Prostaglandin F2alpha (PGF2alpha) and prolactin secretion in rats.

Plasma prolactin and F-prostaglandins (PGF) were measured anesthetized male Sprague-Dawley rats before and at 15, 30, 45 and 60 minutes following i.v. injection of either PGF2alpha (4 mg/kg), chlorpromazine, 1 mg/kg or chlorpormazine (1 mg/kg) after pretreatment with i.p. indomethacin (2 mg/kg). Following PGF2alpha administration, plasma prolactin levels increased significantly only at 15 and 30 minutes in spite of extremely high PGF levels throughout 60 minutes. Besides the expected rise in plasma prolactin, chlorpromazine caused a transient but statistically significant increase in PGF. Indomethacin blocked the chlorpormazine-induced PGF rise but not prolactin increase. Animals stressed with ether anesthesia showed elevation of plasma prolactin, which was not blocked by indomethacin although PGF concentration fell. Theese results indicate that PGF2alpha can stimulate prolactin release. This effect does not appear to be physiologic since very high PGF levels are required. Furthermore, blockade of prostaglandin synthesis by indomethacin does not prevent the release of prolactin in response to chlorpormazine or stress. Our findings do not support a possible role of PGFs as intermediaries in prolactin release. However, it is possible that PGFs may work through other mechanisms not investigated in our study.     

Central cardiovascular and thermal effects of prostaglandin F2α in rats

Administration of PGF_2α (0.2–6.4 μg) into the lateral cerebral ventricle (i.c.v.) induced dosedependent increases in blood pressure, heart rate and body temperature in urethane-anaesthetised rats, but had no effect on these parameters when the same dose range was administered intravenously. Peripheral pretreatment with sodium meclofenamate (50 mg/kg s.c.) shifted all the dose-response curves for PGF_2α (i.c.v.) to the left, but indomethacin (50 mg/kg s.c.) did not significantly affect those changes. Central pretreatment with sodium meclofenamate or indomethacin (1.25 mg per rat i.c.v.) failed to modify significantly the effects of centrally administered PGF_2α.The results support previous suggestions that PGF_2α may participate in the central control of the cardiovascular and thermoregulatory systems, and also suggest that there may be differences in the sites and/or modes of action between sodium meclofenamate and indomethacin.     

Luteolysis, estrus and ovulation, and blood prostaglandin F after intramuscular administration of 15, 30 or 60 mg prostaglandin F2α

During diestrus in three consecutive estrous cycles, each of six heifers was given (im) 30 mg, 15 mg (twice at 6-hr intervals) and 60 mg prostaglandin F_2α (PGF_2α) tham salt. Neither the decline in blood progesterone, the increase in blood estradiol, the duration or the peak of the LH surge, the interval to onset of estrus, nor the interval to ovulation was affected significantly by dose of PGF_2α. Thus, relative to that after 30 mg PGF_2α im, two injections of 15 mg at 6-hr intervals or 60 mg PGF_2α did not hasten luteolysis. Thirty mg was an ample im dose of PGF_2α to cause luteolysis. Regardless of im dose of PGF_2α, blood PGF peaked at about 6.0 ng/ml within 10 minutes and returned to basal values (<1.0 ng/ml) within 90 minutes. In another trial, after a single iv injection of 5 mg PGF_2α, blood PGF peaked (25 ng/ml) within 5 minutes and returned to basal values within 15 minutes. During a 30-minute infusion (0.5 mg/minute) of PGF_2α, blood PGF plateaued at 29.5 ng/ml with a metabolic clearance rate of 17.0 liters per minute.     

