[Show abstract][Hide abstract] ABSTRACT: Mild gestational hyperglycemia is often associated with fetal overgrowth that can predispose the offspring to metabolic diseases later in life. We hypothesized that unfavorable intrauterine environment may compromise the development of placenta and contribute to fetal overgrowth. Therefore, we developed a rat model and investigated the effects of maternal dysglycemia on fetal growth and placental gene expression. Female rats were treated with single injection of nicotinamide plus streptozotocin (N-STZ) 1-week before mating and were studied at gestational day 21. N-STZ pregnant females displayed impaired glucose tolerance that is associated with a lower insulin secretion. Moderate hyperglycemia induced fetal overgrowth in 40% of newborns, from pregnancies with 10 to 14 pups. The incidence of macrosomia was less than 5% in the N-STZ pregnancies when the litter size exceeds 15 newborns. We found that placental mass and the labyrinthine layer were increased in macrosomic placentas. The expression of genes involved in placental development and nutrient transfer was down regulated in the N-STZ placentas of macrosomic and normosomic pups from pregnancies with 10 to 14 ones. However, we observed that lipoprotein lipase 1 (LPL1) gene expression was significantly increased in the N-STZ placentas of macrosomic pups. In pregnancies with 15 pups or more, the expression of IGFs and glucose transporter genes was also modulated in the control placentas with no additional effect in the N-STZ ones. These data suggest that placental gene expression is modulated by gestational conditions that might disrupt the fetal growth. We described here a new model of maternal glucose intolerance that results in fetal overgrowth. We proposed that over-expression of LPL1 in the placenta may contribute to the increased fetal growth in the N-STZ pregnancies. N-STZ model offers the opportunity to determinate whether these neonatal outcomes may contribute to developmental programming of metabolic diseases in adulthood.
PLoS ONE 05/2013; 8(5):e64251. DOI:10.1371/journal.pone.0064251 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetic variants in the FTO (fat mass- and obesity-associated) gene have the highest association of all obesity-associated genes. Its placental expression was shown to relate to birth weight, suggesting that it may participate in the control of fetal weight gain. To gain more insight into the implication of FTO in fetal growth, we measured its placental expression in samples including extremes of abnormal fetal growth, such as after intrauterine growth restriction (IUGR) or macrosomia in both rats and humans. In rats, fetal growth was modulated by maternal nutritional modifications. In humans, placental villi were collected from pathological pregnancies (i.e. with IUGR or fetal macrosomia). Placental FTO mRNA expression was reduced by IUGR but was not significantly affected by macrosomia in either rats or humans. Our data suggest that placental FTO may participate in interactions between the in utero environment and the control of fetal growth under IUGR conditions by modulating epigenetic processes.
Journal of Developmental Origins of Health and Disease 12/2012; 4(2):134-138. DOI:10.1017/S2040174412000748 · 0.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An association is established between schizophrenia and the development of metabolic alterations including cardiovascular diseases, type 2 diabetes and obesity. Perinatal insults, such as undernutrition, have been shown to increase the propensity to develop these pathologies, reinforcing the idea that schizophrenia may have a neurodevelopmental origin. Moreover, the use of second generation antipsychotics (SGAs) also known as "atypical" neuroleptics has also been demonstrated to exacerbate metabolic anomalies in patients with schizophrenia. SGAs are able to cross the placental barrier and have been detected in milk from women receiving atypical neuroleptics treatment during the perinatal period. To date, the consequences of such treatment have only been examined on the birth weight and the cognitive capacities of the child from women with schizophrenia, but no data is available concerning the putative long-term effects of SGAs on their body weight and metabolic parameters. We have recently reported that rat offspring from prenatally undernourished mothers exhibit a low birth weight associated with modified sensitivity to clozapine and aripiprazole in adulthood reinforcing the idea that some forms of schizophrenia may be acquired during early development. In view of these observations, the risks of perinatal exposure to SGAs must be weighed against the growing evidence that maternal psychiatric illness poses risks to the fetus/newborn as well as for long-term susceptibility to diseases. Thus, metabolic follow-up of children born from mothers treated by SGAs during the perinatal period will be clearly recommended, in particular if they exhibit alterations of their body weight during this early critical period.
