Effects of pancreatectomy on the growth and metabolite concentrations of the sheep fetus.

The effects of fetal pancreatectomy on the growth and metabolism of the fetal sheep were investigated in chronically catheterized animals during the last third of gestation. Fetal pancreatectomy reduced body weight and crown-rump length at delivery near term (term 145 days). Body weight was affected more than body length so the ratio of weight to length was significantly less after pancreatectomy than in intact animals (P less than 0.05). Pancreatectomized fetuses appeared to maintain a normal growth rate for 5-10 days after surgery but thereafter showed no further significant increase in body weight. When all the data from the intact and pancreatectomized fetuses were combined, there was a significant positive correlation between the plasma insulin concentration in utero and the body weight at delivery near term. The majority of organs studied were reduced in absolute weight after pancreatectomy but only the spleen and thymus were proportionally lighter when the weights were expressed as a percentage of body weight. Brain and placental weights were similar in intact and pancreatectomized fetuses. Over the range of values observed in utero, there were significant inverse correlations between the log plasma insulin level and the mean plasma concentrations of glucose, lactate, fructose and alpha-amino-nitrogen in individual intact and pancreatectomized fetuses. Insulin infusion into pancreatectomized fetuses restored the metabolite concentrations to their normal values within 48 h of infusion. The results demonstrate that insulin has a vital role in regulating fetal growth and metabolism in utero.

Pancreatic alpha cell function in the fetal and newborn pig.

Plasma glucagon concentrations were measured in chronically catheterized fetal pigs during the last third of gestation and compared with the values observed in anaesthetized fetuses of similar gestational age. The mean plasma concentration of glucagon in the chronically catheterized fetuses was 10.0 +/- 1.4 (S.E.M.) pmol/l (n = 11; term = 114 +/- 2 days). Concentrations were increased after catheterization and fell to baseline values within 48 h of surgery. Arginine infusion evoked a rapid release of glucagon in chronically catheterized fetuses between 105 and 108 days of gestation; the mean maximum increment in plasma glucagon was 15.4 +/- 4.5 pmol/l (n = 5). Plasma glucagon concentrations increased with increasing gestational age in both anaesthetized and chronically catheterized fetuses. Between 95 and 110 days of gestation, glucagon levels were significantly higher in anaesthetized fetuses than in chronically catheterized animals with similar normal pH values. Catheterization and prematurity had no apparent effect on plasma glucagon levels at birth. The plasma concentrations at birth were similar to those observed in the chronically catheterized fetuses in utero provided the piglets did not become acidotic during delivery. Significantly higher plasma levels of glucagon were found in newborn piglets with acidaemia (pH less than 7.3) than in piglets with normal pH values at birth (pH greater than 7.3). When all the data from the newborn piglets were combined, there was a significant negative correlation (r = -0.79, n = 39, P less than 0.01) between blood pH and the plasma concentration of glucagon at birth. These observations demonstrate that the fetal alpha cells are functional and responsive in utero and at birth.

Fetal and maternal endocrine changes during the induction of parturition with the PGF analogue, cloprostenol, in chronically catheterized sows and fetuses.

