Modulation of prostanoid synthesis by antimicrobials.
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Amphotericin B↗
Biomedical subjects
M D Mitchell
Publications and source records attributed to M D Mitchell.
Stimulation of prostaglandin E2 production in amnion cells in culture by a substance(s) in human fetal and adult urine.
A protein or protein-associated substance(s) in human fetal urine effects a 10- to 600-fold increase in prostaglandin E2 (PGE2) synthesis by human amnion cells maintained in monolayer culture; the increase in PGE2 synthesis is maximal by 12 h. Fetal urine did not cause a similar increase in PGE2 synthesis is maximal by 12 h. Fetal urine did not cause a similar increase in PGE2 synthesis in cells derived from other human tissues tested. A similar PGE2 synthesis-stimulatory activity is present in adult urine and the activity in adult urine is correlated inversely (p less than 0.001) with creatinine concentration. These findings are suggestive that a substance produced in, or excreted by, kidney acts to induce PGE2 synthesis in a tissue-specific manner.
Amnion↗
Stimulation of prostaglandin biosynthesis by urine of the human fetus may serve as a trigger for parturition.
Urine of the human fetus stimulated prostaglandin biosynthesis in vitro by increasing the conversion of arachidonic acid into prostaglandins. The stimulatory activity in urine from fetuses delivered at term after labor of spontaneous onset was greater than that in urine from fetuses delivered by cesarean section at term before the onset of labor. Such stimulation of prostaglandin biosynthesis by the fetal membranes, by way of a substance released into the urine and thence into amniotic fluid, could serve as a signal for the initiation of parturition.
Adult↗
The effects of ritodrine on prostaglandin metabolite concentrations in the blood of pregnant baboons.
To investigate the relationship between beta sympathomimetic drugs and prostaglandins, we measured prostaglandin metabolites in the plasma of pregnant baboons that were given the drug ritodrine. Animals were at a mean gestation of 120 days, which is equivalent to 27 weeks in women. Ritodrine was infused i.v. at a rate of 23 micrograms/min or 80 micrograms/min for 4 h. Plasma concentrations of 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM), 11-deoxy-13,14-dihydro-15-keto-11,16-cyclo-prostaglandin E2 (PGEM-11), and 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha) were determined as indicators of the precursors, prostaglandin F2 alpha, prostaglandin E2, and prostacyclin (PGI2), respectively. At the 23 micrograms/min ritodrine infusion rate plasma levels of 6-keto-PGF1 alpha were decreased by 51% (+/- 15%) in the animals receiving the drug (p less than 0.005) whereas corresponding levels in control animals did not differ significantly from pre-infusion levels. At the 80 micrograms/min ritodrine infusion rate, the plasma levels of 6-keto-PGF1 alpha decreased by 66% (+/- 18%) compared with pre-infusion levels (p less than 0.001) but again the levels in control animals were not changed significantly. Plasma levels of PGFM and PGEM-11 in animals during ritodrine treatment did not differ significantly from baseline values.
Animals↗
Conversion of arachidonic acid to lipoxygenase products by human fetal tissues.
[14C]Arachidonic acid was converted to several lipoxygenase products by homogenates of human fetal tissues as determined by thin-layer chromatography. The net conversions of [14C]arachidonic acid to radiolabeled lipoxygenase products were high (greater than or equal to 5%) in the case of fetal liver and brain, and low (less than or equal to 2%) in the case of fetal adrenal, heart, and kidney.
Arachidonic Acid↗
Progesterone withdrawal without parturition.
It has been demonstrated that administration of 100 mg of trilostane (an inhibitor of 3 beta-hydroxysteroid dehydrogenase) to late pregnant sheep will rapidly lower circulating levels of progesterone and that delivery ensues. Our intention was to reduce the dose of trilostane in order to separate the latter two sequelae and thereby obtain insight into the relationship between progesterone and prostaglandin biosynthesis. At the dose chosen (10 mg) the treatment did not induce parturition in 4 chronically catheterized sheep during late pregnancy. Circulating progesterone concentrations declined precipitously in all ewes but recovered to near basal values by 24 h after administration of trilostane. Circulating concentrations of 13,14-dihydro-15-keto-prostaglandin F2 alpha rose slightly but significantly at 4-5 h after administration of trilostane but never reached values normally associated with labor. Plasma estradiol levels were unchanged by treatment. These results are consistent with the view that progesterone withdrawal must be of a critical magnitude and duration for prostaglandin biosynthesis to be sufficiently stimulated to induce labor in sheep during late gestation.
