Evidence of a role for melatonin in fetal sheep physiology: direct actions of melatonin on fetal cerebral artery, brown adipose tissue and adrenal gland

Although the fetal pineal gland does not secrete melatonin, the fetus is exposed to melatonin of maternal origin. In the non-human primate fetus, melatonin acts as a trophic hormone for the adrenal gland, stimulating growth while restraining cortisol production. This latter physiological activity led us to hypothesize that melatonin may influence some fetal functions critical for neonatal adaptation to extrauterine life. To test this hypothesis we explored (i) the presence of G-protein-coupled melatonin binding sites and (ii) the direct modulatory effects of melatonin on noradrenaline (norepinephrine)-induced middle cerebral artery (MCA) contraction, brown adipose tissue (BAT) lypolysis and ACTH-induced adrenal cortisol production in fetal sheep. We found that melatonin directly inhibits the response to noradrenaline in the MCA and BAT, and also inhibits the response to ACTH in the adrenal gland. Melatonin inhibition was reversed by the melatonin antagonist luzindole only in the fetal adrenal. MCA, BAT and adrenal tissue displayed specific high-affinity melatonin binding sites coupled to G-protein ( K _d values: MCA 64 ± 1 p m , BAT 98.44 ± 2.12 p m and adrenal 4.123 ± 3.22 p m ). Melatonin binding was displaced by luzindole only in the adrenal gland, supporting the idea that action in the MCA and BAT is mediated by different melatonin receptors. These direct inhibitory responses to melatonin support a role for melatonin in fetal physiology, which we propose prevents major contraction of cerebral vessels, restrains cortisol release and restricts BAT lypolysis during fetal life.     

The proliferative status of haematopoietic progenitor cells in the developing murine liver and adult bone marrow

A class of primitive progenitor cells with high proliferative potential in vitro (HPP-CFC), has been identified in fetal liver and adult bone marrow both in murine and human systems. The kinetic properties of HPP-CFC₂ and the more mature granulocyte-macrophage colony forming units (CFU-GM) derived from murine fetal liver on d13, d15 and d19 of gestation, newborn liver and neonatal liver on d3 and d8 postpartum have been evaluated and compared with the kinetic properties of these progenitor cell populations derived from adult bone marrow. The frequency of HPP-CFC₂ in fetal liver was found to be greatest on d15 of gestation then subsequently declined in newborn and neonatal liver. Similarly, the highest proportion of HPP-CFC₂ engaged in DNA synthesis (53±3%) was detected in d15 fetal liver. This proportion decreased to 13±2% in the liver 1 wk after birth, which is comparable to the number of HPP-CFC₂ derived from adult BM which were in S-phase (10±1%). Production of CFU-GM was found to be greater in adult bone marrow than in either fetal or newborn liver. While the proportion of CFU-GM in S-phase was high in all 3 tissue samples, the greatest proportion of cycling CFU-GM (50±2%) was detected in d15 fetal liver. These results suggest that HPP-CFC₂ derived from fetal liver are actively cycling while HPP-CFC₂ derived from adult bone marrow are relatively quiescent. In contrast, a high proportion of CFU-GM derived from fetal, newborn liver and adult bone marrow are engaged in DNA synthesis.     

Increased uncoupling protein-2 mRNA abundance and glucocorticoid action in adipose tissue in the sheep fetus during late gestation is dependent on plasma cortisol and triiodothyronine

The endocrine regulation of uncoupling protein-2 (UCP2), an inner mitochondrial protein, in fetal adipose tissue remains unclear. The present study aimed to determine if fetal plasma cortisol and triiodothyronine (T₃) influenced the mRNA abundance of UCP2, glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and 2 (11βHSD2) in fetal adipose tissue in the sheep during late gestation. Perirenal–abdominal adipose tissue was sampled from ovine fetuses to which either cortisol (2–3 mg kg⁻¹ day⁻¹) or saline was infused for 5 days up to 127–130 days gestation, or near term fetuses (i.e. 142–145 days gestation) that were either adrenalectomised (AX) or remained intact. Fetal plasma cortisol and T₃ concentrations were higher in the cortisol infused animals and lower in AX fetuses compared with their corresponding control group, and increased with gestational age. UCP2 and GR mRNA abundance were significantly lower in AX fetuses compared with age-matched controls, and increased with gestational age and by cortisol infusion. Glucocorticoid action in fetal adipose tissue was augmented by AX and suppressed by cortisol infusion, the latter also preventing the gestational increase in 11βHSD1 mRNA and decrease in 11βHSD2 mRNA. When all treatment groups were combined, both fetal plasma cortisol and T₃ concentrations were positively correlated with UCP2, GR and 11βHSD2 mRNA abundance, but negatively correlated with 11βHSD1 mRNA abundance. In conclusion, plasma cortisol and T₃ are both required for the late gestation rise in UCP2 mRNA and differentially regulate glucocorticoid action in fetal adipose tissue in the sheep during late gestation.     