European journal of pharmacology 06/2011; 667(1-3):13-6. DOI:10.1016/j.ejphar.2011.05.076 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Maternal undernutrition leads to intrauterine growth retardation and predisposes to the development of pathologies in adulthood. The hypothalamo-pituitary-adrenal axis is a major target of early-life programming. We showed previously that perinatal maternal 50% food restriction leads to hypothalamo-pituitary-adrenal axis hyperactivity and disturbs glucocorticoid feedback in adult male rats. To try to better understand these alterations, we studied several factors involved in corticosterone sensitivity. We showed that unlike the restricted expression of 11 beta-HSD2 mRNA, the 11 beta-HSD1, glucocorticoid, and mineralocorticoid receptor genes are widely distributed in rat. In contrast to the hypothalamus, we confirmed that maternal undernutrition modulates hippocampal corticosterone receptor balance and leads to increased 11 beta-HSD1 gene expression. In the pituitary, rats exhibited a huge increase in both mRNA and mineralocorticoid receptor binding capacities as well as decreased 11 beta-HSD1/11 beta-HSD2 gene expression. Using IN SITU hybridization, we showed that the mineralocorticoid receptor gene was expressed in rat corticotroph cells and by other adenopituitary cells. In the adrenal gland, maternal food restriction decreased 11beta-HSD2 mRNA. This study demonstrated that maternal food restriction has both long-term and tissue-specific effects on gene expression of factors involved in glucocorticoid sensitivity and that it could contribute, via glucocorticoid excess, to the development of adult diseases.
Hormone and Metabolic Research 05/2008; 40(4):257-61. DOI:10.1055/s-2008-1058064 · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiological and experimental studies have demonstrated that perinatal alterations such as maternal undernutrition are frequently associated with the onset of several chronic adult diseases. Although the physiological mechanisms involved in this "fetal programming" remain largely unknown, it has been shown that early exposure to undernutrition programs hypothalamic-pituitary-adrenal (HPA) axis throughout lifespan. However, the wide spectrum of experimental paradigms used (species, sex, age of the animals, and duration and severity of undernutrition exposure) has given rise to variable results that are difficult to interpret. To circumvent this problem, we used the same experimental protocol of maternal food restriction to study the effects of a severe maternal undernutrition on the HPA axis activity in the male rat offspring throughout the life, namely from fetal stage to adulthood. Mothers exposed to food restriction received 50% (FR50) of the daily intake of pregnant dams during the last week of gestation and lactation. In FR50 fetuses, HPA axis function was reduced and associated with a decreased placental 11beta-HSD2 activity and a greater transplacental transfer of glucocorticoids. At weaning, maternal food restriction reduced HPA axis activity in response to an ether inhalation stress. In young adults (4-month-old), only fine HPA axis alterations were observed, whereas in older ones (8-month-old), maternal undernutrition was associated with chronic hyperactivity of this neuroendocrine axis. Interestingly, excessive glucocorticoids production is observed in a growing number of pathologies such as metabolic, cognitive, immune and inflammatory diseases, suggesting that they could, at least in part, result from fetal undernutrition and thus have a neurodevelopmental origin.