Induction of 20α-hydroxysteroid dehydrogenase in rat corpora lutea of pregnancy by prostaglandin F2α

20α-OH-SDH is a marker of luteolysis in rat corpora lutea and appearance of this enzyme is inhibited by prolactin but stimulated by LH or hCG. PGF₂α induced 20 α-OH-SDH activity in corpora lutea of pregnant rats and a significant fall in peripheral plasma progesterone concentrations when administered i.m. for two consecutive days. Rats treated with PGF₂ α on days 8 and 9 of pregnancy were resorbing implants by day 10. Exogenous progesterone, but not estrogen, prevented implant resorption, yet 20 α-OH-SDH appeared in the corpora marking luteolysis. HCG, LH and prolactin, but not FSH, prevented pregnancy termination and inhibited induction of 20 α-OH-SDH in rats treated with PGF₂ α in early pregnancy. PGF₂α also induced 20α-OH-SDH in luteal tissue of intact and hypophysectomized rats treated on days 14 and 15 of pregnancy, but neither exogenous steroids or gonadotrophins blocked the induction of the enzyme in rats treated at this time. The increase in lutein 20α-OH-SDH activity during the peripartal period was partially blocked by administration of the prostaglandin biosynthesis inhibitor, indomethacin, suggesting a role for endogenous prostaglandins in the induction of 20α-OH-SDH at term. It appears that PGF₂α acts directly on the ovary to induce 20α-OH-SDH activity by preventing the luteotrophic action of prolactin. Other luteal NADPH-dependent dehydrogenase activities are not markedly stimulated following PGF₂α administration.     

The excretion of prostaglandin F2α in milk of cows

Prostaglandin F_2α (PGF_2α) was measured by immunoassay in plasma and milk of four cows (six experiments). After 30 mg PGF_2α im, plasma PGF_2α peaked at 15 minutes (2.4 ± 0.7 ng/ml) and declined toward basal values by 3 hours; maximum milk PGF_2α (0.91 ± 0.12 ng/ml) occurred at 1 hour. The average excretion rate in milk was 2.9 μg/day 0.9 μg (0.003%) of which was due to the 30 mg PGF_2α injected. In six non-pregnant control cows, daily changes of milk PGF_2α and progesterone were not consistently related.     

Effects of prostaglandins E2, I2 and F2α, arachidonic acid and indomethacin on pressor responses to norepinephrine in conscious rats

The effects of prostaglandins E₂ (PGE₂), I₂ (PGI₂) and F₂α (PGF₂α), arachidonic acid and indomethacin on pressor responses to norepinephrine were examined in conscious rats. Intravenously infused PGE₂ (0.3, 1.25 μg/kg/min), PGI₂ (50, 100 ng/kg/min), PGF₂α (1.8, 5.4 μg/kg/min) and arachidonic acid (0.7, 1.4 mg/kg/min) did not change the basal blood pressure. Both PGE₂ and PGI₂ significantly attenuated pressor responses to norepinephrine, whereas PGF₂α significantly potentiated them. Arachidonic acid, a precursor of the prostaglandins (PGs), significantly attenuated pressor responses to norepinephrine. Since the attenuating effect of arachidonic acid was completely abolished by the pretreatment with indomethacin (5 mg/kg), arachidonic acid is thought to exert an effect through its conversion to PGs. On the contrary, intravenously injected indomethacin (0.2–5.0 mg/kg) facilitated pressor responses to norepinephrine in a dose-related manner without any direct effect on the basal blood pressure. These results suggest that endogenous PGs may participate in the regulation of blood pressure by modulating pressor responses to norepinephrine in conscious rats.     

Intra-amniotic prostaglandin F2α and urea for abortion

Prostaglandin F_2α (PGF_2α) 20 mg combined with urea 80 g was injected intra-amniotically in 20 patients to induce mid-trimester abortion. Abortion resulted in all subjects within 24 hours in a mean time of 12 hours 38 minutes (range 5 hours 50 minutes to 20 hours 45 minutes).Plasma sex steroids were evaluated before and hourly for 5 hours after the injection. A progressive decline in levels occurred with time. Decreases in plasma progesterone, estrone, estradiol and estriol were significant as soon as one hour after injection.Gastrointestinal side effects occurred with a greater frequency than when a comparable dose of PGF_2α is given alone and 2 patients had small cervical lacerations requiring suture. Further studies are indicated to establish whether a lower dose of PGF_2α will be associated with fewer side effects and be as effective.     

