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MS 0692 Received 9 February 2000; accepted after revision 11 May 2000.
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ABSTRACT |
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INTRODUCTION |
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Angiotensin-converting enzyme (ACE) is responsible for the metabolism of a number of small peptides (Skidgel & Erdos, 1993). Principally, it catalyses the activation of angiotensin II (AII) from angiotensin I (AI) and the degradation of bradykinin, and, therefore, is an important component of both the renin-angiotensin (RAS) and kallikrein-kinin systems. The enzyme appears to have an active role in the control of cardiovascular and renal function both before and after birth. Mice in which the ACE gene has been mutated or inactivated have low blood pressure and abnormal renal morphology and function (Krege et al. 1995; Hilgers et al. 1997). Similarly, administration of the ACE inhibitor captopril to the sheep fetus during late gestation causes a reduction in blood pressure (Robillard et al. 1983), while maternal treatment in a variety of experimental animals during pregnancy causes hypotension, hypoxaemia and renal dysfunction in the fetus, and has been associated with increased fetal mortality (Broughton Pipkin et al. 1982; Lumbers et al. 1992; Harewood et al. 1994).
In adult animals, ACE is found membrane-bound in a number of tissues, primarily in the vascular endothelium, and is present in blood in a soluble form (Skidgel & Erdos, 1993). The majority of the conversion of AI to AII, and the degradation of bradykinin, take place in the pulmonary circulation (Ng & Vane, 1967; Friedli et al. 1973). In the fetus, ACE protein and mRNA have been detected in a variety of tissues, including the placenta, lungs and kidneys, from early in gestation (Wigger & Stalcup, 1978; Schutz et al. 1996; Wintour et al. 1996), although the pulmonary concentration in utero is low compared to that measured in adult life (Kokubu et al. 1977; Wallace et al. 1979; Sim & Seng, 1984). At birth, however, the lungs and other tissues need to have sufficient amounts of ACE in order to maintain the normal activities of the RAS and kallikrein-kinin systems in the neonate. In several species, tissue and circulating concentrations of ACE in the fetus have been shown to increase towards term (Kokubu et al. 1977; Wallace et al. 1979; Sim & Seng, 1984; Raimbach & Thomas, 1990; Forhead et al. 1998, 2000b), although the control of these maturational changes is unknown.
Close to term, glucocorticoids induce enzyme activity in many fetal tissues in preparation for delivery and extrauterine life (Fowden et al. 1998). Indeed, in the sheep and horse fetus, the rise in plasma ACE seen towards term closely parallels the prepartum increase in plasma cortisol concentration (Forhead et al. 1998, 2000b). Glucocorticoids have been shown to stimulate ACE gene transcription and protein synthesis in adult vascular cells in vitro (Mendelsohn et al. 1982; Dasarathy et al. 1992; Fishel et al. 1995), although their role in the ontogenic changes in tissue and circulating ACE concentrations in utero has not been established.
Therefore, the aims of the present study were (a) to examine the ontogeny of ACE concentration in the lungs and kidneys of fetal, newborn and adult sheep, and (b) to investigate the effects of cortisol infusion on tissue and plasma ACE concentrations in the ovine fetus.
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METHODS |
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Animals
Seven Welsh Mountain lambs, six non-pregnant adult ewes and thirty-four ewes carrying fetuses of a known gestational age were used in this study. Twenty-four of the pregnant ewes carried twins while the remainder had single fetuses. All adult animals were maintained on 200 g day-1 concentrates with free access to hay, water and a salt-lick block. The lambs were aged between 1 and 7 days and were suckled naturally by their mothers.