[Show abstract][Hide abstract] ABSTRACT: There is now compelling evidence, coming both from animal and human studies that an early exposure to undernutrition is frequently associated with low birth weight and programs HPA axis alterations throughout the lifespan. Although animal models have reported conflicting findings arising from differences in experimental paradigms and species, they have clearly demonstrated that such programming not only affects the brain but also the pituitary corticotrophs and the adrenal cortex. In fetuses, maternal undernutrition reduces HPA axis function and implicates a reduction of placental 11beta-HSD2 activity and a greater transplacental transfer of glucocorticoids (GRs). In young adults, usually only fine HPA axis alterations were observed, whereas in older ones, maternal undernutrition was frequently associated with chronic hyperactivity of this neuroendocrine axis. In humans, evidence of HPA axis dysregulation in people who were small at birth has recently emerged. Thus, we suggest that such alterations in adults may be implicated in the aetiology of several disorders related to the metabolic syndrome as well as to immune or inflammatory diseases. To reverse such programming, recent experimental reports have shown that postnatal environmental interventions, dietary modifications and the use of agents modulating the epigenomic state could partly restore physiological functions and thus open new therapeutic strategies.
[Show abstract][Hide abstract] ABSTRACT: Human epidemiological studies have shown that low birth weight is associated with hypertension in adulthood. Rodent models of intrauterine growth retardation (IUGR) support these findings because offspring from undernourished dams develop hypertension. Angiotensin-converting enzyme 2 (ACE2) is a newly described renin-angiotensin system (RAS) component that competes with ACE for angiotensin peptide hydrolysis and therefore may modulate blood pressure. However, ACE2 potential participation in hypertension programming remains unknown, although RAS alterations were reported in IUGR models. Hence, we first investigated the tissue distribution of ACE2 and ACE in the rat and then whether hypertension programming differentially affects both enzymes. Using multiplex RT-PCR and in situ hybridization, we show that ACE2 mRNA is widely expressed and coregionalized with ACE. Moreover, tissues involved in blood pressure homeostasis (lung, heart, and kidney) express high levels of both enzymes. Enzymatic assays reveal that ACE2 and ACE are coactive in these tissues. Adult (4-month-old) offspring from 70% food-restricted dams throughout gestation (FR30 rats) present mild hypertension, impaired renal morphology, as well as elevated plasma angiotensin II and aldosterone, suggesting alterations of the systemic RAS. In FR30 rats, we show that ACE2 and ACE activities are increased only in the lung, whereas their mRNA expression is not significantly altered, showing that the enzymes display tissue-specific sensitivity to programming. Our results indicate that ACE2 and ACE are coexpressed in numerous rat tissues and that their increased activity in the lung of FR30 rats may participate in hypertension programming.
[Show abstract][Hide abstract] ABSTRACT: Dehydration is a classic homeostatic stressor in rats that leads to a series of endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. During the last decade, it has been well established that perinatal food restriction is associated with the onset of diseases in adults. Our previous demonstration of long-term alterations in HPA axis activity in both basal conditions and after a 72-hour dehydration period in 4-month-old rats exposed to a 50% maternal food restriction (FR50) in late gestation and lactation prompted us to investigate whether such perinatal undernutrition further affects HPA axis activity in mature animals. As previously described in 4-month-old rats under basal conditions, 8-month-old FR50 rats showed reduced body weight and an enhanced ratio between mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA levels in the hippocampus, as well as increased pro-opiomelanocortin (POMC) mRNA levels in the adenohypophysis. In addition, numerous additional alterations appeared in mature rats. In the hypothalamus, levels of vasopressin (VP) mRNAs were increased both in the paraventricular nucleus (PVN) and in the supraoptic nucleus (SON). In the adenohypophysis, GR and prohormone-convertase 2 (PC2) mRNA levels were significantly increased, whereas prohormone-convertase 1 (PC1) mRNA was not affected by maternal undernutrition. Interestingly, undernourished animals exhibited high plasma levels of total and free corticosterone in spite of normal corticotropin (ACTH) levels, an indication that HPA basal activity is enhanced by maternal undernutrition in 8-month-old animals. Dehydration for 72 h induced a rise in ACTH plasma levels, but did not modify total and free corticosterone plasma levels in 8-month-old FR50 animals. In the adenopituitary, POMC mRNA levels were decreased after dehydration but PC1 mRNA levels were unaffected. The present study indicates that maternal food restriction during the perinatal period dramatically affects the activity of the HPA axis until the age of 8 months. We speculate that higher basal HPA activity and an inadequate HPA response after dehydration in mature animals may contribute to diseases such as hypertension, known to develop with aging in perinatally growth-restricted rats.