The action of prostaglandin E2 and F1α on myocardial ischaemia-infarction arrhythmias in the dog

Prostaglandin E₂ and F_1α infusions have been tested for their ability to reduce the arrhythmias associated with occlusion of the left descending coronary artery in the anaesthetised dog. At 1 μg/kg/min both PGs reduced the incidence of premature ventricular contractions occurring during 25-min occlusions, while not reducing the incidence of ventricular fibrillation occurring on occlusion release. When infused for 5-min periods at 1 to 16 μg/kg/min, neither PGE₂ nor PGF_1α effectively reduced the frequency of ventricular arrhythmias occurring 24 hr after a permanent coronary occlusion.     

Effectiveness of prostaglandin F2α in restoration of HMG-HCG induced ovulation in indomethacin-treated rhesus monkeys

Six mature female rhesus monkeys were treated with HMG-HCG in control cycles at doses adjusted to induce ovulation while avoiding superovulation. Occurrence of ovulation was determined by observation of fresh ovulation points at laparotomy 48 to 120 hours following HCG. In subsequent cycles animals were treated with indomethacin (treatment days 4 through 10) together with the established dose of HMG_HCG. In 8 cycles indomethacin 5 mg/kg was given i.m. once daily; in 9 cycles 10 mg/kg i.m. was administered in 2 divided doses. Following this, PGF_2^α (3 mg t.i.d. s.c.) was administered for 3 days together with indomethacin 10 mg/kg and HMG-HCG, beginning on the day prior to HCG. Determinations of progesterone were performed by RIA on treatment days 4, 7, 10, and 11. Eleven of the 13 control cycles were ovulatory. With indomethacin 5 mg/kg/day, 5 of 8 cycles were ovulatory but ovulation was delayed in 2 instances. Of 9 cycles using indomethacin 10 mg/kg/day only 1 was ovulatory. When PGF_2^α was administered in subsequent cycles along with indomethacin (10 mg/kg) and HMG-HCG, ovulation occurred in 13 of 19 cycles. These data suggest that local ovarian PGF_2^α may be essential in the mechanics of follicle rupture in gonadotropin-treated rhesus monkeys.     

Corpus luteum susceptibility to prostaglandin F2α (PGF2α) luteolysis in hysterectomized prepuberal and mature gilts

The susceptibility of induced corpora lutea (CL) of prepuberal gilts and spontaneously formed CL of mature gilts to prostaglandin F_2α (PGF_2α) luteolysis was studied. Prepuberal gilts (120 to 130 days of age) were induced to ovulate with Pregnant Mare Serum Gonadotropin and Human Chorionic Gonadotropin (HCG). The day following HCG was designated as Day 0. Mature gilts which had displayed two or more estrous cycles of 18 to 22 days were used (onset of estrus = Day 0). Gilts were laparotomized on Day 6 to 9, their CL marked with sterile charcoal and totally hysterectomized. On Day 20, gilts were injected IM with either distilled water (DW), 2.5 mg PGF_2α or 5.0 mg PGF_2α. An additional group of prepuberal gilts was injected with 1.25 mg PGF_2α, a dose of PGF_2α equivalent, on a per kilogram body weight basis, to the 2.5 mg PGF_2α dose given to the mature gilts. The percentages of luteal regression on Day 27 to 30 for mature and prepuberal gilts given DW, 2.5 mg PGF_2α and 5.0 mg PGF_2α were 0.0 vs 4.4, 43.5 vs 96.8 and 47.7 vs 91.6, respectively; the percentage of luteal regression for the prepuberal gilts given 1.25 mg PGF_2α was 75.1. These results indicate that induced CL of the prepuberal gilt were more susceptible to PGF_2α luteolysis than spontaneously formed CL of the mature gilt and that pregnancy failure in the prepuberal gilt could be due to increased susceptibility of induced CL to the natural luteolysin.     