Animals↗
Chronic stimulation of uterine prostaglandin synthesis during cervical ripening before the onset of labor.
Concentrations of 13,14-dihydro-15-keto-PGF2 alpha (PGFM) were measured in plasma of six carefully selected primigravid women with an unripe cervix at term before and at various intervals after extra-amniotic insertion of a Foley catheter with or without methylhydroxyethylcellulose (Tylose) gel. The procedure caused an acute elevation of PGFM levels within 5 min (P less than 0.025), which was maintained for at least 6 hours in the absence of uterine activation at 179 +/- 32% of the initial values (P less than 0.01). Extra-amniotic administration of Tylose gel caused an increase in PGFM levels which was both higher and more prolonged (greater than 12 hours) than insertion of a Foley catheter alone. The observations indicate that cervical ripening without concomitant uterine activation is associated with an increase in PGFM levels. They also demonstrate that prolonged activation of (intra) uterine prostaglandin synthesis may occur several hours before the onset of labor-like uterine activity. A chance finding further suggests that spontaneous rupture of the membranes too may be preceeded by an increase in (intra) uterine prostaglandin synthesis. In their totality these observations lend strong support to the proposition that an increase in (intra) uterine prostaglandin production is a prerequisite to rather than a consequence of the initiation of labor.
Amnion↗
Biosynthesis of prostaglandins by tissues of the human fetus.
Human fetal tissues have been superfused and prostaglandin (PG)E2, PGF2 alpha and 6-keto-PGF1 alpha have been measured in the effluents using specific radioimmunoassays. In general, the rates of production of 6-keto-PGF by the tissues studied were greater than the rates of production of PGF2 alpha which in turn were greater than the rates of production of PGE2.
6-Ketoprostaglandin F1 alpha↗
Renal thromboxane excretion in Brattleboro rats with hereditary hypothalamic diabetes insipidus. Effect of vasopressin treatment.
Rats with hereditary hypothalamic diabetes insipidus (Brattleboro strain) which are devoid of vasopressin, excrete significantly increased amounts of immunoreactive thromboxane B2 in urine. The increase was corrected by treatment with vasopressin. These results suggest that, in the intact organism, thromboxane synthesis may be under tonic inhibitory control by vasopressin although other renal mechanisms explaining the increase in thromboxane cannot be excluded. Our observations further support an involvement of prostaglandins and thromboxanes in the regulation of water metabolism.
Animals↗
Excretion of 6-keto-PGF1 alpha and PGE2 in rats with hereditary hypothalamic diabetes insipidus.
We measured the urinary excretion of a stable metabolite of prostacyclin, 6-keto-PGF1 alpha, and of PGE2 in homozygous Brattleboro rats, a strain with hereditary hypothalamic diabetes insipidus. Excretion of both prostaglandins was largely increased compared to both heterozygous Brattleboro rats and Long-Evans rats. These results are in contrast to previously published observations demonstrating a subnormal excretion of PGE2 in Brattleboro rats. It is suggested that prostaglandin synthesis may be under tonic inhibitory control by vasopressin both in the kidney and in the endothelial cells of blood vessels. The findings further support the view that prostaglandins play an important role in the regulation of water excretion and in the pathogenesis of polyuric conditions.
6-Ketoprostaglandin F1 alpha↗
Suppression of plasma 6-keto-prostaglandin F1 alpha and 13,14-dihydro-15-keto-prostaglandin F2 alpha by aminoglutethimide in advanced breast cancer.
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6-Ketoprostaglandin F1 alpha↗
Hypokalaemia stimulates prostacyclin synthesis in the rat.
1. To examine the hypothesis that the normalcy of blood pressure, despite an increase in circulating angiotensin II, and the blood pressor hyporesponsiveness to infusion of pressor agents which are associated with hypokalaemia, are due to overproduction of prostacyclin, the principal prostaglandin (PG) synthesized by the vascular endothelium, we studied the effect of experimental hypokalaemia on the urinary excretion of immunoreactive 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin, in the rat. 2. The animals were fed on a potassium-deficient diet for 9 days. Twenty-four hour urine samples were collected daily for measurement of urinary excretion of immunoreactive 6-keto-PGF1 alpha, PGE2 and 13,14-dihydro-15-keto-PGF2 alpha (PGFM). 3. Hypokalaemia caused significant increases of the three prostaglandins measured. 4. We conclude that hypokalaemia is a potent stimulus of both renal and vascular prostaglandins. The results suggest that an increase in prostacyclin synthesis in peripheral blood vessel walls may be responsible for the resistance of blood pressure to infusion of pressor substances as well as for the normalcy of blood pressure, despite the presence of high circulating angiotensin II concentrations, in conditions associated with hypokalaemia.
