Effects of indomethacin, prostaglandin E2, prostaglandin F2 alpha and 6-keto-prostaglandin F1 alpha on hatching of mouse blastocysts

The present study has been performed to investigate how PGs would participate the hatching process. Effects of indomethacin, an antagonist to PGs biosynthesis, on the hatching of mouse blastocysts were examined in vitro. Furthermore, it was studied that prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha) or 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were added to the culture media with indomethacin. The hatching was inhibited by indomethacin yet the inhibition was reversible. In the groups with indomethacin and PGE2, no improvement was seen in the inhibition of hatching and the inhibition was irreversible. In the groups with indomethacin and PGF2 alpha, inhibition of hatching was improved in comparison with the group with indomethacin. In the groups with indomethacin and 6-keto-PGF1 alpha, no improvement was seen. The above results indicated that PGF2 alpha possibly had an accelerating effect on hatching and a high concentration of PGE2 would exert cytotoxic effect on blastocysts.     

Effects of indomethacin and prostaglandin F2alpha on parturition in the hamster.

In the hamster administration of indomethacin twice a day on days 14 to 16 of pregnancy delayed the onset of parturition; a delay of 5 and 8 hours was observed following treatments of 300 or 600 mug/injection of indomethacin, respectively. Injection of PGF2alpha to the indomethacin treated hamsters on day 15 of pregnancy, on the other hand, advanced the onset of parturition. Treatments of indomethacin and/or PGF2alpha did not affect the duration of parturition.     

Endocrine secretion of prostaglandin F2alpha in cyclic gilts is decreased by intrauterine administration of exogenous oxytocin

When administered systemically, oxytocin (OT) stimulates secretion of uterine prostaglandin F2alpha (PGF2alpha) in swine, but the role of endometrially-derived OT in control of PGF2alpha release is not clear. This study determined the effect of exogenous OT, administered into the uterine lumen of intact cyclic gilts, on PGF2alpha secretion during late diestrus. Intrauterine infusion of 40USP units OT (in 30 ml 0.9% saline) was performed for 30 min (1 ml/min) into each uterine horn between 7:00 and 9:00 h on days 10, 12, 14 and 16 after estrus. Beginning 20 min before infusion, samples of jugular venous blood were drawn at 5-10-min intervals for 140 min for quantification of 13,14-dihydro-15-keto-PGF2alpha (PGFM), the major stable metabolite of PGF2alpha. Progesterone was analyzed in samples collected 0, 60 and 120 min after initiation of OT infusion. Treatment with OT did not alter plasma concentrations of PGFM on days 10 or 12 but decreased (P<0.001) PGFM concentrations for 40 min after onset of infusion on day 16. Concentrations of PGFM also were reduced in the pre-treatment samples on day 14 (P=0.05) and day 16 (P<0.001) in OT-infused gilts. Plasma progesterone declined (P<0.01) between days 10 and 16 in control-infused gilts but did not decline until after day 14 (P<0.001) in gilts infused with OT. These results indicate that when OT is administered into the uterine lumen of pigs during late diestrus, it has an anti-luteolytic effect to reduce endocrine secretion of PGF2alpha and delay the decline in progesterone that occurs during luteolysis.     

Effects of indomethacin, prostaglandin E2 and prostaglandin F2 alpha on mouse blastocyst attachment and trophoblastic outgrowth in vitro

A study was performed in order to investigate the participation of prostaglandins (PGs) during implantation. The effects of indomethacin on mouse blastocyst attachment and trophoblastic outgrowth were examined in vitro. Studies were also carried out on cultures supplemented with PGE2 and/or PGF2 alpha along with indomethacin. (1) Blastocyst attachment and trophoblastic outgrowth were inhibited by indomethacin dose-dependency. (2) In the cultures supplemented with indomethacin and PGE2 or PGF2 alpha, respectively, the inhibitory effects of indomethacin were reduced. (3) In the cultures supplemented with all three substances with treatment (1) and (2), inhibition of indomethacin was partially reversed, but still lower than control group without indomethacin. The above results indicate that both PGE2 and PGF2 alpha have a promoting effect on implantation, and PGF2 alpha was more effective than PGE2.     

Histophysiological studies of prostaglandin F2alpha on isolated organs. I. Effect of prostaglandin F2alpha on the heart.

The physiological and histochemical effects of PGF2alpha on isolated rabbit hearts were examined. The results showed a positive inotropic effect. The coronary flow increased. From the histochemical studies, adenosine triphosphatase (ATP-ase) and succinic dehydrogenase activities were increased while that of alkaline phosphatase was decreased. Glycogen granules were depleted. These findings were discussed on a histophysiological basis.     

