Effects of flunixin meglumine on endotoxin-induced prostaglandin F2 alpha secretion during early pregnancy in mares

The role of prostaglandin F2 alpha (PGF2 alpha) in embryonic loss following induced endotoxemia was studied in mares that were 21 to 44 days pregnant. Thirteen pregnant mares were treated with a nonsteroidal anti-inflammatory drug, flunixin meglumine, to inhibit the synthesis of PGF2 alpha caused by Salmonella typhimurium endotoxin given IV. Flunixin meglumine was administered either before injection of the endotoxin (group 1, -10 min; n = 7), or after endotoxin injection into the mares (group 2, 1 hour, n = 3; group 3, 2 hours, n = 3); 12 pregnant mares (group 4) were given only S typhimurium endotoxin. In group 4, the secretion of PGF2 alpha, as determined by plasma 15-keto-13,14-dihydro-PGF2 alpha concentrations, was biphasic, initially peaking at 30 minutes followed by a second, larger peak approximately 105 minutes after the endotoxin was given IV. When flunixin meglumine was administered at -10 minutes, synthesis of PGF2 alpha was inhibited for several hours, after administration of flunixin meglumine at 1 hour, the second secretory surge of PGF2 alpha was blocked, and administration of the drug at 2 hours did not substantially modify the secretion of PGF2 alpha. Plasma progesterone concentrations were unchanged after endotoxin injections were given in group 1. In group 2, progesterone values decreased less than 2 ng/ml and remained low for several days. In group 3 and group 4, progesterone concentrations decreased to values less than 0.5 ng/ml by 48 hours after endotoxin injections were given.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxytocin modulates the pulsatile secretion of prostaglandin F2alpha in initiated luteolysis in cattle

Subluteolytic doses of prostaglandin F2alpha analogue (oestrophan) given i.m. and oxytocin (OT) antagonist (CAP) and noradrenaline (NA) infused into the abdominal aorta were used to test the importance of luteal OT in pulsatile secretion of prostaglandin F2alpha (PGF) during luteolysis in heifers (n = 17). In experiment 1, heifers were pre-infused for 30 minutes with saline on either day 17 of the oestrous cycle (group 1; n = 4) or on day 18 of the oestrous cycle (group 2; n = 3), and with CAP (8 mg per animal) on day 17 of the oestrous cycle (group 3; n = 4). Next, heifers were injected with oestrophan (30 microg per animal). Injection of oestrophan in Group 3 increased OT concentrations (P < 0.001) to values similar to those observed during spontaneous luteolysis (50 to 70 pg ml(-1)). PGFM concentrations in this group also increased (P < 0.001), but were lower (P < 0.05) than the values in groups 1 and 2, CAP given prior to oestrophan decreased both PGFM elevation (P < 0.06) and its area under the curve (P < 0.01), compared to the saline pretreated heifers. In experiment 2 NA (4 mg) was infused twice for 30 minutes at five hour intervals to release OT on day 17 of the oestrous cycle (n = 6). However, during hormone analysis it appeared that three of six heifers had elevated PGFM concentrations (group 1) and three others did not (group 2). NA caused the correlated increase of progesterone and OT secretion (r = 0.68; P < 0.05) in both groups but it only influenced PGF secretion in group 1 only (P < 0.05). We postulate that OT can amplify and modulate the course of induced luteolysis as a regulator of the amplitude of pulsatile PGF secretion. PGF analogue stimulates secretion of endogenous PGF from the uterus in cattle and this may be an important component of the luteolytic response to exogenous PGF.     

Effect of an oxytocin antagonist on prostaglandin F2 alpha secretion and the course of luteolysis in sows.

