Karen J. Gibson

The selfish brain and the barker hypothesis.

1. Brain sparing is a feature of intra‐uterine growth retardation (IUGR). This implies that there is a redistribution of metabolic supply so that body growth slows to a greater extent than brain growth.

EFFECTS OF LOSARTAN ON THE CARDIOVASCULAR SYSTEM, RENAL HAEMODYNAMICS AND FUNCTION AND LUNG LIQUID FLOW IN FETAL SHEEP

1. The angiotensin type 1 (AT1) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125–132 days gestation). Losartan reduced the fetal systolic (P < 0.01) and diastolic (P < 0.01) pressor response to 5 μg angiotensin II (AngII) i.v. from 27.4 ± 1.5 to 7.4 ± 0.9 and from 17.5 ± 1.3 to 5.4 ± 0.6 mmHg, respectively, after 1h and to 6.1 ± 0.5 and 4.4 ± 0.5 mmHg, respectively, after 2h. Maternal pressor responses to 5 μg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P < 0.05) after losartan administration, but fetal heart rate did not change.

EFFECTS OF HYPOXAEMIA ON FOETAL HEART RATE, VARIABILITY AND CARDIAC RHYTHM

1. Experiments were carried out in 30 chronically catheterized foetal sheep (128‐144 days; term 150 days) and in seven of these foetuses before, during and after acute hypoxaemia. The extent to which changes in sympathoadrenal activity and cardiac vagal activity affected the foetal cardiac response to hypoxaemia was measured. Three measurements were used: foetal heart rate (FHR), heart rate variability (HRV; measured as the coefficient of variation in pulse interval) and power spectral density (PSD; measured over the frequency ranges of 0.04‐1.3 Hz). Cardiac vagal activity was blocked by atropine, β‐adrenoceptor activity was blocked by propranolol.

Effects of intrafetal IGF-I on growth of cardiac myocytes in late-gestation fetal sheep

Intrafetal insulin-like growth factor (IGF)-I promotes cardiac hypertrophy in the late-gestation fetal sheep; whether these effects are sustained is unknown. IGF-I was infused for 4 days at 80 microg/h from 121 to 125 days of gestation, and its effects at 128 days, 3 days after the infusion stopped, were determined by comparison with untreated fetal sheep. After IGF-I treatment, fetal weights were similar to those in control fetuses but kidney weights were bigger (P < 0.05), as were spleen weights of male fetuses (P < 0.05). Cardiac myocytes were larger in female than male fetal sheep (P < 0.001). IGF-I increased male (P < 0.001) but not female myocyte volumes. IGF-I did not alter the proportions of uni- or binucleated right or left ventricular myocytes. Female fetal sheep had a greater proportion of binucleated cardiac myocytes than males (P < 0.05). IGF-I-treated fetuses had a slightly greater proportion of right ventricular nuclei in cell cycle phase G(2)/M and a reduced proportion of G(0)/G(1) phase nuclei (P < 0.1). Therefore, evidence for IGF-I-stimulated cardiac cell hyperplasia in fetal sheep in late gestation was limited. In conclusion, the greater sizes and larger proportion of binucleated cardiac myocytes in female fetal sheep suggest that myocyte maturation may occur earlier in females than in males. This may explain in part the male sex-specific responsiveness of cardiac hypertrophy to IGF-I in late gestation. If IGF-I-stimulated cardiomyocyte growth is accompanied by maturation of contractile function, IGF-I may be a potential therapeutic agent for maintaining cardiac output in preterm males.

Effects of glucocorticoid exposure on growth and structural maturation of the heart of the preterm piglet.