Developmental regulation of hepatic and renal gluconeogenic enzymes by thyroid hormones in fetal sheep during late gestation

Tissue glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinase (PEPCK) activities were investigated in sheep fetuses after experimental manipulation of thyroid hormone status. Increments in hepatic and renal G6P and PEPCK activities seen between 127–130 and 140–145 days of gestation (term, 145 ± 2 days) were abolished when the normal prepartum rise in plasma triiodothyronine (T₃), but not cortisol, was prevented by fetal thyroidectomy (TX). At 127–130 days, hepatic and renal G6P, and renal PEPCK, activities were similar in intact and TX fetuses; however, hepatic PEPCK was increased by TX. At 140–145 days, tissue G6P and PEPCK activities in TX fetuses were lower than in intact fetuses. In immature fetuses infused with cortisol (2–3 mg (kg body wt) ⁻¹ day ⁻¹) for five days, hepatic and renal enzyme activities were increased to those seen in mature fetuses near term. After five days of T₃ infusion (8–12 μg (kg body wt) ⁻¹ day ⁻¹), G6P and PEPCK activities in the liver and kidney were greater than in saline-infused fetuses, but only renal G6P and PEPCK increased to the level seen close to term. Therefore, in fetal sheep, thyroid hormones are important for the prepartum rises in G6P and PEPCK activities in the liver and kidney and may mediate, in part, the maturational effects of cortisol.     

Timing of fetal exposure to stress hormones: effects on newborn physical and neuromuscular maturation

The purpose of the study was to determine the specific periods during pregnancy in which human fetal exposure to stress hormones affects newborn physical and neuromuscular maturation. Blood was collected from 158 women at 15, 19, 25, and 31 weeks' gestation. Levels of placental corticotropin-releasing hormone (CRH) and maternal cortisol were determined from plasma. Newborns were evaluated with the New Ballard Maturation Score. Results indicated that increases in maternal cortisol at 15, 19, and 25 weeks and increases in placental CRH at 31 weeks were significantly associated with decreases in infant maturation among males (even after controlling for length of gestation). Results also suggested that increases in maternal cortisol at 31 weeks were associated with increases in infant maturation among females, although these results were not significant after controlling for length of gestation. Findings suggest that stress hormones have effects on human fetal neurodevelopment that are independent of birth outcome.     

Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep

Prenatal exposure to elevated maternal glucocorticoids (dexamethasone (DEX) or cortisol (CORT)) for 2 days early in pregnancy can 'programme' alterations in adult offspring of sheep, including elevated arterial pressure. DEX treatment also results in greater angiotensin II type 1 (AT₁) receptor expression in the medulla oblongata in late gestation fetuses than in saline (SAL)- or CORT-exposed animals. We hypothesized that this would result in functional changes in brainstem angiotensinergic control of cardiovascular function in DEX- but not CORT-exposed animals. To test this hypothesis, cardiovascular responses to intracerebroventricular ( i.c.v. ) angiotensin II were examined in adult male offspring exposed to DEX (0.48 mg h⁻¹; n = 7), CORT (5 mg h⁻¹, n = 6) or SAL ( n = 9) from 26 to 28 days of gestation. Increases in mean arterial pressure during i.c.v. infusion of angiotensin II (1 or 10 μg h⁻¹) were significantly greater in the DEX group (10 ± 1 mmHg at 1 μg h⁻¹) compared with SAL (6 ± 1 mmHg) or CORT (6 ± 1 mmHg) animals ( P < 0.05). i.c.v. infusion of the AT₁ antagonist losartan significantly decreased cardiac output and heart rate in DEX animals, but not in SAL or CORT animals. Thus, increased expression of brainstem AT₁ receptor mRNA after prenatal DEX is associated with increased responsiveness of cardiovascular control to activation of brain AT receptors by exogenous and endogenous angiotensin II. The altered role of the brain RAS in sheep exposed prenatally to DEX was not observed in sheep exposed prenatally to cortisol, suggesting these two glucocorticoids have distinct programming actions.     

