Effect of pregnancy on oxytocin-induced release of prostaglandin F2 alpha in heifers

The effect of pregnancy on the release of prostaglandin F2 alpha (PGF2 alpha) in response to oxytocin (OT) has been examined. Fourteen cyclic heifers received one intravenous injection of 1 IU OT (n = 6) or 100 IU OT (n = 8) 17, 18, or 19 days (Day 17-19) after the onset of estrus (Day 0). Five of these animals also received 100 IU OT at Days 6 and 13 to determine the effect of OT at different times of the cycle. Frequent blood samples were taken for 60 min before and for 90 min after OT injection for the measurement of 15-keto-13,14-dihydro-PGF2 alpha (PGFM) by radioimmunoassay. The experiment was then repeated using the same animals at Day 17-19 of pregnancy (confirmed by the recovery of an embryo the day after OT injection). Following the injection of 1 IU OT, plasma PGFM reached its peak within 30 min with the increase significantly lower (P less than 0.05) in pregnant (1.13 +/- 0.10-fold) than in nonpregnant animals (2.07 +/- 0.27-fold). However, because only 3 of the 6 cyclic animals showed a response to 1 IU OT, the dose was increased to 100 IU in subsequent experiments. The animals that received 100 IU at Days 6 and 13 had no significant increase in PGFM concentrations (1.18 +/- 0.05-fold and 1.01 +/- 0.04-fold, respectively). At Day 17-19 the increase in plasma PGFM reached its peak 5-15 min after 100 IU OT and the increase was significantly greater in nonpregnant (3.23 +/- 0.17-fold) than in pregnant (1.21 +/- 0.02-fold; P = 0.003) heifers. Six of 11 animals injected at Day 17-19 of the cycle showed a decrease in progesterone (P4) the day after OT administration. These data show that the release of PGF2 alpha in response to OT is suppressed in pregnant animals in vivo, suggesting an antiluteolytic role for the embryo in luteostasis.     

Effect of dexcloprostenol on endogenous prostaglandin F2alpha release in dairy heifers

Cloprostenol was previously believed to be unable to release endogenous prostaglandin F2alpha (PGF2alpha) when administered during early bovine diestrus. A prostaglandin release is, however, seen in late diestrus. The aim of this study is to find out whether dexcloprostoenol (containing the only biologically active isomer, d-isomer, of cloprostenol) induces endogenous PGF2alpha release during early and late diestrus. Twelve heifers of the Finnish Ayrshire breed were allocated into two equal groups. Their estrous cycles were synchronized with dexcloprostenol. A further luteolysis was induced with 0.15 mg of dexcloprostenol either on Day 7 (group D7 or early diestrus) or on Day 14 (group D14 or late diestrus) after ovulation. Blood for progesterone and the PGF2alpha metabolite 15-ketodihydro-PGF2alpha determinations was collected immediately before dexcloprostenol treatment and thereafter every second hour for 48 h. Five of the six heifers in both groups showed significantly increased blood levels of 15-ketodihydro-PGF2alpha at some time during the 48-h experimental period. The intervals from treatment to the first significant increases of the PGF2alpha metabolite were 32.8+/-2.3 h (min. 30 h, max. 36 h) and 20.0+/-4.2 h (min. 14 h, max. 24 h) in groups D7 and D14, respectively (P < 0.01). We have concluded that dexcloprostenol induced endogenous PGF2alpha release in most cases, regardless the time of its administration (early or late diestrus). This release, however, differs from that observed during spontaneous luteolysis.     

Effects of progesterone and oestradiol-17 beta on oxytocin-induced release of prostaglandin F-2 alpha in heifers

Seven bilaterally ovariectomized heifers were used in 4 experiments and received: (1) saline injections, as control; (2) one injection of oestradiol (3 mg; i.v.); (3) two i.v. injections of oxytocin (100 i.u.) 6 h apart; or (4) one oestradiol injection 30 min after the first oxytocin injection and a second oxytocin injection 6 h later. All experiments were performed without progesterone and then after 7, 14 and 21 days of progesterone treatment. Frequent blood samples were taken for 1 h before and 7 h after the first injection of oxytocin or oestradiol for the measurement of 13,14-dihydro-15-keto-PGF-2 alpha (PGFM) by radioimmunoassay. After 7, 14 and 21 days of progesterone priming, oestradiol caused a significant increase (P less than 0.001) in plasma PGFM after 6 h but not before. After 7, 14 and 21 days of progesterone, there was a significant increase (P less than 0.005) in PGFM after the first oxytocin injection and a similar increase following the second. The oxytocin-induced increase in PGFM after 14 and 21 days of progesterone was significantly higher (P less than 0.001) 6 h after oestradiol injection than before the oestradiol injection. There was no significant effect of oestradiol on the response to oxytocin in animals that received no progesterone or in those animals that received progesterone for only 7 days. These results show that, under the influence of progesterone, oestradiol enhances the oxytocin-induced release of PGF-2 alpha, and suggest a possible synergistic action of these hormones for the induction of luteolysis in heifers.     

