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The ontogeny of hepatic growth hormone (GH) receptors (GHR), as measured by responses of both plasma insulin-like growth factor-I (IGF-I) and hepatic GHR to an exogenous bGH stimulus, was examined using sheep of different ages (Days 1-7, 14-21, 28-35, and 56-63 of life, and yearlings). The IGF-I response to bGH was first examined in yearling sheep using two doses of bGH (0.1 and 0.2 mg/kg LW/d). Based on these results, lambs in four groups up to Day 63 of life were treated for 5 d with bGH (n = 10) at a dose of 0.15 mg/kg LW/d or with saline (n = 10). Jugular blood samples were taken once daily on Days - 1, 4, and 5 of treatment. bGH treatment in lambs up to Day 63 of life had little effect on plasma concentrations of GH, insulin, glucose or urea, but significantly (P < 0.05) increased circulating concentrations of IGF-I at all ages and of NEFA at Day 62/63 of life. In contrast, bGH treatment at either dose in yearlings significantly increased these parameters, except for plasma urea concentrations which were decreased in bGH-treated yearlings. However, the responses of plasma IGF-I concentration to bGH stimulus in lambs up to Day 63 of life were small compared to those in yearling sheep. Consistent with this, bGH treatment failed to affect hepatic GH binding in young lambs, but up-regulated it in yearling sheep. Furthermore, basal (unstimulated) GH binding did not differ between sheep of 7 vs. 63 vs. 365 d of age, despite the greater IGF-I responses to bGH in the latter group. It is suggested that hepatic GHR in lambs up to Day 63 of life are not fully functional compared to the situation in yearlings.

The effects of recombinant ovine placental lactogen and bovine growth hormone on milk yield, milk composition, and concentrations of blood hormones and metabolites were compared in ewes during an established lactation. Beginning on d 17 of lactation, ewes were treated for 5 d with twice daily subcutaneous injections of ovine placental lactogen (n = 9), bovine growth hormone (n = 10) at a dose of 0.10 mg/d per kg of body weight, or saline (n = 10). Circulating concentrations of ovine placental lactogen were 24.6 +/- 1.6 ng/ml on d 5 for ewes treated with ovine placental lactogen, but concentrations of ovine placental lactogen were undetectable in ewes treated with either saline or bovine growth hormone. Treatment with bovine growth hormone increased circulating concentrations of growth hormone, insulin-like growth factor-I, and nonesterified fatty acids and decreased urea concentrations relative to those in ewes treated with ovine placental lactogen or saline. Compared with saline treatment, no parameters were affected by treatment with ovine placental lactogen. Treatment with bovine growth hormone or ovine placental lactogen treatment had no significant effects on plasma concentrations of insulin, glucose, or creatinine. Treatment with bovine growth hormone, but not ovine placental lactogen, increased yields of milk, fat, and lactose. Weight of the mammary gland was increased by bovine growth hormone, but not by ovine placental lactogen. Despite the fact that ovine placental lactogen is a potent somatogen, it does not appear to exhibit the same galactopoietic activity as bovine growth hormone in lactating ewes.

The metabolic effects of ovine placental lactogen (oPL) alone and in combination with bovine GH (bGH) were investigated in comparison with the identical dose of bGH alone in the well-fed postnatal lamb. The animals were treated by twice daily intramuscular injection for 5 days with oPL (n = 7), bGH (n = 7) or bGH+oPL (n = 7) at a dose of 0.3 mg/kg per day or saline (n = 9). bGH and bGH+oPL treatments, but not oPL treatment, resulted in significantly (P < 0.01) higher plasma IGF-I levels than saline treatment. The rate of net protein catabolism (NPC) was significantly (P < 0.05) reduced to the same extent by bGH and bGH+oPL treatment compared with saline treatment. In contrast, oPL did not affect the rate of NPC. Blood glucose and insulin:glucose ratio were significantly (P < 0.05) elevated in the bGH+oPL group, whereas they were not significantly altered by either bGH or oPL treatment. These results suggest that oPL alone is not somatogenic or anticatabolic in the postnatal lamb despite the earlier evidence that oPL can bind to the oGH receptor (oGHR). However, oPL appeared to augment some of the effects of bGH when administered together, particularly with respect to carbohydrate metabolism. Potentiation of the diabetogenic effect of bGH by oPL may lead to insulin resistance during pregnancy. The lack of any obvious actions by oPL treatment alone may support the hypothesis that oGHR homo-dimerization is required for the full activation of GHR-mediated effects, since oPL binding does not initiate homo-dimerization of the oGHR.

We have reported previously that levels of insulin-like growth factor I (IGF-I) and IGF-II in fetal sheep plasma decrease with maternal starvation and increase following an infusion of glucose to the starved fetus, while a fetal infusion of insulin elevates UGF-I alone. We now report the changes in the circulating IGF-II/M6P receptor and plasma IGF binding proteins (IGFBPs), as measured by western blotting and ligand blotting, respectively, in fetus and mother during this study. In fetal plasma, the circulating IGF-II/mannose-6-phosphate (M6P) receptor, IGFBP-3 and IGFBP-4 were reduced during starvation. While circulating IGF-II/M6P receptor and IGFBP-4 levels were increased following the fetal insulin or glucose infusion, IGFBP-3 was unchanged and increased only after 48 h of maternal refeeding. Both IGFBP-1 and IGFBP-2 increased with starvation but while IGFBP-1 levels returned to control values following both insulin and glucose infusion, levels of IGFBP-2 were not reduced significantly by either infusion or by refeeding. In maternal plasma, levels of IGFBP-3 and IGFBP-4 decreased while IGFBP-1 and IGFBP-2 increased after 48 h of starvation. Levels of each IGFBP were unaltered following the fetal infusions but returned to values obtained during the control period after refeeding. These data show that each of the IGF carrier proteins is sensitive of changes in nutrition, either acutely, such as IGFBP-1, or chronically, as for IGFBP-3. This suggests that the circulating IGF-II/M6P receptor and the IGFBP's may modulate IGF activity in the fetus during different nutritional states.

