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Biomedical subjects

J R Challis

Publications and source records attributed to J R Challis.

At least 199 records · Page 11Linked to original sources
PubMed1985

Possible role of uterine contractions in the short-term fluctuations of plasma ACTH concentration in fetal sheep.

Uterine contractions, induced by the administration of oxytocin to sheep between d 123-144 of pregnancy, were associated with a mean transient decrease in fetal PaO2 of 2.8 mm Hg within 5 min. These changes were associated with a rapid increase in the concentration of ACTH in fetal plasma. There was a significant (P less than 0.05) increase in the percentage change (+40 to +47%) over basal ACTH levels in fetal plasma at +5, +15 and +20 min after oxytocin. Administration of saline had no significant effect on intrauterine pressure, fetal PaO2 or fetal plasma ACTH levels. We speculate that increases in uterine activity and/or transient decreases in fetal PaO2 may contribute to short-term fluctuations in plasma ACTH in fetal sheep.

Adrenocorticotropic Hormone↗
PubMed1984

Adrenocorticotropic activity of an extract from sheep placental tissue at term.

We have performed experiments to determine possible adrenocorticotropic activity in placental tissue of a sheep at term. The placental tissue was homogenized and extracted with 0.1 mmol/L of ammonium bicarbonate. The adrenocorticotropic activity of the term placental extract was compared to that of the vehicle (saline solution) and synthetic adrenocorticotropic hormone (ACTH). A single bolus injection of term placental extract had no significant effect on the plasma concentration of cortisol or progesterone. In a separate protocol, a bolus injection of ACTH was administered before and after a 48-hour continuous infusion of term placental extract, ACTH, or saline solution. The infusion of term placental extract or ACTH caused a significant increase in the basal cortisol and progesterone concentrations and a greater progesterone response following the second ACTH bolus. In vitro, the isolated adrenal cells from the term placental extract- and ACTH-infused animals showed a significantly greater ability to produce cortisol in the presence of exogenous substrate and ACTH. We concluded that placental tissue from sheep at term contains a substance which, when infused in vivo, has a corticotropic effect on the adrenal glands.

Adrenal Glands↗
PubMed1984

Relation between fetal arterial PO2 and oxytocin-induced uterine contractions in pregnant sheep.

The relation between oxytocin-induced type A uterine contractions and fetal arterial PO2, measured continuously with an intravascular oxygen electrode, was studied in nine chronically catheterized sheep during late pregnancy. Oxytocin provoked dose-related increases in intrauterine pressure (IUP) and decreases in fetal PaO2. There was a significant positive relationship between changes in IUP and the maximum decrease in fetal PaO2 (average r = 0.696, df = 92; P less than 0.001). We conclude that changes in uterine activity contribute to transient fetal hypoxemia, and that administration of exogenous oxytocin provides an experimental paradigm to examine the consequences of this relationship.

Animals↗
PubMed1984

In vivo adrenocorticotropin (1-24)-induced accumulation of cyclic adenosine monophosphate by ovine fetal adrenal cells is inhibited by concomitant infusion of metopirone.

Activation of the ovine fetal adrenal gland after pulse ACTH (P-ACTH) administration is associated with an increase in plasma cortisol levels. We have investigated whether cortisol may play a role in this adrenal activation process. The ability of fetal adrenal cells to accumulate cAMP in response to ACTH in vitro was compared in fetuses (day 132 of gestation) that had received infusions (100 h) in utero of 1) saline or saline + tartrate (0.5 ml for 15 min/2 h) (n = 4); 2) P-ACTH (66.6 ng/min for 15 min/2 h) (n = 4); 3) P-ACTH + metopirone (31.3 mg/h) (n = 4), to inhibit 11 beta-hydroxylase activity. Control fetuses showed no significant increase in plasma cortisol levels throughout the infusion and there was no significant accumulation of cAMP by fetal adrenal cells in vitro in response to ACTH. There was a significant (P less than 0.05) increase in plasma cortisol concentrations from 2.21 +/- 0.47 (mean +/- SEM) ng/ml at 0 h to 35.7 +/- 11.6 ng/ml at 96 h in fetuses receiving P-ACTH in vivo. In these fetuses there was a significant (P less than 0.05) accumulation of cAMP after addition of ACTH by fetal adrenal cells in vitro (mean increment delta = 48 pmol). This rise in plasma cortisol was prevented in fetuses receiving P-ACTH + metopirone. Further, metopirone treatment prevented the increase in fetal adrenal weight and accumulation of cAMP after in vitro ACTH that normally followed ACTH treatment in vivo. This effect was not overcome by further addition of guanylylimido-diphosphate. These experiments raise the possibility that cortisol might mediate the increase in cAMP accumulation resultant upon in vivo P-ACTH treatment.