Suppression of oxytocin-induced prostaglandin F2alpha release after intra-uterine nordihydroguariaretic acid administration in ewes

Intrauterine administration of the 5-lipoxygenase inhibitor nordihydroguariaretic acid (NDGA; 5 mg, bid) on Days 9-14 of the ovine estrous cycle (estrus = Day 0) delayed luteolysis and extended the duration of the estrous cycle (20+/-1, SD, vs. 16+/-1 days; P < 0.01). In control ewes, plasma concentrations of 13,14,dihydro-15-keto prostaglandin F2alpha increased significantly (P < 0.001) following i.v. administration of oxytocin (10 i.u.) on Day 14; in the nordihydroguariaretic acid-treated ewes, however, there was no such increase. In addition, concentrations of endometrial oxytocin receptors were significantly less (P < 0.01) in the nordihydroguariaretic acid-treated ewes (218+/-60 vs. 579+/-66 fmol/mg tissue). These results suggest that 5-lipoxygenase products of arachidonate metabolism may be involved in the control of ovine luteal function.     

Role of phospholipase C in mediating oxytocin-induced release of prostaglandin F2 alpha from ovine endometrial tissue

Two experiments were conducted to determine if the ability of oxytocin to stimulate release of prostaglandin (PG)F2 alpha from ovine uterine tissue involved activation of phospholipase C (PLC). In the first experiment, 9 ewes were injected with progesterone for 11 d (12 mg/d, im). On days 11 and 12, ewes received an injection of estradiol (100 micrograms, im). Caruncular endometrial tissue was collected on d 13 and incubated in the presence or absence of oxytocin (10(-6) M). Concentrations of PGF2 alpha and its metabolite, 13,14-dihydro-15-keto-PGF2 alpha (PGFM), in culture media were determined by radioimmunoassay. PLC activity was determined by measuring the intracellular accumulation of 3H-inositol phosphates after preincubation with 3H-inositol. Concentrations of PGF2 alpha and total PGF (PGF2 alpha + PGFM) in culture media were greater for explants treated with oxytocin than for controls (p. less than .02, p less than .06, respectively). A similar effect of oxytocin on intracellular concentrations of 3H-inositol phosphates was observed (p less than .01). A second experiment was conducted to determine if agonists of second messengers, produced by activation of PLC, could stimulate release of PGF2 alpha from ovine endometrial tissue. Seven ewes were treated with progesterone and estradiol as in experiment 1. Explants of caruncular tissue from each ewe were incubated with 1) control medium, 2) A23187 (10(-5) M), 3) oxytocin (10(-6) M), 4) phorbol 12-myristate 13-acetate (PMA, 10(-7) M), 5) PMA + A23187 and 6) PMA + oxytocin. Significant stimulatory effects of oxytocin, PMA and A23187 on concentrations of PGF2 alpha and total PGF in culture media were observed (p. less than .05, p less than .1, p less than .1, respectively). In conclusion, oxytocin stimulated release of PGF2 alpha and activity of PLC in explants of ovine endometrial tissue in vitro. Second messengers associated with activation of PLC enhanced release of PGF2 alpha from ovine endometrial tissue.     