Inadequate maintenance of systemic blood flow in neonates following preterm birth is associated with increased morbidity and mortality, and may be due in part to structural immaturity of the myocardium. Maternal glucocorticoid administration is associated with improved cardiovascular function, and possibly promotes structural maturation of the myocardium. This study assessed the structural maturity of the myocardium in male and female preterm and term piglets, and preterm piglets exposed to a regimen of maternal glucocorticoids as used clinically. In preterm, term and glucocorticoid exposed preterm piglets cardiomyocyte maturity was examined by measuring the proportion of binucleated myocytes and the volumes of single living ventricular cardiomyocytes with fluorescence microscopy. Ventricular apoptosis and proliferation were measured by immunohistochemistry. Preterm piglet hearts had fewer binucleated myocytes, smaller myocytes, and more proliferative and fewer apoptotic nuclei than term hearts. Maternal glucocorticoid treatment resulted in increased binucleation with no increase in myocyte volume, and levels of proliferation and apoptosis that were more similar to the term heart. Atrial weights were increased and in female piglets there was an increase in the ratio of left to right ventricular weight. The observed changes in atrial mass and myocyte structural maturation correlated with changes in cardiac function of isolated hearts of littermates. In conclusion, the association between increased myocardial maturation following glucocorticoid exposure, improved cardiac function in littermates, and clinical improvement in human neonatal cardiac function exposed to antenatal glucocorticoids, suggests that glucocorticoid exposure contributes to improved cardiovascular function in preterm infants by promoting myocardial structural maturity.

Mechanisms by which the pregnant ewe can sustain increased salt and water supply to the fetus.

1. Nine chronically catheterized pregnant ewes were monitored before, during and after 1 week in which fetal urine was drained continuously, to determine whether they could compensate for the resulting loss of salt and water and increase net supply across the placenta to the fetus. 2. Fetal growth and urine and lung liquid production were not affected by loss of all fetal fluids. 3. When fetal urine was drained, the increase (P less than 0.05) in maternal drinking was greater than the extra amount of fluid lost. Thus, maternal plasma osmolality fell (P less than 0.01). When fetal urine again flowed into the amniotic and allantoic cavities, maternal drinking did not fall significantly and plasma osmolality remained low. Maternal urine flow rate increased (P less than 0.05) and its osmolality fell (P less than 0.02). 4. Maternal food intake increased (P less than 0.005) during fetal urine drainage. 5. Maternal plasma renin activity increased (P less than 0.05), her urinary sodium excretion fell (P less than 0.005) and the Na(+)‐K+ ratio in both her urine and faeces decreased (P less than 0.01 and P less than 0.05 respectively) when fetal urine was drained. Maternal urinary and faecal sodium conservation continued after drainage ceased because of continued loss of sodium in lung liquid. 6. It is concluded that the ewe can compensate for inappropriate loss of salt and water from the conceptus.

The effects of asphyxia on renal function in fetal sheep at midgestation

To determine whether damage to the fetal kidneys plays a role in the formation of hydrops fetalis following a severe asphyxial episode, six chronically catheterised fetal sheep, at 0.6 gestation (90 days; term 150 days), were subjected to 30 min of complete umbilical cord occlusion. During the occlusion period, mean arterial pressure, heart rate and renal blood flow decreased (P < 0.001). There were falls in arterial pH and PO2 and a rise in PCO2 (P < 0.001). Urine flow rate decreased (P < 0.005), as did the excretion rates of sodium and osmoles (P < 0.05). However, by 60 min after release of occlusion, urine flow rate was similar to control values. By the end of day 1, most renal variables returned to normal. At post‐mortem, 72 h after occlusion, all asphyxiated fetuses showed gross signs of hydrops. Body weight was higher (P < 0.05) due to fluid accumulation in the peritoneal (P < 0.001) and pleural cavities (P < 0.05) as well as subcutaneously (P < 0.05). Amniotic/allantoic fluid volume was increased (P < 0.05). Kidney histology was normal except for clusters of apoptotic cells in some proximal tubules. In conclusion, this severe asphyxial episode caused surprisingly little damage to the kidney and the changes in renal function were very transient. Thus renal damage was not important in the development of hydrops. Possibly, the midgestation fetal kidney has a limited capacity to increase urinary salt and water excretion in response to increased fluid delivery across the placenta.