1-Methyl-3-isobutylxanthine↗
PubMed1984

Formation of unconjugated estrogens from estrone sulfate by dispersed cells from human fetal membranes and decidua.

Experiments were performed to determine the ability of isolated cells from human amnion, chorion, and decidua to hydrolyze estrone sulfate (E1S) to free estrone (E1) and estradiol (E2). Tissues were obtained from eight women after spontaneous onset of labor and vaginal delivery and from eight women undergoing elective cesarean section at term before the onset of labor. The tissues were obtained immediately after delivery, dispersed into isolated cell preparations using 0.05% collagenase, and incubated in Krebs-Ringer bicarbonate at 37 degrees C for 4 h. E1 and E1S were measured by specific RIAs. All three tissues from both patient groups produced E1 and E2 in a dose-dependent fashion from the E1S precursor. In both patient groups, chorion and decidua cells produced significantly more E1 and E2 than amnion cells. The chorion cells from the spontaneous labor group produced significantly more E1 than chorion cells from the cesarean section group. The chorion and decidua cells from the spontaneous labor group produced significantly more E2 than corresponding cells from the cesarean section group. The hydrolysis of E1S to E1 and E2 was significantly inhibited in a dose-dependent fashion by increasing concentrations of oxytocin and (Bu)2cAMP. Dispersed cells from amnion, chorion, and decidua also converted [3H]E1S to radiochemically pure [3H]E1. Chorion and decidua cells were significantly more active in this respect than amnion. The presence of excessive amounts of dehydroepiandrosterone sulfate (DHAS) did not significantly alter this reaction. All three tissues also hydrolyzed [3H]dehydroepiandrosterone sulfate, but in chorion and decidua, this activity was significantly less than the hydrolysis of [3H]E1S. We conclude that human amnion, chorion, and decidua possess the capability to hydrolyze E1S to free estrogen and that this activity in chorion and decidua is increased after spontaneous vaginal delivery. It is possible that this activity and its regulation are important factors in the local synthesis of free estrogen, which, in turn, may influence myometrial contractility.

Adult↗
PubMed1984

Comparison of leucine enkephalin and adrenocorticotrophin effects on adrenal function in fetal and adult sheep.

At Day 120-125 of gestation equimolar amounts of ACTH and leu-enkephalin injected in vivo provoked similar rises in plasma cortisol concentrations in chronically catheterized fetuses. There was no concomitant change in plasma DHEA concentrations, or in maternal cortisol concentrations. At term (Days 135-140) 2 out of 5 animals responded similarly to both leu-enkephalin and ACTH injections with a rise in plasma cortisol concentrations, but the other 3 animals, in which basal cortisol concentrations had already risen, showed no response to either agonist. In adult sheep, ACTH provoked a significant increase in the plasma cortisol concentrations, but equimolar amounts of leu-enkephalin were without effect. There was a significant output of cortisol in response to ACTH administration by collagenase-dispersed adrenal cells from term sheep fetuses in vitro. Leu-enkephalin had no effect on cortisol output from dispersed adrenal cells when added by itself, or with ACTH. We conclude that leu-enkephalin is able to function as a stimulator of pituitary-adrenal function during fetal life. The lack of effect of leu-enkephalin on adrenal cells implies that its action is exerted not directly at the adrenal gland, but indirectly at the level of the hypothalamus or pituitary through stimulation of the release of other corticotrophic substances.

Adrenal Glands↗
PubMed1984

Early changes in prostaglandin concentrations in ovine maternal and fetal plasma, amniotic fluid and from dispersed cells of intrauterine tissues before the onset of ACTH-induced pre-term labour.