Concanavalin A-affinity Molecular Variants of Rat AFP: Differences Among Amniotic Fluid, Fetal Serum, Newborn Serum and Maternal Serum

The concanavalin A-affinity molecular variants of rat alpha-fetoprotein were measured in amniotic fluid, fetal serum, newborn serum and maternal serum. During the last 6 days of gestation, 54% ± 2% (mean ± S.E.M.) of the amniotic fluid alpha-fetoprotein does not react with concanavalin A. At 17 days gestation, 54% ± 4% of the fetal serum alpha-fetoprotein does not react with concanavalin A. Between 18 and 21 days gestation the percentage of the concanavalin A-nonreactive molecular variant of fetal serum alpha-fetoprotein decreases to 43% and remains at 43% ± 0.4% through the 28-day newborn period studied. Following day 18 of gestation the proportions of the alpha-fetoprotein concanavalin A-affinity molecular variants in serum and in amniotic fluid are different (p<0.001). On day 21 of gestation, 41% of the alpha-fetoprotein present in maternal serum does not react with concanavalin A. These results suggest that during late gestation yolk sac and fetal liver synthesize different patterns of alpha-fetoprotein concanavalin A-affinity molecular variants and that on day 21 of gestation the major portion of the maternal serum alpha-fetoprotein is derived from fetal serum.     

Effect of feeding on the diurnal rhythm of plasma cortisol and adrenocorticotrophic hormone concentrations in the pregnant ewe and sheep fetus.

The effects of two different feeding regimes on the 24 h profiles of maternal and fetal plasma cortisol and adrenocorticotrophic hormone (ACTH) concentrations were studied in eight pregnant ewes between 123 and 144 days of gestation. Once daily-fed ewes (n = 4) received 1 kg of lucerne-chaff at 11.00 h, and multi-fed ewes (n = 4) received 100-200 g of lucerne-chaff at 09.00, 11.00 and 13.00 h and then 150 g until 09.00 h the following day. There were significant differences between the two feeding groups in the 24 h profile of maternal plasma osmolality; once daily feeding at 11.00 h was associated with a peak in maternal plasma osmolality at 15.00 h whereas maternal plasma osmolality reached plateau levels at around 17.00 h in the multi-fed group. There were also differences between the two feeding groups in the 24 h profiles of maternal and fetal plasma glucose. Maternal and fetal plasma glucose reached peak concentrations at 19.00 h in the once daily-fed ewes in contrast to the multi-fed group, where a plateau in maternal and fetal plasma glucose was reached between 19.00 h and 09.00 h the following day. A significant diurnal variation in the plasma concentrations of cortisol was present in the once daily-fed ewes from 123 days gestation and in their fetuses after, but not before, 135 days gestation. Plasma cortisol peaked at 11.00 h in the ewes and at 13.00 h in the fetuses of this group. In the once daily-fed group there was also a significant diurnal variation in maternal and fetal plasma ACTH; plasma ACTH concentrations were highest at 11.00 h in the ewes aged between 123 and 144 days and in fetuses after 135 days gestation. In the multi-fed group, whilst ACTH was highest at 09.00 h in the ewes and at 13.00 h in the fetuses, there was no significant diurnal variation in the plasma concentrations of cortisol in the ewes or fetuses of this group at any stage between 123 and 144 days gestation.     

