings are discussed in reference to the structure-activity requirements necessary for pulmonary transport and subsequent metabolism.     

The human placental anti-aggregating factor is neither prostacyclin, nor a prostacyclin metabolite

Using PGH₂ as substrate, we have previously demonstrated that human placenta synthetizes mainly PGE₂, TxB₂ and PGD₂(1,2). Other reports have shown that placental tissue generates a substance which inhibits ADP-induced platelet aggregation and which was supposed to be PGI₂ (3). The present study indicates that the stability of that substance is different from the stability of prostacyclin (released by umbilical artery pieces). By GC-MS and multiple ion-monitoring, we have shown the presence of 6 keto-PGF_1α (the stable metabolite of PGI₂) in the umbilical artery incubation medium, while no trace of 6-keto-PGF_1α could be found in the placental medium. No conversion of AA to 6-keto-PGF_1α by placental microsomes was observed, even in the presence of antioxidants. The placenta possesses, in addition to the known 15-OH-PGDH and Δ-13 reductase activities, a weak 9 OH pGDH which is specific for PGF_2α (and not PGI₂ nor 6-keto-PGF_1α). GC-MS analysis is showed that the expected metabolites of PGI₂ through those three enzymes were not found in the placental medium, indicating that neither PGI₂ synthesis nor metabolism could be demonstrated in the placenta.     

Hypoxia enhances prostaglandin synthesis in renal mesangial cell cultures

In view of recent findings which suggest that renal prostaglandins mediate the effect of hypoxia on erythropoietin production, we have studied whether hypoxia is a stimulus for in vitro prostaglandin synthesis. Studies were carried out in rat renal mesangial cell cultures which produce erythropoietin in an oxygen-dependent manner. Production rates of PGE₂ and in specified samples also of 6-keto-PGF_1α, as a measure of PGI₂, and PGF_2α were determined by radioimmunoassay after incubation at either 20% O₂ (normoxic) or 2% O₂ (hypoxic) in gas permeable dishes for 24 hrs. Considerable variation in PGE₂ production was noted among independent cell lines. PGE₂ production appeared to be inversely correlated to the cellular density of the cultures. In addition, PGE₂ production was enhanced in hypoxic cell cultures. The mean increase was 50 to 60%. PGF_2α and 6-keto-PGF_1α increased by about the same rate. These results indicate that hypoxia is a stimulus for in vitro prostaglandin production.     

Metabolism of PGI2 by 15-hydroxyprostaglandin-dehydrogenase and Δ-reductase in different vascular beds of the cat in vivo

The metabolism of endogenous PGI₂ (released by angiotensin II or bradykinin) and exogenous PGI₂ by 15-hydroxy-PG-dehydrogenase and Δ¹³-reductase was studied in five different vascular beds of the anaesthetized cat. Plasma concentrations of 6-keto-PGF_1α (the product of spontaneous hydrolysis of PGI₂) and 6,15-diketo-13,14-dihydro-PGF_1α (the metabolite formed from PGI₂ by 15-hydroxy-PG-dehydrogenase and Δ¹³-reductase) were determined in the efferent vessels of the respective vascular beds by specific radioimmunoassays.No major metabolism of PGI₂ by 15-hydroxy-PG-dehydrogenase and Δ¹³-reductase was detected in the head and the hindlimbs of the cat. In the lung exogenous (circulating) PGI₂ was not metabolized, whereas PGI₂ synthetized in the lung itself was converted to 6,15-diketo-13,14-dihydor-PGF_1α. No significant amounts of 6,15-diketo-13,14-dihydro-PGF_1α-immunoreactivity were detected in hepatic venous blood after infusion of PGI₂ into the portal vein. However as also no 6-keto-PGF_1α was found, the liver seems to efficiently extract PGI₂ from the circulation. The cat kidney had the highest capacity of all vascular beds investigated to release endogenous and exogenous PGI₂ as 6-15-diketo-13,14-dihydro-PGF_1α. In other organs (vascular beds) investigated PGI₂ is either metabolized less efficiently by the 15-hydroxy-PG-dehydrogenase or further transformed to other metabolites.     

Effect of alpha-adrenergic stimulation on prostacyclin and renin release in the rat kidney

The relationship between renin secretion and PGI₂ production, in response to intrarenal infusion of norepinephrine, was examined in the isolated perfused rat kidney. Infusion of norepinephrine in a dose which caused substantial vasoconstriction (100 ng/min), markedly increased urinary excretion of 6-keto PGF_1α, the stable derivative of PGI₂, without significantly altering renin secretion measured in the effluent perfusate. No change in urinary 6-keto PGF_1α occurred when vasoconstriction was prevented by infusing the alpha-adrenoceptor blocking drug phenoxybenzamine (2 × 10³ ng/min) alongside norepinephrine 100 ng/min). However, under these conditions there was marked stimulation of renin secretion which, as has been demonstrated previously, is mediated by a beta-adrenoceptor. There were significant increase in urine flow rates during both vasoconstrictor and non-vasoconstrictor infusions. These findings clearly indicate that in the rat kidney prostacyclin production and renin release in response to norepinephrine are dissociated.     

Platelet activating factor (PAF) stimulates release of PGI2 from inflamed rabbit gallbladder cell cultures

This study examines the hypothesis that PAF stimulates release of PGI₂ from inflamed rabbit gallbladder explant cell cultures. New Zealand white rabbits underwent bile duct ligation for 72 h (72 h BDL), or sham operation, Sham and 72 h BDL gallbladder explants were placed in culture, and the cells grown to 75% confluence. The cells were exposed to increasing concentrations of PAF for 60 min. The media analyzed for eicosanoid release by EIA and the cells analyzed for cyclooxygenase and prostacyclin synthase content by immunoblot analysis. PAF increased release of 6-keto-PGF_1α from the 72 h BDL gallbladder cell cultures in a dose-related manner which was inhibited by indomethacin preincubation by 90%. The increased 72 h BDL cell release of 6-keto-PGF_1α was not associated with changes in the content of cyclooxygenase or prostacyclin synthase. PAF did not alter eicosanoid release from sham control cell cultures. These data suggest that PAF can only up-regulate endogenous 6-keto-PGF_1α release from the 72 h BDL cells that had been previously stimulated by inflammation. PAF may thus contribute to gallbladder distention and injury by chronic stimulation of inflamed gallbladder PGI₂ release.     

Inhibitory effect of insulin on prostacyclin production by isolated rat adipocytes

Physiologic concentrations of insulin completely inhibited the norepinephrine-induced increment in the production of 6-keto-prostaglandin (PG) F_1α, the stable derivative of prostacyclin (PGI₂), by isolated rat adipocytes. The inhibition of PGI₂ production by insulin in isolated rat adipocytes supports the view that the elevated plasma level of 6-keto-PGF_1α in rats with non-ketotic diabetes mellitus and diabetic ketoacidosis is derived at least in part from production of PGI₂ by the adipocyte cell mass.     

Increased thromboxane A2 production but normal prostacyclin by the placenta in hypertensive pregnancies

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 and measuring the release of 6-keto-prostaglandin F_1α (6-keto-PGF_1α) 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-PGF_1α (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-PGF_1α 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<0.05) and hypertensive women (4.1±0.4 ng/g/min; p<0.025). This may explain the occurrence of microthrombi and infarctions in placentae of hypertensive women.