The role of oxytocin (OT) in the regulation of prostaglandin F2 alpha (PGF2 alpha) secretion during luteolysis in gilts was studied using a highly specific OT antagonist (CAP-581). In Experiment 1 gilts on Days 14 to 19 of the oestrous cycle in Latin square design were used, to determine the dose and time of application of OT and CAP. In Group I (n = 6) gilts were treated intravenously with saline or with 10, 20 and 30 IU of OT. Concentrations of the main PGF2 alpha metabolite i.e. 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) were measured in blood samples as uterine response to the treatment. Twenty IU of OT was the most effective to stimulate PGFM release and this dose was used after CAP treatment in gilts of Groups II, III and IV. Gilts of Group II (n = 3) were injected into the uterine horns (UH) with saline (5 ml/horn) or CAP (2 mg, 3 mg and 4 mg; half dose/horn) and OT was injected (i.v.) 30 min thereafter. Any of the CAP doses given into the UH affected PGFM plasma concentrations stimulated by OT. In Group III (n = 4) gilts were infused (i.v.) for 30 min with CAP (9 mg, 14 mg and 18 mg/gilt) followed by 20 IU of OT. All doses of CAP effectively inhibited OT-stimulated PGF2 alpha release, therefore 9 mg was selected for the further studies. Gilts of Group IV (n = 4) received OT 4, 6 and 8 h after CAP to define how long CAP blocks the OT receptors. Concentrations of PGFM increased after any of this period of time. Thus, we concluded that 9 mg of CAP infused every 4 h will effectively block OT receptors. In Experiment 2, gilts (n = 4) received CAP as a 30-min infusion every 4 h on Days 12-20 of the oestrous cycle. Control gilts (n = 3) were infused with saline. CAP infusions diminished the height of PGFM peaks (P < 0.05). Frequency of the PGFM (P < 0.057) and OT (P < 0.082) peaks only tended to be lower in the CAP-treated gilts. Peripheral plasma concentrations of progesterone (P4) and oestradiol-17 beta (E2) and the time of luteolysis initiation as measured by the decrease of P4 concentration were the same in CAP- and saline-treated gilts. The macroscopic studies of the ovaries in gilts revealed lack of differences between groups. We conclude that OT is involved in the secretion of luteolytic PGF2 alpha peaks but its role is limited to controlling their height and frequency. Blocking of OT receptors did not prevent luteolysis in sows.     

Exogenous prostaglandin F2 alpha promotes uterine involution in the cow

Three newly delivered dairy cows were given prostaglandin F_2α during the immediate postpartum period. PGF_2α was administered from day 3–13 post partum in doses of 25 mg twice daily. Endogenous release of PGF_2α and progesterone was studied in blood plasma during the experimental period. Rectal examination of the uterus was performed every second day in order to establish the end of uterine involution. Uterine involution in the three cows was completed days 16, 23 and 20, respectively. These figures are to be compared with earlier investigations of uterine involution times, which show about 27 days. It was concluded that PGF_2α had a positive effect on the uterine muscular tone.Key words: uterine involution, prostaglandin F_2α, bovine     

Effect of prostaglandin F2 alpha administration on early pregnancy in ewes

Two trials were conducted with ewes to determine the effects of prostaglandin F2 alpha (PGF) administration during the first week of gestation. In trial 1, ewes (n = 134) were checked for breeding activity once daily and half of them received 10 mg PGF im at either 0, 24, 48, 72, 96, 120 or 144 h after detection of a breeding mark. The other half served as uninjected controls. In trial 2, ewes (n = 153) were checked for breeding activity twice daily. Two-thirds of the ewes received 10 mg PGF at either 24, 36, 48, 60, 72, 84, 96, 108, 120 and 132 h following detection of a breeding mark. The other one-third of the ewes served as uninjected controls corresponding to treatment times of 24, 48, 72, 96 or 120 h. In trial 1, the percentage of ewes lambing as a result of first service decreased as time of administration of PGF increased. The first-service pregnancy rate was 87.5% for ewes given PGF at 0 h and 0% for ewes given PGF at 144 h. Fewer (P less than .05) ewes given PGF at 96, 120 or 144 h after first mating lambed than control ewes. Similarly in trial 2, fewer (P less than .05) ewes given PGF at 96, 108, 120 or 132 h after first mating lambed than did controls. The total number of ewes lambing as a result of the entire breeding season did not differ (P greater than .05) between treated and control ewes in trial 1 (88.2 vs 87.3%) or trial 2 (85.7 vs 83.3%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hormonal regulation of oxytocin-induced prostaglandin F(2alpha) secretion by the bovine and ovine uterus in vivo

In long-term ovariectomized ewes and cows, endometrial oxytocin receptors rest at relatively high levels but oxytocin is unable to induce prostaglandin F(2alpha) release. A series of studies were carried out to investigate the roles of physiological levels of progesterone and estradiol in "activating" these receptors in terms of permitting oxytocin-induced prostaglandin F(2alpha) release. In long-term ovariectomized cows, treatment with progesterone, but not estradiol, resulted in the induction of responsiveness to oxytocin. This responsiveness appeared within 2 d of progesterone treatment, reached a maximum by 6 d and was maintained to Day 18. In ovariectomized ewes, while estradiol treatment did induce temporary responsiveness to oxytocin after 3 d of treatment, treatment with progesterone was required to induce sustained responsiveness that appeared by Day 9 of treatment and was maintained to Day 12. Measurement of endometrial receptors for oxytocin revealed a significant decline in oxytocin receptors by Day 6 of progesterone treatment when responsiveness to oxytocin was maximal, demonstrating that receptor concentrations were not a limiting factor. The most likely mechanism by which progesterone treatment induces responsiveness to oxytocin may be through the up regulation of post receptor signaling pathways and/or enzymes involved in prostaglandin synthesis.     