Development of cardiovascular function in the horse fetus

In mammals, the mechanisms regulating an increase in fetal arterial blood pressure with advancing gestational age remain unidentified. In all species studied to date, the prepartum increase in fetal plasma cortisol has an important role in the maturation of physiological systems essential for neonatal survival. In the horse, the prepartum elevation in fetal cortisol and arterial blood pressure are delayed relative to other species. Hence, the mechanisms governing the ontogenic increase in arterial blood pressure in the horse fetus may mature much closer to term than in other fetal animals. In the chronically instrumented pony mare and fetus, this study investigated how changes in fetal peripheral vascular resistance, in plasma concentrations of noradrenaline, adrenaline and vasopressin, and in the maternal-to-fetal plasma concentration gradient of oxygen and glucose relate to the ontogenic changes in fetal arterial blood pressure and fetal plasma cortisol concentration as term approaches. The data show that, towards term in the horse fetus, the increase in arterial blood pressure occurs together with reductions in metatarsal vascular resistance, elevations in plasma concentrations of cortisol, vasopressin, adrenaline and noradrenaline, and falls in the fetal : maternal ratio of blood   P _a,O2  and glucose concentration. Correlation analysis revealed that arterial blood pressure was positively related with plasma concentrations of vasopressin and noradrenaline, but not adrenaline in the fetus, and inversely related to the fetal : maternal ratio of blood   P _a,O2  , but not glucose, concentration. This suggests that increasing vasopressinergic and noradrenergic influences as well as changes in oxygen availability to the fetus and uteroplacental tissues may contribute to the ontogenic increase in fetal arterial blood pressure towards term in the horse.     

Increased oestradiol level in seminal plasma in infertile men

Seminal hormonal patterns in fertile and infertile men wereinvestigated. Follicle-stimulating hormone (FSH), luteinizinghormone (LH), prolactin, testosterone and oestradiol were assessedby radioimmunoassay, and dehydroepiandrosterone sulphate (DHAS)by bioluminescence assay, on blood and seminal plasma of 23fertile men and 83 infertile men. For fertile men, mean FSH,LH, testosterone and DHAS concentrations were lower and meanoestradiol was higher in seminal than in blood plasma; prolactindid not differ. For infertile men, mean seminal FSH and LH showeda moderate but significant increase compared with fertile men;testosterone, DHAS and prolactin did not differ but mean seminaloestradiol was significantly increased. Of the infertile men,53% had seminal oestradiol concentration above the 90^th percentilevalue for fertile men. The meaning of this seminal oestradiolincrease is unclear since it is not known whether it is thecause or the consequence of the alteration of spermatogenesisin infertile men. Further studies are required to explore thepossible therapeutic implications.     

Effect of maternal nutrient restriction in early gestation on responses of the hypothalamic-pituitary-adrenal axis to acute isocapnic hypoxaemia in late gestation fetal sheep

Epidemiological and experimental evidence suggests that maternal undernutrition during pregnancy may alter development of fetal organ systems. We have demonstrated previously that fetal hypothalamic-pituitary-adrenal (HPA) axis responses to exogenous corticotropin-releasing hormone (CRH) + arginine vasopressin (AVP), or adrenocorticotrophin hormone (ACTH), are reduced in fetuses of mildly undernourished ewes. To examine these effects further we tested HPA axis responses to acute isocapnic hypoxaemia in fetal sheep at 114-129 days gestation (dGA), following 15% reduction in maternal nutritional intake between 0 and 70 dGA. Fetuses from control (C) and nutrient-restricted (R) ewes were chronically catheterised and plasma ACTH and cortisol responses were determined at 114-115, 120-123 and 126-129 dGA during hypoxaemia (1 h) induced by lowering the maternal inspired O2 fraction (FI,O2). Basal plasma cortisol concentrations and HPA axis responses at 114-115 and 120-123 dGA did not differ between C and R fetuses. At 126-129 dGA, both plasma ACTH (P < 0.01) and cortisol (P < 0.05) responses were smaller in R fetuses compared to C fetuses. Fetal blood gas status, fetal body weight, body proportions and organ weights did not differ between the groups. We conclude that mild maternal undernutrition alters development of the fetal HPA axis producing a reduction in pituitary and adrenal responsiveness to endogenous stimuli.     