A novel effect of indomethacin on prostaglandin F2 alpha synthesis and metabolism by the human prostate

Human prostate tissue has been found to be an excellent organ for synthesizing and metabolizing prostaglandin F₂ alpha. Employing ³H-arachidonic acid as substrate, tritium incorporation into PGF₂ alpha and three different metabolites, namely, 15-keto-PGF₂ alpha, 13, 14-dihydro-PGFP₂ alpha, and 13, 14-dihydro-15-keto-PGF₂ alpha, has been shown. The identity of these substances was corroborated by gas chromatography and chemical ionization mass spectrometry. Indomethacin has been widely reported as an inhibitor of PGF₂ alpha synthesis. In our experiments, upon adding indomethacin, slight to no inhibition of PGF₂ alpha synthesis was seen. Instead, we found a highly significant increase in the incorporation of the tritium of arachidonic acid into 15-keto-PGF₂ alpha. We interpret these findings as evidence that the indomethacin may block not PGF₂ alpha synthetase, but the Δ13-reductase, thus causing the accumulation of this enzyme's substrate, 15-keto-PGF₂ alpha.     

The effect of prostaglandin F2 alpha administration on progesterone after hysterectomy of guinea-pigs

It is believed that in guinea-pigs the main luteolytic agent is prostaglandin F2 alpha (PGF2a)_and that it is synthesised in the uterus. In this study non-pregnant guinea-pigs were hysterectomised at Day 5 of the estrous cycle. Peripheral progesterone levels in animals from which the uterus had been removed remained elevated for an extended time. The results suggested the corpora lutea (CL) had an inherent life span in excess of the length of the estrous cycle. However after a time the levels of circulating progesterone declined, suggesting there might have been a reduction of a stimulating factor or the appearance of a non-uterine luteolysin. If after hysterectomy PGF2a was administered 4 and 5 days later then there was a reduction in the mean progesterone level but the decline did not continue. The CL at the stage of the experimental procedure were sensitive to luteolysin but they had retained their capability to resist endocrinological insult. The study provided further support for the contention that control of PGF2a activity is vital for progesterone maintenance. Additionally, the cells of the CL have the potential to be the site of some of the PGF2a control.     

The effect of prostaglandin F2 alpha administration on progesterone after hysterectomy of guinea-pigs

It is believed that in guinea-pigs the main luteolytic agent is prostaglandin F2 alpha (PGF2a) and that it is synthesised in the uterus. In this study non-pregnant guinea-pigs were hysterectomised at Day 5 of the estrous cycle. Peripheral progesterone levels in animals from which the uterus had been removed remained elevated for an extended time. The results suggested the corpora lutea (CL) had an inherent life span in excess of the length of the estrous cycle. However after a time the levels of circulating progesterone declined, suggesting there might have been a reduction of a stimulating factor or the appearance of a non-uterine luteolysin. If after hysterectomy PGF2a was administered 4 and 5 days later then there was a reduction in the mean progesterone level but the decline did not continue. The CL at the stage of the experimental procedure were sensitive to luteolysin but they had retained their capability to resist endocrinological insult. The study provided further support for the contention that control of PGF2a activity is vital for progesterone maintenance. Additionally, the cells of the CL have the potential to be the site of some of the PGF2a control.     

Effect of prostaglandin F3 alpha on gastric mucosal injury by ethanol in rats: comparison with prostaglandin F2 alpha

In humans eicosapentaenoic acid can be converted to 3-series prostaglandins (PGF3 alpha, PGI3, and PGE3). Whether 3-series prostaglandins can protect the gastric mucosa from injury as effectively as their 2-series analogs is unknown. Therefore, we compared the protective effects of PGF3 alpha and PGF2 alpha against gross and microscopic gastric mucosal injury in rats. Animals received a subcutaneous injection of either PGF3 alpha or PGF2 alpha in doses ranging from 0 (vehicle) to 16.8 mumol/kg and 30 min later they received intragastric administration of 1 ml of absolute ethanol. Whether mucosal injury was assessed 60 min or 5 min after ethanol, PGF3 alpha was significantly less protective against ethanol-induced damage than PGF2 alpha. These findings indicate that the presence of a third double bond in the prostaglandin F molecule between carbons 17 and 18 markedly reduces the protective effects of this prostaglandin on the gastric mucosa.     