Parturition was induced in 8 catheterized sows 24-27 h after a single injection of the prostaglandin F (PGF) analogue, cloprostenol (200 micrograms, intramuscular), given at 105-106 days (4 sows) and 109-111 days (4 sows); term = 115 days. All catheterized fetuses were in good condition during the course of the induction and a normal percentage of live births occurred, although the subsequent viability of the piglets appeared to depend on the presence of an adequate suckling reflex. Maternal endocrine changes following cloprostenol included: (1) a rapid drop in plasma progesterone, which fell to below 5 ng/ml within 4 h, (2) a subsequent rise in 13, 14 dihydro-15-oxo prostaglandin F (PGFM) at about 6 h, with an increase in the venous-arterial difference across the uterus, (3) a large prepartum rise in PGFM from about 12 h, (4) a transient rise and fall in plasma cortisol immediately after the cloprostenol and a subsequent rise during labour, and (5) no detectable change in total unconjugated plasma oestrogen. During failed induction (2 sows) maternal progesterone levels remained above 5 ng/ml. In the fetuses, no changes in plasma progesterone were detectable following cloprostenol or during labour although there was a significant increase at birth. Fetal plasma cortisol concentrations had increased significantly 2 h after the cloprostenol, but a much greater cortisol surge began at 16-20 h reaching a maximum at birth. Fetal plasma oestrogen levels also increased just before delivery. These findings show that when farrowing is induced prematurely, the majority of the maternal endocrine changes are similar to those preceding spontaneous labour. However, the gradual rise in fetal plasma cortisol, which normally begins 4-6 days before term, is circumvented; instead a very rapid fetal cortisol surge begins after rather than before the drop in maternal progesterone and rise in PGFM. This results in high neonatal plasma cortisol levels in both catheterized and non-operated piglets and may well account for their viability.

Pancreatic beta cell function in the fetal pig and sow.

Insulin secretion was investigated in acutely anaesthetized and chronically catheterized sows and their fetuses during late gestation. In the conscious animals, the mean fetal concentration of plasma insulin was 8.4 +/- 1.5 microunits/ml which was significantly less than the corresponding maternal value of 33.9 +/- 6.5 microunits/ml (n = 12, P less than 0.01). The plasma concentrations of insulin and glucose in the new-born piglets from these litters were not significantly different from the values observed in utero. The plasma concentration of insulin in the anaesthetized fetuses was significantly less than that in the chronically catheterized piglets over the same range of glucose levels. In the chronically catheterized animals, both fetal and maternal levels of insulin rose with increasing concentrations of plasma glucose while under acute conditions there was no correlation between the endogenous concentrations of insulin and glucose in either the fetuses or their mothers. Infusion of exogenous glucose (0.5 g as a 50% solution in 0.9% NaCl) stimulated the release of insulin in all the chronically catheterized fetuses studied but rarely increased the concentration of insulin in the anaesthetized fetusus. The present findings show that anaesthesia and surgery depress pancreatic beta cell function in the pig, particularly in the fetus.

Changes in plasma pancreatic polypeptide and gastrin in sows after eating and atropine.

Changes in plasma gastrin, pancreatic polypeptide and pulse rate were examined in three adult female pigs in which venous cannulae had been placed and in two of which arterial cannulae allowed sampling of arterial blood or recording of pulse rate. Gastrin, pancreatic polypeptide and pulse rate increased when the pigs ate after fasting overnight. Pancreatic polypeptide was reduced to or below resting levels following administration of atropine (25, 50 or 100 micrograms/kg intravenously) after which gastrin remained at about its previous levels or rose and pulse rates rose. It is concluded that in the pig, as in other species, there is a cholinergic muscarinic (atropine sensitive) mechanism contributing both to postprandial increases of pancreatic polypeptide and of gastrin.

Carbohydrate metabolism in the fetal pig during late gestation.

In acute experiments on pregnant sows under sodium pentobarbitone anaesthesia, acid base balance, oxygenation and plasma metabolite concentrations were well maintained in the dam and all fetuses which remained undisturbed in utero, irrespective of the duration of the experiment. Fetal liver glycogen concentrations were also unaffected by the time of removal of the fetus. By contrast, intravascular catheterization and withdrawal of blood led to fetal hyperglycaemia and depletion of hepatic glycogen although blood gas and pH values were not changed by these procedures. In the 1 1/2--2 h sampling period following catheterization the normal positive umbilical venous-arterial differences in plasma glucose and lactate generally became reversed. These changes were prevented by the administration of hexamethonium (10--15 mg . kg-1 i.v.) but the drug did not block the fall in hepatic glycogen in catheterized fetuses. Both adrenaline and noradrenaline, which were each infused intravenously at 2.7--3.9 or 0.6--0.9 microgram . kg-1 . min-1, resulted in fetal hyperglycaemia and lacticacidemia together with a fall in arterial blood pH; hepatic glycogen concentrations in these fetuses were also reduced. The apparent sensitivity of the glycogenolytic mechanism to surgical trauma and haemorrhage in the fetal piglet is discussed in relation to findings in other species.