The changes with time in intrauterine tissue production and concentrations of PGE-2, PGF-2 alpha, 6-keto PGF-1 alpha and PGFM (13,14-dihydro-15-keto PGF-2 alpha) in maternal and fetal plasma and amniotic fluid were investigated during the first 72 h of pulsatile administration of ACTH1-24 to chronically catheterized fetal sheep. By 72 h there were no changes in the frequency, maximum amplitude or duration of uterine contractions compared to preinfusion values. Basal concentrations of PGE-2 in maternal and fetal plasma were generally higher than those of PGF-2 alpha, while 6-keto PGF-1 alpha values were intermediate. The concentrations of all PGs increased in amniotic fluid during ACTH infusion. In fetal plasma and in maternal vena caval plasma, however, there were significant increases only in PGF-2 alpha and PGFM. No changes were observed in plasma concentrations for any PG during saline infusion. The mean output of PGE-2, PGF-2 alpha and 6-keto PGF-1 alpha by dispersed cells prepared from chorioallantois and fetal and maternal cotyledons was consistently higher after ACTH for 72 h than from saline-infused animals, although significance (P less than 0.05) was achieved only for PGE-2 in chorioallantois . There are 3 conclusions. (1) Increases in ovine intrauterine tissue PG production precede the occurrence of increased myometrial contractile activity after ACTH treatment of fetal sheep. The results imply a causal relationship between rising PG and later myometrial contractions, rather than PG changes resulting from enhanced uterine activity. (2) The major site(s) of increased PG output in vitro from endogenous precursors are fetal structures, especially the chorio-allantoic membranes. (3) Although PGE-2 may be the major circulating PG during late gestation, there is a selective increase in plasma PGF-2 alpha concentrations before the onset of delivery.

Adrenocorticotropic Hormone↗
PubMed1984

Effects of naloxone on the breathing, electrocortical, heart rate, glucose and cortisol responses to hypoxia in the sheep fetus.

Continuous infusions of naloxone HC1 (0.5 mg/kg or 3.8 mg/kg) or saline were given intravenously to fetal sheep at 119 to 137 days of gestation during a one hour period of air administration and a one hour period of hypoxia induced by having ewes breathe 9% O2, 3% CO2 and 88% N2. Fetal carotid PaO2 fell to 13.0 +/- 0.5 mmHg during hypoxia with no change in pH. During hypoxia, plasma cortisol concentration increased significantly more in naloxone-infused fetuses than controls. Ewes, whose fetuses received naloxone, showed a significant increase in cortisol during hypoxia whereas no increase was observed in controls. There were no significant differences between saline and naloxone-infused fetuses during hypoxia in fetal breathing incidence, amplitude, frequency, number of deep inspiratory efforts per hour, heart rate, electrocortical activity or in the rise in plasma glucose caused by hypoxia. Results suggest that endogenous opiates may have a role in modulating cortisol production in the ewe and fetus during hypoxia but do not have a role in mediating the decrease in incidence of breathing activity or rise in plasma glucose. During air administration, naloxone significantly increased fetal breath amplitude, fetal and maternal plasma glucose, fetal heart rate, and the number of electrocortical changes per hour. This suggests endogenous opiates may have a more important role in the normoxic pregnant ewe and fetus.

Animals↗
PubMed1983

Steroid modulation of pregnenolone to progesterone conversion by human placental cells in vitro.

Studies were performed to examine the production of progesterone by human placental cells in vitro. Samples of placentas from 22 women at term after spontaneous onset of labor and vaginal delivery were utilized. The tissue was dispersed into isolated cells with the use of collagenase, and suspensions of these cells were incubated with pregnenolone as substrate in the presence or absence of other compounds which may regulate progesterone production. These cell preparations produced progesterone in a dose-related fashion with exogenous pregnenolone. The conversion of pregnenolone to progesterone occurred rapidly, with most of the conversion completed during the first hour of incubation. The conversion was inhibited by dehydroepiandrosterone, estrone, androstenedione, and testosterone (p less than 0.001 in all cases). The inhibitory effect of androstenedione and testosterone was not dependent on aromatization to estrogen. Dihydrotestosterone and 5 alpha-pregnanedione resulted in a significant increase in the amount of progesterone present (p less than 0.001). In preliminary experiments, gonadotropin-releasing hormone, salbutamol, and propranolol were without significant effect in this system. We conclude that this system is a useful model for studying progesterone production by human placental tissue, and that placental progesterone production may be significantly influenced by the presence of other steroid hormones.

Androstenedione↗
PubMed1983

Stimulation of ovine myometrial activity by 6-keto prostaglandin E1.

6-keto prostaglandin E1 (6KE) is a metabolite of PGI2, which we have shown previously inhibits spontaneous myometrial activity. In the present study we examined the effects of 6KE on uterine electrical and mechanical activity in non-pregnant ovariectomized sheep. 6KE stimulated uterine activity in a dose-dependent fashion. The effect was enhanced by pre-treatment with estradiol (E2). It was not influenced by pre-treatment with meclofenamic acid and was not associated with significant changes in the concentrations of 13,14 dihydro 15-keto PGF2 alpha in vena cava plasma. After E2 treatment, 6KE had 0.2-0.3 of the stimulatory activity of PGF2 alpha. In the absence of E2, the uterine response to both 6KE and PGF2 alpha was decreased. In animals in which spontaneous myometrial activity was inhibited by PGI2, the uterus remained responsive to 6KE. We conclude that in the ovariectomized non-pregnant sheep 6KE stimulates uterine activity, and that the effect is independent of endogenous PG production.

