Depressed placental prostaglandin E1 metabolism in toxemia of pregnancy

³H-Prostaglandin E₁ metabolism has been assessed in 15,000 × g supernatant preparations from human placentas of normal and toxemic pregnancies. The ability of the toxemic tissue to metabolize ³H-PGE₁ is depressed in direct relationship to the severity of the disease. This impaired metabolism of prostaglandin E₁ appears to be a biochemical characteristic of the toxemia of pregnancy.     

Effect of prostaglandins E1, E2 and F2α on neutrophil aggregation

Recently we have found that chemotactic factors stimulate neutrophils in suspension to aggregate. Because of an obvious analogy to platelet aggregation, we examined the influence of three prostaglandins on this process. Prostaglandins E₁, E₂ and F_2α alone did not cause aggregation of the neutrophils but were able to partially inhibit the aggregation response induced by the synthetic chemotactic tripeptide, formly-methionyl-leucyl-phenylalanine. The minimal inhibitory concentrations for prostaglandins E₁, E₂ and F_2α were 10⁻⁷, 10⁻⁶ and 10⁻⁵M, respectively. These results are similar to those found for the prostaglandin-induced inhibition of platelet aggregation. It may be, therefore, that neutrophil aggregation, like platelet aggregation, is modulated by intracellular prostaglandins and other products of arachidonic acid metabolism.     

The metabolism of prostaglandin E2 in perinatal rabbit lungs

The inactivation of prostaglandin E₂ (PGE₂) was studied in isolated perfused lungs of fetal and neonatal rabbits. 200 nmol of ¹⁴C-PGE₂ was infused into the pulmonary circulation and the metabolites of PGE₂ were analysed from the nonrecirculating perfusion effluent. The amount of the main metabolite, 13,14-dihydro-15-keto-PGE₂, increased significantly between the 28th and 30th day of fetal life, remained relatively constant at the time of birth and increased again between 1st and 7th postnatal day. In contrast the amount of 15-keto-PGE₂ remained relatively stable during the studied period. The activity of NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase (15-OH-PGDH) was determined from the 100.000 g supernatant fraction of fetal, neonatal and maternal rabbit lungs using ¹⁴C-PGE₂ (20 μM) as the substrate. In the lungs of late fetal rabbits the activity of 15-OH-PGDH was significantly higher compared to the early postnatal period. Maternal rabbit lungs possessed, however, very high activities compared to the studied perinatal lungs. The results show, that the activity of the pulmonary 15-OH-PGDH is high already during the late fetal period. The inactivation of PGE₂ in isolated perfused lungs seems, however, to increase during the last prenatal days. Thus it seems possible that the uptake mechanism could be the rate limiting step in the metabolism of PGE₂ in rabbit lungs during the perinatal period.     

Molecular conformation of prostaglandin E2

The crystal and molecular structure of prostaglandin E₂ (PGE₂) has been determined by X-ray diffraction. The compound crystallizes in the triclinic space group P1 with Z = 1 and , , , α = 87.347°, β = 94.042°, and γ = 91.010°. Gauche-gauche interactions appear in both side chains. The efficient molecular packing and hydrogen bonding network appears to stabilize the observed molecular conformation.     

Urinary excretion of prostaglandin E2 and prostaglandin F2α in potassium-deficient rats

Potassium-deficiency was induced in rats by dietary deprivation of potassium. The animals became polyuric and urine osmolality decreased more then three-fold compared to controls. Urinary excretion of prostaglandin E₂ (PGE₂) and prostaglandin F_2α (PGF_2α) did not increase during 2 weeks of potassium depletion. Partial inhibition of renal prostaglandin synthesis by meclofenamate did not increase the urine osmolality after water deprivation. These results make unlikely the hypothesis that the polyuria of potassium-deficiency, is the result of enhanced renal synthesis of prostaglandins with subsequent antagonism of the hydro-osmotic effect of vasopressin. Male animals consistently excreted less PGE₂ than female animals.     

Bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E1

We evaluated in a double-blind study the bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E₁ (PGE₁-carbinol), described recently as a nonirritant bronchodilator in animals. Fifteen asthmatic patients received by inhalation single doses of 1, 10, and 30 μg PGE₁-carbinol, 55 μg PGE₂, and placebo (10% ethanol in normal saline, which was also used as diluent for the PGs). Such pulmonary function tests as forced expiratory volume in 1 second, forced vital capacity, and maximal expiratory flow were monitored during 2 hours following inhalation of each compound. 10 and 30 μg PGE₁-carbinol produced significant but short-acting bronchodilation, similar to that caused by 55 μg PGE₂. One-third of the patients reported mild cough and throat irritation during and shortly after inhalation of 30 μg PGE₁-carbinol or 55 μg PGE₂. Placebo and 1 μg PGE₁-carbinol produced minimal side effects, but neither agent caused bronchodilation. In an adjunctive, unblinded trial, the same patients received 400 μg fenoterol. Fenoterol caused greater bronchodilation 15 and 30 minutes after inhalation than did the PGs in the double-blind study.     

Effect of prostaglandin E1 on hepatic cyclic AMP activity, carbohydrate and lipid metabolism

Prostaglandin E₁ (PGE₁) failed to stimulate rat liver cyclic AMP (cAMP), induce hyperglycemia, glycogenolysis or lipolysis or prevent epinephrine-induced hyperglycemia in isolated perfused rat liver, even though other known glycogenolytic agents (glucagon and epinephrine) activated cAMP in this same system. The data do not support a physiologic role for PGE₁ on hepatic glycogenolysis or lipolysis. Although the effects of PGE₁ on gluconeogenesis, lipogenesis, ureogenesis or amino acid transport in isolated perfused liver were not investigated, if PGE₁ is subsequently found to influence these metabolic parameters, such alterations would probably occur independent of a change in cAMP activity.     

A calcitonin-like action of prostaglandin E1

The pharmacological effects of PGE₁ (6 and 9 days, 21,250 μg/kg per day subcutaneously) upon the growth and the bone resorption of mammals were studied using the proximal tibia and upper incisor of immature rats along with lead acetate as a time marker, and upon the serum calcium and inorganic phosphorus levels. The following results were obtained. 1. PGE₁ hardly affected the body weight or the weight of organs of the rats but apparently inhibited the longitudinal growth of proximal tibia in a dose related manner. 2. PGE₁ clearly inhibited not only the longitudinal growth (incisor growth) but also the appositional growth (dentin formation) of incisal dentin. 3. The grade of the inhibitory effect on the growth was in the order of bone growth >dentin formation >incisor growth. 4. The occurrence of osteoporosis due to a low calcium diet was inhibited by the simultaneous administration of PGE₁, the mechanism being considered to be mainly due to the inhibitory effect on the bone resorption. 5. PGE₁ lowered the level of serum calcium and the lowering effect was not observed in the thyro-parathyroidectomized rat. From the facts that the above effects were exactly the same as those of calcitonin (1), the possibility that the subcutaneous injection of PGE₁ may induce a calcitonin-like action, a part of which may dependent on the calcinonin secretion is suggested.     

Stereospecificity of enzymatic reduction of prostaglandin E2 to F2α

Antibodies directed toward PGF_2β were prepared in rabbits. The serologic specificity of the immune reaction was determined by inhibition of sodium borohydride-reduced (³H) PGE₂ anti-PGF_2β binding by several prostaglandins. The antibodies to PGF_2β recognize the β-hydroxyl configuration in the cyclopentane ring of PGF_2β. With the use of both anti-PGF_2α and anti-PGF_2β, the product of PGE₂ reduction by 9-ketoreductase purified from chicken heart was identified as PGF_2α. Guinea pig liver and kidney homogenates were examined for PGE 9-ketoreductase activity. Although enzyme activity was present, no evidence of PGF_2β production was found.     