Prostaglandins in maternal and fetal plasma and in allantoic fluid during the second half of gestation in the mare.

The concentrations of the primary prostaglandins (PG) F-2alpha and E-2 and the metabolite 13,14-dihydro-15-oxo-prostaglandin (PGFM) in maternal and fetal plasma and in allantoic fluid were measured in chronically catheterized mares and fetuses. A gradual rise in all 3 PGs occurred with increasing gestational age. PGE-2 and PGF-2 alpha levels were highest in the allantoic fluid and lowest in the maternal plasma, whereas PGFM concentrations were greatest in maternal plasma. Significant venous-arterial plasma differences in PGFM concentration were detected across the uterine circulation between 180 and 280 days gestation. The 3--5-fold rise in maternal PGFM associated with fasting or intrauterine surgery was virtually abolished by meclofenamic acid, a prostaglandin synthetase inhibitor. Increases in PGE-2 and PGF-2 alpha in the fetal fluids preceded premature delivery of the foal, while PG changes in maternal plasma were minimal even 10--20 h before delivery.

Effect of cortisol on liver glycogen concentrations in hypophysectomized, adrenalectomized and normal foetal lambs during late or prolonged gestation.

1. The changes in liver glycogen concentration in normal, adrenalectomized and hypophysectomized foetal lambs have been examined during the last third of gestation using a biopsy technique to remove one or more samples of liver from the same foetus at different gestational ages. 2. The rate of glycogen deposition increased sharply from about 130 days' gestation in normal lamb foetuses whereas after hypophysectomy or adrenalectomy liver glycogen concentrations remained low even when gestation was prolonged. 3. I.V. infusions of cortisol (4-10 mg/day) for 52 hr resulted in four- to fivefold increases in liver glycogen in all three groups of foetuses. The level of glycogen in the liver appeared to be related to log plasma corticosteroid concentration in all foetuses whether they had received cortisol infusions or not. 4. Little or no change occurred in glycogen concentration in other foetal tissues apart from a decrease in the glycogen levels in peri-renal fat of adrenalectomized and hypophysectomized foetuses after cortisol infusion. There were also no detectable changes in foetal plasma lactate, urea or alpha amino nitrogen following the cortisol infusions. Foetal plasma glucose values rose slightly but this change was significant only in the adrenalectomized group. 5. The 52 hr cortisol infusions to the foetus resulted in a slight but significant fall in maternal plasma progesterone in the last few hours of the infusion period.

The effects of bilateral adrenalectomy or hypophysectomy of the foetal lamb in utero.

1. Foetal hypophysectomy or bilateral adrenalectomy, carried out in utero at about 100 or 125 days gestation respectively, increased the length of gestation in sheep. It was confirmed that pregnancy was not prolonged significantly if hypophysectomy or adrenalectomy was carried out on one of a pair of twins. The hypophysectomized foetus was, however, smaller and the adrenalectomized foetus larger, than the unoperated twin. 2. In about half of the previously operated foetuses intravascular catheters were inserted into both mother and foetus, either at about 125 days, for a comparison with normal catheterized foetuses, or during the post-mature period. Both adrenalectomized and hypophysectomized foetuses appeared to have little resistance to stress or infection and the majority survived only 1-2 weeks after the insertion of catheters. 3. Maternal peripheral plasma oestrogen, progesterone and corticosteroid concentrations did not appear to be altered by either foetal hypophysectomy or adrenalectomy and were maintained in the normal range during prolonged gestation. 4. Foetal plasma oestrogen concentrations were significantly lower after hypophysectomy or adrenalectomy than values found in control lambs. Plasma progesterone values were low in all three groups of foetuses. 5. Plasma corticosteroid concentrations after foetal hypophysectomy (12-6 ng/ml.) or adrenalectomy (14-7 ng/ml.) were in the same range as the values for control lambs before the pre-partum rise (14-6 ng/ml.). However, there was a small but significant maternal-to-foetal plasma corticosteroid gradient in the two operated groups whereas this difference was not found in the control animals. 6. Tissue glycogen concentrations were measured in non-catheterized adrenalectomized and hypophysectomized foetuses. In these two groups, whether examined before 149 days or after prolonged gestation, liver glycogen concentrations were 30-40% of those in non-catheterized control foetuses at term. In other respects there was little apparent difference between adrenalectomized and control foetuses. 7. Hypophysectomized foetuses had significantly higher glycogen concentrations in heart, skeletal muscle and lung compared with control or adrenalectomized lambs. Plasma glucose and fructose values were also low in this group compared with control foetuses.