Alprostadil↗
PubMed1983

Estradiol-17 beta and 2-hydroxyestradiol-17 beta-induced differential production of prostaglandins by cells dispersed from human intrauterine tissues at parturition.

Prostaglandin (PGE, 6-keto PGF1 alpha) output by cells dispersed from human amnion and decidua in the presence of increasing levels (0-5000 ng/ml) of estradiol-17 beta (E2) or 2-hydroxyestradiol-17 beta (2-OH E2) was studied in relation to parturition. Tissues were obtained from women at term either before (CS) or after (SL) spontaneous labor and vaginal delivery. In the absence of estrogens, the output of both PGs from amnion increased significantly with labor. No significant increase in decidua PG output occurred with labor. Neither estrogen influenced CS amnion PG output. However, both E2 and 2-OH E2 stimulated SL amnion PGE output (2-OH E2 greater than E2) while having no affect on 6-keto PGF1 alpha output. Only the highest dose of 2-OH E2 stimulated PGE output in CS decidua, but both estrogens significantly inhibited 6-keto PGF1 alpha output in this tissue. In SL decidua only 2-OH E2 significantly stimulated PGE, and neither estrogen affected 6-keto PGF1 alpha output. These results might suggest that estrogens modulate PG biosynthesis at the level of endoperoxide to primary PG conversion.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Estradiol modulation of ovine uterine activity.

The effects of continuous estradiol-17 beta (E2) infusion (100 micrograms/24 h and 1 mg/24 h) on spontaneous myometrial activity and uterine responsiveness to oxytocin (OT) and prostaglandin (PG) F2 alpha were measured in nonpregnant sheep. Continuous recordings were made of intrauterine pressure (IUP) and uterine electromyographic (EMG) activity. Continuous E2 infusion resulted in an accentuated pattern of uterine quiescence alternating with periods of high activity lasting 6-8 h. Short (3-10 min) periods of elevated resting IUP and intense EMG activity increased in frequency after E2. E2 also increased the rate of rise of IUP cycles. Within 30 h of commencement of E2 infusion the uterine response to a bolus challenge of OT or PGF2 alpha increased significantly; dose-related responses to OT and PGF2 alpha were measured after 4 days E2 infusion. The response to OT was not abolished by infusing meclofenamic acid. We conclude that: (i) continuous E2 infusion results in a pattern of uterine activity characterized by alternating high activity and quiescence, and increased frequency of occasional rises in basal IUP; (ii) E2 induced increases in OT and PGF2 alpha responses are consistent with other reports that E2 increases OT and PGF2 alpha binding to myometrium; (iii) the E2 effect on OT response is probably independent of enhanced PG synthesis.

Animals↗
PubMed1983

Prostaglandin synthesis by human amnion is dependent upon extracellular calcium.

Prostaglandin (PG) E and F output was studied in collagenase-dispersed amnion cells to determine the effect of extracellular Ca2+ upon PG synthesis. In the presence of 2.5 mM CaCl2, PGE and PGF output (picograms per 10(5) cells per 3 h) by cells obtained at term prior to labour following elective cesarean section (CS) was 183 +/- 39 and 127 +/- 23, respectively. This increased to 435 +/- 111 (p less than 0.025) and 241 +/- 49 (p = 0.056) from cells obtained after spontaneous labour and delivery at term (SL). Exclusion of CaCl2 from the medium (plus 0.1 mM EGTA) significantly reduced (p less than 0.025) PGE output in CS and SL cells (83 +/- 22 and 183 +/- 47, respectively) and PGF output in CS cells (70 +/- 17). PGE output in both CS and SL cells was unchanged when CaCl2 concentrations in the medium were decreased from 2.5 to 0.25 mM, but significantly attenuated (p less than 0.01) when extracellular CaCl2 was decreased from 0.25 to 0 mM. The voltage-sensitive Ca2+ channel blocker, D-600, decreased PGE output in the presence of (2.5 mM) CaCl2 to levels observed in the absence of CaCl2. Ionophore A23187 restored PGE output in the presence of D-600 and Ca2+. PGE output from CS amnion cells was stimulated by A23187 and elevated extracellular K+ (40 mM). In each case, exclusion of CaCl2 from the medium eliminated the response. These results suggest that PG output by human amnion is dependent, in part, upon the presence of extracellular Ca2+ and that Ca2+ may enter the cell via a potential-sensitive mechanism.

