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S J Lye

Publications and source records attributed to S J Lye.

At least 19 recordsLinked to original sources
PubMed1994

Localization of endoglin, a transforming growth factor-beta binding protein, and of CD44 and integrins in placenta during the first trimester of pregnancy.

Endoglin is an integral membrane glycoprotein that binds transforming growth factor-beta 1 (TGF beta 1) with high affinity and is predominantly expressed on human endothelial cells. Characterization of this homodimeric protein from human term placenta has shown that it is particularly abundant on the syncytiotrophoblast. Immunofluorescence staining of sections of first trimester placenta now reveals that endoglin is found at even higher levels on the syncytiotrophoblast of samples ranging from 6 to 12 wk of gestation. Very low levels are observed on the undifferentiated cytotrophoblast cells that can be identified by their expression of the alpha 6 beta 4 integrin, a receptor for laminin. Within the villi, blood vessels and stromal cells are negative for endoglin but positive for alpha 1 beta 1 integrin, a receptor for collagens and laminin. Stromal cells also express CD44, a hyaluronic acid receptor. Of particular interest is the up-regulation of endoglin expression in the transition from polarized undifferentiated to non-polarized intermediate cytotrophoblasts (CTB) as the cells align in columns to invade the uterus. This occurs in parallel with the acquisition of alpha 5 beta 1 integrin (fibronectin receptor) and precedes the loss of alpha 6 beta 4 integrin. CD44 and alpha 1 beta 1 integrin are noticeably absent from the CTB within the columns but are expressed at very high levels throughout the placental bed. Endoglin is undetectable within the decidua; thus, intermediate CTB that have invaded the placental bed express alpha 5 beta 1 integrin and cytokeratins but not endoglin.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1992

Failure of ritodrine to prevent preterm labor in the sheep.

OBJECTIVES: The purpose of this study was to determine whether continuous infusion of ritodrine could prevent preterm delivery in sheep. STUDY DESIGN: Sheep in preterm labor induced by RU 486 (mifepristone) received infusions of either ritodrine (n = 5) or saline solution (n = 5), and the progress of labor was monitored. beta 2-Adrenergic receptor density and function (agonist-induced cyclic adenosine monophosphate production) was measured in myometrial samples from both groups. RESULTS: Ritodrine initially inhibited labor contractions. This inhibition was only maintained for 16 hours, after which both the amplitude and frequency of electromyographic bursts and contractions returned. The failure of the myometrium to respond to ritodrine (desensitization) was associated with significant reductions in agonist-induced cyclic adenosine monophosphate production and beta 2-adrenergic receptor concentration in myometrial tissue collected from these animals compared with the saline solution-treated controls. CONCLUSIONS: Continuous infusion of ritodrine to sheep in preterm labor produces only a transient inhibition of contractions. This desensitization is caused by a down-regulation of myometrial beta 2-adrenergic receptors.

Animals↗
PubMed1992

Evidence for an intrinsic control of myometrial contractile periodicity in sheep during pregnancy.

Reduction in concentration of prostaglandins in plasma by administration of sodium meclofenamate to pregnant sheep failed to alter the frequency or duration of electromyographic activity bursts or the response to oxytocin of myometrial tissue transplanted to the omentum. However, a significant (P < 0.05) delay (8.6 +/- 3.8 versus 1.3 +/- 0.3 min) in the myometrial response to oxytocin was observed when the hormone was administered 1 min after a spontaneous burst of electromyographic activity compared with 15 min after a burst, indicating a period of refractoriness. Similarly, the myometrial threshold for electrical stimulation was higher at 10-25% of the interval between contractions than close to the expected time of the next contraction. Stimulation of the myometrium at intervals of 30 s revealed a cycling of the electrical stimulation threshold: significantly higher voltages were required to elicit responses between spontaneous bursts of electromyographic activity (18.0 +/- 2.2 V) than during bursts (11.3 +/- 1.6 V). In contrast, there was no voltage differential in animals close to labour (< 24 h). These data provide no evidence to support a role for prostaglandins in the generation of contractions during pregnancy, but suggest that periodicity of contractions is associated with inherent changes in myometrial responsiveness to stimulation, which could occur as a result of a cycling of the resting membrane potential.