Effects of prostaglandin F2α (PGF2α) on the length of pseudopregnancy in normal and IUD bearing hamsters

Prostaglandin F_2α (PGF_2α) at 14, 30 or 50 μg/hamster/day from Days 3–5 of pseudopregnancy (PSP) shortens PSP from a mean length of 9.1 to 5.6–7.9 days, depending on the dose of PGF_2α administered. Bilateral intrauterine device (BIUD) bearing hamsters exhibit a mean length of PSP of 9.2 days, which is comparable to that in normal saline controls. Combination of PGF_2α (14 μg/day on Days 3–5 of PSP) and BIUD also resulted in shortening of PSP although the mean length of PSP resulted from the combined treatment was not significantly different from those PSP animals treated with 14 μg/day of PGF_2α alone. It is concluded that the antifertility effect of intrauterine device possibly is attributed to a small and continuous release of PGF which interferes with the normal implantation processes but does not curtail PSP.     

Effectiveness of prostagland in F2α in restoration of HMG-HCG induced ovulation in indomethacin-treated rhesus monkeys

Six mature female rhesus monkeys were treated with HMG-HCG in control cycles at doses adjusted to induce ovulation while avoiding superovulation. Occurrence of ovulation was determined by observation of fresh ovulation points at laparotomy 48 to 120 hours following HCG. In subsequent cycles animals were treated with indomethacin (treatment days 4 through 10) together with the established dose of HMG-HCG. In 8 cycles indomethacin 5 mg/kg was given i.m. once daily; in 9 cycles 10 mg/kg i.m. was administered in 2 divided doses. Following this, PGF₂α (3 mg t.i.d. s.c.) was administered for 3 days together with indomethacin 10 mg/kg and HMG-HCG, beginning on the day prior to HCG. Determinations of progesterone were performed by RIA on treatment days 4, 7, 10, and 11. Eleven of the 13 control cycles were ovulatory. With indomethacin 5 mg/kg/day, 5 of 8 cycles were ovulatory but ovulation was delayed in 2 instances. Of 9 cycles using indomethacin 10 mg/kg/day only 1 was ovulatory. When PGF₂α was administered in subsequent cycles along with indomethacin (10 mg/kg) and HMG-HCG, ovulation occurred in 13 of 19 cycles. These data suggest that local ovarian PGF₂α may be essential in the mechanics of follicle rupture in gonadotropin-treated rhesus monkeys.     

Effects of indomethacin, prostaglandin E2, prostaglandin F2α and 6-keto-prostaglandin F1α 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 F_2α (PGF_2α) or 6-keto-prostaglandin F_1α (6-keto-PGF_1α) were added to the culture media with indomethacin. (1) The hatching was inhibited by indomethacin yet the inhibition was reversible. (2) In the groups with indomethacin and PGE₂, no improvement was seen in the inhibition of hatching and the inhibition was irreversible. (3) In the groups with indomethacin and PGF_2α, inhibition of hatching was improved in comparison with the group with indomethacin. (4) In the groups with indomethacin and 6-keto-PGF_1α, no improvement was seen. The above results indicated that PGF_2α possibly had an accelerating effect on hatching and a high concentration of PGE₂ would exert cytotoxic effect on blastocysts.     

Effect of prostaglandin F2α on uterine or ovarian secretion of prostaglandins E and F2α in vivo in 90–100 day hysterectomized, intact or ovariectomized pregnant ewes

Vehicle or 8 or 16 mg of PGF_2α per 58 kg body weight was given intramuscularly to intact, hysterectomized or ovariectomized 90–100 day pregnant ewes in three separate experiments. Both doses of PGF_2α increased PGF_2α in ovarian venous plasma compared with controls at 72 hr post treatment in intact (P≤0.05) but did not in hysterectomized (P≥0.05) 90–100 day pregnant ewes. Concentrations of PGE in ovarian venous blood of intact ewes did not differ (P≥0.05) between treatment groups and were equivalent to concentrations of PGE determined in uterine venous plasma. PGE was decreased in ovarian venous plasma by PGF_2α in hysterectomized ewes (P≤0.07). PGE in uterine venous plasma averaged 6 ng/ml over the 72-hr treatment period in intact and ovariectomized 90–100 day pregnant ewes and was 12 fold greater (P≤0.05) than PGF_2α which averaged 500 pg/ml in uterine venous plasma. Both PGF_2α and PGE increased (P≤0.05) by 64 hr in uterine venous plasma of the 8 mg PGF_2α — treated intact pregnant ewes. A significant quadratic increase (P≤0.05) was observed for PGF_2α and PGE in the vehicle and both PGF_2α treatment groups of intact ewes at the end of the 72-hr sampling period. It is concluded that the uterus and ovaries secrete significant quantities of PGE but little PGF_2α during midgestation. In addition, PGF_2α increased uterine secretion of PGE . PGE may be a placental stimulator of ovine placental secretion of progesterone or PGE may protect placental steroidogenesis from actions of PGF_2α.     

