Induction of Labour by Simultaneous Intravenous Administration of Prostaglandin E2 and Oxytocin

In a group of 20 matched primigravid patients labour was induced by forewater amniotomy followed by intravenous oxytocin (Syntocinon) administered in escalating doses. Ten of these patients, in a double-blind trial, also received prostaglandin E₂ infused simultaneously with the oxytocin. In the combined prostaglandin-oxytocin group there was a noticeable reduction in the dosage of oxytocin required to produce effective uterine action, and the duration of labour was also reduced. No side effects were observed.     

Mechanism of increased renal prostaglandin E2 in uranyl nitrate-induced acute renal failure

We have previously demonstrated that decreased cortical prostaglandin metabolism can contribute significantly to an increase in renal tissue levels and activity of prostaglandin E₂ in bilateral ureteral obstruction, a model of acute renal failure. In the present study, we have further investigated whether alterations in prostaglandin metabolism can occur in a nephrotoxic model of acute renal failure. Prostaglandin synthesis, prostaglandin E₂ metabolism (measured as both prostaglandin E₂-9-ketoreductase and prostaglandin E₂-15-hydroxydehydrogenase activity), and tissue concentration of prostaglandin E₂ were determined in rabbit kidneys following an intravenous administration of uranyl nitrate (5 mg/kg). No changes in the rates of cortical microsomal prostaglandin E₂ and prostaglandin F_2α synthesis were noted at the end of 1 and 3 days, while medullary synthesis of prostaglandin E₂ fell by 47% after 1 day and 43% after 3 days. Cortical cytosolic prostaglandin E₂-9-ketoreductase activity was found to be decreased by 36% and 76% after 1 and 3 days respectively. No significant changes were noted in cortical cytosolic prostaglandin E₂-15-hydroxydehydrogenase activity after 3 days. Cortical tissue levels of prostaglandin E₂ increased by 500% at the end of 3 days. These data demonstrate that in nephrotoxic acute renal failure, decreased prostaglandin metabolism (i.e., prostaglandin E₂-9-ketoreductase activity) can result in increased tissue levels of prostaglandin E₂ in the absence of increased prostaglandin synthesis and suggest that alterations in prostaglandin metabolism may be an important regulator of prostaglandin activity in acute renal failure.     

Uterine vein prostaglandin levels in late pregnant dogs

We studied the uterine venous plasma concentrations of prostaglandins E₂, F_2α, 15 keto 13,14 dihydro E₂ and 15 keto 13,14 dihydro F_2α in late pregnant dogs in order to evaluate the rates of production and metabolism of prostaglandin E₂ and F_2α in pregnancy $\text{in vivo}$. We used a very specific and sensitive gas chromatography-mass spectrometry assay to measure these prostaglandins. The uterine venous concentrations of prostaglandin E₂ and 15 keto 13,14 dihydro E₂ were 1.35±.27 ng/ml and 1.89±.37 ng/ml, respectively; however, we could not find any prostaglandin F_2α and very little of its plasma metabolite in uterine venous plasma. Since uterine microsomes can generate prostaglandin F_2α and E₂ from endoperoxides, prostaglandin F_2α production $\text{in vivo}$ must be regulated through an enzymatic step after endoperoxide formation. Prostaglandin E₂ is produced by pregnant canine uterus in quantities high enough to have a biological effect in late pregnancy; however, prostaglandin F_2α does not appear to play a role at this stage of pregnancy.     

Does 15-hydroxy prostaglandin dehydrogenase contribute to prostaglandin inactivation in brain?

15-Methyl prostaglandin E₂, a compound which is not a substrate for 15-hydroxy prostaglandin dehydrogenase, is a more potent pyretic agent than prostaglandin E₂ when injected into the third ventricle of conscious cats. This finding raises the possibility that 15-hydroxy prostaglandin dehydrogenase contributes to prostaglandin inactivation in brain, notwithstanding its low activity.     