6-Ketoprostaglandin F1 alpha↗
Inhibition of prostaglandin biosynthesis in human adipose tissue by glucocorticosteroids.
Cultured stromal cells derived from human sc adipose tissue synthesized and secreted into the medium prostaglandin E2 (PGE2), PGF2 alpha, and 6-keto-PGF1 alpha, a metabolite of prostacyclin. PGE2 was quantitatively the major PG formed by these cells. Dexamethasone inhibited PG biosynthesis in a concentration- and time-dependent manner; dexamethasone (2.5 X 10(-10) M) caused greater than 50% inhibition of PGE2 synthesis after 24 h of incubation and 90% inhibition after 48 h. The effect of dexamethasone to inhibit PGE2 synthesis was blocked by simultaneous incubation of cells with cortisol-21-mesylate, an antagonist of the binding of glucocorticosteroids to cytosolic receptors. (Bu)2cAMP (1 mM), forskolin (10 microM), and 1-methyl-3-isobutylxanthine (0.1 mM) markedly stimulated PGE2 biosynthesis in cultured adipose stromal cells. The inhibitory effect of dexamethasone on PGE2 synthesis was attenuated by simultaneous incubation of cells with (Bu)2cAMP. The results of this study suggest that glucocorticosteroids inhibit PG biosynthesis in adipose tissue stromal cells, whereas cAMP and certain analogs thereof stimulate PG biosynthesis and overcome the inhibitory action of glucocorticosteroids.
6-Ketoprostaglandin F1 alpha↗
Prostaglandin secretion by the neocortex and fetal zones of the human fetal adrenal gland.
Previously, we reported that the human fetal adrenal (HFA) gland secretes various prostaglandins (PGs) in vitro and that PG secretion is inhibited by endogenously synthesized glucocorticosteroids. In this investigation, the neocortex (NC) and fetal zone (FZ) of the HFA gland were separated by microdissection and maintained as tissue fragments in organ culture. The rate of PG secretion into the culture medium was determined by measuring various PGs using specific RIAs in media collected at 24-h intervals. During the first 24 h in culture, the secretion rates of PGF2 alpha and PGE2 were 6- and 7-fold greater by NC [14 +/- 5 and 9.9 +/- 3 ng mg protein-1 24 h-1 (mean +/- SE)], respectively, than by FZ tissue (2.5 and 1.4 ng mg protein-1 24 h-1). The secretion rates of PGFM and PGD2 were 2-fold greater in NC tissue than in FZ tissue, but the secretion rates of thromboxane B2 were similar in both zones of HFA tissue. In another study, the patterns of secretion of PGF2 alpha and PGE2 were determined as a function of days in culture. The secretion rates of PGF2 alpha and PGE2 fell rapidly in NC from 19.0 +/- 11 and 38.3 +/- 9.7 ng mg protein-1 24 h-1, respectively, to 1.3 +/- 7.2 and 4.8 +/- 3.3 by day 4. In contrast, the secretion rates of PGF2 alpha and PGE2 rose 8- and 3-fold in FZ tissue (from 0.7 +/- 0.2 and 0.9 +/- 0.6 ng mg protein-1 24 h-1, respectively, to 5.9 +/- 0.5 and 3.1 +/- 1.2 by day 4). The addition of ACTH or dexamethasone inhibited PG secretion in both zones, but to a greater degree in FZ tissue than in NC tissue. In summary, the NC secretes larger quantities of PG than the FZ, and the patterns of secretion are different in the two zones. The secretion of PGs is inhibited more in FZ than in NC tissue by ACTH and glucocorticosteroids.
Adrenal Glands↗
Lipoxygenase activity in human uterine and intrauterine tissues: new prospects for control of prostacyclin production in pre-eclampsia.