While the GH receptor (GHR) plays a key role during adult life, its role during fetal development is not well understood. Recent data suggest that GHRs are present in ovine fetal hepatic tissue at mid-gestation. However, the levels of GHR expression are markedly lower in fetal hepatic tissue in comparison with postnatal values. The present study investigates whether the neonatal induction of the hepatic GHR and plasma levels of IGF-I follow a pattern of strictly age-related development or whether birth-associated processes stimulate this increase. Stereotaxic electrolytic lesioning of the fetal paraventricular nuclei was employed to prolong gestation markedly. We compared the hepatic binding of ovine placental lactogen (oPL) and oGH and plasma levels of IGF-I in these post-mature fetuses with those in pre-term fetuses, pregnant mothers and lambs which were of the same conceptional age as the post-mature fetuses. While specific binding of both 125I-labelled oGH and 125I-labelled oPL to hepatic microsomal membranes was fully reversible in all groups, the specific binding of 125I-labelled oGH was significantly (P < 0.001) lower than specific binding of 125I-labelled oPL in all groups of animals. There was no difference in specific 125I-labelled oGH or 125I-labelled oPL binding in livers or plasma levels of IGF-I in post-mature fetuses in comparison with pre-term fetuses. In contrast, a major increase (P < 0.001) in 125I-labelled oGH and 125I-labelled oPL binding and plasma IGF-I levels was observed in lambs.(ABSTRACT TRUNCATED AT 250 WORDS)

Primed constant infusions of [14C]urea were used to determine the acute effect of passive immunization against circulating free and protein-bound insulin-like growth factor-I (IGF-I) on the rate of net protein catabolism (NPC) in castrated male lambs fasted for 48 h. Following an intravenous bolus of 50 ml IGF-I antiserum, the rate of NPC increased to a peak 30 min after injection of 1.69 +/- 0.16 g/kg per day from a baseline value of 1.45 +/- 0.22 g/kg per day (P < 0.05, n = 4). In three animals given 50 ml equivalents of the purified immunoglobulin fraction, NPC increased from 1.31 +/- 0.20 to 1.59 +/- 0.16 g/kg per day (P < 0.05). A similar trend was observed in animals given 25 ml antiserum (n = 4). The rate of NPC did not increase following a bolus of non-immune serum in control animals and the rate of NPC in the treated lambs returned to control levels within 60 min of antibody injection. Plasma insulin and glucose concentrations in both the treated and control groups were unchanged throughout the study. These data suggest that circulating IGF-I has a physiological role in regulating whole body protein turnover during starvation and possibly other catabolic states. The effect of immunoneutralization of circulating IGF-I is transient and this suggests that while IGF-I has an endocrine role in the regulation of protein turnover, other regulatory mechanisms are involved.

Castrate yearling male sheep were treated for 8 weeks with either 50 micrograms/kg body wt/8 hourly sc insulin-like growth factor-I (IGF-I) (n = 10) or with saline (n = 9). IGF-I treatment increased plasma IGF-I from 235 +/- 17 to 347 +/- 16 ng/ml (P less than 0.001). There was a gradual divergence in body wt (P less than 0.10) between treatment groups. Food intake did not change significantly. The weight of the spleen corrected for body wt increased by 40% (P less than 0.001) and there was a marginal increase in adjusted kidney wt (P less than 0.1). There was no effect of IGF-I on carcass weight or dimensions, or on long bone length, although the weight per unit length of the tibia (P less than 0.05) and femur (P less than 0.10) were increased. There was no effect on wool growth. Plasma IGF binding proteins (IGFBPs) were quantified by ligand blot analysis. In the IGF-I treated group, IGFBP-1 showed a transient increase (P less than 0.05) at day 3 but was similar in both groups at day 55 of treatment. IGFBP-2 was suppressed (P less than 0.05) by day 55 and IGFBP-3 and 4 did not change. Plasma glucose was elevated (P less than 0.05) and plasma insulin was suppressed (P less than 0.01) from 280 +/- 32 pg/ml to 124 +/- 30.4 pg/ml, plasma urea (P less than 0.01) and creatinine (P less than 0.05) were reduced in the IGF-I treated group. The somatogenic effect of IGF-I in this study was minimal suggesting that in the well fed animal with an intact somatotropic axis IGF-I treatment at doses which double plasma IGF-I does not enhance somatic growth performance. However, the marked splenomegaly shows the sensitivity of splenic growth to systemic IGF-I. The suppression of insulin with chronic IGF-I treatment was accompanied by hyperglycaemia--this may explain in part the lack of a significant anabolic response and may limit the utility of IGF-I therapy unless higher doses with insulin-like effects are used.

Plasma and mammary efferent lymph concentrations of insulin-like growth factor I (IGF-I) were determined in lactating ewes before and after treatment with GH (10 mg/day) for 3 days. The lymph:plasma ratio of IGF-I increased from 0.34 to 0.47 after GH treatment when the IGF-I content of plasma increased by 19.4 nmol/l (from 32.1 nmol/l) and lymph by 13.7 nmol/l (from 10.7 nmol/l). This increase in the relative content of IGF-I in lymph was associated with increased lymph content of IGF-I in a lower molecular mass pool (nominally 50 kDa) derived by size exclusion chromatography. GH treatment increased the total binding capacity for IGF-I in both high (150 kDa) and low (50 kDa) molecular mass pools of plasma and the 150 kDa pool in lymph but there was a proportionally greater increase in 50 kDa total binding in lymph relative to plasma. Further, GH treatment increased the 'saturation' of the 50 kDa binding proteins but decreased the 'saturation' of the 150 kDa fraction, in both plasma and lymph. Ligand blot analysis of IGF-binding proteins (IGFBPs) in plasma and lymph showed that GH treatment of lactating sheep increased IGFBP-3 and decreased IGFBP-2 in plasma and lymph. Radioimmunoassay of IGFBP-2 showed that while GH treatment reduced the plasma content of IGFBP-2 by about half, the lymph:plasma ratio was increased from 0.68 to 0.87. GH treatment of lactating ewes not only increased the IGF-I content of plasma but increased the apparent efficiency of transfer of IGF-I across capillary endothelium to mammary efferent lymph.

In humans the IGF binding proteins (BP) are closely related to metabolic status. In this paper we have examined the influence of controlled feed intake and GH treatment on IGF binding proteins in growing lambs. Analyses were performed on plasma samples from animals maintained on two levels of feed intake (1.75% body weight as lucerne pellets or 3% body weight which is approximately equivalent to an ad libitum intake) either with or without recombinant bovine growth hormone (BST; 0.25 mg/kg body weight/day) administration. Samples used for the analyses reported in this paper were collected at 9.00 hr following 41 d of treatment. Total plasma IGF-I was increased on the higher plane of nutrition (P less than .01) and by BST (P less than .001) but only on high feed intake. IGF is associated with BP of 150 kDa and 40-50 kDa in sheep plasma. 150 kDa bound IGF-I was increased on the higher plane of nutrition (P less than .05) and by BST treatment (P less than .001) but only on the higher feed intake. By contrast no change in 40-50 kDa bound IGF-I was observed with treatment. Unbound IGF-I was also found in sheep plasma (2-5% of total) but demonstrated only minor changes in relation to treatment. Saturation analysis gave estimates of total binding capacity and saturation of the IGF-BP. In ovine plasma the binding capacity of the 150 kDa species is in excess of bound IGF (P less than .001). Saturation did not change with treatment despite the observed differences in 150 kDa bound IGF-I. Thus BP(s) contained in the 150 kDa fraction were responsive to treatment. By contrast large differences in saturation of the 40-50 kDa species were observed (P less than .001) despite little treatment dependent change in bound IGF-I. IGF-BP(s) in the 40-50 kDa fraction were elevated in the low nutrition group and suppressed on the higher feed intake resulting in near saturation. These data strongly suggest that the IGF BP are modulated according to metabolic status in the sheep.