[Show abstract][Hide abstract] ABSTRACT: The effects of a 3-day water deprivation were studied in adult female rats in order to know what are the different zones of the adrenal gland and the hormonal factors involved in the growth and the activity of the adrenal gland. Water deprivation significantly increased plasma renin activity (PRA), plasma Angiotensin II (AII), vasopressin (AVP), epinephrine, aldosterone and corticosterone concentrations but did not modify the plasma adrenocorticotropin hormone (ACTH) level. Water deprivation significantly increased the absolute weight of the adrenal capsule containing the zona glomerulosa without modification of the density of cells per area unit suggesting that the growth of the adrenal capsule was due to a cell hyperplasia of the zona glomerulosa. Water deprivation significantly increased the density of AII type 1 (AT(1)) receptors in the adrenal capsule but did not modify the density of AII type 2 (AT(2)) receptors in the adrenal capsule and core containing the zona fasciculata, the zona reticularis and the medulla. The treatment of dehydrated female rats with captopril, which inhibits the angiotensin converting enzyme (ACE) in order to block the production of AII, significantly decreased the absolute weight of the adrenal capsule, plasma aldosterone and the density of AT(1) receptors in the adrenal capsule. The concentration of corticosterone in the plasma, the density of AT(2) receptors and the density of cells per unit area in the zona glomerulosa of the adrenal capsule were not affected by captopril-treatment. In conclusion, these results suggest that AII seems to be the main factor involved in the stimulation of the growth and the secretion of aldosterone by the adrenal capsule containing the zona glomerulosa during water deprivation. The low level of plasma ACTH is not involved in the growth of the adrenal gland but is probably responsible for the secretion of corticosterone by the zona fasciculata.
[Show abstract][Hide abstract] ABSTRACT: We investigated the effects of individual natriuretic peptides (atrial natriuretic peptide, ANP; brain natriuretic peptide, BNP, and C-type natriuretic peptide, CNP) on rat corticotropin-releasing factor stimulated adrenocorticotropic hormone (ACTH) secretion by the pituitary gland of 21-day-old rat fetuses in vitro and on pro-opiomelanocortin gene expression using in situ hybridization.
Graded concentrations of ANP, BNP, or CNP (10(-10), 10(-9), and 10(-8) mol/l) induced a log dose dependent inhibition of ACTH secretion induced by rat corticotropin-releasing factor (10(-10) mol/l). These natriuretic peptides showed equipotent effects on a molar basis. Moreover, ANP, BNP, or CNP at 10(-10) mol/l reduced significantly the pituitary pro-opiomelanocortin mRNA expression. In addition, the immunoreactive ANP, BNP, and CNP cells were localized in the anterior lobe, but not in the intermediate lobe of the fetal pituitary gland.
These data suggest that the fetal pituitary gland may be both a source and a target for natriuretic peptides that might control ACTH synthesis and release via an endocrine and/or paracrine mechanism. The natriuretic peptides could participate, as well as glucocorticoids, in the control of the corticotropin-stimulating activity of the fetal rat in late gestation.
Hormone Research 02/2003; 59(3):142-8. DOI:10.1159/000069068 · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The first aim of this work was to investigate, under basal conditions in adult male rats, the long-term consequences of perinatal maternal food restriction on the plasma concentrations of vasopressin (VP), aldosterone and atrial natriuretic peptide (ANP) and on plasma renin activity (PRA). Furthermore, under these same conditions, the hypothalamic VP gene expression as well as the density (B(max)), affinity (K(d)) and gene expression of ANP receptors were determined in kidneys and adrenals. The second aim of this work was to examine the responsiveness to dehydration in perinatally malnourished rats. Thus, the latter parameters were studied in these rats after 72 h water deprivation.
