Effects of somatostatin and adrenergic blockade on glucagon, insulin and glucose in exercising sheep

This study was conducted to characterize the mechanisms of hyperglycaemia in exercising sheep. Sheep were run on a treadmill for 45 min (5.5 km h-1, 8% incline) during adrenergic blockade (propranolol or phentolamine mesylate infusions) and during suppression of the rise in glucagon by infusion of somatostatin (SRIF). Propranolol did not alter the glucagon, insulin or glucose responses, except it tended to increase the metabolic clearance of glucose, presumably as a result of blocking the beta-adrenergic inhibition of glucose uptake. Phentolamine mesylate administration was associated with a suppression of the rise in glucagon concentrations, a reversal of alpha-adrenergic inhibition of insulin release and a reduction in glucose appearance during exercise. SRIF prevented the rise in glucagon and reduced insulin concentrations to below resting values. Propranolol and phentolamine mesylate did not alter the glucagon, insulin or glucose response to SRIF. However, SRIF prevented the insulin rise that occurred during phentolamine administration. The increment in glucose appearance produced in response to exercise was the same for SRIF, plus phentolamine mesylate and phentolamine mesylate in the first 25 min of exercise, but was significantly less than in the controls. During the last 20 min of exercise, glucose appearance was not significantly different from the control for any of the groups. The depression by SRIF and alpha-adrenergic blockade of the increment in glucose appearance due to exercise was associated with an impairment of the glucagon response. It appears, therefore, that glucagon may stimulate glucose production early in exercise in sheep directly, as well as by having a permissive effect.     

The effects of adrenergic blockade on fetal response to hypoxia

The actions of the adrenergic blocking agents propranolol and phentolamine upon the responses of 124-135 days fetal sheep to hypoxia induced by causing pregnant ewes to breathe 9% O2 and 3% CO2 in N2 have been studied. During hypoxia fetal heart rate fell and any tendency for this to return was prevented by propranolol and stimulated by phentolamine. The ability of the fetal heart rate to return during hypoxia appears to be related to the rise in plasma catecholamines. Hypoxia induced increases in plasma ACTH and cortisol and in plasma metabolites appear to have the same characteristics as those changes induced by catecholamine infusion; the former being largely an alpha-receptor effect and the latter being beta-receptor mediated. The results indicate but do not prove that many of the fetal responses to hypoxia could be caused by the rise in plasma catecholamines.     

Blood glucose and insulin relationships in the human mother and fetus before onset of labour

The effects of a maternal intravenous glucose load on the fetal plasma levels of glucose and insulin have been studied in 11 patients before the onset of labour. Within five minutes the fetal plasma glucose concentration rose significantly, indicating a rapid transfer of glucose across the placenta. Following this, the rate of fall in fetal plasma glucose closely reflected that in the mother.Serial fetal insulin estimations carried out in 8 of the 11 subjects following maternal glucose showed an early rise in fetal insulin in four and a delayed rise in one; in the remaining three there was no definite change.It is concluded that the blood glucose level of the fetus is controlled by that of the mother, but that the fetal pancreas at term may respond to hyperglycaemia by the secretion of insulin.     

CEREBRAL METABOLIC AND CIRCULATORY CHANGES INDUCED BY HYPOXIA IN STARVED RATS

In order to study cerebral metabolic and circulatory effects of hypoxia under conditions of restricted glucose supply, the arterial P_o2, was reduced to 25–30mm Hg in artificially ventilated and lightly anaesthetized rats that were starved for 24 or 48 h prior to experiments. Arterial glucose concentrations, that were initially around 6μmol g^-1, were significantly reduced after 15min of hypoxia, and decreased to 50^o of control after 30min. In animals studied after 30min of hypoxia (24 h of starvation), cerebral blood flow had increased 4-fold and there was a moderate (25%) rise in cerebral oxygen consumption. During the course of hypoxia, cerebral cortical concentrations of glucose fell to low values. In spite of this, concentrations of pyruvate and lactate rose with time, and the sum of citric acid cycle intermediates (citrate, α-ketoglutarate, fumarate. malate and oxaloacetate) increased. Changes in amino acids were dominated by a fall in aspartate and a rise in alanine concentration. There was a moderate reduction in phosphocreatine and a slight rise in ADP concentration, but concentrations at ATP and AMP were unchanged. The changes observed are similar to those previously obtained in fed animals. It is concluded that even if blood glucose concentrations fall to 3μmol g^-1, and cerebral energy flux is maintained, substrate supply is sufficient to cover the energy requirements of the tissue. Hypoxia was accompanied by increases in the lactate/pyruvate and β-hydroxybutyrate acetoacetate ratios of blood. In the tissue, NADH/NAD⁺ ratios derived from the lactate, malate and β-hydroxybutyrate dehydrogenase systems rose, while that derived from the glutamate dehydrogenase reaction fell. It is concluded that the latter system is not well suited for estimating mitochondrial redox changes in brain tissue.     