Surgical procedure
Under halothane anaesthesia (1·5 % in O2-N2O) with positive pressure ventilation and using surgical techniques described previously (Comline & Silver, 1972), forty-three of the fetuses were catheterised at least 5 days before the study began (Table 1). Food, but not water, was withheld for 18-24 h before surgery. Catheters were inserted into the femoral artery of the ewe and into the femoral artery and vein of the fetus. All catheters were exteriorised through the flank of the ewe and secured in a plastic bag sutured to the skin. From the day after surgery, the catheters were flushed daily with heparinised saline solution (100 i.u. ml-1 heparin in 0·9 % saline). Antibiotic (procaine penicillin, Depocillin, Mycofarm, Cambridge, UK) was administered I.M. to all ewes on the day of surgery and for 3 days thereafter. The fetuses were given 100 mg ampicillin (Penbritin, Beecham Animal Health, Brentford, UK) and 2 mg gentamicin (Frangen-100, Biovet Ltd, Mullingar, Ireland) I.V. at surgery.
Table 1. The numbers and gestational ages of the fetuses used in the different treatment groups
| Treatment | Gestational age (days) | No. of fetuses |
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| At catheterisation | At delivery | ||
| Saline infusion | 97-104 | 111-114 | 6 |
| 115-119 | 127-132 | 16 | |
| Cortisol infusion | 97-104 | 111-114 | 6 |
| 115-118 | 127-132 | 15 | |
| Untreated | - | 142-145 | 7 |
Experimental procedure
Tissues were collected from the fetuses at one of three gestational age ranges (term = 145 ± 2 days, mean ± S.E.M.; Table 1): mean gestational ages for the three groups were 113 ± 1 (n = 12), 129 ± 1 (n = 31) and 143 ± 1 (n = 7) days. Six of the fetuses delivered at 113 days and 15 of the fetuses delivered at 129 days had been infused with cortisol (2-3 mg kg-1 day-1 I.V.) for the previous 5 days; the remainder of the fetuses at these two gestational ages were infused with saline at the same rate (0·9 % NaCl, 2·5 ml day-1; Table 1). All of the fetuses were delivered by Caesarean section under general anaesthesia (20 mg kg-1 sodium pentobarbitone I.V.) and tissues were collected after administration of a lethal dose of barbiturate. Lungs and kidneys taken from the fetuses were immediately frozen in liquid nitrogen and stored at -80°C until analysis.
Umbilical arterial blood samples (4-5 ml) were taken from all of the fetuses at delivery and placed into EDTA-containing tubes for the measurement of plasma cortisol. The plasma ACE concentration could not be measured in samples containing EDTA as ACE activity requires the presence of zinc. In five of the saline-infused fetuses and six of the cortisol-infused fetuses delivered at 129 days, daily arterial blood samples (4-5 ml) were taken from the indwelling catheters from 2 days before and throughout the infusion. These blood samples were collected into heparin-containing tubes for the measurement of plasma cortisol and ACE. All blood samples were centrifuged at 1000 g and 4°C for 5 min, and the plasma was removed and stored at -20°C until analysis.
Pulmonary and renal tissues were collected from the lambs and non-pregnant adult ewes immediately after administration of a lethal dose of sodium pentobarbitone (200 mg kg-1 I.V.).
Biochemical analyses
Tissue and plasma ACE concentrations were determined by an enzyme assay adapted from Raimbach & Thomas (1990) and Hurst & Lovell-Smith (1981). Samples of lung (1 g fetal and neonatal, 250 mg adult tissue; random regions of lung) and kidney (500 mg renal cortex from all animals) were homogenised by hand in 5 ml ice-cold buffer (0·25 M H3BO3, 2·5 M NaCl, pH 8·3) and freeze-dried overnight. Each sample was resuspended in 2 ml deionised water and centrifuged at 33 000 g and 4°C for 10 min. The supernatant was removed and stored at -20°C until analysis. The remaining pellet was homogenised in 2 ml deionised water a second time and the supernatant removed after centrifugation as before. The concentration of ACE was determined in each supernatant and these two values were combined to give the tissue ACE concentration. Tissue protein content was measured in the original homogenate by the Lowry method (Lowry et al. 1951).