Injections of WGA-HRP and CTB-HRP were made into the cervical vagus or the nodose ganglion in a series of lambs, in order to define the sensory projections and motor origins of the vagus nerve. Injections into the nodose ganglion were much more successful than injections into the cervical vagus in effecting the desired result. The former produced labelling of both descending and ascending components of the solitary tract (TS). The descending component terminated massively in all ipsilateral and certain contralateral subnuclei of the nucleus of the solitary tract (nTS) and in the upper cervical spinal cord. Patchy terminations were also observed within the interpolated subnucleus of the nucleus of the spinal trigeminal tract, and within Lamina I of the upper cervical cord. The ascending component of TS terminated in rostral regions of the nTS, and in specific portions of the principal sensory trigeminal nucleus and the lateral parabrachial and Kölliker-Fuse nuclei. The motor origins of the vagus nerve arose almost completely ipsilaterally in the dorsal motor nucleus of the vagus, the nucleus ambiguus, and the caudal portion of the nucleus retroambiguus situated in the lateral part of the intermediate grey at upper cervical spinal levels. Labelled neurons in the nucleus dorsomedialis of the upper spinal cord were thought not to project their axons into the cervical vagus.

The effect on young lambs of 0.25 mg recombinant bovine GH (bGH)/kg per day on plasma concentrations of insulin-like growth factor-I (IGF-I), glucose, specific hepatic GH binding and body composition changes was examined at two levels of nutrition (lucerne pellets; 3 and 1.7% of body weight/day). Lambs on low levels of nutrition had low plasma IGF-I (P less than 0.001). Plasma concentrations of IGF-I were increased by bGH treatment at both levels of nutrition, with the high nutrition group showing the greatest IGF-I response after 3 and 40 days of bGH treatment. Plasma glucose, after 40 days, was higher overall (P less than 0.05) in lambs on high nutrition. bGH treatment increased plasma glucose, with the response being greater in the well-fed lambs. Specific binding of GH to liver membranes was highest in lambs on high nutrition and on bGH treatment; no significant interaction between nutrition and bGH treatment was detected, indicating that specific binding of GH was increased proportionally by bGH at both nutritional levels. The major change in body composition was the reduced level of fatness in lambs treated with bGH. There was no significant effect of bGH on body weight although bGH treatment tended to increase weight gain of well-fed lambs and decreased weight loss of poorly nourished lambs. The results show that, although there was a significant (P less than 0.05) bGH/nutrition interaction for IGF-I there was no such interaction for body weight/components or specific GH binding to the liver. The results indicate that an increase in plasma IGF-I does not necessarily result in increases in growth or changes in carcass composition.

A study was undertaken to examine the ontogeny of circulating insulin-like growth factor-1 (IGF-1) concentrations in sheep. The trial was a balanced 2 x 2 factorial design incorporating the effects of sex and rearing rank with a total of 48 animals. Blood sampling was initiated four weeks post-weaning (about 3 months of age) and continued every 2 weeks for 6 months and then every 4 weeks for 7 months. Fecal egg counts and plasma concentrations of non-esterified fatty acids (NEFA) were also determined. IGF-1 concentration was positively related to live weight throughout the trial, even when adjusted to common sex and rearing rank. Sex of lamb had a significant effect on plasma IGF-1 concentrations with concentrations in males being greater than those in females. Puberty in females, as determined by date of first estrus, was associated with an increase in plasma IGF-1 concentrations. Although puberty in males was not measured, a surge in plasma IGF-1 concentrations around the approximate time of puberty in males resulted in a marked divergence between the sexes which remained throughout the study. Rearing rank did not influence plasma IGF-1 concentrations beyond 7 months of age. Plasma IGF-1 concentrations tended to be negatively associated with plasma NEFA concentrations and fecal egg counts but relationships were only occasionally significant. IGF-1 levels were highly repeatable, concentrations at the first sample being significantly correlated with those at all subsequent samples. Implications of these results in relation to potential use of plasma IGF-1 concentration as a genetic marker for productivity are discussed.

We investigated the distribution of radiolabelled IGF-1 in the late gestation ovine fetus by exclusion gel chromatography following intravenous injection of 125I rh (recombinant human) met-IGF-1 into the chronically instrumented fetal lamb (120-130 days, n = 7). One minute after injection of 125I rh met-IGF-1 into the fetal femoral vein, 20.9 +/- 3.1% of the counts circulated in the 150K binding protein region, 55.0 +/- 3.7% in the 50K binding protein region and 18.7 +/- 0.6% in the free or 7K region. The chromatographic profiles obtained in the fetus were in general similar to those previously seen in the adult sheep. After an initial equilibration phase the half life of IGF-1 associated with the 150K binding fractions were 412.1 +/- 103.6 min. Two phases of clearance were observed for IGF-1 in association with the 50K binding fractions, an initial phase with a half life of 30.6 +/- 4.5 min followed by a second phase with a half life of 202.3 +/- 10.3 min. The 7K or 'free' form of IGF-1 had an initial half life of 12.6 +/- 5.1 min. Chromatography of samples of fetal tracheal fluid, fetal urine, amniotic fluid, maternal uterine venous plasma and maternal systemic plasma showed no movement of intact IGF-1 out of the fetal circulation into the fetal fluids or into the maternal circulation. However, when simultaneous samples were obtained from the fetal femoral artery and umbilical vein, higher radioactivity was consistently observed in the fetal femoral artery raising the possibility of placental uptake of IGF-1.(ABSTRACT TRUNCATED AT 250 WORDS)