Amnion↗
PubMed1983

Changes in the diurnal rhythms of plasma cortisol in women during the third trimester of pregnancy.

We have examined whether there are changes in the day-night variation in plasma cortisol in normal women during the third trimester of pregnancy. Maximum cortisol values at 07.30-10.30 h were similar at 30-31, 34-35 and 38-39 weeks of pregnancy. The daily increment in plasma cortisol (fold change) was greater, and the trough values lower at 30-31 than at 38-39 weeks. The time taken for plasma cortisol to fall to 50% of the morning maximum values was longer at 38-39 weeks than at 30-31 weeks of pregnancy. These changes in cortisol rhythms may have implications with respect to alterations in circadian patterns of maternal steroid concentrations as well as fetal biophysical functions.

Circadian Rhythm↗
PubMed1983

Relation between diurnal changes in peripheral plasma progesterone, cortisol, and estriol in normal women at 30-31, 34-35, and 38-39 weeks of gestation.

To determine the relation of diurnal changes in plasma progesterone to those in cortisol and estriol we measured the concentrations of progesterone, cortisol and estriol in samples of plasma taken at 30- to 60-min intervals throughout 24 h from women at 30-31, 34-35, and 38-39 weeks of gestation. Plasma progesterone showed a significant diurnal rhythm at 30-31 and at 34-35 weeks of pregnancy, with troughs at 04.30-10.00 h. Major peaks occurred between 15.30 and 02.30 h. There was no diurnal rhythm in progesterone at 38-39 weeks. Plasma progesterone showed a significant negative correlation with plasma cortisol at 30-31 and 34-35 but not at 38-39 weeks. Plasma progesterone showed a significant positive correlation with estriol at 34-35 and at 38-39 weeks. We suggest that daily fluctuations in plasma progesterone may be related to the concentration of plasma cortisol, either directly by competition for binding sites on transcortin, or indirectly after modulation of fetal pituitary-adrenal function by maternally derived glucocorticoid.

Circadian Rhythm↗
PubMed1983

Activation of ovine fetal adrenal function by pulsatile or continuous administration of adrenocorticotropin-(1-24). I. Effects on fetal plasma corticosteroids.

ACTH given as a continuous infusion to fetal sheep causes an increase in plasma cortisol concentrations and premature labor. However, the effects on fetal adrenal responsiveness in vivo and the mode of ACTH administration on plasma corticosteroids are unknown. We examined the effects on plasma corticosteroids of giving the same total amount of ACTH to fetal sheep in utero either as pulses (P-ACTH; 66.7 ng/min for 15 min every 2 h) or continuously (C-ACTH; 0.5 micrograms/h) for 72 h. We determined the changes in vivo in fetal adrenal responsiveness during P-ACTH treatment, and we examined the ability of continued P-ACTH administration to induce premature labor. Both modes of ACTH administration led to a significant (P less than 0.05) increase in the fetal plasma cortisol (F) concentration compared with that in saline-treated controls, but C-ACTH resulted in significantly higher (P less than 0.05) F values than P-ACTH treatment. There was a small increase in the F-binding capacity of fetal plasma during both P-ACTH and C-ACTH, but there was no difference in the cortisol-binding capacity between the two treatments. Twenty minutes from the start of P-ACTH, there was an acute elevation in plasma F to values similar to those found with C-ACTH administration. The magnitude of this response rose significantly (P less than 0.05) between days 1-4 of P-ACTH treatment. There was no significant change in fetal plasma corticosterone during either P-ACTH or C-ACTH, resulting in a 4- to 6-fold increase in the plasma F to corticosterone ratio of both groups. In animals in which P-ACTH treatment was continued beyond 72 h, fetal plasma F continued to rise, and premature labor occurred after 99.0 +/- 4.1 (+/- SE) h. Fetal adrenal weights were not significantly different between P-ACTH for 72 or 100 h or C-ACTH for 72 h, although in each of these groups, the glands were heavier than those in control fetuses. We conclude that activation of fetal adrenal function is demonstrable in vivo during P-ACTH administration. This is reflected by selective F hypersecretion and may lead to premature delivery.

Adrenal Glands↗