Animals↗
PubMed1991

Purification and characterization of pregnant sheep myometrium myosin light chain kinase.

Myosin light chain kinase (MLCK) has been purified from the myometrium of pregnant sheep. The Mr of the enzyme was determined from SDS-polyacrylamide gels to be 160,000. It requires Ca2+ and calmodulin for activation, and phosphorylates the 20,000-Da light chains of myosin at a rapid rate. The specific activity for the myosin light chains from turkey gizzards and rabbit uterine muscle are 7.7 and 5.4 mumol/min/mg, respectively. The Km for the former substrate is 40 microM and the Vmax of the reaction is 19 mumol/min/mg. Polyclonal antibodies raised against the enzyme cross-reacted with pregnant sheep myometrium (psm), turkey gizzard (tg), and chicken gizzard MLCK. Affinity purification of the antibodies on tg-MLCK Sepharose resulted in the preparation of two fractions of antibodies with different reactivity toward these proteins. Fraction A antibodies which did not bind to the affinity column cross-reacted only with psm-MLCK while Fraction B antibodies which bound to the column cross-reacted with all three proteins. Western blots of extracts of turkey gizzards, human myometrium, and various tissues from sheep showed cross-reactivity of both fractions of antibodies with a 160,000-Da protein in the extracts of sheep smooth muscles. Only Fraction B antibodies cross-reacted with a protein (130,000 Da) in turkey gizzards and human myometrium extracts. Prolonged tryptic digestion of psm-MLCK produced large fragments Mr approximately 60,000 which appears to be similar to that formed from tg-MLCK, and some smaller peptides. Fraction A antibodies cross-reacted with the small peptides while Fraction B antibodies cross-reacted with the large fragments but not vice versa. Further analysis of the tryptic peptides suggests that the epitopes of Fraction A antibodies are localized in a peptide which appears to be in the NH2-terminal region of the molecule.

Animals↗
PubMed1990

Characterization of myometrial desensitization to beta-adrenergic agonists.

Continuous exposure of ovine myometrial strips exposed to isoproterenol (10 microM) resulted in only transient inhibition with contractions returning within 60 min. Rechallenging these strips with isoproterenol failed to induce inhibition, confirming the occurrence of desensitization. In contrast, exposure of myometrial tissue to isoproterenol for only 5 min did not result in desensitization. Myometrial strips exposed to isoproterenol demonstrated a significant increase in cAMP content associated with inhibition of contractile activity and a subsequent fall in cAMP content upon desensitization. Elevation of endogenous cAMP levels by either inhibition of cAMP-dependent phosphodiesterase activity (0.5 mM isobutylmethylxanthine, in ovine strips) or direct activation of adenylyl cyclase (10 microM forskolin, in rat strips) induced a rapid and significant inhibition of myometrial contractile activity in desensitized tissue. Scatchard analysis of the binding of the beta-adrenoceptor antagonist, [125I]iodocyanopindolol, revealed a significant reduction in the concentration of beta-adrenergic receptors (but no change in binding affinity) in desensitized myometrial tissue. Incubation of desensitized tissue with fresh buffer for 3 h induced only a partial recovery in responsiveness to isoproterenol. These data suggest that prolonged, but not acute, exposure of the myometrium to beta-adrenergic agonists induces a state of desensitization that is associated with a down-regulation of beta-adrenoceptors but maintenance of postreceptor function.

Adrenergic beta-Agonists↗
PubMed1990

Local and systemic control of myometrial contractile activity during labour in the sheep.