Parity effects on maternal behaviour are not related to circulating oestradiol concentrations in two breeds of sheep

Primiparous females of many species, including the sheep, do not show as competent maternal behaviour as multiparous mothers. In this study we investigated whether circulating concentrations of oestradiol might be related to this response, since breed differences in oestradiol concentrations have been shown to correlate with maternal behaviours. Oestradiol concentrations were measured in plasma collected at 2-weekly intervals from primiparous and multiparous ewes of two breeds (Scottish Blackface and Suffolk) throughout gestation, and maternal behaviour was recorded at parturition. Circulating oestradiol concentrations, and the ratio of oestradiol to progesterone concentration (O:P ratio) were higher in late pregnancy in Blackface ewes, but there were no significant effects of ewe parity. However, there was a significant interaction between breed and parity as O:P ratio was lower in primiparous Suffolk ewes compared to multiparous. This relationship was not seen in Blackface ewes. Blackface ewes of both parities groomed their lambs more frequently and made more low-pitched vocalisations than Suffolk ewes. Primiparous ewes were more likely to move as the lamb attempted to suck, and to show withdrawal or aggression towards the lamb. Primiparous Suffolk ewes also made more high pitched bleats than other classes of ewe. The data support previous studies which show an effect of breed on circulating oestradiol and O:P ratio but suggest that parity effects on maternal behaviour may be mediated by sensitivity to circulating concentration of oestradiol rather than variations in the plasma concentrations of this hormone.     

Maternal corticotropin-releasing hormone and habituation in the human fetus

Elevated concentrations of maternal corticotrophin-releasing hormone (CRH) during the 2nd and early 3rd trimester of human pregnancy are associated with spontaneous preterm birth, but the effects of maternal CRH on the fetus are unknown. Maternal plasma was collected for analysis of CRH concentration, m = 156.24 +/- 130.91 pg/ml, from 33 pregnant women during Weeks 31-33 of gestation. Immediately after collection of plasma, fetal heart rate (FHR) measures were obtained in response to a challenge with a series of vibroacoustic stimuli. Fetuses of mothers with highly elevated CRH did not respond significantly to the presence of a novel stimulus in a repeated series, p = 0.016. These effects on the FHR response were not related to parity, fetal gender, medical (antepartum) risk, or eventual birth outcomes. Impaired dishabituation in these fetuses of mothers with high concentrations of CRH suggests that neurological systems rich with CRH receptors that support learning and memory, such as parahippocampal regions, may be targets for maternal/placental CRH, with implications for fetal neurological development.     

Effects of pulsatile cortisol infusion on sleep-EEG and nocturnal growth hormone release in healthy men

SUMMARY  This study investigates the short-term effects of pulsatile cortisol administrations upon sleep electroencephalogram (EEG) and spontaneous release of growth hormone (GH) in humans. Ten young healthy male volunteers received intravenous injections of either placebo or cortisol every 60 min between 17.00 hours and 06.00 hours (1 mg kg^-1 BW with a loading dose of 20% starting at 17.00 hours, followed by a dose of 6% every hour until 06.00 hours). The amount of rapid eye-movement (REM) sleep was significantly reduced (placebo: 19.9 ± 1.8; cortisol: 12.2 ± 1.5%; P < 0.05), whereas the time spent in slow-wave sleep (SWS) was significantly increased (placebo: 9.4 ± 1.6; cortisol: 13.9 ± 1.9%; P < 0.05). The SWS-promoting effect was most prominent during the first hours of sleep, but tended to persist also during the second half of the night. The pulsatile cortisol administration augmented the total amount of plasma GH concentrations (mean area under the time course curve, AUC, placebo: 3.2 ± 0.5; cortisol: 4.4 ± 0.6 [ng × 1000 × ml min^-1]; P < 0.05) due to an increase of GH release before sleep onset, and during the second half of the night, while the GH surge at sleep onset remained unchanged.
Our data are in accordance with the hypotheses that cortisol-induced changes of both sleep-EEG and GH secretion involve a common mechanism that includes activation of the hypothalamic-somatotrophic (growth hormone releasing hormone-growth hormone) system.     

Fetal exposure to excess glucocorticoid is unlikely to explain the effects of periconceptional undernutrition in sheep