Phosphatidylethanolamide derivatives of prostaglandins E1 and E2

Prostaglandins E₁ (PGE₁) and E₂ (PGE₂) have been coupled with the amine group of phosphatidylethanolamine (PE) by means of dicyclohexylcarbodiimide. These complexes basically mimic the relaxant and contractile effects of the corresponding free prostaglandins (PGs) on various smooth muscle preparations, but exhibit a delayed onset of action and a lower affinity for the PG receptors. The complexes are comparable with the free, parent PGs, in their intrinsic activities. The same holds true for the effects on blood pressure and on the motility of the uterus . The PGE₂-PE complex is hydrolysed to release obviously free PGE₂ by cell-free homogenates prepared from various tissues, but not by blood plasma. The PGE₂-PE complex is immunologically indistinguishable from the free PGE₂.     

Labour induction using buccal prostaglandin E2

Prostaglandins may remain in the circulation for some two hours after oral therapy and any resultant hypertonus may be difficult to treat in these circumstances. Buccal administration based on the concept that tablets could be discarded should this occur, has been evaluated in 30 patients. Effective uterine stimulation occured in 90% of subjects receiving a dose of 1mg hourly. No hypertonus occured but two patients had a prolonged contraction on a single occasion during labour. The fact that the tablets dissolve rapidly and in addition produce an unpleasant taste with a high incidence of nausea and vomiting, indicates buccal prostaglandins do not have advantages over alternative methods of oxytocic administration.     

Prostaglandins E1 and E2 stimulate the proliferation of pulmonary artery smooth muscle cells

Prostaglandins E₁ and E₂ are thought to be inhibitors of the growth of systemic vascular smooth muscle cells (SMC). However, their effect on the proliferation of SMC from the pulmonary artery (PA) has not been described and was the subject of this investigation. Cultures of bovine PA SMC were exposed to PGE₁ and PGE₂ under various conditions and their growth was assessed. PGE₁ and PGE₂ did not inhibit the growth of PA SMC in 10% fetal calf serum (FCS), but instead caused a dose dependent (10 ng - 1 μg/ml) increase in [³H]-thymidine incorporation when added to cultures containing 0.5% FCS; the highest doses resulted in 95% and 75% increases in [³H]-thymidine uptake at 24 hours with PGE₁ and PGE₂ respectively. This was accompanied by a modest increase in actual cell numbers (e.g., 20% with 1 μg/ml PGE₁). Furthermore, PGE₁ could mimic insulin-like growth factor (IGF-1) by potentiating the stimulation of SMC growth by fibroblast growth factor, suggesting that PGE₁ may act as a progression factor in the growth cycle of these cells. There was, however, no effect of PGE₁ on the proliferation of bovine aortic SMC. We conclude that, contrary to most reported effects on systemic SMC, PGE₁ and PGE₂ do not inhibit the proliferation of PA SMC but rather stimulate it.     

Prostaglandin E1 inhibits the pulmonary vascular pressor response to hypoxia and prostaglandin F2α

In the anesthetised dog an infusion of exogenous prostaglandin E₁ (100μG/min) inhibits the pulmonary vascular pressor response to hypoxia. Both 25 and 100 μG/min PGE₁ can reduce the transient pulmonary hypertension caused by a bolus of prostaglandin F_2α. This suggests that hypoxia and PGF₂α may share a final common pathway in producing pulmonary vasoconstriction. These results may help to explain the mechanism by which endotoxin inhibits the pulmonary vascular response to hypoxia. This effect is probably achieved by stimulating the production of an endogenous dilator prostaglandin. Exogenous PGE₁ can mimic this effect.     

Contraction of seminal vesicle and prostaglandin E1

It was studied how PGE₁ would affect the responses of isolated human seminal vesicles to adrenalin. PGE₁ in the final concentration of 1.3 μg/ml suppressed the contraction of human seminal vesicle that would have occurred in reaction to adrenalin added one minute later. When the concentration of PGE₁ was increased to 6.7 μg/ml, the inhibitory action was further enhanced. The meanings of this phenomenon were discussed.     