This study was conducted on 4-Month-old male rats from mothers exposed to 50% food restriction (FR50) during the last week of gestation and lactation and on age-matched control animals (C). At this stage, both C and FR50 rats were killed by decapitation between 0900 h and 1000 h in order to determine parameters under basal conditions or after 72 h water deprivation. Plasma VP, ANP and aldosterone levels and PRA were determined by radioimmunoassay. Hypothalamic VP gene expression was determined in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) by in situ hybridization. The B(max) and K(d) values of ANP receptors were evaluated from Scatchard plots. ANP receptor gene expression was determined by Northern blot analysis.
Under basal conditions, perinatal malnutrition reduced body weight, absolute weight of kidneys and adrenals, and haematocrit. Compared with control rats, FR50 rats had significantly greater plasma VP and aldosterone levels but PRA, plasma ANP levels, plasma osmolality and hypothalamic VP gene expression were not significantly different. Perinatal malnutrition did not significantly affect glomerular ANP receptor density, but in adrenals it decreased both B(max) and K(d) values of ANP-B receptors (biological receptors) and increased B(max) of ANP-C receptors (clearance receptors). ANP-B(A) (receptor subtype A of ANP-B receptors) receptor gene expression was not significantly affected, whereas ANP-C receptor gene expression was enhanced in both adrenals and kidneys in FR50 rats. After 72 h dehydration, control rats showed a significant rise in haematocrit, plasma osmolality, PRA, circulating levels of VP and aldosterone and VP gene expression in both PVN and SON but showed a decrease in plasma ANP levels. B(max) of ANP-B receptors was decreased whereas B(max) of ANP-C receptors was enhanced in both adrenals and kidneys. ANP-B(A) receptor gene expression was not significantly affected in either kidneys or adrenals in dehydrated control rats. Similarly, ANP-C receptor gene expression was unaffected in kidneys whereas it was significantly enhanced in adrenals. In FR50 rats, the effects of water deprivation were qualitatively similar to those reported in controls concerning plasma parameters except for plasma VP levels which tended to rise (not significant) but this increase was only very slight compared with controls. Moreover, unlike controls, VP gene expression in both PVN and SON was not enhanced after dehydration in FR50 rats. In kidneys, dehydrated FR50 rats, like controls, upregulated ANP-C receptors, but they were unable to downregulate ANP-B receptors. In adrenals, unlike controls, FR50 rats enhanced ANP-B receptor density whereas they decreased both ANP-C receptor density and expression after 72 h dehydration. Similar to controls, the expression of ANP-B(A) receptors in both kidneys and adrenals as well as the expression of ANP-C receptors in kidneys, were unaffected in dehydrated FR50 rats.
Perinatal malnutrition had long-lasting effects on regulation of the fluid and electrolyte balance under basal conditions. The main effects were a significant rise in circulating levels of VP and aldosterone, and changes in density of adrenal ANP-binding sites and ANP-C receptor gene expression in both adrenals and kidneys. Perinatal malnutrition also affects the responsiveness to water deprivation with alterations in both hypothalamic VP gene expression and regulation of ANP-binding sites.