Periconceptional undernutrition alters fetal growth, metabolism and endocrinology in late gestation. The underlying mechanisms remain uncertain, but fetal exposure to excess maternal glucocorticoids has been hypothesized. We investigated the effects of periconceptional undernutrition on maternal hypothalamic–pituitary–adrenal axis function and placental 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) activity. Ewes received maintenance feed (N, n = 20) or decreased feed from −60 to +30 days from mating to achieve 15% weight loss after an initial 2-day fast (UN, n = 21). Baseline plasma samples and arginine vasopressin (AVP)–corticotrophin-releasing hormone (CRH) challenges were performed on days −61, −57, −29, −1, +29, 33, and 49 from mating (day 0). Maternal adrenal and placental tissue was collected at 50 days. Baseline plasma levels of adrenocorticotrophic hormone (ACTH) and cortisol decreased in the UN group ( P < 0.0001). ACTH response to AVP–CRH was greater in UN ewes during undernutrition ( P = 0.03) returning to normal levels after refeeding. Cortisol response to AVP–CRH was greater in UN ewes after the initial 2-day fast, but thereafter decreased and was lower in UN ewes from mating until the end of the experiment ( P = 0.007). ACTH receptor, StAR and p450c17 mRNA levels were down-regulated in adrenal tissue from UN ewes. Placental 11βHSD2 activity was lower in UN than N ewes at 50 days ( P = 0.014). Moderate periconceptional undernutrition results in decreased maternal plasma cortisol concentrations during undernutrition and after refeeding, and adrenal resistance to ACTH for at least 20 days after refeeding. Fetal exposure to excess maternal cortisol is unlikely during the period of undernutrition, but could occur later in gestation if maternal plasma cortisol levels return to normal while placental 11βHSD2 activity remains low.     

Raised dietary n-6 polyunsaturated fatty acid intake increases 2-series prostaglandin production during labour in the ewe

Preterm labour is the major cause of perinatal morbidity and mortality in humans. The incidence is around 10% and the causes are often unknown. Consumption of dietary n -6 polyunsaturated fatty acids (PUFAs) in western societies is increasing. These are metabolized to arachidonic acid, the precursor for 2-series prostaglandins (PGs), major signalling molecules during labour. This study investigated the effect of dietary supplementation with linoleic acid (LA, 18: 2, n -6) on parturition. Ewes were fed a control or LA-supplemented diet from 100 days gestation. Labour was induced using a standardized glucocorticoid challenge (dexamethasone, Dex) to the fetus, starting on day 139. Electromyographic (EMG) activity and fetal and maternal circulating PG concentrations were monitored. One third of LA-fed ewes delivered early (pre-Dex) although basal uterine EMG activity preceding Dex was higher in control ewes  ( P < 0.05)  . A steep increase in EMG activity occurred 18–38 h after the start of Dex infusion. Twice basal EMG activity (defined as established labour) occurred on average 7 h earlier in the LA-supplemented ewes  ( P < 0.05)  . The basal concentrations of maternal and fetal PGFM and fetal PGE₂ were approximately doubled in LA-supplemented ewes before the start of Dex infusion  ( P < 0.01)  . The rise in fetal PGE₂ and maternal oestradiol concentrations post-Dex occurred earlier in the LA-supplemented ewes. All PG measurements remained significantly higher in the LA-supplemented ewes during labour onset. This study suggests that consumption of a high LA diet in late pregnancy can enhance placental PG production and may thus increase the risk of preterm labour.     

Increased glomerular angiotensin II binding in rats exposed to a maternal low protein diet in utero

In the rat, protein restriction during pregnancy increases offspring blood pressure by 20–30 mmHg. We have shown in an earlier study that this is associated with a reduction in nephron number and increased glomerular sensitivity to angiotensin II (Ang II) in vivo . Hence, we hypothesized that exposure to a maternal low-protein diet increases glomerular Ang II AT₁ receptor expression and decreases AT₂ receptor expression. To test this hypothesis, pregnant Wistar rats were fed isocalorific diets containing either 18% (control) or 9% (LP) protein from conception until birth. At 4 weeks of age, the kidneys of male offspring were harvested to measure cortical AT₁ and AT₂ receptor expression, ¹²⁵I-Ang II glomerular binding, tissue renin activity, tissue Ang II and plasma aldosterone concentrations. AT₁ receptor expression was increased (62%) and AT₂ expression was decreased (35%) in LP rats. Maximum ¹²⁵I-Ang II (¹²⁵I-Ang II) binding ( B _max) was increased in LP rats (control n = 9, 291.6 ± 27.4 versus LP n = 7, 445.7 ± 27.4 fmol (mg glomerular protein)⁻¹, P < 0.01), but affinity ( K _D) was not statistically different from controls (control 2.87 ± 0.85 versus LP 0.84 ± 0.20 pmol ¹²⁵I-Ang II, P = 0.059). Renal renin activity, tissue Ang II and plasma aldosterone concentrations did not differ between control and LP rats. Increased AT₁ receptor expression in LP rat kidneys is consistent with greater haemodynamic sensitivity to Ang II in vivo . This may result in an inappropriate reduction in glomerular filtration rate, salt and water retention, and an increase in blood pressure.     