The relative contribution of systemic versus local (intrauterine) factors in the activation and stimulation of the sheep myometrium during labour was examined using an in-vivo myometrial explant preparation. Myometrial tissue alone (MYO) or with attached endometrium (ENDO/MYO) was removed from the pregnant uterine horn, sutured to a stainless-steel frame and placed into the omental fat. After 7-10 days the explants developed a pattern of electromyographic activity qualitatively similar to that of the uterine myometrium. Induction of preterm labour by infusion of ACTH (66.6 ng/min for 15 min every 2 h) to the fetus resulted in a reduction in plasma progesterone concentrations and increases in values of oestradiol-17 beta and 13,14-dihydro 15-keto PGF-2 alpha in maternal plasma. The onset of labour, which followed these endocrine changes, was characterized by an increase in EMG burst frequency and reduction in burst duration occurring simultaneously in both the uterine myometrium and in the explants. The response of the uterine and explant myometrium to oxytocin also exhibited a parallel significant increase over the 24-h period leading to delivery. No differences were apparent between the explants containing myometrial tissue alone or those comprising endometrial and myometrial tissue. There was no significant change in uterine or explant EMG activity, or oxytocin responsiveness, after saline administration to the fetus. The pattern of EMG activity changes during spontaneous labour were not distinguishable from those during ACTH-induced labour. As with oxytocin, the responsiveness of the explants to electrical stimulation increased significantly at labour compared to pre-labour. These data suggest that factors within the systemic circulation play a major role in both the onset of labour contractions and the increased response to electrical or hormonal (oxytocin) stimulation during parturition in sheep.

Adrenocorticotropic Hormone↗
PubMed1988

Discordant accelerated pulmonary maturation after adrenocorticotropic hormone-induced labor in twin sheep fetuses.

To examine the role of parturition on lung maturation in sheep, we studied parameters of lung development in singleton fetuses treated with pulsatile adrenocorticotropic hormone or saline solution from day 127 or twin pregnancies in which one fetus only received pulsatile adrenocorticotropic hormone from day 127 until labor occurred. These parameters were compared with those of term fetuses (145 days). Pulsatile adrenocorticotropic hormone provoked labor in a mean (+/- SEM) of 102.6 +/- 6.6 and 181.0 +/- 18.0 hours in single and twin pregnancies, respectively. Adrenal/body weight ratios increased similarly in adrenocorticotropic hormone-treated single and twin fetuses at delivery, and basal cortisol levels were two- to threefold higher prepartum in adrenocorticotropic hormone-treated fetuses. Little change in plasma cortisol levels occurred in singletons treated with saline solution or in twins not infused with adrenocorticotropic hormone. The lung weight/body weight was not altered in any group. Lung distensibility and stability were doubled to term values in fetuses treated with pulsatile adrenocorticotropic hormone compared with controls and untreated twins. Mean lavage phosphatidylcholine levels rose from 0.07 to 0.11 mg/gm in saline solution-treated or untreated fetuses to 0.20 to 0.23 mg/gm in pulsatile adrenocorticotropic hormone-treated singletons or twins, compared with 0.63 mg/gm at term. Phosphatidylcholine production increased from 0.51 dpm/gm/hr in saline solution-treated fetuses to 0.73 and 0.89 dpm/gm/hr in the single and twin pulsatile adrenocorticotropic hormone-infused fetuses, respectively; phosphatidylcholine production was 0.62 dpm/gm/hr in the noninfused twin. Lungs of twins treated with pulsatile adrenocorticotropic hormone were morphologically more mature than those of untreated twins. We conclude that fetal endocrine responses to exogenous adrenocorticotropic hormone, rather than the stimuli associated with labor per se, are responsible for lung maturation in the fetal sheep.

Adrenocorticotropic Hormone↗
PubMed1988

The effects of pulsed adrenocorticotropin1-24 administration to one twin on the endocrine and uterine activity changes during twin pregnancy in sheep.