The formation of lipoxygenase metabolites by human uterine and intrauterine tissues was evaluated using [1-14C]arachidonic acid (AA) as substrate. The major lipoxygenase product synthesized by human amnion, decidua vera and placenta was identified as 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE); smaller amounts of 5-HETE and 5-HETE (lactone form) were also formed. In chorion laeve only a trace amount of 12-HETE was detected. Human myometrium and cervical tissue converted [1-14C]AA to 5-HETE and 12-HETE in almost equal amounts. The formation of lipoxygenase products in all tissues was markedly inhibited by nordihydroguaiaretic acid (NDGA) an inhibitor of lipoxygenase activity and slightly stimulated or inhibited by indomethacin, an inhibitor of cyclooxygenase activity. These results are indicative that uterine and intrauterine tissues are probably potential sources of lipoxygenase products during pregnancy and parturition. Since 12-hydroperoxy-eicosatetraenoic acid (12-HPETE), the labile precursor of 12-HETE potently inhibits prostacyclin biosynthesis, our findings are suggestive of the possibility that aberrant lipoxygenase activities may contribute to the complications of pre-eclampsia.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Prostaglandin production by human trabecular cells: in vitro inhibition by dexamethasone.
In addition to the well-known ability of prostaglandins (PGs) to raise intraocular pressure (IOP), it recently has been reported that moderate and low doses of PGE2 and PGF2 alpha significantly reduce IOP in a variety of experimental animals. These studies suggested to us that PGs might serve as endogenous regulators of outflow facility in the meshwork if these autacoids were produced and secreted by human trabecular cells. To examine this possibility, media from well-defined trabecular cell material were assayed using specific radioimmunoassays. Morphologically differentiated human trabecular cells produced high levels of PGE2, and somewhat lower levels of PGF2 alpha and 6KF1 alpha in the presence and absence of serum. In a typical experiment, the following PG levels were detected in the cell culture media after 24 hours: PGE2; 225; PGF2 alpha, 33.5; 6KF1 alpha, 12.7 ng/ml with the presence of 10% fetal calf serum; and PGE2, 30.0; PGF2 alpha, 4.8; 6KF1 alpha, 3.6 ng/ml in serum-free media. Since glucocorticoids are known to inhibit PG pathways in other tissues, this effect was examined in the cultured trabecular cells. Moderate concentrations of dexamethasone (DEX) produced a marked inhibition in the levels of all three PGs. For PGE2 production, 10(-8) M DEX inhibited approximately 75%, and 10(-7) M DEX inhibited approximately 90%. More detailed dose-response studies revealed that the I50 for inhibition of PG production by dexamethasone was less than 10 nM, thus indicating that the steroid effect probably involved high affinity glucocorticoid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Alprostadil↗
PGE2 and 6-keto-PGF1 alpha excretion in Brattleboro rats with hereditary hypothalamic diabetes insipidus.
Brattleboro rats, a strain with hereditary hypothalamic diabetes insipidus, were found to excrete significantly higher amounts of both renal (PGE2) and vascular (6-keto-PGF1 alpha) prostaglandins than control Long-Evans rats. The increased prostaglandin synthesis was reversed by vasopressin treatment. These results suggest that in the intact organism prostaglandin synthesis in the kidneys and in the endothelial cells of blood vessels may be under tonic inhibitory control by vasopressin. The findings further support the view that prostaglandins play an important role in the regulation of water excretion and in the pathogenesis of polyuric conditions.
6-Ketoprostaglandin F1 alpha↗
Raised prostaglandin levels in the third stage of labor.
Serial measurements of maternal peripheral plasma concentrations of 13,14-dihydro-15-keto-prostaglandin F (PGFM) and oxytocin were made during the three stages of labor and in the immediate puerperium. PGFM levels increased a labor progressed, and reached maximal levels before placental separation had occurred. The mean value in the second stage of labor was significantly higher than that in the first stage (p less than 0.01); similarly, the value 5 minutes after delivery, before expulsion of the placenta, was significantly greater than that in the second stage of labor (p less than 0.01). There was no significant difference between the mean PGFM concentration at placental separation and the level 5 minutes after delivery or in the second stage of labor. Two hours after delivery of the placenta, PGFM levels were not significantly different from values observed in the first stage of labor. Peripheral plasma concentrations of oxytocin did not change significantly at any stage of labor or 2 hours post partum. These results suggest that prostaglandins have a role in the third stage of labor, and this finding may have important clinical implications.
Female↗