The functions of prolactin in the fetus remain speculative. No obvious physiological role has been found for the prolactin present in the fetal or maternal plasma and amniotic fluid compartments. The aim of the present study was to investigate changes in fetal plasma prolactin following intracerebroventricular (i.c.r.) administration to the fetus of artificial cerebrospinal fluid of different tonicities. A lateral ventricle catheter was placed in 11 fetuses at 107-128 days of gestation. Either isotonic artificial cerebrospinal fluid (300 mOsm.1(-1);n = 9), 15% polyethylene glycol (340 mOsm.1(-1);n = 5), or 7% distilled water in isotonic artificial cerebrospinal fluid (270 mOsm.1(-1);n = 9) was infused i.c.v. at 35 mu1.min-1 for 240 min. At 180 min thyrotropin releasing hormone (TRH) was administered through a fetal a fetal jugular catheter. Fetal carotid arterial blood gases, plasma osmolality and concentrations of prolactin, vasopressin (AVP), and norepinephrine (NE) were measured. Administration of hypotonic artificial cerebrospinal fluid produced an increase in fetal plasma prolactin from 46.6 +/- 36 ng.ml-1 at 0 min to 83.3 +/- 49 ng.ml-1 at 180 min (mean +/- SEM; P less than 0.05). No changes in either AVP or NE were observed. Administration of hypertonic artificial cerebrospinal fluid produced a decrease in plasma prolactin from 85 +/- 57 at time 0 to 49 +/- 35 at 180 min (P less than 0.05). No changes in either AVP or NE were observed. Fetal plasma prolactin, AVP, and NE did not change during control infusion of isotonic artificial cerebrospinal fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The respiratory effects of corticotrophin-releasing factor (CRF) and the CRF antagonists alpha-helical CRF 9-41 (alpha hCRF) and [DPhe 12, Nle 21-38] rCRF (12-41) (DPhe CRF) have been studied in unanaesthetized fetal lambs of 125-140 days gestation. 2. CRF when given as a 10 micrograms bolus followed by a 5 micrograms h-1 infusion into a lateral cerebral ventricle caused prolonged continuous fetal breathing movements which were stimulated in both amplitude and frequency but which did not persist during hypoxia. 3. Lower doses of CRF (20 ng bolus followed by 10 ng h-1) increased the amplitude but not the frequency of fetal breathing movements which did not become continuous. 4. At higher doses (20 micrograms bolus followed by 10-15 micrograms h-1) CRF induced cerebral convulsions which were also associated with fetal breathing movements of increased amplitude and frequency. 5. The CRF antagonists alpha hCRF and DPhe CRF both inhibited fetal breathing movements and induced a prolonged apnoea which was resistant to the stimulatory effects of 5-6% hypercapnia. 6. We conclude that CRF stimulates breathing movements in the fetal lamb. The finding that administration of the CRF antagonists alone cause apnoea suggests that CRF may have a tonic role in the regulation of fetal breathing movements.

The disappearance of glycerol from plasma was studied after a single intravenous injection to estimate its volume of distribution (Vdist), plasma clearance rate, and rate constant for irreversible loss (kd). Studies were repeated before and after birth of the lamb to test whether loss of the placenta could account for rapidly increasing plasma concentrations in the newborn. The disappearance of glycerol was closely described by a double-exponential model in each instance. In fetal sheep Vdist averaged 0.41 +/- 0.15 (SD) 1/kg fetal wt (n = 15). This volume decreased to 0.33 +/- 0.11 l/kg (n = 8) soon after functionally removing the placenta (by snaring the umbilical cord and maintaining the fetus with intrauterine ventilation), but the change was not significant. In newborn lambs 1-3 days of age, Vdist averaged 0.45 +/- 0.11 l/kg (n = 5, NS). Plasma clearance rate also did not change significantly, averaging 7.9 +/- 2.9, 7.9 +/- 3.8, and 9.0 +/- 5.9 ml.min-1.kg-1 in the fetus, after simulated birth, and in the newborn lamb, respectively, kd also was not altered measurably and averaged 0.020 +/- 0.006, 0.024 +/- 0.007, and 0.019 +/- 0.007 min-1 during the same time periods. Similar results were obtained by using three widely different amounts of infused glycerol. The results indicate that removal of glycerol does not depend on placental function to an appreciable extent. It is concluded that plasma glycerol concentration reflects principally glycerol turnover and, hence, lipolysis before and after birth.

The physiological role of placental lactogen (PL; chorionic somatomammotrophin) in the ewe has been investigated by infusion of ewes (n = 3) on day 131 of pregnancy with sufficient ovine PL (oPL) antibody to neutralize circulating oPL for at least 12 h. Effectiveness of the antibody neutralization was defined both in vitro and in vivo according to rigorous criteria. Control ewes (n = 3) were infused simultaneously with an equivalent amount of pooled goat gamma globulin. Since both sets of ewes had previously been catheterized with jugular, utero-ovarian and femoral vein catheters and a femoral arterial catheter, it was possible to measure whole body glucose kinetics as well as muscle and uterine glucose, free fatty acid (FFA) and 3-hydroxybutyrate extraction. In addition, plasma levels of insulin, GH, prolactin, insulin-like growth factor-I (IGF-I), IGF-II, progesterone and cholesterol were determined in femoral arterial samples. Neutralization of maternal oPL did not significantly affect whole body glucose metabolism, uterine and muscle glucose extraction, or 3-hydroxybutyrate extraction by muscle. A trend towards lower plasma FFA levels was observed after prolonged infusion, but was not statistically significant. However, plasma insulin levels rose significantly during antibody infusion after an early fall. These observations are rationalized in terms of the known requirements of ruminant metabolism during pregnancy, and contrasted with the accepted model for the role of human PL in the metabolic adjustments of pregnancy. No change in plasma IGF-I, IGF-II or GH was observed, providing no support for the concept that oPL is responsible for maternal somatomedin generation during pregnancy. Similarly, plasma prolactin did not differ between antibody-treated and control groups. Finally, antibody neutralization had no influence on either plasma progesterone or cholesterol, mitigating against a role for oPL in progesterone production during late pregnancy in the ewe.

Fetal plasma growth hormone concentrations were measured in 15 pregnant ewes over the last 5 days before delivery. In five chronically catheterized pregnant ewes that underwent spontaneous vaginal delivery 146 +/- 2 days (mean +/- SD) of gestation, fetal plasma growth hormone concentrations fell from 124.6 +/- 44.1 ng X ml-1 5 days before delivery to 35.2 +/- 31.3 ng X ml-1 at delivery. In three fetuses in which premature delivery was induced by the infusion of cortisol to the fetus at 128 days of gestation, fetal plasma growth hormone levels fell from 195 +/- 19.1 ng X ml-1 to 70.7 +/- 25.5 ng X ml-1 over the last 5 days of intrauterine life. In seven fetuses in which premature delivery was induced with infusion of synthetic adrenocorticotropin to the fetus beginning at 120 or 130 days of gestation, the fetal plasma growth hormone level did not fall (175.6 +/- 75.7 to 158.9 +/- 60.1 ng X ml-1). Fetal plasma cortisol concentrations at delivery were significantly higher in the cortisol-infused fetuses (214 +/- 38.4 ng X ml-1) than in both control (94.4 +/- 33.7 ng X ml-1) and adrenocorticotropic hormone-infused fetuses (94.5 +/- 31.9 ng X ml-1). The fall in the fetal plasma growth hormone level in cortisol-induced fetuses may be due to the higher fetal plasma cortisol concentrations achieved in the cortisol-infused compared with the adrenocorticotropic hormone-infused fetuses in which no comparable decrease in growth hormone was observed. These findings suggest that there are significant differences in the fetal response to various experimental regimens used for the induction of premature labor in the sheep.