Tissue extracts and plasma samples were incubated in the presence of excess hippuryl-L-histidyl-L-leucine (20 mM HHL, Sigma Chemical Company, Poole, UK), a synthetic substrate of ACE. Tubes containing 25-50 µl of plasma or homogenate sample, 100 µl deionised water, 250-275 µl buffer (0·25 M H3BO3, 2·5 M NaCl, pH 8·3) and 100 µl HHL were incubated in a waterbath at 37°C for 15 min. The reaction was terminated by the addition of 500 µl hydrochloric acid (1 M HCl). Each sample analysed was accompanied by a tube of sample to which hydrochloric acid was added before the incubation with HHL ('sample blank'); the amount of hippurate generated in these 'sample blank' tubes was subtracted from that measured in the samples. Once the reaction had been terminated, 500 µl sodium hydroxide (1 M NaOH), 2 ml phosphate buffer (0·22 M KH2PO4, pH 8·3) and 1·5 ml colour reagent (0·16 M cyanuric chloride in 1,4-dioxane) were added to all tubes and these were centrifuged at 2000 g for 10 min. The absorbance of the supernatant was measured at 382 nm using a double-beam spectrophotometer and hippurate concentration was determined from a standard curve (20-100 µM hippurate). Addition of captopril to the incubation mixture abolished the ACE-induced production of hippurate. The intra- and inter-assay coefficients of variation were 3·6 and 4·3 %, respectively. Tissue ACE concentration was expressed as nanomoles of hippurate generated per minute per milligram protein, while plasma ACE concentration was measured in units per litre where 1 unit equals 1 µmol of hippurate generated in 1 min.
Plasma cortisol concentration was determined by radioimmunoassay as described previously (Robinson et al. 1983). The intra- and inter-assay coefficients of variation were 8·5 and 11·8 %, respectively, and the lower limit of detection was 1·0-1·5 ng ml-1.
Statistical analysis
All data are presented as means ± S.E.M. of n samples. Statistical differences in the variables measured between the fetuses, lambs and adult ewes were determined by factorial ANOVA followed by the Tukey test. Statistical differences between fetuses of different treatment groups were assessed by Student's unpaired t test. Within-group changes in plasma cortisol and ACE in the saline and cortisol-infused fetuses were determined by ANOVA for repeated measures followed by the Dunnett's test, and differences between the two groups of infused fetuses at individual time points were assessed by factorial ANOVA. Relationships between the variables measured were analysed by Pearson and partial correlations. Differences where P < 0·05 were regarded as significant.
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RESULTS |
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Ontogeny of pulmonary and renal ACE concentrations
In the fetuses, pulmonary and renal ACE concentrations increased significantly near term (P < 0·001 in both cases, Fig. 1A and B); peak tissue ACE concentrations were observed in the fetuses studied at 143 days of gestation (Fig. 1A and B). When values from all untreated and saline-infused fetuses were combined, significant relationships were seen between gestational age and both pulmonary (r = 0·79, n = 29, P < 0·0001) and renal ACE (r = 0·49, n = 25, P < 0·05) concentrations.
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Mean (± S.E.M.) concentrations of pulmonary ACE (A), renal ACE (B) and plasma cortisol (C) in fetuses at 113, 129 and 143 days of gestation, and in lambs and adult ewes. Columns with different letters are significantly different from each other (P < 0·05). NA, not available. | ||
The ontogenic increments in pulmonary and renal ACE in the fetuses coincided with the prepartum rise in plasma cortisol (Fig. 1). Overall, irrespective of gestational age, plasma cortisol concentration correlated significantly with tissue ACE concentrations in both the fetal lungs (r = 0·83, n = 29, P < 0·0001; Fig. 2) and kidneys (r = 0·53, n = 25, P < 0·01). Partial correlation analysis showed that, in the lungs, the circulating cortisol concentration (r = 0·57, P < 0·01) was a more important determinant of ACE content than gestational age (r = 0·42, 0·01 < P < 0·05), whereas, in the kidneys, ACE concentration was not correlated with either plasma cortisol or gestational age when independent of the other variable (r = 0·27 and 0·15, respectively, P > 0·05 in both cases).