European Journal of Endocrinology 01/2003; 147(6):835-48. DOI:10.1530/eje.0.1470835 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dehydration, a classic homeostatic stressor in rats, leads to a series of well characterized endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. In this study, the hypothesis to be tested was that a 50% maternal food restriction (FR50) in late gestation and lactation may have long-term repercussions on HPA axis responsiveness to dehydration in offspring. For this purpose, we studied HPA axis activity in 4-month-old control (C) and perinatally malnourished male rats after a 72-hour water deprivation period. Furthermore, we investigated the long-lasting effects of perinatal maternal malnutrition on the basal activity of the HPA axis. Under basal conditions, rats exposed to perinatal malnutrition showed reduced body weight, enhanced mineralocorticoid receptor (MR) mRNA levels in CA2 and CA3 hippocampal areas, but decreased glucocorticoid receptor (GR) mRNA levels in CA1, CA3 and dentate gyrus (DG) areas. In contrast, the levels of corticotropin-releasing hormone (CRH) and vasopressin (VP) mRNAs in the hypothalamic paraventricular nucleus (PVN) as well as of VP mRNA in the supraoptic nucleus (SON) were unaffected by maternal undernutrition. Expression of proopiomelanocortin (POMC) in the adenohypophysis was significantly enhanced, whereas prohormone convertase-1 (PC1) was not affected. Perinatal malnutrition reduced absolute adrenal weight but did not affect circulating levels of adrenocorticotropin (ACTH), corticosterone and free corticosterone as well as corticosteroid-binding globulin (CBG) binding capacity. Seventy-two hours of dehydration induced a decrease in body weight and CRH mRNA levels in PVN of controls as well as of FR50 rats, but also led to a rise in plasma corticosterone and free corticosterone without changing CBG binding capacity. Dehydration also induced an increase in adenopituitary POMC (C) and PC1 (FR50), PVN and SON VP (C) and GR in CA1 hippocampal area (FR50) mRNA levels and plasma ACTH (C), but a decrease in MR in DG (C) and GR in CA3 and DG (C) mRNA levels. We conclude that maternal food restriction during the perinatal period affects (1) the adult basal activity of the HPA axis with mainly opposite effects on hippocampal MR and GR gene expression and an increase in adenopituitary POMC gene expression, and (2) the responsiveness to water deprivation in adults. In the latter case, the rise in plasma ACTH levels, adenopituitary POMC gene expression, hypothalamic VP gene expression, and the decrease in hippocampal MR gene expression in DG and GR gene expression in CA3 and DG observed in controls are lacking in FR50 rats. In contrast, drastic adenopituitary PC1 gene expression occurred in FR50 rats but not in control animals.
[Show abstract][Hide abstract] ABSTRACT: This study aimed at determining, in the term pregnant rat, whether maternal and fetal plasma atrial natriuretic peptide (ANP) concentrations were modified in response to an oral sodium load, and to investigate whether any changes in plasma concentrations were able to modify the density and affinity of the different ANP-binding site subtypes in maternal and fetal kidneys and adrenal glands.
Pregnant rats kept in metabolic cages were divided into two groups. The normal sodium diet group had free access to rat chow and tap water whereas the high sodium diet group received 1% NaCl as drinking water for 10 consecutive days from day 11 to day 21 of gestation with free access to standard rat chow. Pregnant rats from both groups were killed by decapitation on day 21 of gestation. The plasma ANP and aldosterone concentrations were determined by RIA. The density and affinity of ANP receptors were determined in the maternal and fetal adrenal glands and kidneys.
In the pregnant rats on the high-salt diet, the sodium and water intakes, as well as the urine volume and sodium excretion, were significantly higher than in the control group. After 10 days of high-salt intake, water and sodium retentions were not significantly different in the two groups, indicating that the pregnant rats were able to excrete excess salt. The high sodium intake did not change the body weight of the pregnant rats but did increase the body weight of the fetal rats. Maternal and fetal hematocrits remained unchanged in both groups, the high sodium intake did not modify plasma sodium concentration in the maternal rats but increased that of the fetuses, indicating an accumulation of sodium in the fetal rats. The dietary sodium intake did not change the plasma ANP concentrations but significantly decreased the plasma aldosterone concentrations in both the maternal and fetal rats. In response to the high-salt diet, the density and affinity of total ANP, ANPb and ANPc receptors were not altered in the maternal isolated renal glomeruli or the adrenal zona glomerulosa membranes or the fetal adrenal gland and kidney membrane preparations.
