The association of prostaglandins E2 and F2α with erythropoiesis regulatory factors

Prostaglandins E₂ and F_2α have regulatory roles, respectively, in the potentiation and inhibition of erythropoietin. Antisera to PGF_2α and EIF, an erythropoiesis inhibitory factor, can be used to resolve the reason for improvement in erythropoiesis following renal dialysis. Concurrent loss of PGE₂ with Ep during treatment with neuraminidase suggests that PGE₂ is bound to Ep by way of sialic acid.     

The concentrations of urinary prostaglandins E and plasma prostaglandins F2α and E during induction of ovulation with human gonadotropins

Plasma prostaglandins F₂α and E (PGF₂α, PGE) and urinary PGE were measured in 10 women treated with human gonadotropins (HMG) and subsequently with human chorionic gonadotropins (HCG). Five women became pregnant (6 pregnancies). There was no correlation between concentrations of plasma PGF₂α or PGE and plasma estradiol or progesterone. Urinary PGE concentrations showed a positive correlation with estradiol before HCG and a negative correlation with progesterone after HCG, only in women who subsequently became pregnant.Higher urinary PGE concentrations before HCG suggest that either HMG or rising estradiol levels stimulate PGE renal production. The significant negative correlation.between urinary PGE and progesterone concentrations, after HCG, in those patients who became pregnant suggests that ovarian production of progesterone may decrease renal production of PGE.     

Effect of prostaglandins E2 and F2α on in vitro development and hatching of caprine blastocysts

Prostaglandin E₂ has been shown to increase the ovine embryo hatching rate, and PGF_2α to reduce the development of rabbit, bovine, and rat embryos. The objective was to determine the effects of PGE₂ and PGF_2α on development of caprine embryos. Estrus was synchronized in does (n = 25) with medroxyprogesterone acetate (MAP) intravaginal sponges for 12 days, and superovulated with 20 units of FSH. On day 6 following estrus, embryos were flushed (n = 128) and incubated individually per well in 25 μl droplets of TCM-199 and BSA (8 mg/ml) for 6 days at 38.5 °C in a 5% CO₂: air with one of the following treatments: (1) control (0.0002% EtOH), (2) PGE₂ (7 ng/ml), (3) PGF_2α (7 ng/ml), (4) low PGE₂:high PGF_2α (3.5 ng/ml:14 ng/ml), (5) balanced PGE₂:PGF_2α (7 ng/ml:7 ng/ml), or (6) high PGE₂:low PGF_2α (14 ng/ml:3.5 ng/ml). Treatment with PGE₂ alone reduced (P < 0.05) the hatching rate (1/15; 7%). The hatching rate of embryos treated with PGF_2α alone (9/18; 50%), low PGE₂:high PGF_2α (8/16; 50%), and balanced PGE₂:PGF_2α (11/16; 69%) were similar to control (6/18; 33%). In contrast, the hatching rate was non-significantly increased (13/18; 72%) with the high PGE₂:low PGF_2α treatment. None of the treatments affected development from the morula to blastocyst stage. From the current data, it can be concluded that PGE₂ alone reduced hatching rate, and PGF_2α alone had no effect on the development of caprine embryos. High concentrations of PGE₂ with PGF_2α improved the hatching rates. Thus, uterine concentrations of PGE₂ may need to reach a threshold level to improve embryo hatching, as previously reported, while increased uterine concentrations of PGF_2α during early pregnancy would not affect development of the embryo.     

Effect of prostaglandins F2α and E2 on sensitivity of rabbit cortical neurons to acetylcholine and noradrenalin

The effect of prostaglandins F₂ and E₂ on unit activity and sensitivity of somatosensory cortical neurons of rabbits to acetylcholine and noradrenalin was investigated by microiontophoresis. Prostaglandin F₂ predominantly inhibited, whereas E₂ increased the spike activity of the neurons. F₂ usually modified the sensitivity of the neurons to acetylcholine, E₂ to noradrenalin. The influence of F₂ on the excitatory effects of acetylcholine, and of E₂ on the inhibitory effects of noradrenalin as a rule was characterized by weakening of the action of the mediators or a change in the sign of the initial responses. It is suggested that prostaglandins of the F group participate in cholinergic, and those of the E group in adrenergic transmission. The prostaglandins studied evidently exert their action through selective inhibition of the activity of adenylate or guanylate cyclases, leading to a decrease in the synthesis of secondary transmitters, namely cyclic AMP and cyclic GMP.B. K. Anokhin Research Institute of Normal Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 12, No. 3, pp. 239–245, May–June, 1980.     