The antihypertensive action of arachidonic acid in the spontaneous hypertensive rat and its antagonism by anti-inflammatory agents

Changes in arterial blood pressure and heart rate were observed in the spontaneous hypertensive (SH) rat following the intravenous administration of arachidonic acid, the precursor of prostaglandin E₂ (PGE₂). The pronounced fall in blood pressure and the increase in heart rate induced by arachidonic acid were also observed in SH rats receiving either prostaglandin E₁ (PGE₁) or PGE₂. In SH rats receiving various anti-inflammatory agents the cardiovascular responses to arachidonic acid were inhibited, but the blood pressure responses to the E-type prostaglandins were not altered. The data are interpreted to suggest that cardiovascular changes induced by arachidonic acid are mediated via its conversion to PGE₂.     

Specific prostaglandine E1 and A1 binding sites in rat a dipocyte plasma membranes

Rat adipocyte plasma membranes sacs have been shown to be a sensitive and specific system for studying prostaglandin binding. The binding of prostaglandin E₁ and prostaglandin A₁ increases linearly with increasing protein concentration, and is a temperature-sensitive process. Prostaglandin E₁ binding is not ion dependent, but is enhanced by GTP. Prostaglandin A₁ binding is stimulated by ions, but is not affected by GTP.Discrete binding sites for prostaglandin E₁ and A₁ were found. Scatchard plot analysis showed that the binding of both prostaglandins was biphasic, indicating two types of binding sites. Prostaglandin E₁ had association constants of 4.9 · 10⁹ 1/mole and 4 · 10⁸ 1/mole, while the prostaglandin A₁ association constants and binding capacities varied according to the ionic composition of the buffer. In Tris-HCl buffer, the prostaglandin A₁ association constants were 8.3 · 10⁸ 1/mole and 5.7 · 10⁷ 1/mole, while in the Krebs—Ringer Tris buffer, the results were 1.2 · 10⁹ 1/mole and 8.6 · 10⁶ 1/mole.Some cross-reactivity between prostaglandin E₁ and A₁ was found for their respective binding sites. Using Scatchard plot analysis, it was found that a 10-fold excess of prostaglandin E₁ inhibited prostaglandin A₁ binding by 1–20% depending upon the concentration of prostaglandin A₁ used. Prostaglandin E₁ competes primarily for the A prostaglandin high-affinity binding site. Similar Scatchard analysis using a 20-fold excess of prostaglandin A₁ inhibited prostaglandin E₁ binding by 10–40%. Prostaglandin A₁ was found to compete primarily for the E prostaglandin low-affinity receptor.All of the bound [³H]prostaglandin E₁, but only 64% of the bound [³H]-prostaglandin A₁ can be recovered unmetabolized from the fat cell membrane. There is no non-specific binding of prostaglandin E₁, but 10–15% of prostaglandin A₁ binding to adipocyte membranes is non-specific. Using a parallel line assay to measure relative affinities for the E binding site, prostaglandin E₁ > prostaglandin A₂ > prostaglandin F_2α. Prostaglandin E₂ and 16,16-dimethyl prostaglandin E₂ were equipotent with prostaglandin E₁, while other prostaglandins had lower relative affinities. 7-Oxa-13-prostynoic acid does not appear to antagonize prostaglandin activity in adipocytes at the level of the receptor.     

The lack of an effect of furosemide on uterine prostaglandin metabolism

We determined the effect of 2 mg/kg intravenous furosemide on the production and metabolism of prostaglandin E₂ in the utero-placental unit of pregnant dogs. Uterine venous prostaglandins E₂ and 15-keto-13,14-dihydro E₂ were measured by gas chromatography-mass spectrometry. Even though the dose of furosemide was adequate to effect a good diuresis, neither the production nor the metabolism of prostaglandin E₂ by the uterus was altered by that dose of the drug. Using radioactive microspheres to measure hemodynamic parameters, we observed no change in uterine vascular resistance while renal vascular resistance decreased. Although the renal concentration of furosemide may be higher than the uteroplacental concentration, there is so far no evidence that usual doses of furosemide enhance the production or inhibit the metabolism of prostaglandin E₂.     