These results suggest that ANP is not involved in the regulation of water and electrolyte balance in maternal and fetal rats during salt-loaded intake.
European Journal of Endocrinology 06/2000; 142(5):524-32. DOI:10.1530/eje.0.1420524 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effects of water deprivation for 3 days were studied in pregnant rats and their fetuses on day 21 of gestation. Maternal water deprivation induced a significant decrease of the body weight in both maternal and fetal rats. This weight loss was accompanied by significant increases in plasma osmolality and haematocrit in both maternal and fetal rats. Similarly, dehydration significantly decreased plasma atrial natriuretic peptide (ANP) concentrations and increased plasma aldosterone concentrations in maternal and fetal rats. Water-deprived maternal rats presented a significant increase in total ANP receptor density in isolated renal glomeruli and adrenal zona glomerulosa membranes. This increase was due to a significant increase in ANPc receptor density in both renal glomeruli and adrenal zona glomerulosa. The densities of total ANP, ANPb and ANPc receptors in fetal kidneys and adrenal glands were not affected by maternal dehydration. These results suggest that the dehydrated maternal rat is able to up-regulate the number of its ANP receptors in its kidneys and adrenal glands, in response to a decrease in plasma ANP concentrations. In contrast, the fetal rat does not seem to be able to regulate its own ANP receptors in response to maternal dehydration, in spite of a decrease in plasma ANP concentrations.
European Journal of Endocrinology 09/1999; 141(2):160-8. DOI:10.1530/eje.0.1410160 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Molecular forms of atrial natriuretic peptide (ANP) were determined by chromatography on Sephadex G50 fine coupled with a radioimmunoassay for rANP(1-28) in left and right atrial extracts and acidified plasmas from 17-, 19- and 21-day-old fetuses and adult female rats. Chromatographic analyses revealed two immunoreactive peaks of rANP with an apparent molecular weight of about 25 and 12 kD, respectively, in all atrial extracts from fetal and adult rats. Only one immunoreactive peak of rANP with an apparent molecular weight of about 3 kD was detected in all fetal plasmas. The 25- and 12-kD ANP molecular forms isolated from fetal atrial tissue and incubated with thrombin for 30 min at 37 degrees C were converted to ANP material with a molecular weight of about 3 kD. These results suggest that the two high molecular weight forms stored in fetal atrial tissue should be precursors of circulating rANP molecules, and the rat fetus should possess the same posttranslational processing of the precursor molecule as the adult rat as early as day 17 of gestation.
Biology of the Neonate 02/1995; 68(4):292-300. DOI:10.1159/000244249 · 1.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The binding of rANP(1-28) to receptors was studied on crude adrenal membranes from fetal rats between day 17 of gestation and term and also neonatal rats between weeks 1 and 4. The binding assays were carried out using 125I-rANP(1-28) as radioligand incubated with membrane preparations (2 mg/ml) for 90 min at 22 degrees C. The binding was specific, saturable and reversible. The Scatchard analysis of the binding data revealed a single class of binding sites of high affinity (kd approximately 10(-10) mol/l) which did not change significantly at all stages of development studied. The binding sites presented a higher affinity for ANP analogues which contained the C-terminal phenylalanine arginine residue. The number of ANP receptors expressed per adrenal increased regularly in fetal and neonatal rats and the perinatal evolution of these concentrations of ANP receptors was related to the increase in the size of the adrenals. When the concentrations of ANP receptors was expressed per microgram DNA, the concentrations of ANP receptors were higher in neonatal rats than in fetal rats and reflected the number of receptors per cell. These results suggest that these binding sites mediate the biological actions of ANF in the adrenal gland during the perinatal period.