Interaction of prostaglandins with blood plasma proteins. Comparative binding of prostaglandins A2, F2α and E2 to human plasma proteins

1. The binding of prostaglandin A(2) and prostaglandin F(2alpha) to human plasma proteins was investigated by DEAE-Sephadex chromatography and polyacrylamide-gel electrophoresis. Both prostaglandins, when added to human plasma in vitro, were found to become bound mainly to plasma albumin. 2. The extent of binding of prostaglandins added to human plasma in low to moderate concentrations was found to be approx. 88, 73 and 58% for prostaglandins A(2), E(2) and F(2alpha) respectively. The order of affinities for the binding of the three prostaglandins to albumin appear to be A(2)>E(2)>F(2alpha). 3. The apparent association constants for the binding of these prostaglandins to human serum albumin were estimated to be approx. 4.8x10(4), 2.4x10(4) and 0.9x10(4) litre/mol for prostaglandins A(2), E(2) and F(2alpha) respectively. The results are compared with previously reported association constants for the binding of long-chain fatty acids to both human and bovine albumins.     

Direct actions of prostaglandins E1, A1, and F2α on myocardial contraction

The inotropic and chronotropic actions of prostaglandin (PG) types PGE₁, PGA₁, and PGF_2α were studied in isolated guinea pig right and left atria, and papillary muscles; rabbit atria; and toad ventricular strips in order to more completely define the cardiac contractile properties of PG. All three prostaglandins, in muscle bath concentrations of 10μg/ml, exerted positive inotropic and chronotropic actions on guinea pig atrium. These contractile effects were persistent after removal of PG from the muscle bath and appeared to limit the relative response to a subsequent dose of PG. The inotropic action of PGE₁ was present over a wide range of bath calcium concentrations (1.1 to 4.4 mM/L). Beta adrenergic receptor blockade, histamine blockade, and pretreatment with reserpine failed to significantly affect the inotropic actions of PG. Norepinephrine and histamine produced more potent inotropic and chronotropic effects on guinea pig atria than did PG and these contractile effects did not exhibit persistence or tachyphylaxis. The prostaglandins did not significantly affect dose response curves for norepinephrine inotropic and chronotropic actions. The prostaglandins had no effect on the force or frequency of contraction in rabbit atria. PGE₁ exerted a positive inotropic effect on toad ventricular myocardium whereas PGA₁ had no effect and PGF_2α had a negative inotropic action.     

In vitro production of prostaglandins E,F, and 6-KETO prostaglandin F1α by human pregnant uterus,decidua and amnion

The production of prostaglandins (PGs) E and F and 6-keto PGF_1α was investigated by using human decidua, amnion, and pregnant myometrium obtained before and after onset of labor, and human nonpregnant myometrium collected during luteal phase. PGs produced were measured by radioimmunoassay developed in our laboratory. The radioimmunoassay for 6-keto PGF_1α is specific and accurate. PGE was formed at an almost constant rate regardless of the condition under which the three tissues tested were obtained, with the amnion showing the highest activity compared with decidua and myometrium. PGF production increased remarkably during labor in the myometrium and decidua but not in the amnion. In the myometrium during labor, PGF levels were three times higher than before labor. The pregnant myometrium produced more PGs than the nonpregnant myometrium. The production of 6-keto PGF_1α, a stable, nonenzymatically formed derivative of PGI₂, was observed to be much higher in the pregnant myometrium than in decidua, amnion, or nonpregnant myometrium. Contrary to the pattern of PGF production, 6-keto PGF_1α was lower during labor. The physiological significance of PG production by decidua, amnion, and myometrium in relation to parturition is discussed.     

Contractile responses of longitudinal and circular smooth muscle of the canine stomach to prostaglandins E and F2α

Muscle strips were excised from the circular and longitudinal layers of the fundus, corpus and antrum, and from the inner portion of the pyloric ring. In general prostaglandin(PG)F₂α as well as PGE₁ and PGE₂ stimulated the longitudinal muscle. However, there were remarkable regional differences. The sensitivity to PGs was greatest in the fundus and corpus (threshold near 10⁻¹⁰ mol/1) and only weak in antrum (threshold 5·10⁻⁸ to 10⁻⁷ mol/1). In longitudinal antrum strips acetylcholine induced a combined phasic-tonic response, whereas PGs produced purely phasic responses. The effects of PGF_2α and PGE on the circular layer were complex. PGF_2α produced excitatory responses in circular fundus and corpus similar to those in the longitudinal layer of the same regions. PGE produced dual responses in circular fundus (excitation at low concentration and strong inhibition at concentration of 10⁻⁷ mol/1). In circular corpus PGE induced pure inhibition (threshold near 10⁻⁹ mol/1). In circular antrum and inner pylorus both PGE and PGF_2α produced inhibition of the phasic activity (threshold 10⁻⁸ to 10⁻⁷ for antrum and 10⁻⁹ mol/1 for inner pylorus). These effects of PGs appeared in the presence of adrenergic and cholinergic blocking agents as well as of tetrodotoxin and were therefore, direct effects on smooth muscle. Indomethacin (10⁻⁷–10⁻⁶ mol/1) suppressed spontaneous tone of the fundus and corpus and increased phasic activity of inner pylorus. This indicates that endogenous PG synthesis may be involved in the control of spontaneous activity in gastric muscle.     