Plasma progestagens and oestrogens in fetus and mother in late pregnancy.

Normal Thoroughbred and catheterized Pony mares and their fetuses were used. Fetal oestrogen and progestagen concentrations in late gestation were much higher than maternal values. A major feature of the umbilical steroid concentrations was a large venous-arterial difference in progestagens and total oestrogens throughout late gestation which may indicate a metabolic cycle in the fetus between progesterone and other steroid metabolites. Metabolites of 20alpha-dihydroprogesterone were present in high concentrations in maternal and fetal plasma. In Thoroughbreds, and to a lesser extent in Pony mares, plasma progestagens rose towards parturition while total plasma oestrogen fell. The only oestrogen which showed a rise in concentration near term was oestradiol-17beta. In one Pony mare and fetus, fetal plasma progestagen fell 24 to 36 hr before parturition when maternal peripheral progestagen concentrations remained high.

A comparative study of blood gas tensions, oxygen affinity and red cell 2,3 DPG concentrations in foetal and maternal blood in the mare, cow and sow.

1. Blood gas tensions, pH, PCV, O(2) affinity and red cell 2,3-diphosphoglycerate (DPG) levels have been measured in uterine and umbilical blood in conscious cows and mares with indwelling vascular catheters and in sows under sodium pentobarbitone anaesthesia.2. Large P(O2) gradients (20-24 mmHg) were observed between the uterine and umbilical venous blood in the cow and pig, while in the mare the corresponding P(O2) difference was only 2.7 +/- 1.7 mmHg. Alterations in maternal arterial P(O2) did not affect the large vein-to-vein P(O2) difference in either ruminant or pig.3. In the cow the presence of different haemoglobin types in the adult (A, AB or B) did not appear to affect the O(2) affinity. In six animals the mean P(50) of the foetal blood (24.8 mmHg) was considerably lower than that of the mother (35.5 mmHg); no changes in P(50) were observed during the last month of gestation. Red cell 2,3-DPG levels were higher in the calf foetus than in the mother, but in the ruminant 2,3-DPG has no effect on the affinity of haemoglobin for O(2) and the differences in P(50) between foetus and mother could be ascribed to the presence of a foetal haemoglobin.4. In the sow large differences in O(2) affinity between foetal and maternal blood were observed, which were related to red cell 2,3-DPG concentration. A rise in foetal blood P(50) during the last half of gestation was associated with increased foetal weight and a rise in red cell 2,3-DPG.5. In the mare the P(50) of the foetal blood was 2-5 mmHg below that of the mother. This difference appeared to be due to the lower 2,3-DPG concentration in the foetal red cells as in the sow; in both species the haemoglobin of the foetus is similar to that of the mother.6. The differences in foetal and maternal O(2) affinity found in the various species and the changes which may occur during gestation or in the perinatal period are discussed in relation to the observed transplacental P(O) (2) gradients and the O(2) requirements of the foetus and neonate.