The lack of an effect of furosemide on uterine prostaglandin metabolism in vivo

We determined the effect of 2 mg/kg intravenous furosemide on the production and metabolism of prostaglandin E₂ in the utero-placental unit of pregnant dogs. Uterine venous prostaglandins E₂ and 15-keto-13,14-dihydro E₂ were measured by gas chromatography-mass spectrometry. Even though the dose of furosemide was adequate to effect a good diuresis, neither the production nor the metabolism of prostaglandin E₂ by the uterus was altered by that dose of the drug. Using radioactive microspheres to measure hemodynamic parameters, we observed no change in uterine vascular resistance while renal vascular resistance decreased. Although the renal concentration of furosemide may be higher than the uteroplacental concentration, there is so far no evidence $\text{in vivo}$ that usual doses of furosemide enhance the production or inhibit the metabolism of prostaglandin E₂.     

Prostaglandin E2, prostaglandin E1 and thromboxane B2 release from human monocytes treated with C3b or bacterial lipopolysaccharide

C3b or lipopolysaccharide treatment of human peripheral blood monocytes in culture stimulates an early release of thromboxane B₂ and a delayed release of prostaglandin E into culture supernatants. Immunoreactive thromboxane B₂ release is maximal from 2–8 h, whereas prostaglandin E release is maximal from 16–24 h after stimulation of monocytes in culture. We further examined this process by comparing the time course of labelled prostaglandin E₂, prostaglandin E₁ and thromboxane B₂ release from human monocytes which were pulse or continuously labelled with [³H]arachidonic acid and [¹⁴C]eicosatrienoic acid. The release of labelled eicosanoids was compared with the release of immunoreactive prostaglandin E and thromboxane B₂. The time course of prostaglandin E₂ release was virtually identical to the release of prostaglandin E₁ in all culture supernatants regardless of labelling conditions. However, release of immunoreactive prostaglandin E paralleled the release of labelled prostaglandin E₁ and E₂ only for continuously labelled cultures. The release of labelled prostaglandin E₁ and E₂ from pulse labelled cultures paralleled the release of thromboxane B₂ and not immunoreactive prostaglandin. In contrast, labelled and immunoreactive thromboxane B₂, quantitated in the same culture supernatants, demonstrated similar release patterns regardless of labelling conditions. These findings indicate that the differential pattern of prostaglandin E and thromboxane B₂ release from human monocytes is not related to a time-dependent shift in the release of prostaglandin E₁ relative to prostaglandin E₂. Because thromboxane B₂ and prostaglandin E₂ are produced through cyclooxygenase mediated conversion of arachidonic acid, these results further suggest that prostaglandin E₂ and thromboxane B₂ are independently metabolized in human monocyte populations.     

Effect of prostaglandin 16,16 dimethyl E2 methyl ester on the pregnant human uterus

The oxytocic properties of prostaglandin 16,16 dimethyl E₂ methyl ester were investigated during the second trimester of pregnancy. As an abortifacient, this compound compared unfavorably to the 15 methyl analogs of prostaglandin E₂, with a lower rate of effectiveness and a relatively high incidence of side effects.     

Partial purification and some properties of human erythrocyte prostaglandin 9-ketoreductase and 15-hydroxyprostaglandin dehydrogenase.

Human erythrocytes were found to contain two prostaglandin metabolizing enzymes: a prostaglandin E 9-ketoreductase catalyzing the reduction of prostaglandin E₂ to form prostaglandin F_2α and a 15-hydroxyprostaglandin dehydrogenase that catalyzes the oxidation of prostaglandin F_2α to form 15-ketoprostaglandin F_2α. Both enzymes are found in the cytoplasmic fraction of erythrocytes and both enzymes use the triphosphopyridine nucleotides as cofactors more effectively than the diphosphopyridine nucleotides. These two enzymes were partially purified from erythrocyte homogenates and some of their properties were studied.     