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Relationship between plasma cortisol and pulmonary ACE concentrations in untreated and saline-infused fetuses at a range of gestational ages (r = 0·83, n = 29, P < 0·0001). | ||
The high level of ACE seen in the fetal lungs close to term was maintained in the lambs and adult ewes (Fig. 1A). No significant difference in pulmonary ACE concentration was observed between fetuses at 143 days of gestation, lambs and adult ewes (Fig. 1A). In contrast, a decrease in renal ACE concentration was seen over the perinatal period (Fig. 1B). Renal ACE concentration in the lambs was significantly lower than that in the fetuses near term (P < 0·05; Fig. 1B). A further increase in ACE concentration was observed in the ovine kidneys later in life: renal ACE concentration in the adult ewes was significantly greater than that in the lambs (P < 0·05; Fig. 1B).
Effect of cortisol infusion on pulmonary and renal ACE concentrations in utero
At both 113 and 129 days of gestation, an exogenous infusion of cortisol significantly increased the plasma cortisol concentration to within the range of values seen in fetuses close to term (Fig. 3C). Plasma cortisol concentration in the cortisol-infused fetuses was significantly greater than that observed in the saline-infused fetuses at the same gestational age (P < 0·0001 at both ages; Fig. 3C), and was similar to that seen in the untreated fetuses at 143 days of gestation (Fig. 3C).
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Mean (± S.E.M.) concentrations of pulmonary ACE (A), renal ACE (B) and plasma cortisol (C) in saline- ( | ||
In both groups of cortisol-infused fetuses, pulmonary ACE concentration was increased to values significantly greater than that seen in their respective groups of saline-infused fetuses (P < 0·01 at both ages; Fig. 3A). However, only at 129 days did the cortisol infusion increase pulmonary ACE concentration to the level seen in the fetuses near term (Fig. 3A). In the fetuses infused with cortisol at 113 days, pulmonary ACE concentration was significantly lower than that observed in the fetuses near term (Fig. 3A). At both 113 and 129 days of gestation, raising plasma cortisol by exogenous infusion had no effect on ACE concentration in the fetal kidneys (Fig. 3B): renal ACE concentration was similar in the saline- and cortisol-infused fetuses at both gestational ages (Fig. 3B).
Effect of cortisol infusion on plasma ACE concentration in utero
In the fetuses studied at 129 days, an exogenous infusion of cortisol also increased the plasma ACE concentration (P < 0·0001, Fig. 4B). Small, but significant, increments in plasma cortisol and ACE were also observed in the saline-infused fetuses during the 5 day period of infusion (P < 0·05 in both cases; Fig. 4). However, on each day of the infusion, plasma cortisol concentration in the cortisol-infused fetuses was significantly greater than that seen in the saline-infused fetuses (P < 0·001 on all days; Fig. 4A). No significant difference in the absolute value of the plasma ACE concentration was observed between the two treatment groups at any time point (Fig. 4B). However, the rise in plasma ACE from baseline was significantly greater in the cortisol-infused fetuses compared to the saline-infused fetuses on days 1 and 5 of the infusion (P < 0·05 on both days; Fig. 4C). Overall, when daily values from all fetuses were combined, a weak, but significant, correlation was observed between plasma concentrations of cortisol and ACE (r = 0·24, n = 88, P < 0·05). In these animals, no significant relationships were identified between plasma ACE and either pulmonary (r = 0·41, n = 11, P > 0·05) or renal ACE (r = 0·53, n = 11, P > 0·05) on the day of delivery.