Interrelationship between plasma estradiol concentration and oxytocin-induced PGF2alpha release in heifers

The objective of this study was to determine if the increase in responsiveness to oxytocin toward the time of luteolysis was correlated with an increase in plasma estradiol in the cow. Six heifers each had a cannula placed in the jugular vein on Day 14 of the estrous cycle. Then, beginning on Day 15, growth of the largest follicles was determined by ultrasonography, and a blood sample was taken via the cannula for the measurement of progesterone and estradiol by radioimmunoassay (RIA). After the first blood sample, 3 more samples were taken at 10-min intervals, 100 IU oxytocin were injected into the vein, and a further 3 blood samples were taken at 15, 30 and 60 min after injection. The concentration of 13,14-dihydro-15-keto prostaglandin F2alpha (PGFM) was measured in these frequent samplings and was used to determine the ability of oxytocin to stimulate PGF2alpha release from the uterus. This procedure was repeated daily for at least 7 d. The results showed that the response to oxytocin increased before luteolysis and that there was a significant increase in the response to oxytocin (P<0.05) before any changes in plasma estradiol or progesterone were detected. These data show that an increase in estradiol secretion from the ovulatory follicle does not appear to initiate luteolysis.     

Effect of oxytocin, prostaglandin F2 alpha, and clenbuterol on uterine dynamics in mares

The effects of oxytocin, prostaglandin F2 alpha (PGF2 alpha), and clenbuterol on uterine contractility and tone during anestrus and diestrus, and during mobility and postfixation of the embryonic vesicle were studied in 51 pony mares. Contractility was assessed by scoring real-time ultrasound images, and tone was assessed by transrectal digital compression. Scoring was done by an operator who had no knowledge of treatment assignments. In anovulatory mares primed with progesterone for 16 d, oxytocin did not significantly alter contractility but did stimulate an increase in tone, whereas clenbuterol depressed both contractility and tone. The PGF2 alpha given on Days 12, 15, and 18 did not significantly alter uterine contractility in pregnant mares, but it increased contractility on all days in nonpregnant mares. Clenbuterol decreased both tone and contractility when given to pregnant mares on the day of embryonic-vesicle fixation, while it decreased tone but not contractility when given on Day 19. Clenbuterol treatment was associated with dislodgment of the fixed embryo in only 1 of 5 mares. However, on Day 19, clenbuterol treatment was associated with a change in shape of the conceptus when viewed in a cross section of the uterine horn. The conceptus shape became more circular rather than irregular or triangular, as indicated by a significant decrease in the variation in the distances between adjacent walls measured in 4 different directions. Results indicated that: 1) oxytocin increased uterine tone but did not alter contractility in progesterone-primed anestrous mares; 2) on Days 12, 15 and 18, PGF2 alpha increased uterine contractility in nonpregnant mares but not in pregnant mares; 3) clenbuterol decreased both tone and contractility at all reproductive states except for a lack of a decrease in contractility on Day 19 of pregnancy; and 4) reduction in uterine tone from clenbuterol treatment on Day 19 was associated with a change in the two-dimensional shape of the in situ conceptus from irregular to a more circular form.     

Differential effects of progesterone treatment on the oxytocin-induced prostaglandin F2 alpha response and the levels of endometrial oxytocin receptors in ovariectomized ewes.

The oxytocin-induced uterine prostaglandin (PG) F2 alpha response and the levels of endometrial oxytocin receptors were measured in ovariectomized ewes after they had been given steroid pretreatment (SP) with progesterone and estrogen to induce estrus (day of expected estrus = Day 0) and had subsequently been treated with progesterone over Days 1-12 and/or PGF2 alpha over Days 10-12 postestrus. The uterine PGF2 alpha response was measured after an i.v. injection of 10 IU oxytocin on Days 13 and 14, using the PGF2 alpha metabolite, 13,14-dihydro-15-keto-PGF2 alpha (PGFM), as an indicator for PGF2 alpha release. The levels of oxytocin receptors in the endometrium were measured on Day 14. During the treatment with progesterone, the peripheral progesterone concentrations were elevated and remained above 1.8 ng/ml until the morning of Day 14. The PGFM responses to oxytocin in untreated controls and SP controls were low on both Days 13 and 14 whereas the levels of endometrial oxytocin receptors in the same ewes were high. Treatment with progesterone either alone or in combination with PGF2 alpha significantly (p less than 0.04) increased the PGFM response on Day 14 and reduced the levels of endometrial oxytocin receptors; treatment with PGF2 alpha alone had no effect. It is concluded that progesterone promotes the PGFM response to oxytocin while simultaneously suppressing the levels of endometrial oxytocin receptors. PGF2 alpha treatment had no effect on either the uterine secretory response to oxytocin or the levels of oxytocin receptors in the endometrium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of exogenous progesterone on prostaglandin F2 alpha release and the interestrous interval in the bovine