Beneficial effects of prostaglandin E2 in endotoxic shock are unrelated to effects on PAF-acether synthesis

The effects of endotoxic shock on the synthesis of PAF-acether by the stomach, duodenum and lung were examined in the rat. Furthermore, the effect of pretreatment with prostaglandin E₂ on endotoxin induced PAF-acether synthesis and changes in vascular permeability were examined. Administration of endotoxin resulted in significant increases in PAF-acether synthesis in all tissues studied. Such increases were apparent within 5–15 minutes of the administration of endotoxin, corresponding to the time when significant hypotension, hemoconcentration and increases in gastrointestinal vascular permeability were first observed. Pretreatment with prostaglandin E₂ resulted in a significant reduction of endotoxin-induced hypotension, hemoconcentration and changes in vascular permeability in the gastrointestinal tract. However, prostaglandin pretreatment did not significantly alter endotoxin-induced PAF-acether release from the gastrointestinal tissues studied. These results demonstrate that prostaglandin E₂ can significantly attenuate several of the systemic and gastrointestinal manifestations of endotoxic shock. The mechanism responsible for these beneficial actions appears to be unrelated to effects of prostaglandin E₂ on PAF-acether synthesis.     

Improved sensitivity of iodinated histamine-prostaglandin radioimmunoassay by prostaglandin methyl esters

Use of (¹²⁵I)-labeled histamine-prostaglandin tracer increases the sensitivity of the radioimmunoassays of prostaglandin derivatives. Six different antisera were produced for prostaglandins and their derivatives (prostaglandins E₁, E₂, F_1α, F_2α, 13,14-dihydro-15-ketoprostaglandin E₂, and 13,14-dihydro-15-ketoprostaglandin F_2α) and were investigated with the corresponding tritiated and lodinated tracers. Displacement of iodinated tracers by the methyl esters of the prostaglandin compounds resulted, in most cases, in a three- to fivefold increase in sensitivity compared to unesterified inhibitors. Esterification also caused some alteration in the specificities observed. Our results suggest that conformational changes in the esterified prostaglandins (tracer and inhibitor) could explain these charges.     

Oral Prostaglandins in the Induction of Labour

Prostaglandins E₂ and F₂α were administered by mouth to induce labour in 24 patients at or past term. The drugs were administered at two-hourly intervals in doses ranging from 0·5 to 1·5 mg for prostaglandin E₂ and from 5 to 15 mg for prostaglandin F₂α. Of the 10 cases in which prostaglandin E₂ was used, labour was successfully induced in eight and there were no side effects. With prostaglandin F₂α labour was induced in 12 of 14 patients nine of whom had gastrointestinal disturbance, mostly of mild degree. With both drugs the infant was apparently unaffected and Apgar scores were satisfactory. Uterine hypertonus was not observed and the postpartum blood loss was within normal limits.     

The influence of prostaglandins on sperm motility

Prostaglandin E₂ and F_2α were measured in ejaculates from 10 fertile and 55 infertile men. Prostaglandin F_2α was negatively correlated with motility (r=0.77; p<0.01) in normal men. In patients with disturbed fertility, prostaglandin F_2α was always higher than in the controls, while prostaglandin E₂ was elevated only in patients with persisting varicocele and in those with very low sperm counts and severely impaired motility. There was neither synthesis of prostaglandins in spermatozoa nor were binding sites for prostaglandin E₂ and F_2α detectable. Inactivation of seminal prostaglandins by incubation with prostaglandin 15-hydroxydehydrogenase resulted in a dramatic fall in motility. The results suggest that prostaglandin F_2α act on motility, but the action is not mediated by receptors.     

Comparison of the effects of prostaglandin I2 and prostaglandin E2 stimulation of the rat kidney adenylate cyclase-cyclic AMP systems

Prostacyclin (Prostaglandin I₂) effects on the rat kidney adenylate cyclase-cyclic AMP system were examined. Prostaglandin I₂ and prostaglandin E₂, from 8 · 10^?4 to 8 · ^?7 M stimulated adenylate cyclase to a similar extent in cortex and outer medulla. In inner medulla, prostaglandin I₂ was more effective than prostaglandin E₂ at all concentrations tested. Both prostaglandin I₂ and prostaglandin E₂ were additive with antidiuretic hormone in outer and inner medulla. Prostaglandin I₂ and prostaglandin E₂ were not additive in any area of the kidney, indicating both were working by similar mechanisms. Prostaglandin I₂ stimulation of adenylate cyclase correlated with its ability to increase renal slice cyclic AMP content. Prostaglandin I₂ and prostaglandin E₂ (1.5 · 10^?4 M) elevated cyclic AMP content in cortex and outer medulla slices. In inner medulla, with Santoquin® (0.1 mM) present to suppress endogenous prostaglandin synthesis, prostaglandin I₂ and prostaglandin E₂ increased cyclic AMP content. 6-Ketoprostaglandin F_1α, the stable metabolite of prostaglandin I₂, did not increase adenylate cyclase activity or tissue cyclic AMP content. Thus, prostaglandin I₂ activates renal adenylate cyclase. This suggests that the physiological actions of prostaglandin I₂ may be mediated through the adenylate cyclase-cyclic AMP system.     