Chronically prepared fetal lambs had basal plasma arginine vasopressin (AVP) levels of 1.6 +/- 0.23 pg/ml throughout the final third of gestation. Fetal AVP levels measured by radioimmunoassay were increased significantly to 5.8 +/- 0.92, 9.95 +/- 0.95, and 10.0 +/- 5 pg/ml in association with surgical stress, acute exteriorization, and acidosis or hypoxia, respectively. At 59-65 days gestation three lamb fetuses had a 50-fold increase in plasma AVP levels after acute exteriorization and hemorrhage indicating that the 0.4 gestation lamb fetus is capable of secreting pituitary AVP stores after intravascular volume change, temperature stress, and tactile stimulation. In six chronically catheterized third trimester fetuses, a 10-min, 20% hemorrhage caused a significant fall in fetal blood pressure, heart rate, and hematocrit. Plasma AVP increased significantly to 24.3 +/- 5.8 ng/ml without change in arterial blood gases or pH. Basal plasma prolactin concentration of 9.0 +/- 2.0 ng/ml was unchanged after hemorrhage in five fetuses.

The effects of cooling have been studied in chronically instrumented unanaesthetized fetal lambs of 106-132 days gestation. Cold stimulation of cutaneous thermoreceptors by means of a coil placed around the fetus in the amniotic cavity induced continuous breathing which was associated with high-voltage electrocortical activity throughout the cooling period. Direct internal cooling by means of an intragastric cooling coil did not alter fetal breathing or sleep-state patterns. Shivering occurred in response to both external and internal cooling, and this response was present as early as 106 days gestation, well before the appearance of high-voltage sleep. In older fetuses there was evidence of a reduction in thermoregulatory responses during low-voltage electrocortical activity, but not of the complete suspension of thermoregulation characteristic of low-voltage (r.e.m.) sleep seen in mature animals. It is concluded that deep regular breathing associated with high-voltage electrocortical activity can be induced by cold stimulation of cutaneous thermoreceptors, but not by a reduction in core temperature alone. Furthermore, fetal responses to cooling are present as early as 106 days gestation.

Specific radioligand assays for the two somatomedins, insulin-like growth factor (IGF)-I and IGF-II, have been used to study the ontogeny of somatomedin secretion in the perinatal lamb. Plasma samples were obtained from sheep fetuses from 54 days of gestation to term (147 days) and from neonatal lambs. All samples were first extracted in acid-ethanol to remove the somatomedin-binding proteins. Concentrations of IGF-I measured by radioimmunoassay were lower (P less than 0.01) in the fetus than in the adult sheep (0.96 +/- 0.17 (S.D.) units/ml, n = 11). Fetal IGF-I values rose (P less than 0.01) from 0.29 +/- 0.15 units/ml (n = 6) at 50-80 days to 0.79 +/- 0.18 units/ml (n = 13) at 140-150 days. While values were similar 0-2 days after birth, they rose (P less than 0.01) to 2.4 +/- 1.3 units/ml (n = 15) 3-7 days after birth. By 60 days they had fallen to adult values. In contrast, IGF-II levels measured by rat placental membrane radioreceptor assay were higher (P less than 0.001) in the fetus (2.71 +/- 1.06 units/ml, n = 18) than in the adult (1.0 +/- 0.17 units/ml) and showed no gestational trend between 50 and 140 days of gestation. Longitudinal studies showed a fall (P less than 0.01) in IGF-II values starting several days before birth. By 12 h after birth, IGF-II concentrations were similar to the adult and showed no subsequent postnatal change. These results demonstrate that IGF-I and IGF-II are not secreted in parallel in the perinatal lamb. There are major changes in the regulation of both IGF-I and IGF-II in relationship to birth. It is suggested that the high fetal IGF-II concentrations appear to be maintained by a stimulus withdrawn before birth. The postnatal rise in IGF-I may be related to the increase in hepatic somatogenic receptors at this age.

The relationships between placental lactogen (PL), insulin-like growth factor (IGF) -1 and -2, insulin, glucose and nonesterified fatty acids (NEFA) were studied in 10 triplet-bearing ewes in late gestation (120-129 days) which were on ad libitum feeding. To extend the range of plasma metabolite concentrations the ewes received a continuous abomasal infusion from 100 days of gestation until delivery. Three were infused with glucose (160 g/day), 2 received sodium caseinate and 3 were infused with control fluid alone. From 120 days the animals were fed 3 hourly intervals from a belt feeder to achieve steady state and at 125-130 days had intravenous plasma samples pooled for analysis. There was no effect of nutritional supplementation on birth weight. Casein supplementation was associated with reduced maternal PL concentrations but glucose supplementation had no effect on PL concentrations. Circulating PL concentrations showed a positive correlation to IGF-2 activity (r = 0.64, P less than 0.05) and a negative relation to IGF-1 concentrations (r = -0.73, P less than 0.05). IGF-1 levels were higher (P less than 0.05) and IGF-2 levels were lower (P less than 0.05) in nutritionally supplemented ewes. In the ewe, NEFA concentrations showed a negative relationship to IGF-1 (r = -0.75, P less than 0.05) and a positive relationship with IGF-2 (r = 0.87, P less than 0.1). Similar relationships were observed in the ewe at term. These observations suggest that nutritional factors and PL may be important determinants of IGF-2 secretion in the late-gestation ewe. They suggest the possibility that IGF-2 mediates the lipolytic effects of PL.(ABSTRACT TRUNCATED AT 250 WORDS)

Pituitary-derived bovine growth hormone (bGH) was administered to six lactating Friesland ewes for 7 d. There was no consistent galactopoietic response, with changes in milk yield varying from 0 to 33% during treatment compared with the pretreatment period. The major effect of bGH on the concentration of milk constituents was to increase fat by 14.2% (P less than 0.05). Treatment resulted in significant increases in arterial plasma concentrations of growth hormone, insulin-like growth factor I and glucose, with decreases in the plasma arterial concentrations of acetate and certain amino acids. There was a marked reduction in haematocrit and in haemoglobin concentration which took at least 3 d to recover. The arterio-venous difference across the mammary gland decreased for O2 during treatment and the veno-arterial difference for CO2 decreased after treatment. Mammary respiratory quotient therefore decreased significantly after bGH treatment. The results suggest that bGH exerts effects at a number of separate loci.

A specific radioimmunoassay for insulin-like growth factor I (IGF-I) has been used to study the distribution of circulating IGF-I on its carrier proteins in sheep. Serum or plasma samples obtained from fetal, neonatal and adult sheep were chromatographed at neutral pH on Sephadex G-200 columns. IGF-I eluted primarily in the 20 000-100 000 dalton region and to a lesser extent in the 20 000-100 000 dalton region in the adult. In the fetus, IGF-I eluted primarily in the 20 000-50 000 dalton region. Studies in the neonatal lamb showed IGF-I activity to fluctuate between different size binding proteins but by 7 days after birth the pattern was similar to that of the adult. When labelled IGF-I and IGF-II were added to serum which was chromatographed over Sephadex G-200 at a neutral pH, binding was displayed in the 50 000-100 000 dalton region for both adult and fetus. However in the fetus, but not in the adult, binding of 125I-labelled IGF-II was also found at greater than 200 000 daltons. These studies demonstrate that the distribution of IGF-binding proteins varies between the adult and the fetal lamb. The appearance of the 150 000 dalton binding protein is coincidental with the appearance of the somatogenic receptor in the infant liver and is consistent with the GH-dependent nature of this form of binding protein in other species. The marked developmental changes in the circulating form of IGF-I in the perinatal lamb may be of functional significance and lead to altered biological availability of circulating IGF-I.