Effect of methylated prostaglandin E2 analogue on insulin secretion in man

Previous studies of the effect of E series prostaglandins /PGs/ on insulin secretion gave conflicting results in animals and little information in man. This study was designed to determine the effect of methylated PGE₂ analogue /15/S/-15-methyl PGE₂ methyl ester/, given orally, intraduodenally or intravenously, on insulin secretion, both under basal conditions and in response to intraduodenal or intravenous administration of glucose in 22 male volunteers. Methylated PGE₂ kept basal serum insulin level unchanged, but significantly reduced insulin response by 15 ± 6 μU/ml to intravenous glucose pulse injection /0.1 g/kg/ or by 45 ± 11 μU/ml to intraduodenal glucose infusion /0.5 g/kg-hr/. Blood glucose level was unaffected in tests with intraduodenal methylated PGE₂, but in tests with intravenous administration it was significantly reduced. These studies demonstrate that methylated PGE₂ analogue given orally, intraduodenally or intravenously results in a potent suppression of insulin response to glucose challenge.     

Effects of prostaglandin E1 on the metabolism in rat parathyroid gland in vitro

We investigated some effects of prostaglandin E₁ on the metabolism of rat parathyroid glands using a culture system containing basal Eagle's medium supplemented with 5–10% heat-inactivated rat serum. Rat parathyroid glands incorporate [³H]fucose and ¹⁴C-labeled amino acids into cellular glycoproteins and secrete some of these into the culture medium. Gel filtration chromatography separates these glycoproteins into three classes, the smallest of which (peak 3) is secreted with immunoreactive parathyroid hormone. In cultures of 48 h, prostaglandin E₁ (1 μg/ml) specifically inhibits the secretion of peak 3 and of parathyroid hormone but has no effect on the incorporation of [³H]-fucose, ¹⁴C-labeled amino acids, or [³H]uridine into parathyroid glands. Cytochalasin B inhibits the secretion of parathyroid hormone and the incroporation of isotopic fucose and amino acids. Cortisol stimulates incorporation of [³H]fucose and the secretion of parathyroid hormone even in the presence of inhibitory doses of prostaglandin E₁. It is concluded that, in organ culture, prostaglandin E₁ inhibits the secretion of parathyroid hormone and of a specific glycoprotein the function of which may be related to the secretion of the hormone.     

Effect of prostaglandin E2 upon release of pancreatic somatostatin-like immunoreactivity

Infusion of prostaglandin E₂ (1 ug/kg/min) in six normal dogs elicited a greater than two-fold rise in pancreaticoduodenal vein somatostatin-like immunoreactivity. Insulin and glucagon also rose. The results raise the possibility that the function of the canine pancreatic D-cell is under prostaglandinergic influence.     

Stimulation of bone formation by prostaglandin E2

We examined the effect of prostaglandin E₂ (PGE₂), in the presence or absence of cortisol, on bone formation in 21-day fetal rat calvaria maintained in organ culture for 24 to 96 h. [³H]Thymidine and [³H] proline incorporation were used to assess DNA and collagen synthesis, respectively. Changes in dry weight and DNA content were assessed after 96 h.PGE₂ (10⁻⁷ M) stimulated both DNA and collagen synthesis in calvaria. The effect on DNA synthesis was early (24 h), transient and limited to the periosteum. Collagen synthesis was stimulated at a later time (96 h), predominantly in the central bone. Cortisol (10⁻⁷ M) inhibited DNA and collagen synthesis. The addition of PGE₂ reversed the inhibitory effects of cortisol on DNA synthesis and content and increased collage synthesis in central bone to levels above control untreated cultures.We conclude that PGE₂ has stimulatory effects on bone formation and can reverse the inhibitory effects of cortisol. Hence the effects of cortisol may be mediated in part by their ability to reduce the endogenous production of prostaglandins.