Effect of Orally Administered Prostaglandin E2 and its 15-Methyl Analogues on Gastric Secretion

The effect of orally administered prostaglandin E₂ and its synthetic 15-methyl analogues on gastric secretion in man was studied. The parent E₂ compound did not inhibit basal secretion, whereas both the 15 (S) 15-methyl-E₂ methyl ester and its isomer, 15 (R) 15-methyl-E₂ methyl ester inhibited basal acid secretion. This action is likely to be a direct one on the parietal cell, and it could prove of value in the treatment of peptic ulcer.     

Prostaglandin stimulation of ovarian ornithine decarboxylase in vitro.

Prostaglandins E₁ and E₂ caused a 5–10 fold stimulation of ornithine decarboxylase activity in granulosa cells isolated from porcine ovarian follicles. The minimally effective concentration of prostaglandin E₂ was 10 ng/ml and the plateau of activity was reached at 500 ng/ml. Prostaglandin F_2α was ineffective. 1-Methyl,3-isobutyl-xanthine, a phosphodiesterase inhibitor, potentiated the effect of both submaximal and maximal effective doses of prostaglandin E₂, suggesting that the effect of prostaglandin E₂ is mediated by cAMP. The effect of prostaglandin E₂ was similar to that of luteinizing hormone and a cAMP analogue, 8-Bromo-cAMP.     

Synthesis of prostaglandin E2 and prostaglandin F2α by toadfish red blood cells

Saline washed red blood cells of the toadfish convert [1-¹⁴C] arachidonic acid to products that cochromatograph with prostaglandin E₂ and prostaglandin F_2α. This synthesis is inhibited by indomethacin (10 μg/ml). Conversion of arachidonic acid to prostaglandin E₂ was confirmed by mass spectrometry. When saline washed toadfish red blood cells were incubated with a mixture of [1-¹⁴C]-arachidonic acid and [5,6,8,9,11,12,14,15,-³H]-arachidonic acid, comparison of the isotope ratios of the radioactive products indicated that prostaglandin F_2α was produced by reduction of prostaglandin E₂. The capacity of toadfish red blood cells to reduce prostaglandin E₂ to prostaglandin F_2α was confirmed by incubation of the cells with [1-¹⁴C] prostaglandin E₂.     

Activation of protein kinase C is coupled to prostaglandin E2 synthesis in swine granulosa cells

We have examined the role of phospholipid-sensitive calcium-dependent protein kinase (protein kinase C) in prostaglandin E₂ synthesis by monolayer cultures of swine granulosa cells. Specific phorbol ester derivatives known to activate protein kinase C significantly augmented the production of prostaglandin E₂. These stimulatory actions were dose and time-dependent, and could be abolished by the cyclooxygenase inhibitor, indomethacin, or the protein synthesis inhibitor, cycloheximide. Moreover, the rank order of potency of phorbol esters in enhancing prostaglandin E₂ production was concordant with that demonstrated for activation of protein kinase C. Phorbol ester in conjunction with the divalent cation ionophore, A23187, increased prostaglandin E₂ production synergistically. In addition, a non-phorbol stimulator of protein kinase C, 1-octanoyl-2-acetylglycerol, also significantly enhanced prostaglandin E₂ biosynthesis. The stimulated synthesis of prostaglandin E₂ was confirmed by high-pressure liquid chromatographic purification of this radiolabeled metabolite of ³H-arachidonic acid, and by capillary gas chromatography high-resolution mass spectrometry. Thus, the present studies indicate that the protein kinase C effector pathway is functionally coupled to prostaglandin E₂ production in the swine granulosa cell.