To test the hypothesis that systemic endocrine events are of more importance than local intrauterine endocrine changes in the control of myometrial activity at labor, we examined the endocrine changes and development of uterine activity in chronically catheterized twin fetal sheep during administration of adrenocorticotropin1-24 (ACTH1-24) to one of the twins. Fetal and maternal plasma cortisol, progesterone, estrone, prostaglandin E2 (PGE2) and 13, 14 dihydro 15-keto prostaglandin F2 alpha (PGFM) were measured before and during pulsatile administration of ACTH1-24 (1 microgram infused over 15 min, every 2 h; P-ACTH) to one fetus in each of six twin pregnancies until parturition was initiated. In all cases, each fetus was in a separate uterine horn. The same hormone measurements were made in each co-twin that remained untreated. Intrauterine pressure and electromyographic activity of each uterine horn were monitored continuously throughout the study. In ewes pregnant with twins, the onset of active labor occurred after a mean infusion interval of 204.0 +/- 29.5 h (SEM), which is considerably longer than has been reported for singleton pregnancies. In the P-ACTH-infused twin, birth was preceded by a progressive rise in plasma cortisol beginning 24 h after the start of infusion. This was followed by a later rise in plasma estrone and PGE2, and by a decline in plasma progesterone. In the uninfused twin, delivery was preceded by a small rise in plasma cortisol that was concomitant with a rise in the concentration of cortisol in the maternal circulation. The concentrations of estrone and progesterone in the uninfused twin did not change significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Ovine fetal urachus--physiological and hormonal control of its contractile activity.

We have investigated whether the ovine fetal urachus near term has the potential to regulate the passage of urine from the bladder into the allantoic cavity. Experiments were performed primarily on longitudinal urachal muscle. In Krebs bicarbonate buffer (pH 7.4 bubbled with 95% O2-5% CO2 at 37 degrees C) the urachus spontaneously developed a prolonged elevated resting tension (RT, 1.1-1.5 g). Intra-abdominal urachus showed a greater development of tension than extra-abdominal urachus, which was associated with the amount of smooth muscle observed in histological specimens. Isoproterenol (1 microM) produced a significant reversible reduction in RT (1.36 +/- 0.15 to 0.67 +/- 0.08 g, P less than 0.01, mean +/- SE). Replacement of normal-O2 buffer (PO2 420.4 +/- 19.5 mmHg) with a low-O2 buffer (PO2 101.3 +/- 4.7 mmHg), or very low-O2 buffer (PO2 38.2 +/- 2.2 mmHg) while maintaining PCO2 and pH constant, produced a reduction in RT (from 1.35 +/- 0.21 to 0.52 +/- 0.13 g and from 1.20 +/- 0.17 to 0.46 +/- 0.04 g, respectively; both P less than 0.01). This effect was reversed when high PO2 was reinstated. Circular muscle showed a similar response when PO2 was reduced. The urachus showed a significant increase in RT (0.74 +/- 0.08 to 1.71 +/- 0.28 g, P less than 0.01) when prostaglandin F2 alpha (PGF2 alpha; 10 microM) was added to the low-O2 buffer. These results demonstrate that the urachus can develop spontaneous contractile activity and responds to alterations in O2, a beta-agonist, and PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

An in-vivo model to examine the electromyographic activity of isolated myometrial tissue from pregnant sheep.