Corpus luteum function in the ewe: Effect of PGF2α and prostaglandin synthetase inhibitors

A series of experiments were conducted to evaluate the effects of mode and frequency of administration and estrous cycle stage on the response of the cycling ewe to PGF_2α. The effects of dexamethasone, arachadonic acid and prostaglandin synthetase inhibitors on estrous cycle length and plasma progesterone levels were also determined.Intramuscular administration of 5 or 10 mg of PGF_2α, on days 8 and 9 after estrus (5 ewes/group), significantly (p<.01) shortened the mean length of the estrous cycle and the interval from the end of treatment to estrus. Mean plasma progesterone levels, 24 hours after initial injection, were significantly (p<.01) lowered. When administered on day 8 only, these doses were considerably less effective in shortening estrous cycle length or lowering plasma progesterone levels. Intravaginal administration of PGF_2α, by polyurethane tampon, was also largely ineffective.Treatment of ewes with 10 mg of PGF_2α i.m., on days 3 and 4 of the estrous cycle, resulted in a return to estrus in 2 days in 25% of the treated animals. Plasma progesterone levels of PGF_2α-treated ewes were significantly lower than controls on the second, third and fourth days after the start of dosing. It would appear that PGF_2α exerts a retarding effect on developing CL functionality.The prostaglandin synthetase inhibitors, aspirin, flufenamic acid and 1-p-chlorobenzylidene-2-methyl-5-methoxy-3-indenylacetic acid, were administered orally or parenterally for 16 days beginning on day 8 of the estrous cycle. These compounds failed to prolong estrous cycle length. Parenteral administration of dexamethasone did not result in PGF_2α release in the cycling ewe, at least not in quantities sufficient to induce luteolysis. The prostaglandin precursor, arachadonic acid, also was not luteolytic when given parenterally to cycling ewes.     

Increased blood LH and testosterone after administration of prostaglandin F2α in bulls

Two types of experiments were conducted to determine the relationship of changes in blood luteinizing hormone (LH) and testosterone in bulls given prostaglandin F_2α (PGF_2α). Episodic surges of LH and testosterone occurred in tandem, apparently at random intervals, on the average once during the 8-hr period after bulls were given saline. In contrast, after sc injection of 20 mg PGF_2α, blood serum testosterone increased synchronously to a peak within 90 minutes four-fold greater than pre-injection values, and the testosterone surges were prolonged about three-fold compared to those in controls. Each of the PGF_2α-induced surges of testosterone was preceded by a surge of blood serum LH which persisted for about 45 minutes and peaked at about 3 ng/ml. In a second experiment, PGF_2α was infused (iv, 0.2 mg/min) for 20 hr; blood plasma testosterone increased from 7.0 ± 0.6 to 16.0±1.5 ng/ml within 2.5 hr and remained near this peak for 10 hr. Then testosterone gradually declined to about 9 ng/ml at the conclusion of the 20-hr infusion. These changes in testosterone were paralleled by similar changes in blood plasma LH, although LH declined 3 hr earlier than testosterone. Random episodic peaks of blood plasma LH and testosterone typical of untreated bulls resumed within 8 hr after conclusion of PGF_2α infusion. In both experiments, the surge of testosterone after PGF_2α was preceded by increased blood LH. We conclude that increased LH after administration of PGF_2α probably caused the increased testosterone. However the mechanisms of these actions of PGF_2α remain to be determined.     