Effects of prostaglandins E1, E2 and F2α on the cardiac chronotropism by affecting the cardiac ganglionic transmission in spinal dogs

The effects of several prostaglandins (PGs) injected through the subclavian artery toward the cardiac sympathetic ganglia of spinal dogs were studied by utilizing changes of the heart rate as indicator of ganglionic function. PGF_2α (10–270 μg) administered intra-arterially in the presence or absence of preganglionic stimulation produced weak positive chronotropic effects, which were increased by physostigmine. This positive chronotropic effect of F_2α after physostigmine was inhibited by hexamethonium plus atropine, and depressed after hemicholinium-3 except for the response elicited by the first dose of F_2α. PGE₁ and E₂ injected during preganglionic stimulation did not affect the heart rate. Intra-arterially administered epinephrine and dopamine depressed dose-dependently transmission in the cardiac ganglia, the effect being inhibited by E₁ and E₂ but not by F_2α. These results suggest that F_2α facilitates the release of acetylcholine from preganglionic nerve ending, whereas E₁ and E₂ antagonize the inhibitory actions of catecholamine in the cardiac ganglia.     

Bioactive eicosanoids: Role of prostaglandin F2α and F2-isoprostanes in inflammation and oxidative stress related pathology

Oxidative stress and inflammation are supposed to be the key players of several acute and chronic diseases, and also for progressive aging process. Eicosanoids, especially prostaglandin F_2α (PGF_2α) and F₂-isoprostanes are endogenous compounds that are involved both in physiology and the above mentioned pathologies. These compounds are biosynthesized mainly from esterified arachidonic acid through both enzymatic and non-enzymatic free radical-catalysed reactions in vivo, respectively. They have shown to possess potent biological activities in addition to their application as biomarkers of oxidative stress and inflammation. Recent advancement of methodologies has made it possible to quantify these compounds more reliably and apply them in various in vivo studies successfully. Today, experimental and clinical studies have revealed that both PGF_2α and F₂-isoprostanes are involved in severe acute or chronic inflammatory conditions such as rheumatic diseases, asthma, risk factors of atherosclerosis, diabetes, ischemia-reperfusion, septic shock and many others. These evidences promote that assessment of bioactive PGF_2α and F₂-isoprostanes simultaneously in body fluids offers unique non-invasive analytical opportunity to study the function of these eicosanoids in physiology, oxidative stress-related and inflammatory diseases, and also in the determination of potency of various radical scavengers, anti-inflammatory compounds, drugs, antioxidants and diet.     

Effects of inhibition of prostaglandin F2α biosynthesis during preluteolysis and luteolysis in heifers

Flunixin meglumine (FM; 2.5 mg/kg) was given to heifers at three 8-h intervals, 16 d after ovulation (first treatment = Hour 0) to inhibit the synthesis of prostaglandin F_2α (PGF), based on plasma concentrations of a PGF metabolite (PGFM). Blood samples were collected at 8-h intervals from 15 to 18 d in a vehicle (control) and FM group (n = 16/group). Hourly samples were collected from Hours −2 to 28 in 10 heifers in each group. Heifers that were in preluteolysis or luteolysis at Hour 0 based on plasma progesterone (P4) concentrations at 8-h intervals were partitioned into subgroups. Concentration of PGFM was reduced (P < 0.05) by FM treatment in each subgroup. For the preluteolytic subgroup, the first decrease (P < 0.05) in P4 concentration after Hour 0 occurred at Hours 24 and 40 in the vehicle and FM groups, respectively. Plasma P4 concentrations 32 and 40 h after the beginning of luteolysis in the luteolytic subgroup were greater (P < 0.05) in the FM group. Concentration at the peak of a PGFM pulse in the FM group was greater (P < 0.05) in the luteolytic than in the preluteolytic subgroup. The peak of a PGFM pulse occurred more frequently (P < 0.001) at the same hour as the peak of an LH fluctuation than at the ending nadir of an LH fluctuation. In conclusion, a reduction in prominence of PGFM pulses during luteolysis delayed completion of luteolysis, and treatment with FM inhibited PGFM production more during preluteolysis than during luteolysis.     