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Mean (± S.E.M.) plasma concentrations of cortisol (A) and ACE (B), and the mean (± S.E.M.) change in plasma ACE (C) concentration from baseline during infusion of saline ( | ||
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DISCUSSION |
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The present study showed that ACE concentration in the lungs and kidneys of the sheep fetus increased close to term. The high concentration of pulmonary ACE observed in the mature fetus resembled that seen in neonatal and adult animals, while renal ACE concentration decreased immediately after birth before increasing to a maximal value in adult life. Similar developmental increases in pulmonary ACE have been observed in utero in a variety of other species (Kokubu et al. 1977; Wallace et al. 1979; Sim & Seng, 1984; Raimbach & Thomas, 1990). In sheep, this study is the first report of developmental changes in tissue ACE concentration, although the metabolism of AI and bradykinin in the lungs has been shown previously to increase from fetal to adult life (Hebert et al. 1972; Friedli et al. 1973). Before birth, the lungs are poorly perfused compared to the adult animal whereas the placenta and fetal membranes are well vascularised and are known to contain significant amounts of ACE (Wigger & Stalcup, 1978; Sim & Seng, 1984). Therefore, with the loss of the placenta at birth, the lungs need to contain sufficient ACE to maintain the normal activities of the RAS and kallikrein-kinin systems in the neonate. In the current study, the peak pulmonary ACE concentration seen in the fetus at term was maintained after birth and into adult life. However, the measurement of systemic pressor responses to AII and bradykinin injected either before or after the pulmonary circulation suggests that although the metabolic function of the lungs increases in the sheep fetus with gestational age, it is still relatively immature at birth and develops further during the postnatal period (Hebert et al. 1972; Friedli et al. 1973). In addition, it has been shown that the ability of the lungs to hydrolyse a synthetic substrate for ACE in vivo increases from 50 % in the lamb to 80 % in the adult animal (Pitt & Lister, 1983). Tissue ACE concentration measured in the present study may not be readily available to the circulating substrates in vivo. For instance, there may be changes in pulmonary blood flow during the postnatal period which expose more of the blood to regions of the lungs with abundant ACE content.
Pulmonary expression of ACE and local changes in AII concentration may have an important role in the maturation of the lungs over the perinatal period. Angiotensin II is known to stimulate vascular smooth muscle cell growth and proliferation both directly and via the actions of locally produced growth factors (Berk et al. 1989; Delafontaine & Lou, 1993; Su et al. 1998). In fetal rabbits, the amount of ACE present in the lungs has been shown to progressively increase with vascularisation (Wigger & Stalcup, 1978). Furthermore, in rats in which the major rise in pulmonary ACE concentration occurs after birth, both vascular ACE activity and AII type 1 receptor mRNA abundance correlate closely with the development and muscularisation of the pulmonary arterial circulation (Morrell et al. 1996). Indeed, a close temporal and spatial association was observed between the vascular expression of ACE and 
-actin, an early marker for smooth muscle differentiation (Morrell et al. 1996).
In the current study, significant amounts of ACE were present in the kidneys of the sheep fetus during late gestation. At 113 days, the concentration of ACE was approximately forty times higher in the kidneys than lungs when expressed per milligram of tissue protein. At 129 and 143 days of gestation, renal ACE was approximately four times higher than pulmonary ACE. Previous studies have demonstrated the importance of ACE and the RAS in normal renal growth and development (Niimura et al. 1995; Tufro-McReddie et al. 1995; Hilgers et al. 1997) and have detected ACE mRNA in the ovine mesonephros and metanephros from as early as 41 days of gestation (Wintour et al. 1996). Within the human fetal kidney, ACE has been localised to the basolateral and apical membranes of epithelial cells of the proximal tubules and to glomerular endothelial cells (Mounier et al. 1987). However, the distribution of ACE in the renal vasculature changes over the perinatal period such that, in childhood and adult life, ACE is found in the proximal tubules and in the peritubular, but not the glomerular, capillaries (Mounier et al. 1987). The transient expression of ACE in the glomerulus during fetal life may have an important role in glomerular development and may account for the perinatal change in renal ACE concentration observed in the present study. In rats, renal ACE activity and gene expression are known to increase from birth to weaning before decreasing to the value seen in the adult animal (Costerousse et al. 1994).
The ontogenic increases in pulmonary and renal ACE concentration seen in the sheep fetus towards term coincided with the prepartum rise in plasma cortisol. Indeed, significant correlations were observed between tissue ACE and plasma cortisol concentrations in utero. Glucocorticoids have been shown previously to stimulate ACE gene expression and protein synthesis in adult pulmonary artery and aortic endothelial cells, aortic smooth muscle cells and alveolar macrophages in vitro (Friedland et al. 1977; Mendelsohn et al. 1982; Dasarathy et al. 1992; Fishel et al. 1995). Indeed, a glucocorticoid-response element has been identified in a regulatory region of the ACE gene (Shai et al. 1990). In the current study, the effects of cortisol infusion on tissue ACE concentration in the sheep fetus were tissue specific. At both 113 and 129 days, prematurely raising the plasma cortisol concentration to within the range of values seen close to term caused an approximate doubling in pulmonary ACE concentration. These findings suggest that the developmental rise in ACE concentration in the lungs of sheep fetus near term is induced, at least in part, by the prepartum cortisol surge. This is consistent with the many other known maturational effects of the glucocorticoids on the fetal lungs close to term (Fowden et al. 1998). However, only at 129 days did the concentration of pulmonary ACE in the cortisol-infused fetuses reach a level similar to that seen in the fetuses studied at 143 days of gestation.