Effects of intracerebroventricular administration of prostaglandins I2, E2, F2α and indomethacin on blood pressure in the rat

The effects of intraventricularly administered prostaglandins I₂ (PGI2), E₂ (PGE2), F_2α (PGF2α) and indomethacin on systemic blood pressure were investigated in conscious rats. PGI2 (1.25 – 10 g/kg) decreased blood pressure in a dose-related manner, whereas PGE2 (100 – 1000 ng/kg) dose-dependently increased blood pressure. Both PGF2α (0.31 – 20 μg/kg) and indomethacin (0.625 – 40 μg/kg) had no effects on blood pressure. These results indicate that intraventricular injection of PGI2 or PGE2 can induce significant changes in blood pressure, while endogenous prostaglandins synthesized in the brain seem to play a minor role in direct regulation of systemic blood pressure in the rat.     

Effect of prostaglandin F2α on ovarian and pituitary function in the mid-luteal phase

The effects of PGF_2α infusion in a dose of 25 μg/min for 5 hours on serum levels of estradiol-17β, progesterone, LH, FSH, TSH and prolactin, and on the pituitary hormone responsiveness to LRH and TRH were studied in 10 apparently healthy cycling women in the mid-luteal phase. No systematic alteration was seen in the pituitary and ovarian hormone levels during PGF_2α infusion, and the pituitary hormone responses to releasing hormones were unaffected. Ovarian steroid production increased in response to increased gonadotropin levels after LRH injection during PGF_2α administration. These results confirm that PGF_2α is not luteolytic in humans and no apparent relationship between PGF_2α and pituitary hormone secretion exists.     

Increased sperm output of rabbits and bulls treated with prostaglandin F2α

Seven rabbits were ejaculated four times once weekly, and saline or 2.5 mg PGF_2α tromethamine salt was injected sc at 4 and 2 hours or at 8 and 4 hours before ejaculation. First ejacula taken at 2 hours after the second injection of PGF_2α contained 150% more (P.07) sperm than those after injections of saline. The comparable difference (60%) at 4 hours after PGF_2α was not significant. PGF_2α did not influence sperm output in second, third or fourth ejacula. After 28 daily sc injections of 5 mg PGF_2α in another experiment, the fertility of four treated rabbits was as high as that for four controls. Without sexual preparation in seven bulls, im injections of 40 or 80 mg PGF_2α 30 minutes before ejaculation resulted in 33% greater (P<.05) sperm output than that after injection of 0, 7 or 20 mg PGF_2α, but the highest sperm output after PGF_2α was 30% less (P<.05) than that after sexual preparation in the same bulls. We conclude that injections of PGF_2α result in increased sperm output in ejacula taken without sexual preparation within 2 hours in rabbits and in bulls.     

Effects of PGF2α and PGF2α, 1–15 lactone on the corpus luteum and on early pregnancy in the rhesus monkey

The effects of prostaglandin (PG)F_2α and PGF_2α, 1–15 lactone were compared in luteal phase, non-pregnant and in early pregnant rhesus monkeys. Animals treated with either PG after pretreatment with human chorionic gonadotropin (hCG) had peripheral plasma progesterone concentrations that were not statistically different from those in animals treated with hCG and vehicle. However, menstrual cycle lengths in monkeys treated with PGF_2α, 1–15 lactone were significantly (P <0.02) shorter than those in vehicle treated animals. In the absence of hCG pretreatment, plasma progesterone concentrations were significantly (P <0.008) lower by the second day after the initial treatment with either PGF_2α or PGF_2α, 1–15 lactone than in vehicle treated monkeys. Menstrual cycle lengths in monkeys treated with either PG were significantly (P <0.04) shorter than those in animals treated with vehicle. There were no changes in plasma progesterone concentrations in early pregnant monkeys treated with PGF_2α, and pregnancy was not interrupted. In contrast, plasma progesterone declined and pregnancy was terminated in 5 of 6 early pregnant monkeys treated with PGF_2α, 1–15 lactone. These data indicate that PGF_2α, 1–15 lactone decreases menstrual cycle lengths in non-pregnant rhesus monkeys. More importantly, PGF_2α, 1–15 lactone terminates early pregnancy in the monkey at a dose which is less than an ineffective dose of PGF_2α.