Somatosensory evoked potentials were recorded in utero from 13 chronically instrumented fetal lambs (97 to 148 days of gestation) following electrical stimulation of the upper lip or upper limb. Several clear and reproducible peaks were observed. Following upper lip stimulation, peaks were seen with mean peak latencies of 9, 13.2, 17.8, 21.3, 33.8 and 206 ms at a gestational age of 125 days. Similar peaks, but of slightly later mean latencies, were seen following limb stimulation. These peaks demonstrated significant gestational age related falls in peak latencies (P less than 0.05). Several of the mid to late latency peaks, notably those occurring at 21.3, 33.8 and 206 ms, demonstrated changes (P less than 0.05) in both latency (longer in low voltage) and amplitude (reduced in low voltage) dependent on electrocorticographic state. Rate of stimulus presentation also had a significant effect on both amplitude and latency of several peaks (P less than 0.05) with this effect lessening with advancing gestational age. Evoked potentials can thus be successfully obtained from chronically instrumented fetal lambs and provide a useful indice for studies of neural maturation.

To investigate the development of fetal thermoregulatory mechanisms the temperature of the ovine fetus in utero was altered by circulating water through a coil placed around the fetus. In 18 fetuses (76-142 days), temperature recordings were made from thermister probes placed in the fetal cranium below the frontal lobes, the fetal rectum, the amniotic cavity and the maternal vena cava. Severe hypothermia was observed during fetal surgery; the maximum decrement in fetal brain temperature ranged between -7.38 degrees C and -0.83 degrees C and was correlated inversely with gestational age (P less than 0.005). The temperature of the live fetal sheep in utero was 39.05 to 40.37 degrees C and was always greater than the maternal temperature by 0.30 to 0.78 degrees C. The amniotic fluid was intermediate in temperature between the fetus and mother. During cooling studies the fetal cranial temperature fell more quickly and to a greater extent (P less than 0.05) than the fetal rectal temperature. When the cooling was continued for 60 min, a steady fall in fetal temperature was observed until a plateau was reached at 20 to 40 min. The recovery time increased with increasing gestational age (P less than 0.001) suggesting that thermoregulation is still immature in late gestation. During prolonged cooling, fetal hypoxaemia and acidosis were observed.

We have studied the ontogenesis of opiate receptors in homogenates prepared from different regions of the ovine brain using 3H-naloxone and 3H-D-Ala2, Met5-enkephalinamide. At the concentration employed (0.5 nM) these 3H-opiates labeled both high (KD less than 0.5 nM) and low (KD greater than 1.3 nM) affinity binding sites. When midgestation fetus (68-77 day), late gestation fetus (83-134 day), and neonate (147-173 day) brain regions were compared the majority of regions showed a steady increase in 3H-opiate binding with development. However, marked variation was noted in postnatal development when neonate and adult (greater than 730 days) brains were compared. In some brain regions binding plateaued or increased slightly (thalamus, hippocampus, temporal cortex, and occipital cortex), while opiate receptor binding decreased significantly from neonate to adult in other regions (hypothalamus, striatum, and midbrain). In the pons/medulla, binding was highest in fetal tissues and declined during postnatal life. A comparison of 3H-naloxone binding in adult ovine and rat brains indicated similar regional distribution and concentrations of opiate receptors between these species, although the ovine midbrain and hippocampus contained only 25-30% of the binding sites present in comparable rat brain regions.

The metabolic clearance of ovine insulin-like growth factor-II (IGF-II) was examined in sheep using 131I-labelled IGF-II. Following i.v. administration the tracer was distributed in a volume similar to that of the vascular space (58.5 +/- 3.3 ml/kg; mean +/- S.E.M., n = 5) and demonstrated a triphasic pattern of clearance. Size-exclusion chromatography of a plasma sample collected 1 min after injection revealed peaks of radioactivity corresponding to hormone complexed to binding proteins of 150 and 40-50 kDa (relative abundance 21 and 65% respectively), a high molecular weight binding protein (greater than 200 kDa; 5%) and 'free' tracer (9%). Chromatography of sequential plasma samples revealed different patterns of clearance for these constituents. Half-lives of 131I-labelled IGF-II complexed to the 150 and 40-50 kDa binding proteins, as calculated from rate constants for their decay, were 351 +/- 30 and 9.6 +/- 1.8 min respectively (n = 5). These differ markedly from estimates for the clearance of IGF-I (545 +/- 25 min, n = 8, and 34 +/- 2.3 min, n = 6) associated with carrier proteins of the same apparent molecular weights. This was reflected in calculated metabolic clearance rates for IGF-I (3.9 +/- 0.5 ml/min) and IGF-II (7.8 +/- 1.0 ml/min). Chromatography also revealed that free IGF-II was reduced to negligible levels by 12 min. In contrast, radioactivity eluting in the position expected for the greater than 200 kDa binding protein was cleared from the circulation very slowly.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied brainstem auditory evoked potentials (BAEPs) in 8 fetal sheep in utero, ranging in gestational age from 105 to 142 days gestation (normal term 147 days). We could not elicit BAEPs prior to 117 days of gestation. After this age rapid maturation was seen, with three discernible peaks observed prior to 120 days and five peaks after 120 days. A significant (P less than 0.05) gestational age related fall in peak latencies and interpeak latencies was observed. The rate of stimulus presentation that could be tolerated without significant changes in wavepeak latency or amplitude also increased with advancing gestational age. In older fetuses (greater than 125 days), where a differentiated electrocorticogram (ECOG) was observed, differences were seen in latency and amplitude of several of the BAEP wavepeaks dependent upon the state. In high voltage ECOG states the amplitudes of wave IV and V were significantly (P less than 0.05) greater than in the low voltage ECOG state and the latencies of wave I, II and V were significantly (P less than 0.05) longer in low as compared to high voltage ECOG state. The BAEP, being obtainable over very short periods of time, appears to provide a useful indice of neural maturation for the sheep fetus in utero.