Insulin‐like growth factor I alters renal function and stimulates renin secretion in late gestation fetal sheep

1 While it is known that treatment with insulin‐like growth factor I (IGF‐I) stimulates growth of the fetal kidney, nothing is known about the short term or long term effects of IGF‐I on fetal renal function. To investigate the acute effects of IGF‐I on fetal renal function and on the activity of the fetal renin‐angiotensin system, studies were carried out in 12 chronically catheterized fetal sheep aged 120 ± 1 days, before and during a 4 h I.V. infusion of IGF‐I at 80 μg h−1. Seven control fetuses were infused over the same period with vehicle (0.1% bovine serum albumin in 0.15 M saline). 2 IGF‐I infusion increased plasma IGF‐I concentrations by about 80%. There was a small fall in arterial PO2 (P < 0.01), arterial PCO2 increased (P < 0.05), plasma lactate levels increased (P < 0.01) and arterial pH fell (P < 0.05). Fractional bicarbonate reabsorption increased and bicarbonate excretion decreased (P < 0.05). 3 Infusions of IGF‐I had no sustained effect on fetal arterial pressure. Glomerular filtration rate (GFR) did not change significantly during IGF‐I infusion, but renal blood flow (RBF) fell (P < 0.05). Therefore filtration fraction relative to control values increased (P < 0.05), suggesting that efferent arteriolar vasoconstriction had occurred. 4 IGF‐I infusion led to an antidiuresis (P < 0.01), a rise in urinary osmolality (P < 0.05) and a fall in free water clearance (P < 0.01). Since fetal PO2 fell, it is probable that these effects were mediated by arginine vasopressin. 5 The excretion rates of sodium, chloride and phosphate were all reduced by 4 h of infusion (P < 0.05), because their fractional reabsorption rates were all increased (sodium, P < 0.01; chloride, P < 0.01; and phosphate, P < 0.05). 6 Plasma renin concentration increased by 275 ± 52% during infusion of IGF‐I (P < 0.005). Plasma renin activity also increased (P < 0.005), while circulating angiotensinogen concentrations fell (P < 0.05). 7 In the adult, IGF‐I increases both RBF and GFR, enhances tubular reabsorption and stimulates the renin‐angiotensin system. In the fetus, however, it decreased RBF and had no effect on GFR, but was associated with enhanced tubular function and intense stimulation of renin secretion. Some of these effects of IGF‐I on fetal renal function may be involved in maturation of the kidney in preparation for life after birth.

Comparison of the transplacental transfer of enalapril, captopril and losartan in sheep.

1 The transplacental transfers of three drugs (enalapril, captopril and losartan) which block the renin angiotensin system and have different lipophilicities were studied in chronically catheterized foetal sheep (125–139 days gestation).

Expression of adrenoceptor subtypes in preterm piglet heart is different to term heart.

Preterm delivery increases the risk of inadequate systemic blood flow and hypotension, and many preterm infants fail to respond to conventional inotrope treatments. If the profile of cardiac adrenoceptor subtypes in the preterm neonate is different to that at term this may contribute to these clinical problems. This study measured mRNA expression of β1, β2, α1A, α2A and α2B-adrenoceptor subtypes by real time PCR in term (113d), preterm (91d) and preterm piglets (91d) exposed to maternal glucocorticoid treatment. Abundance of β-adrenoceptor binding sites in the left ventricle was measured using saturation binding assays. Relative abundance of β1-adrenoceptor mRNA in untreated preterm hearts was ∼50% of term abundance in both left and right ventricles (P<0.001). Trends in receptor binding site density measurements supported this observation (P = 0.07). Glucocorticoid exposure increased β1-adrenoceptor mRNA levels in the right ventricle of preterm hearts (P = 0.008) but did not alter expression in the left ventricle (P>0.1). Relative abundance of α1A-adrenoceptor mRNA was the same in preterm and term piglet hearts (P = >0.1) but was reduced by maternal glucocorticoid treatment (P<0.01); α2A-adrenoceptor mRNA abundance was higher in untreated and glucocorticoid exposed preterm piglet hearts than in term piglets (P<0.001). There was no difference between male and female piglets in mRNA abundance of any of the genes studied. In conclusion, there is reduced mRNA abundance of β1-adrenoceptors in the preterm pig heart. If this lower expression of β-adrenoceptors occurs in human preterm infants, it could explain their poor cardiovascular function and their frequent failure to respond to commonly used inotropes.