Strips (2.5 x 3.5 cm) of myometrium alone (MYO) or endometrium/myometrium (ENDO/MYO) were removed from the pregnant horn of sheep (Day 110 of gestation) and transplanted to sites within the omental fat. These explants developed regular bursts of electromyographic (EMG) activity over a period of 7-10 days, as well as a dose-dependent stimulatory response to oxytocin (50-200 mU i.v.). The frequency (per 2 h) of EMG bursts in the MYO (5.3 +/- 0.2) and ENDO/MYO (5.2 +/- 0.3) explants was significantly greater (P less than 0.05) than that of the uterine myometrium (3.0 +/- 0.1), while burst duration (min) in MYO (4.1 +/- 0.2) and ENDO/MYO (4.1 +/- 0.2) explants was significantly (P less than 0.05) less than in the uterine myometrium (7.3 +/- 0.1). The EMG bursts were asynchronous between the explants and uterus, although systemic administration of oxytocin produced a synchronous burst of EMG activity in all three tissues. No differences in EMG activity or responsiveness were apparent between MYO and ENDO/MYO explants. Histological examination of the explant tissue revealed the presence of smooth muscle fibres regularly orientated into two layers; some loss of endometrial tissue was apparent in ENDO/MYO explants. To validate the mechanical integrity of this model we examined the in-vitro contractile activity of myometrial strips prepared from the explants. The strips developed regular spontaneous contractions and demonstrated a dose-dependent stimulation in response to the addition of oxytocin (10(-10) to 10(-4) M) to the bath fluid. These results suggest that spontaneous contractures during pregnancy are probably not due to pulsatile release of stimulants into the systemic circulation, or the direct diffusion of stimulants from intrauterine tissues to the myometrium but are probably caused by factors within the myometrium itself.

Animals↗
PubMed1987

Beta-adrenergic receptor agonist infusion increases plasma prostaglandin F levels in pregnant sheep.

Recent evidence of a stimulatory effect of beta-adrenergic receptor agonists on prostaglandin production by human fetal membranes in vitro prompted us to investigate whether prostaglandins are increased during beta-agonist infusion in vivo. On days 120 to 125 of gestation, blood samples were drawn from the aorta and vena cava of five crossbred ewes at 15-minute intervals for 1 hour before, during, and for 1 hour after a 3-hour infusion of isoproterenol (0.16 microgram/kg/min) or normal saline solution. Plasma prostaglandin F2 alpha levels increased (177% +/- 13% SEM over baseline; p less than 0.002) in maternal aorta, while plasma 13,14-dihydro-15-keto prostaglandin F2 alpha levels increased in both aorta and vena cava (354% +/- 47% and 309% +/- 75% over baseline, respectively; p less than 0.002) during isoproterenol infusion but not during saline solution infusion. No change was seen in plasma prostaglandin E2 levels. The increase in plasma stimulatory prostaglandins in the pregnant ewe during beta-agonist infusion is compatible with the increased uterine activity observed after myometrial desensitization by continuous beta-agonist infusion.

Adrenergic beta-Agonists↗
PubMed1987

Effects of beta-adrenergic agonist infusions on myometrial activity and plasma prostaglandin levels in the nonpregnant sheep.

Recent studies have reported that beta-adrenergic agonists stimulate the production of stimulatory prostaglandins (PGs) by intrauterine tissues in vitro. These drugs are used clinically to inhibit uterine contractions; consequently an increase in stimulatory PGs in vivo might have potentially adverse effects. We have, therefore, investigated whether beta-adrenergic agonists increase plasma PG concentrations in vivo. Samples of peripheral (aorta) and uterine venous enriched (vena cava) blood from nonpregnant sheep were collected at 15-min intervals for 1 h before, 3 h during, and 1 h postinfusion of either (a) the beta-adrenergic agonist isoproterenol (Isop) at a dose of 0.16 microgram.kg-1.min-1; (b) Isop at a dose of 0.08 microgram.kg-1.min-1; or (c) saline, 1 mL/h via a jugular vein catheter. The sheep were also equipped with intrauterine recording balloons to record intrauterine pressure and myometrial electromyographic (EMG) electrodes to measure EMG activity. Infusion of Isop at 0.16 microgram.kg-1.min-1 produced a significant initial inhibition of uterine activity, although contractions returned (within 60 min) despite continued administration of Isop. Plasma PGE2 (but not PGF2 alpha or 13,14-dihydro-15-keto-PGF2 alpha (PGFM] concentrations were significantly elevated during the Isop infusion. Administration of Isop at 0.08 microgram.kg-1.min-1 produced no effects on uterine contractile activity but was associated with a significant elevation in plasma PGE2 (but not PGF2 alpha or PGFM) concentrations. No changes in plasma PGE2, PGF2 alpha, or PGFM occurred during saline infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1987

The relationship between fetal breathing movements and prostaglandin E2 during ACTH-induced labour in sheep.