In contrast, exogenous cortisol had no influence on renal ACE concentration at either gestational age studied. The rise in ACE seen in the kidneys near term may therefore be independent of the prepartum cortisol surge. In ovine fetal kidneys, the gene expression and enzyme activity of 11
-hydroxysteroid dehydrogenase type 2 (11-HSD2), which metabolises cortisol to inactive cortisone, are known to increase from 85 days to peak levels at term (Langlois et al. 1995; Wood & Srun, 1995). In contrast, low 11-HSD activity has been detected in the lungs of fetal sheep over the same period of gestation (Wood & Srun, 1995). Therefore, compared to the fetal ovine lungs, the kidneys may be exposed to less cortisol at the cellular level. Alternatively, exogenous cortisol may have been ineffective at these early gestational ages because of deficiencies in either glucocorticoid receptors and/or the secondary mechanisms mediating the glucocorticoid action on ACE. In sheep, the glucocorticoid receptor mRNA level in the fetal kidneys remains unchanged throughout gestation before decreasing after birth (Yang, 1992). However, to date, the ontogeny of the receptor protein has not been quantified in the fetal kidneys of this species.
The ontogenic increments in pulmonary and renal ACE observed in the sheep fetus near term may be partly responsible for the rise in plasma ACE seen in utero in a number of species, including the sheep (Raimbach & Thomas, 1990; Forhead et al. 1998, 2000b). Circulating ACE appears to originate from proteolytic cleavage of the membrane-bound enzyme from the tissues (Skidgel & Erdos, 1993), and, hence, its plasma concentration is likely to be determined by tissue ACE synthesis and/or enzyme release into the blood. The regulation of the proteolytic cleavage of the tissue enzyme is unclear. However, the cortisol-induced rise in pulmonary ACE concentration might be expected to cause a significant increase in plasma ACE in these fetuses. The circulating concentration of ACE was increased by 5 days of cortisol infusion but it did not reach the high level seen in the sheep fetus close to term (50·5 ± 2·9 U l-1, Forhead et al. 1998). Therefore, the prepartum cortisol surge may be only one of the factors responsible for the ontogenic rise in plasma ACE in utero.
Finally, the present findings may provide a mechanism for the glucocorticoid-induced hypertension observed in utero. Previous studies have shown that cortisol increases blood pressure in fetal sheep partly via activation of the RAS (Tangalakis et al. 1992; Forhead et al. 2000a). A cortisol-induced increase in pulmonary ACE concentration may contribute to the hypertension observed in these studies and may explain, in part, the high blood pressure seen in adult animals exposed to glucocorticoids in utero (Seckl, 1998).
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The authors are grateful to Paul Hughes and Malcolm Bloomfield for technical assistance, and to Sue Nicholls for the care of the animals. This work was funded by The Birth Defects Foundation, UK. A.J.F. was in receipt of a Research Lectureship from Newnham College, Cambridge.
Corresponding author
A. J. Forhead: Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Email: ajf1005{at}cam.ac.uk
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) and cortisol-infused (
) fetuses. * P < 0·05, significantly different from saline-infused fetuses at the same gestational age.
) and cortisol (
) into sheep fetuses delivered at 129 days. The bar denotes the period of infusion. Time points with different letters are significantly different from each other (P < 0·05); lowercase letters refer to values from saline-infused fetuses while uppercase letters refer to values from cortisol-infused fetuses. * P < 0·05, significantly different from saline-infused fetuses at the same gestational age.