The ontogenesis of the pulsatility of GH in the ovine fetus was determined by obtaining blood samples at 20-min intervals for 3-h periods from fetuses (n = 33) at various stages of development (76-147 days gestation), and in neonatal life (n = 19). A significant increase (P less than 0.01) in the GH mean, nadir and maximum, and pulse height was observed between the ages of 100 and 130-139 days of gestation. An analysis of the difference in the mean, maximum and nadir concentrations between 100 and 139 days of gestation revealed that males had higher GH levels than females (P less than 0.05). There was a significant fall in plasma GH concentrations from 140 days of gestation to term, but before the onset of active labour. There was a more rapid fall in the circulating levels of fetal GH directly following birth. Immediately before birth fetal GH levels were still relatively high, but within 60 min of birth they had fallen by more than 80%. It is suggested that these changes in the pulsatile pattern of GH release are a consequence of both maturational changes in the hypothalamic-pituitary unit and the effects of pregnancy-related factors on GH release. The sexually dimorphic nature of GH release in the adult is also observed in the sheep fetus during late gestation.

The effect of immunizing against somatostatin (SRIF), with SRIF conjugated to bovine thyroglobulin, was examined in cross-bred sheep fed either cut pasture or lucerne pellets. Plasma concentrations of GH were unaffected by SRIF immunization, but were lower in pellet-fed sheep. Plasma concentrations of insulin-like growth factor I (IGF-I) increased after immunization in sheep on both diets. Pasture-fed sheep had lower plasma concentrations of IGF-I than those on pellets. Sheep showed a small increase in growth rate in response to immunization. Immunization had no effect on carcass composition and did not affect plasma concentrations of IGF-II, free fatty acids or glucose. The results show that even though SRIF immunization increases plasma concentrations of IGF-I, it does not necessarily result in a large increase in growth rate.

1. The effects of stereotaxically placed lesions made throughout the mid-brain and upper pons were studied in chronically instrumented fetal lambs from 120 days gestation, after recovery in utero. 2. Isocapnic hypoxia caused an increase in the rate and depth of breathing movements in fetuses in which bilateral lesions encompassed the upper lateral pons in the region of and slightly rostral to the principal sensory and motor nuclei of the trigeminal nerve. 3. Fetal lambs with lesions which did not bilaterally encompass the upper lateral pons showed the normal fetal depressive response to hypoxia. 4. None of the lesions induced permanent continuous breathing as previously described in mid-brain transected fetuses, although periods of continuous breathing lasting several hours were seen at times in some fetuses with lesions in the upper lateral pons. 5. It is concluded that an area in the lateral pons close to areas with well known involvement in respiratory control is involved in the hypoxic depression of breathing in the fetal lamb.

Clearance of protein-bound forms of insulin-like growth factor-I (IGF-I) from the circulation of sheep was determined using single injections of 131I-labelled ovine or [Thr59]-human IGF-I, in the 'free' form or prebound to 50 or 150 kDa plasma binding protein fractions. The half-life of circulating protein-bound forms of IGF-I was determined by size-exclusion chromatography of plasma samples taken over a 24- to 26-h experimental period. IGF-I bound to lower molecular weight binding protein(s) (approximately 50 kDa) showed a half-life of 26-40 min (mean 34 min; n = 6), while the half-life of a high molecular weight fraction (150 kDa) was considerably longer (range 398-603 min; mean 545 min; n = 8). Metabolic clearance of IGF-I following administration of free tracer ranged from 3.0 to 5.3 ml/min in sheep (n = 4) weighing 26.0-28.5 kg. Tracer distribution volume was 59 ml/kg liveweight (n = 4). Tracer degradation products were first detected in plasma 8 h after i.v. administration. No differences in stability of the purified ovine and recombinant human IGF-I tracer preparations were observed. However, a fraction of the [Thr59]-IGF-I tracer did not possess binding activity and this was associated with excretion of a greater proportion of administered radioactivity (over 22 h) in urine in animals receiving [Thr59]-IGF-I tracer (18.4-19.3%) compared with ovine IGF-I (7.1-11.0%).(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate the ontogenesis of gamma-aminobutyric acid (GABA) mediated regulation of growth hormone release, the GABA agonist muscimol (250-300 micrograms/kg, i.v.) or antagonist, picrotoxin (300-500 micrograms/kg, i.v.) was administered to the chronically catheterized ovine fetus, infant lamb or adult ewe. Neither agent affected growth hormone release in fetuses younger than 105 days of gestation or in infant lambs or adult sheep. In fetuses between 115 and 140 days of gestation muscimol inhibited (n = 5, P less than 0.02) and picrotoxin stimulated (n = 5, P less than 0.001) fetal growth hormone secretion. These observations indicate the presence of tonic GABA mediated inhibition of growth hormone release in the late gestation fetus and are evidence that fetal GH secretion is not entirely unrestrained. Compared to other neurotransmitter systems potentially regulating growth hormone secretion, the GABA-ergic system is intermediate in its appearance. The presence of a growth hormone response to GABA agonists and antagonists in the fetal but not in the postnatal period is further evidence of the particularly prominent role of GABA as a neurotransmitter in the immature brain.

It has been suggested that selection based on insulin-like growth factor-1 (IGF-1) concentrations could be used as a mechanism to improve efficiency of growth in young animals. However, there is the strong possibility that selection on IGF-1 levels could cause correlated changes in other traits. The present study was designed to determine if selection based on phenotypic IGF-1 concentrations has any impact on reproductive performance of ewes. In study one, the breeding performance and ovulation rate of oestrus-synchronised ewes selected for either "Low" or "High" phenotypic IGF-1 concentrations, and that of a control line, were compared. In study two, ewes were also superovulated using eCG and the above parameters measured. In study one, both Low and High line ewes were less (P < 0.05) likely to be bred in the 4-day period post-synchronisation only, and more (P < 0.05) likely to return to service than Control ewes. These relationships were not observed in study two. In study two, but not in study one, High line ewes were more likely (P < 0.05) to be mated in the post-synchronised period only, than Control and Low line ewes. In both studies the proportion not mated did not differ between the ewe lines. Conception rates were lower (P < 0.05) in both the Low and High lines than in the Control lines in study one, although the Low and High lines did not differ. In study two, conception rates did not differ between ewe lines. In study one, average ovulation rates were lower (P < 0.05) in the Low than in the Control and High line ewes, which did not differ (0.96, 1.15 versus 1.21 corpora lutea per ewe respectively). Average ovulation rates in study two differed (P < 0.05) between all groups such that the Control line ewes had higher rates than the Low line, which in turn had higher rates than the High line (1.74, 1.46 versus 1.22 corpora lutea per ewe respectively). In study two, eCG increased (P < 0.05) the proportion of ewes with multiple ovulations (19.9 versus 64.4%) and the average number of corpora lutea (1.82 versus 1.13). The inconsistency of results across the two studies makes clear conclusions difficult. This variation may have been caused by between year differences in nutrition and/or reproductive interventions. However, given that differences between IGF-1 selection lines were apparent for some reproductive parameters, within individual studies, the results suggest care should be exercised when selection is based on phenotypic IGF-1 concentration. [ABSTRACT FROM AUTHOR]