We measured fetal breathing movements and fetal carotid arterial prostaglandin E concentrations during adrenocorticotrophin-induced labour in 6 pregnant sheep and in 6 control animals starting at day 127. The 6 ACTH-treated animals went into labour on average 97 h after the onset of infusion and the incidence of fetal breathing movements diminished during the last 12h before the onset of labour. There was a significant negative relationship between the incidence of fetal breathing movements and fetal carotid arterial prostaglandin E concentrations (r = -0.88; P less than 0.001) in ACTH treated animals. These data suggest a role for prostaglandin E in the diminution of fetal breathing movements prior to the onset of labour.

Adrenocorticotropic Hormone↗
PubMed1986

Myometrial desensitization to continuous but not to intermittent beta-adrenergic agonist infusion in the sheep.

Infusion of the long-acting beta-adrenergic agonist ritodrine (3 micrograms/kg/min) caused by rapid inhibition of uterine activity in the ovariectomized, nonpregnant sheep. This inhibition could only be maintained for 6.4 +/- 0.8 hours, with high-frequency activity returning by 11.4 +/- 2.6 hours despite continuous infusion of ritodrine. Intermittent administration of ritodrine did not prolong uterine relaxation, probably as a consequence of its long half-life. Continuous infusion of the short-acting beta-agonist isoproterenol (0.16 micrograms/kg/min) initially inhibited uterine contractions but high-frequency activity returned by 50 minutes. In contrast, intermittent infusion of isoproterenol (30 minutes on and 30 minutes off) significantly inhibited the frequency of contractions during each of the infusion periods for the duration of the study (13 hours). Our data demonstrate that either continuous administration of beta-agonists or intermittent administration of the long-acting beta-agonist ritodrine resulted in myometrial desensitization in the sheep. In contrast, intermittent administration of the short-acting beta-adrenergic agonist isoproterenol prevented the onset of myometrial desensitization.

Adrenergic beta-Agonists↗
PubMed1986

Ovine fetal adrenal maturation at term and during fetal ACTH administration: evidence that the modulating effect of cortisol may involve cAMP.

Exogenous ACTH1-24 promotes adrenal maturation in fetal sheep, and this effect appears to be modulated in part by cortisol (Challis et al. 1985). We have examined whether similar changes in adrenal metabolism of progesterone occur with ACTH-induced labour as at spontaneous term and whether the site of cortisol modulation is on adrenal steroidogenesis or at the level of cAMP generation. Chronically catheterized fetal sheep were infused in utero for 100 h between days 127 and 131 of pregnancy with P-ACTH, P-ACTH + metopirone, P-ACTH + metopirone + cortisol, or saline. After 100 h the metabolism of [3H]progesterone was measured in adrenal homogenates. Similar incubations were performed with adrenal tissue from fetal sheep at day 130 of pregnancy and at spontaneous labour. In the treatment groups of sheep, cAMP output by dispersed adrenal cells in response to ACTH added in vitro was also determined. Similar qualitative patterns of [3H]progesterone metabolism were found in adrenal homogenates after in vivo ACTH or at term. At both times there was an increase in cortisol and in total 17 alpha-hydroxycorticosteroid accumulation and also evidence for increased activity of 11 beta-hydroxylase enzyme. The formation of total 17 alpha-hydroxycorticosteroids was not affected significantly by concurrent treatment in vivo with metopirone +/- cortisol. The accumulation of cAMP in vitro was increased after in vivo ACTH, attenuated after ACTH + metopirone, but statistical significance over controls was restored after ACTH + metopirone + cortisol treatment. We conclude that ACTH-induced labour and spontaneous parturition in sheep is associated with qualitatively similar changes in progesterone metabolism by the fetal adrenal gland.(ABSTRACT TRUNCATED AT 250 WORDS)

17-Hydroxycorticosteroids↗
PubMed1986

Prostaglandin concentrations in ovine maternal and fetal tissues at late gestation.