Effects of indomethacin and prostaglandin F2α on ovulation and ovarian contractility in the rabbit

The present investigation was carried out to determine whether inhibition of ovulation in the rabbit by administration of indomethacin can be correlated with any change in ovarian contractility at ovulation time and can be reversed by administration of prostaglandins. Indomethacin was adminstered intra-muscularly using three different schedules in a dose of 5 mg/kg. A reduced number of ruptured follicles following HCG was noted in all groups treated with indomethacin. Infusion of PGF_2α into the aorta (1 μg/kg/min.) could reverse this effect. Less pronounced ovarian contractility was observed after indomethacin treatment, but infusion of PGF_2α immediately enhanced contractility in ovaries from indomethacin treated rabbits. The inhibition of ovulation in the rabbit associated with indomethacin adminstration may be related to suppression of ovarian contractions. These data also suggest that prostaglandins may play a significant role in the mechanism of ovulation through an influence on ovarian contractility.     

Serum selenium predicts levels of F2-isoprostanes and prostaglandin F2α in a 27 year follow-up study of Swedish men

Low concentrations of selenium (Se) predict mortality and cardiovascular diseases in some populations. The effect of Se on in vivo indicators of oxidative stress and inflammation, two important features of atherosclerosis, in human populations is largely unexplored. This study investigated the longitudinal association between serum selenium (s–Se) and a golden standard indicator of oxidative stress in vivo (8-iso-prostaglandin F_2α, a major F₂-isoprostane), an indicator of cyclooxygenase (COX)-mediated inflammation (prostaglandin F_2α), high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and serum amyloid A protein (SAA) in a follow-up study of 27 years. The s–Se was measured in 615 Swedish men at 50 years of age in a health investigation. The status of oxidative stress and inflammation was evaluated in a re-investigation 27 years later by quantification of urinary 8-iso-PGF_2α and 15-keto-dihydro- PGF_2α (a major metabolite of PGF_2α) and serum hsCRP, SAA and IL-6. Men in the highest quartile of s–Se at age 50 had decreased levels of 8-iso-PGF_2α compared to all lower quartiles and decreased levels of PGF_2α compared to all lower quartiles at follow-up. These associations were independent of BMI, diabetes, hyperlipidemia, hypertension, smoking, α-tocopherol and β-carotene at baseline. The s–Se was not associated with hsCRP, SAA or IL-6 at follow-up. In conclusion, high concentrations of s–Se predict reduced levels of oxidative stress and subclinical COX-mediated (but not cytokine-mediated) inflammation in a male population. The associations between Se, oxidative stress and inflammation, respectively, might be related to the proposed cardiovascular protective property of Se.     

Antagonistic Action of Aerosols of Prostaglandins F2α and E2 on Bronchial Muscle Tone in Man

Experiments were carried out in healthy male volunteers to investigate the effect of the inhalation of prostaglandin F₂α (PGF₂α) on airways resistance and the influence of the subsequent inhalation of prostaglandin E₂ (PGE₂). Airways resistance, which reflects the tone of smooth muscle in the larger airways in man, was measured by total body plethysmography.The inhalation of PGF₂α (40-60 μg) caused an increase in airways resistance in all subjects. Both PGE₂ (55 μg) and isoprenaline (550 μg) given by metered aerosol promptly reversed the bronchoconstriction induced by PGF₂α, but isoprenaline was more effective in this respect.A role for these prostaglandins in the control of bronchial muscle tone is discussed.     