A number of studies have shown an increase in the birth weight of lambs in response to mid pregnancy shearing. The present study sought to determine whether the birth weight effect of mid-pregnancy shearing is mediated through changes in maternal insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-I (IGFBPI) concentrations. Single- and twin-bearing ewes from three genetically divergent IGF-I lines were either left unshorn or shorn at a mean day 90 of pregnancy (P90). Maternal plasma concentrations of IGF-I and IGFBP-I were measured at P89, P108 and P136. Lamb liveweight at birth and weaning were measured, and plasma concentrations of IGF-I determined at weaning. Shearing increased the birth weight of twin lambs by over 350 g (P < 0.05) without having any effect on singleton birth weight. The increased birth weight of twin lambs born to shorn ewes was associated with a decline in maternal plasma IGF-I concentration (P < 0.05) from P108 to P136. Low IGF-I line ewes had lower (P < 0.001) plasma IGF-I than high IGF-I line ewes at each stage measured but higher plasma IGFBP-I at P89 and P108. Birth weights were higher in lambs born to low IGF-I line ewes than in those born to high IGF line ewes. These results suggest that the difference in birth weight between twin lambs from shorn and unshorn dams was mediated through a decline in maternal plasma IGF-I concentrations in late pregnancy. In support of previous studies, there was an inverse relationship between IGF-I selection line and lamb birth weight. [ABSTRACT FROM AUTHOR]

Three insulin-like growth factor (IGF-1) sheep genetic selection lines (Low, Control and High) based on phenotypic IGF-1 concentrations post-weaning have previously shown a negative relationship between IGF-1 concentration and lamb birth-weight. The present study was designed to determine if dam nutritional regimen in late pregnancy affected this relationship. Nineteen Low, 66 Control and 51 High IGF-1 selection line pregnant ewes were either offered a restricted or ad-lib nutritional regimen from day 91 of pregnancy. The ewe nutritional regimens resulted in differences (P < 0.05) in ewe liveweight and condition score in late pregnancy. IGF-1 concentrations of High and Low line ewes differed (P < 0.05) throughout the late-pregnancy period with Control line concentrations being intermediate. In late pregnancy, ad-lib ewes had higher (P < 0.05) IGF-1 concentrations than restricted ewes. Neither IGF-1 selection line or nutrition regimen consistently affected ewe glucose, non-esterified fatty acids (NEFA), β-hydroxybuterate or lactate concentrations. Under ad-lib nutritional conditions the birthweights of High line lambs were lighter (P < 0.05) than Control lambs. This relationship was not observed under the restricted nutritional regimen. The interaction between IGF-1 selection line and dam nutrition for lamb birthweight may explain the previously reported variability in the birthweight response between IGF-1 selection lines. We speculate that under conditions of ad-lib dam pregnancy nutrition, High IGF-1 selection line ewes partition resources away from the placenta resulting in poorer foetal nutrition. [ABSTRACT FROM AUTHOR]

The present study was designed to determine the effect of IGF-1 selection on lamb birth-weight and to establish the role of the maternal IGF-1 genotype on foetal growth. Nineteen high (H) line ewes were mated to high line rams (HH), 21 low (L) line ewes were mated to H line rams (LH), 25 control (C) line ewes were mated to control rams (CC), 35 H ewes were mated to L rams (HL) and 24 L ewes were mated to L rams (LL); the resultant lambs were used in this study. HH lambs were significantly (P < 0.05) lighter at birth than both LL and CC lambs. HL and LH lambs did not differ in birthweight from either LL or HH lambs. HH lambs grew significantly (P < 0.05) faster than LH lambs and faster than LL lambs (P = 0.05). HH lambs had significantly (P < 0.05) higher IGF-1 concentrations than LL lambs post-weaning. HL and LH IGF-1 concentrations were intermediate and differed significantly (P < 0.05) from both LL and HH lambs. The results of this study suggest that the difference in foetal growth between the selection lines is not influenced by maternal genotype, but is instead influenced by foetal genotype, and this warrants further examination. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to investigate (1) the safety of fetal magnesium sulfate treatment and (2) possible beneficial effects on the brain during perinatal asphyxia.Study Design: In 20 chronically instrumented fetal lambs (gestational age 125.8 +/- 3.5 days) four total umbilical cord occlusions for 5 minutes were repeated at 30-minute intervals. Fetuses received either saline solution (n = 11) or magnesium sulfate (n = 9) as a bolus of 300 mg intravenously 2 hours before occlusions, followed by an infusion of 100 mg/hr until 1 hour after occlusions.Results: In the treated fetuses plasma magnesium levels rose from 0.85 +/- 0.20 to 2.23 +/- 0.40 mmol/ L. Occlusions induced asphyxia, associated with mortality; 4 of 11 fetuses in the control group versus 1 of 9 in the magnesium-treated group died (not significant). Fetal electroencephalographic activity decreased and cerebral impedance increased during occlusions. Maximum spike and seizure activity occurred 5 to 10 hours after asphyxia. Neuronal loss was primarily localized in the corpus striatum. Magnesium caused no alterations in blood pressure, heart rate, or cerebral and peripheral blood flow, nor did it influence electrophysiologic responses or neuronal loss.Conclusions: Administration of magnesium sulfate was safe but did not offer significant cerebral protection from asphyxia in the near-term fetal lamb. [ABSTRACT FROM AUTHOR]

Objective: Brief repetitive total umbilical cord occlusions were used to induce fetal asphyxia and to evaluate the interrelationships with hypotension and fetal heart rate decelerations.Study Design: In 21 chronically instrumented fetal lambs (gestational age 126.8 +/- 0.6 days), repetitive total umbilical cord occlusion was performed 1 out of 2.5 minutes (n = 7), 2 out of 5 minutes (n = 9), or not at all (shams, n = 5). Occlusions proceeded until fetal blood pressure was < 20 mm Hg or failed to recover to baseline before the next occlusion.Results: At the nadir of asphyxia pH (mean +/- SEM) was 6.84 +/- 0.02, base excess 23.1 +/- 1.0 mmol/L, and lactate 14.2 +/- 0.4 mmol/L. Two fetuses died. The pattern of fetal heart rate decelerations remained relatively consistent throughout the experiments. In contrast, after an initial phase of sustained hypertension a progressive fall in trough blood pressure occurred after approximately 15 minutes of occlusion. The blood pressure recovery time in almost all fetuses lengthened abruptly near the end of the occlusion series, at a variable metabolic threshold. This was accompanied by a significant delay in fetal heart rate recovery in only five fetuses.Conclusions: Fetal compromise presented with the development of hypotension, without change in the pattern of fetal heart rate response. These data illustrate the limited diagnostic value of fetal heart rate monitoring to identify the development of cardiovascular compromise associated with severe decelerations in the previously healthy fetus. [ABSTRACT FROM AUTHOR]