Maternal and fetal sheep organs were measured for their concentrations of prostaglandins (PG) E2, F2 alpha, 13,14-dihydro-15-keto PGF2 alpha (PGFM), 6-keto PGF1 alpha (hydrolysis produce of PGI2), and 6-keto PGE1 (enzymatic product of PGI2) by radioimmunoassay at day 131 of pregnancy (0.90 gestation). It was observed that the concentrations of PGFM were greater (p less than 0.01) in maternal endometrium than in any other maternal tissue or any other PG measured in endometrium. The lowest concentrations of PG in maternal tissues were in the myometrium, while PGE2 and 6-keto PGF1 alpha were present in maternal lungs in high concentrations. Fetal prostaglandin concentrations were high in the chorioallantois, fetal portion of the cotyledons and amnion, while they were very low in the kidney, liver, and lung. Fetal lung concentrations were lower than maternal lung concentrations (p less than 0.01) for all PG measured. In fetal aorta and ductus arteriosus, 6-keto PGF1 alpha concentrations were significantly greater (p less than 0.05) than all other measured PG, while in umbilical artery and vein 6-keto PGF1 alpha levels were equal to PGE2 levels. 6-Keto PGE1 concentrations were consistently among the lowest in all tissues measured. These results suggest that the endometrium may serve as a metabolic barrier to PG diffusing from the chorioallantois to the myometrium, that the capacity of pulmonary tissue to produce PG may increase with age, that the fetal membranes and cotyledons may be one major source of circulating PG in the fetus, and that 6-keto PGF1 alpha is the major metabolite of PGI2 in ovine tissues.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Androstenedione metabolism in the late gestation sheep fetus.

We have determined metabolic parameters for androstenedione (A) in chronically catheterized late gestation (day 130) sheep fetuses. The MCR (MCRA) was 3210 +/- 229 (SEM, n = 12) ml/min, the fetal arterial whole blood concentration of A [A] was 65 +/- 5 pg/ml, and the blood production rate (PRA) was 204 +/- 20 ng/min. Pulsatile administration of ACTH in amounts that raised fetal arterial plasma cortisol concentrations by 5- to 7-fold increased [A] to 154 +/- 20 pg/ml and PRA to 471 +/- 31 ng/min with no change in MCRA. In the presence of metopirone to block fetal adrenal cortisol output, ACTH treatment still provoked elevations in [A] (to 198 +/- 23 pg/ml) and PRA (539 +/- 158 ng/min), without altering MCRA. The major radiolabeled product in blood of infused [3H]A was [3H]testosterone; smaller amounts of phenolic steroids were formed. Extensive metabolism of [3H]A occurred in whole blood in vitro. The major product was [3H]testosterone; the 17-oxidoreductase activity was associated with the red blood cells. Umbilical vein [A] was greater than umbilical artery [A]; ACTH treatment increased [A] in both vessels. Concomitant metopirone abolished the arteriovenous difference by eliminating the ACTH-induced increase in venous [A], although arterial [A] rose significantly. The venous [A] and the arteriovenous gradient were restored with exogenous glucocorticoid treatment to the fetus. Collagenase-dispersed fetal adrenal cells secreted A. Adrenal cells from fetuses pretreated with ACTH in vivo had higher basal and ACTH-induced output of A in vitro than cells from fetuses pretreated with saline in vivo. We conclude that the MCRA in fetal sheep is extremely high, in part due to conversion of A to testosterone in fetal blood. The elevated PRA after ACTH plus metopirone and the lack of an umbilical arteriovenous gradient of [A] in this, but not other groups of fetuses, suggests a source of A production independent of the cortisol-induced changes in the placenta. Direct evidence is provided for fetal adrenal secretion of A which is enhanced by ACTH pretreatment of the fetus in vivo and for the utilization of circulating A in the fetus as a precursor for estrogen in both fetal and maternal compartments.

Adrenal Glands↗