Enzymatic formation of prostaglandin F2α in human brain

Prostaglandin (PG)E₂ 9-ketoreductase, which catalyzes the conversion of PGE₂ to PGF₂, was purified from human brain to apparent homogeneity. The molecular weight, isoelectric point, optimum pH, Km value for PGE₂, and turnover number were 34,000, 8.2, 6.5–7.5, 1.0 mM, and 7.6 min^–1, respectively. Among PGs tested, the enzyme also catalyzed the reduction of other PGs such as PGA₂, PGE₁, and 13,14-dihydro-15-keto PGF₂, but not that of PGD₂, 11-PGE₂, PGH₂, PGJ₂, or ¹²-PGJ₂. The reaction product formed from PGE₂ was identified as PGF₂, by TLC combined with HPLC. This enzyme, as is the case for carbonyl reductase, was NADPH-dependent, preferred carbonyl compounds such as 9,10-phenanthrenequinone and menadione as substrates, and was sensitive to indomethacin, ethacrynic acid, and Cibacron blue 3G-A. The reduction of PGE₂ was competitively inhibited by 9,10-phenanthrenequinone, which is a good substrate of this enzyme, indicating that the enzyme catalyzed the reduction of both substrates at the same active site. These results suggest that PGE₂ 9-ketoreductase, which belongs to the family of carbonyl reductases, contributes to the enzymatic formation of PGF₂ in human brain.Special issue dedicated to Dr. Sidney Udenfriend.     

Comparison of various semen extenders and addition of prostaglandin F2α on pregnancy rate in cows

This investigation comprises three trials. Trial 1 consists of an in vitro comparison of three semen extenders: two egg yolk based (customized Tris-egg yolk-glycerol and Triladyl®), the third (AndroMed®) soybean lecithin based. With regard to post-thaw motility, the phytoextender AndroMed® proved to be superior (59±3% v. 53±2% and 53±2%, P<0.05). It had earlier been shown that addition of the commercial prostaglandin F_2α preparation Dinolytic® before freezing compromises post-thaw motility; therefore, in Trial 2, Dinolytic® was added after thawing. Frozen-thawed spermatozoa tolerated addition of Dinolytic® at a concentration of 30% (v/v). In Trial 3, cows were inseminated using straws in which diluted semen and Dinolytic® were frozen in the same straw, separated by an air bubble, so intermingling could only take place in the course of insemination. Pregnancy rates at Dinolytic® dosages of 0%, 30% or 60% amounted to 44%, 41% and 56%, respectively (P>0.05), a result that encourages a large-scale field study, which is envisioned.     

Metabolism of 16,16-dimethyl-Prostaglandin F2α in the cynomolgus monkey and the human female

The prostaglandin analog, 16,16-dimethyl-prostaglandin F_2α, tritium labeled in the 9β position, was administered by intramuscular injection into female cynomolgus monkeys and intravenous injection into human female subjects. The same products were found in the urine of both the monkey and the human female. The structures of three metabolites appearing in the urine from both species were determined. The main metabolite was the dinor derivative of 16,16-dimethyl-PGF_2α, which generally represented about 65% of the excreted amount of radioactivity in the urine from the cynomolgus monkey and about 45% in the urine from the human female. The other two metabolites were an ω-hydroxy metabolite of dinor-16,16-dimethyl-PGF_2α and the tetranor derivative of 16,16-dimethyl-PGF_2α. Studies on the disappearance of 16,16-dimethyl-PGF_2α from the circulation in human females showed a much longer half-life of this compound than of PGF_2α.     

Physiologic and nonphysiologic effects of exogenous prostaglandin F2α on reproductive hormones in mares

Responses to intravenous treatment of mares with prostaglandin F2α (PGF) 8 d after ovulation were studied in three groups (n = 4/group): control (no treatment), bolus (single treatment with 2.5 mg PGF), and infusion (0.1 mg PGF during 2 h). Infusion resulted in a 13,14-dihydro-15-keto-PGF2α (PGFM) concentration (559 ± 44 pg/mL) that was not different from the mean concentration for the major portion of a natural PGFM pulse associated with luteolysis (569 ± 45 pg/mL; n = 5). Progesterone in the bolus group increased (P < 0.03) between 0 (17.8 ± 3.5 ng/mL) and 2 min (25.3 ± 4.8 ng/mL), peaked at 10 min (28.5 ± 4.6 ng/mL), and then decreased. In the infusion group, progesterone decreased (P < 0.05) during 1 min (17.2 ± 1.3 ng/mL) to 15 min (13.5 ± 1.5 ng/mL) after the beginning of infusion and decreased (P < 0.05) similarly to the bolus group during 2 to 12 h; concentrations were lower (P < 0.05) at each hour than in controls. Interval between ovulations was shorter (P < 0.05) in the bolus (19.3 ± 2.0 d) and infusion (18.8 ± 2.1 d) groups than in controls (24.3 ± 1.3 d). Concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and cortisol increased (P < 0.05) within 10 min in the bolus group but did not change in the infusion group. Results supported the hypothesis that increases in progesterone, FSH, LH, and cortisol after a bolus luteolytic PGF treatment are nonphysiologic. Past conclusions on the nature of the luteolytic mechanism are problematic if based on responses to treatment with a single luteolytic bolus of PGF.