Effect of prostaglandin F2 alpha on the secretion of human prolactin

This study examines the role of PGF2a (prostaglandin F2alpha) in increasing the secretion rate of human prolactin. 11 women (mean gestational period, 18 weeks) seeking pregnancy termination were divided into 4 groups: 1) Group 1 consisted of 6 women who received 30 mg initially of PGF2a injected intramuscularly and an additional 15 mg after 24 hours if abortion had not occured; mean induction to termination period was 38 hours; 2) Group 2 comprised of 3 women who received PGF2a (500-1500 ug) via the transcervical route at 1 to 2 hourly interval; average number of injections was 20; mean induction to termination period, 24 hours; 3) Group 3 had 2 women receiving hypertonic saline by intraamniotic injection; mean induction to termination period was 51 hours; 4) Group 4 had 4 women who served as controls; mean observation period, 20 hours. Venous blood samples were heparinized in tubes at intervals of 2 to 3 hours. A homologous radioimmunoassay using highly purified human prolactin (for iodination and standards) plus rabbit antihuman prolactin measured serum prolactin. Spikes of serum prolactin up to 550 ng/ml were observed at irregular intervals in 5 women in Group 1; the spikes were less frequent and of smaller amplitude in Groups 3 and 4. The increase in serum prolactin was dramatic and more sustained in Group 2 patients and peaked towards the end of the prostaglandin infusion. Serum prolactin of Group 2 patients were significantly higher than those of Groups 3 and 4 (p0.01). 5 of 9 women whose pregnancies were terminated by PGF2a lactated. However, there was no significant difference between the mean serum prolactin levels in women who lactated (136 ng/ml) and those who did not (120 ng/ml). Although PGF2a is not a lactogenic hormone, this study shows that PGF2a stimulates the secretion of human prolactin during second trimester pregnancy. The fact that the transcervical route caused a significant increase in serum prolactin and the intraamniotic route did not is attributed to the increased systemic absorption of PGF2a following transcervical administration. No correlation was seen between the presence or absence of lactation and the serum prolactin level following pregnancy termination with PGF2a.     

Inhibition of ovulation in rabbits by intrafollicular injection of indomethacin and prostaglandin F antiserum

Indomethacin, an inhibitor of prostaglandin biosynthesis, was 100% effective in blocking luteinizing hormone (LH)-induced ovulation when administered via microinjection directly into 22 follicles in twelve rabbits, 5 hours after intravenous injection of the gonadotropin. Ovulation was similarly blocked in 24 of 25 follicles injected with antiserum prepared against prostaglandin F_2α. Antiserum against prostaglandin E₂, at the same dosage (100 μg lyophilized serum per follicle), was considerably less effective, preventing ovulation in only 6 of 14 follicles. Control follicles injected with the phosphate buffer vehicle, or with normal rabbit serum, underwent normal ovulation and luteinization. LH injection caused a striking increase in concentration of F-type prostaglandins in follicles shortly before ovulation, an increase which was prevented by i.v. or intrafollicular injection of ovulation-blocking blocking dosages of indomethacin. These findings provide evidence in support of a role for prostaglandins, acting at the follicular level, in the process of ovulation.     

Effect of prostaglandin F2 alpha on biliary secretion in the rat

The effects of PGF2 alpha on biliary secretion of rats have been investigated. PGF2 alpha' at the dose of 100 micrograms/kg, produces a choleretic activity during the first 20 min after the injection. The effects are discussed by comparison to those observed in dogs, where a mechanism involving the canicolar level has been hypothesized.     

Peroxisomal chain-shortening of prostaglandin F2 alpha

We have recently reported that prostaglandin F2 alpha can be chain-shortened by isolated rat liver peroxisomes. In the present study it is further established by cell fractionation experiments that the enzymes involved in this reaction are localized to peroxisomes. Under the conditions employed, the highest activity was found in the light mitochondrial fraction. Further fractionation of the light mitochondrial fraction by sucrose density gradient centrifugation showed that the prostaglandin oxidation activity comigrated with peroxisomal marker enzymes. Di(2-ethylhexyl)phthalate treatment resulted in a tenfold increased capacity for the conversion of prostaglandin F2 alpha into tetranorprostaglandin F1 alpha. The reaction was not inhibited by KCN. The reaction was further characterized with respect to cofactor requirements. The prostaglandin oxidation was found to be completely dependent on NAD, CoA, ATP, Mg2+ and was stimulated by FAD. Incubation of prostaglandin E2 with peroxisomes resulted in conversion into several products. After alkaline hydrolysis, one of these was identified as tetranorprostaglandin B1.