The present study was developed to determine if administration of progesterone, early in the estrous cycle of the cow, stimulated an advanced pulsatile release of PGF2 alpha from the uterine endometrium resulting in a decreased interestrous interval. Twenty-three cyclic beef cows were randomly assigned to receive either sesame oil or progesterone (100 mg) on Day 1, 2, 3 and 4 of the estrous cycle. Peripheral plasma concentrations of progesterone and the metabolite of prostaglandin F2 alpha, 15-keto-13,14-dihydro-prostaglandin F2 alpha (PGFM) were measured by radioimmunoassay. Administration of exogenous progesterone increased peripheral plasma concentration of progesterone in treated (3.67 ng/ml) compared to control (1.28 ng/ml) cows from Day 2 through 5 of the estrous cycle. Progesterone administration shortened the interestrous interval (16.7 d) compared to controls (21.6 d). The shortened interestrous intervals in treated cows resulted from an earlier decline in peripheral plasma progesterone. Decline of peripheral plasma progesterone concentrations is coincident with an increased pulsatile release of PGFM in both progesterone treated and control cows. Results indicate that administration of exogenous progesterone stimulates an earlier maturation of endometrial development, causing an advanced release of PGF2 alpha which shortens the interestrous interval of the cow.     

Control of bovine uterine prostaglandin F2 alpha release in vitro

Prostaglandin F2 alpha (PGF2 alpha) release from the uterus causes luteolysis in ruminants, and oxytocin is thought to be a regulator of this release. In the present study, we have examined the mechanisms involved in oxytocin stimulation of PGF2 alpha secretion by bovine endometrium in vitro. Endometrial tissue explants, obtained from heifers at Day 19 or 20 (n = 3) and Day 0 (estrus, n = 5) of the estrous cycle, were incubated for 2 h and 6 h, and PGF2 alpha concentration in the medium was determined by radioimmunoassay (RIA). Basal PGF2 alpha release increased for up to 6 h and was significantly stimulated after 2 h of incubation with 100 microU and 1000 microU of oxytocin at Day 0 but not at Day 19 or 20. Secretion of PGF2 alpha was not affected by cholera toxin (10 ng/ml) or the cyclic nucleotide analogs dibutyryl cyclic adenosine 3',5'-monophosphate and dibutyryl cyclic guanosine 3',5'-monophosphate at a concentration of 1 mM. A protein kinase A inhibitor (500 microM) had no effect on the oxytocin-induced release of PGF2 alpha. Both the phorbol ester, 12-myristate-13-acetate (100 mM), and the non-phorbol stimulator of protein kinase C, 1-octanoyl-2-acetylglycerol (500 microM), significantly stimulated PGF2 alpha secretion to the same extent as oxytocin. Neither basal nor stimulated PGF2 alpha release was affected by the calcium ionophore A23187 (0.1-5.0 microM). However, PGF2 alpha secretion was sensitive to cycloheximide (1 microgram/ml) suggesting that protein synthesis may be involved. In conclusion, these data suggest that the stimulation of PGF2 alpha by oxytocin is via the protein kinase C effector pathway.     

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.     

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.     

Fertilization rate after synchronization of the oestrous cycle in heifers with prostaglandin F2alpha.

Oestrus was synchronized in 31 heifers by the intrauterine administration of PGF₂α than salt. Nineteen were given 2 doses of 0.5mg 24 hr apart, and 10 of these received 1500 I.U. of PMSG i.m. 24 hr before the treatment with PGF₂α. The remaining 12 heifers in the experiment were given a single dose of 2mg followed at the beginning of oestrus by 1500 I.U. of HCG i.m. Of 9 heifers which received only the two doses of 0.5mg (Group 1), 7 were observed to have corpora lutea when slaughtered 56–72 hr after the onset of oestrus, and four fertilized eggs were recovered. In those which received PMSG before the double injection of PGF₂α(Group 2), 118 corpora lutea were observed at slaughter and 34 fertilized eggs were recovered. Each heifer which received a single injection of PGF₂α and HCG had a corpus luteum, and 9 fertilized eggs were recovered. Unovulated follicles were most commonly observed in the PMSG-treated heifers but they were also observed in the heifers given the double injection treatment. It was observed that in the two-injection treatments, whether or not given PMSG, time of ovulation relative to the onset of oestrus was variable, and eggs were found in the uterus before the expected time.     