Effect of prostaglandin F2 alpha on adrenal-produced steroid hormones in cows

Ovariectomized, nonlactating cows were treated with IM injections of either physiologic saline solution or prostaglandin F2 alpha. Plasma concentrations of cortisol increased significantly by 30 to 60 minutes after injection of prostaglandin F2 alpha, but there were no significant increases in plasma concentrations of estradiol, progesterone, or testosterone. After saline solution treatment, there were no increases in any of the hormones measured.     

Oxytocin stimulates secretion of prostaglandin F(2alpha) from endometrial cells of swine in the presence of progesterone

Oxytocin (OT) stimulates endometrial secretion of prostaglandin (PG) F(2 alpha) during corpus luteum regression in swine but there is differential responsiveness to OT among endometrial cell types. To determine if progesterone influenced responsiveness of luminal epithelial, glandular epithelial, and stromal cells to 100 nM OT during luteolysis in swine, cells were isolated from endometrium of 15 gilts by differential enzymatic digestion and sieve filtration on day 16 postestrus and cultured continuously in the presence of 0, 10 or 100 nM progesterone. For phospholipase C (PLC) activity and PGF(2 alpha) secretion, stromal cells were most responsive to OT (P<0.01) in the absence of progesterone, whereas luminal epithelial cells were unresponsive and glandular epithelial cells displayed an intermediate response to OT (P<0.09). Progesterone enhanced PLC activity linearly in glandular epithelial cells (P<0.05) and influenced it quadratically in stromal cells (P=0.05). The effect of OT and progesterone on PLC activity in luminal epithelial cells was not significant, and progesterone did not increase PLC activity in response to OT in any cell type. Culture in the presence of progesterone, enhanced PGF(2 alpha) secretion in response to OT in luminal epithelial cells (P<0.05) but not in glandular epithelial or stromal cells. Progesterone also increased overall PGF(2 alpha) release from glandular epithelial (P<0.05) and stromal cells (P<0.06) across both levels of OT treatment. These results indicate that progesterone enhanced PGF(2 alpha) secretion from luminal epithelial cells in response to OT and increased basal PGF(2 alpha) release from glandular epithelial and stromal cells.     

Prostaglandin F2 alpha and prolactin in experimental hypogalactia in sows

Peripheral plasma concentrations of 13,14-dihydro-15-keto-prostaglandin F2alpha(PGFM), progesterone, prolactin and oestrone were determined in 20 sows for two days before and three weeks after parturition. Groups of four sows each received one of the following five treatments post partum: 30 ml sterile 0.9 per cent saline solution intrauterinely; ovariectomy and 30 ml saline solution intrauterinely; 10 ml Lugol's iodine plus 20 ml saline solution intrauterinely; ovariectomy and 10 ml Lugol's iodine plus 20 ml saline solution intrauterinely, or progesterone (0.5 mg [kg bodyweight]-1 intramuscularly). Saline solution and iodine were administered every 48 hours, starting immediately after parturition, for one week. Ovariectomy was performed within eight hours of delivery. Progesterone was given every third day for 12 days. Piglet weight gains were used as a reflection of milk yield. In all sows, oestrone values were elevated before parturition, but fell by the end of delivery and were very low during lactation. PGFM concentrations rose during the last two days of pregnancy to reach maximal values at the time of delivery. Plasma progesterone levels declined concomitantly with the rise in PGFM values before parturition. Basal values of progesterone were achieved within 24 hours after delivery in control sows receiving saline treatment. Progesterone values fell immediately after ovariectomy in sows receiving saline or iodine treatment but were slightly elevated for one week in sows that received only intrauterine iodine treatment, suggesting that complete regression of corpora lutea is prevented by suppression of post parturient uterine prostaglandin production. Sows injected with progesterone maintained plasma values of about 5 to 15 nmol litre-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

The induction of parturition in sows using prostaglandin F2alpha

Intramuscular injections (10 mg) of prostaglandin F2alpha were administered to 19 pregnant sows in one herd on either the 112th or 113th day of gestation and a similar number of untreated sows served as controls. Induced sows for up to 6h after injection generally showed more walking, drinking defaceating and postural changes. Over the last 20 h prepartum they spent more time lying and urinated more frequently. Mean interval from injection to onset of parturition in treated sows was 24.5 h and 16 of them commenced farrowing during the working day, compared with 6 in the control group. Induction of parturition did not influence litter size at birth, piglet body-weights at birth or 14 days of age, the incidence of the mastitis, metrititis agalactae syndrome, re-breeding interval of the sow or size of the subsequent litter at birth. Farrowing time was significantly longer (6.48 h v 4.08 h) for treated sows and litter pre-weaning mortality was higher but not significantly so. Most piglet deaths in each group resulted from overlaying or starvation but mortality from anaemia and septicaemia occurred only in the treated group. It is considered that the technique could have practical application on well-managed intensive pig units.