[Show abstract][Hide abstract] ABSTRACT: The effects of rat corticotrophin-releasing factor (rCRF), arginine vasopressin (AVP) and oxytocin (OT) were investigated in vivo in 21-day-old rat fetuses injected through the umbilical vein and in vitro on perifused anterior pituitary glands from 21-day-old rat fetuses. In vivo, rCRF (1.25 pmol.50 microliter-1.fetus-1), AVP (5 pmol.50 microliter-1.fetus-1) alone and rCRF in association with AVP or oxytocin (12.5 pmol.50 microliter-1.fetus-1) increased plasma adrenocorticotrophic hormone (ACTH) and corticosterone levels only 30 min after the start of injection. During the first 10 min of the sampling period, the injection of these peptides alone or in combination and the injection of saline decreased the plasma ACTH concentration, which was lower than that of uninjected fetuses, but had no effect on the plasma corticosterone concentration. In vitro, the release of ACTH by perifused anterior pituitary glands was increased strongly by rCRF (4 pmol/0.5 ml) but only slightly by AVP (92 pmol/0.5 ml) and oxytocin (198 pmol/0.5 ml). Arginine vasopressin and oxytoxin potentiated the release of ACTH stimulated by rCRF in vitro but not in vivo. Our results suggest that rCRF is the major peptide that controls ACTH secretion in the fetal rat at term. In conclusion, the rise of the ACTH level observed only 30 min after injection of rCRF or AVP suggests the existence of a factor able to inhibit the ACTH response after injection of these peptides. This factor might be elicited by the blood volume expansion.
European Journal of Endocrinology 04/1994; 130(3):313-9. DOI:10.1530/eje.0.1300313 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effect of a blood volume expansion (1-1.5% of body weight) on atrial natriuretic factor (ANF) and adrenocorticotropic hormone (ACTH) secretions were investigated in 21-day-old rat fetuses injected intravenously through the umbilical vein with 50 microliters of isotonic saline. Basal ANF and ACTH concentrations were determined in the plasma with specific radioimmunoassays over a 30-min observation period. The basal plasma ANF concentration increased rapidly 1 min after blood volume expansion and then decreased to the control value 5 min later. The basal plasma ACTH concentration decreased during the first 10 min after injection and then increased to the control value 30 min after intravascular volume load. The results suggest that the fetal rat in late gestation is able to respond to blood volume expansion by increasing ANF secretion.
Biology of the Neonate 02/1994; 65(6):390-5. DOI:10.1159/000244068 · 1.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effects of rat corticotropin-releasing factor (rCRF, 1.25 pmol/50 microliters/fetus), arginine vasopressin (AVP, 5 pmol/50 microliters/fetus) and oxytocin (OT, 12.5 pmol/50 microliters/fetus) alone or in association were investigated in 21-day-old rat fetuses injected intravenously through the umbilical vein. Blood samples were collected 15 and 30 min after injection for the determination of corticosterone concentration and the different plasma molecular adrenocorticotropic hormone (ACTH) forms isolated by chromatography on Sephadex G50 fine. All the plasma samples chromatographed 15 and 30 min after injection of the different peptides showed 3 different molecular ACTH forms: big ACTH (> 20,000 molecular weight), intermediate ACTH (= 13,000) and little ACTH (= 4,500). The injection of rCRF or AVP alone and rCRF in association with AVP or OT increased the concentrations of big ACTH 15 min and little ACTH 30 min after injection. The injection of OT alone or in association with AVP did not change the concentration of the 3 molecular ACTH forms 15 and 30 min after injection. The rise of big ACTH 15 min after injection was not associated with a significant increase in plasma corticosterone concentration, whereas the increase in little ACTH 30 min later enhanced plasma corticosterone concentration. Our results suggest that rCRF or AVP alone and rCRF in association with AVP or OT injected intravenously in the fetal rat produced a selective release of the molecular ACTH forms and the increase in the plasma corticosterone concentration occurred when the proportion of little ACTH which is the predominant ACTH form in the fetal rat was enhanced.
Biology of the Neonate 02/1994; 65(5):331-9. DOI:10.1159/000244080 · 1.74 Impact Factor