Synchronization of estrus in beef heifers with a norgestomet implant and prostaglandin F2alpha

In a 5-year study (1973-1977), 281 cycling beef heifers were treated with a 7-day norgestomet (SC21009) ear implant and an intramuscular injection of prostaglandin F(2alpha) (PGF(2alpha)) at the time of implant removal or 24 hr before implant removal. Percentages of heifers in estrus by 36, 48, 60, 72, and 120 hr after implant removal were 32.4, 52.7, 71.6, 80.1, and 93.2, respectively. Onset of estrus occurred an average of 49.8 +/- 4.7 hr after treatment. Percentages of heifers in estrus 36 hr after treatment were 5.7 and 51.7 for those with a corpus luteum and those without a corpus luteum (or determined regressing by palpation) at implant removal, respectively. When PGF(2alpha) was injected 24 hr before implant removal, 55% of the heifers were in estrus by 36 hr after implant removal compared to 30% when PGF(2alpha) was injected at the time of implant removal; however, by 60 hr after implant removal the difference was 76% vs. 71%. First-service conception rates for synchronized and nonsynchronized heifers were 62.2% and 59.6%, respectively. During 1976 and 1977 heifers were checked for estrus every 4 hr and inseminated 2, 6, 10, 14, 18, 22, 26, or 30 hr after first detected to be in standing estrus. Conception rate was not significantly affected by time of insemination but tended to be higher for heifers bred 26 and 30 hr after first being detected in standing estrus (78.9% and 70.0% vs. average 59.2%). Treatment with a 7-day norgestomet implant plus a single injection of PGF(2alpha) 24 hr before or at implant removal appears to be a practical technique for synchronizing estrus in cycling heifers without affecting conception.     

Direct inhibitory effect of progesterone on oxytocin-induced secretion of prostaglandin F(2alpha) from bovine endometrial tissue

The effect of progesterone on oxytocin-induced secretion of prostaglandin (PG) F(2alpha) from bovine endometrial tissue explants was examined. Endometrial tissue from the late luteal phase were preincubated for 20 h in control medium. Explants were then treated for 6 h with control medium, oxytocin (10(-7) M), progesterone (10(-5) M), or both hormones. Oxytocin increased the medium concentration of 13,14-dihydro-15-keto-PGF(2alpha), whereas progesterone completely suppressed the stimulatory effect of oxytocin. In experiment 2, isolated endometrial epithelial cells were incubated with progesterone (10(-5) M), oxytocin (10(-7) M), and combinations of these hormones with or without actinomycin D (1 ng/ml). Only oxytocin stimulated secretion of PGF(2alpha), and this response was suppressed by progesterone. Oxytocin induced a rapid increase in intracellular concentrations of Ca(2+) detected within 1 min of exposure of epithelial cells from the same cows. Progesterone pretreatment diminished this response. In experiment 3, direct effects of progesterone (2 nM-20 microM) on binding of (3)H-oxytocin to the membrane preparation from epithelial cells were determined by saturation analysis. Oxytocin binding was suppressed by progesterone at every dosage tested. Progesterone is capable of suppressing the ability of oxytocin to induce endometrial secretion of PGF(2alpha). This effect appears to be mediated through a direct interference in the interaction of oxytocin with its own receptor.     

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.     

Endothelin-1 stimulates prostaglandin F2 alpha release from human endometrium

Despite a key role in the pathogenesis of menorrhagia, the factors controlling the uterine vascular bed are poorly understood. This study has assessed the effects of the potent vasoconstrictor endothelin (ET)-1 on prostaglandin (PG) release from human endometrial explants in short-term culture. There was no significant difference between the production of PGF2 alpha in proliferative and secretory tissue (1709 and 2434 pg/mg/h--median values, range 70,3745 and 219,6700 pg/mg/h). Less PGE was released than PGF2 alpha, and the amount did not vary with the phase of the menstrual cycle (308 and 296 pg/mg/h (range 65,387 and 105,429) for proliferative and secretory tissue). ET-1 (10 and 100 nM) and arachidonic acid (AA, 30 microM), stimulated PGF2 alpha release from proliferative, but not secretory endometrium, by 78%, 86% (P less than 0.01) and 80% respectively, compared with control tissue. No effect was seen on PGE release. ET-1 may play a role in the local control of the endometrial vascular bed either directly, or via the release of PGF2 alpha.     

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.