Automatic CPAP based on impedance-comparison of constant CPAP with an individual pressure range

Summary Introduction   Self-adjusting positive airways pressure treatment based on the impedance of the airways (APAP_FOT) has proven effective in obstructive sleep apnoea syndrome. To avoid patient discomfort during periods of high treatment pressure we lowered the upper pressure limit with APAP_FOT and investigated whether this provided equally as effective treatment as constant CPAP. Methods   37 patients (33 males, 57.9 ± 9.9 years, BMI 32.5 ± 3.8 kg/m²) underwent after diagnostic polysomnography and manual nCPAP titration two treatment nights in randomized order, one with constant nCPAP (mode 1), one with APAP_FOT (mode 2). Under APAP_FOT treatment pressure varied between 4 hPa (set lower limit for all patients) and 13.3 ± 1.4 hPa (individually variable upper pressure limit). Results   AHI was reduced from 32.8 ± 18.1/h to 4.6 ± 4.9/h (mode 1, p < 0.01) and to 5.0 ± 4.1/h (mode 2, p < 0.01). Rapid eye movement sleep (REM) and respiratory arousals improved significantly with both modes. With APAP_FOT, the mean pressure was 5.7 ± 1.7 hPa as compared to 8.3 ± 1.4 hPa with constant nCPAP (p < 0.01). Conclusions   APAP_FOT with a reduced upper pressure is as effective as constant nCPAP for OSAS. With APAP_FOT the mean pressure is substantially reduced.     

Transplacental passage of mifepristone and its influence on maternal and fetal steroid concentrations in the second trimester of pregnancy

The maternal and fetal endocrine effects of the maternal administration of the anti-progestin mifepristone in mid-pregnancy have been investigated. Mifepristone and the metabolite RU 42,633 were detected in the fetal circulation and in the amniotic fluid 4, 24 and 48 h after oral ingestion. Maximum fetal plasma concentrations of mifepristone occurred 4 h after treatment indicating rapid placental transfer of the drug. No significant changes in progesterone, cortisol, oestradiol or aldosterone concentrations were detected in the maternal circulation after mifepristone treatment. No significant changes occurred in the fetal progesterone, oestradiol or cortisol concentrations, but a significant increase in fetal aldosterone occurred 4 and 24 h after treatment. The significance of these results is discussed in relation to the possible therapeutic uses of mifepristone for inducing labour.     

Melatonin secretion in the Mashona mole-rat, Cryptomys darlingi--influence of light on rhythmicity

The hormone melatonin is synthesised and secreted from the pineal gland in darkness and triggers the daily and seasonal timing of various physiological and behavioural processes. The Mashona mole-rat, Cryptomys darlingi, lives in subterranean burrows that are completely sealed and is therefore rarely, if ever, exposed to light under natural conditions. Hence, this species is of particular interest for studies on rhythms of melatonin secretion. We investigated how plasma melatonin concentrations of the Mashona mole-rat responded to exposure to a long-term standard photoperiod of 12 h light, 12 h dark (12:12 LD), constant light (LL) and constant dark (DD). In addition, we examined whether plasma melatonin concentration was coupled to locomotor activity. Mashona mole-rats displayed rhythms of plasma melatonin concentration that appeared entrained to the standard LD photoperiod, suggesting that the mole-rat is capable of perceiving and entraining to this photic zeitgeber. Furthermore, under chronic constant lighting conditions (DD, LL), circadian rhythms in plasma melatonin concentration were observed, suggesting the possible existence of an endogenous rhythm. Light suppressed melatonin secretion, but constant light did not abolish the rhythm of plasma melatonin concentration. Between active and non-active animals, no difference in plasma melatonin concentration was found for any of the sequential photoperiods (LD1 DD, LD2, LL), tentatively suggesting that the rhythm of melatonin secretion is uncoupled from that of locomotor activity.