The effect of hyperglycaemia on the rates of appearance and metabolic clearance of glucose in sheep (Ovis aries)

Glucose appearance and utilization before and during glucose infusions were examined in insulin treated alloxan-diabetic (ITA) and intact sheep. During hyperglycaemia in ITA sheep glucose appearance was reduced to 35% of the preinfusion values whereas in intact sheep it was 17% of preinfusion values. Hyperglycaemia per se appears to inhibit glucose appearance. The utilization of glucose was not proportional to glucose concentrations in ITA sheep, but was in intact sheep where insulin concentrations increased during hyperglycaemia.     

Adrenergic effects on plasma levels of glucagon, insulin, glucose and free fatty acids in rabbits

Adrenergic effects on plasma levels of glucagon, insulin, glucose and free fatty acids were studied in fasted rabbits by infusing epinephrine, norepinephrine, isoproterenol, phentolamine (an adrenergic alpha-receptor blocking drug) and propranolol (an adrenergic beta-receptor blocking drug). The adrenergic effects on the plasma levels of insulin, glucose and free fatty acids were similar to those found in other species. The plasma levels of insulin were increased by beta-receptor stimulation (isoproterenol, phentolamine + epinephrine) and decreased by alpha-receptor stimulation (epinephrine, norepinephrine, propranolol + epinephrine). The plasma levels of glucose were increased by both alpha- and beta-receptor stimulation, and the epinephrine-induced hyperglycaemia was only blocked by combined infusions with phentolamine and propranolol. The plasma levels of free fatty acids were increased by saline and further increased by beta-receptor stimulation (isoproterenol), while epinephrine and norepinephrine gave variable results. Alpha-receptor stimulation (propranolol + epinephrine) slightly decreased the plasma levels of free fatty acids. The plasma levels of glucagon, however, were mainly increased by alpha-receptor stimulation (epinephrine, norepinephrine, propranolol + epinephrine) and increased only to a minor extent by beta-receptor stimulation (isoproterenol, phentolamine + epinephrine) in rabbits. This is in contrast to results reported for humans, where beta-receptor stimulation seems to be most important in stimulating glucagon release.     

Ontogeny of the insulin response to glucose in fetal and adult sheep

The purpose of the present experiments was to examine in sheep whether the fetal insulin response to glucose was present by day 110 (d110) of pregnancy and whether the magnitude of the fetal insulin response changed between d110 and d145 (term). We also compared the responses observed in fetuses to those of adult nonpregnant sheep. Basal concentrations of glucose measured in plasma collected from the fetal femoral artery rose progressively between d110 and d145 of gestation, but did not attain the plasma glucose concentrations measured in adult sheep. Peak glucose concentrations in fetuses were achieved 10 min following the bolus injection of glucose (0.8 g/kg estimated fetal body weight) into the fetal femoral vein, and peak values increased with gestational age. Significantly higher peak glucose concentrations were achieved in adult sheep. The concentration of insulin rose rapidly in fetuses at d110, and a similar time course of insulin release in plasma was seen at all gestational ages. The peak plasma insulin concentrations were achieved at 20 min and were significantly greater in older (d140-145) than younger (d125-130) fetuses (p less than 0.05). Peak insulin values in fetuses were much less than in adult sheep. In adult sheep glucose and insulin concentrations remained elevated at 120 min following the injection of glucose, whereas in the fetus the concentration of insulin had returned to preinjection values by 60 min. The insulin/glucose ratio did not change in fetal lambs over the last one third of gestation and was not different from the adult sheep.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of insulin and glucose on the production and utilization of glucose in sheep (Ovis aries)

1. The rates of appearance (RA) and metabolic clearance rates (MCR) of glucose were determined during the infusion of insulin plus glucose in sheep. 2. During euglycaemia 50% inhibition of RA of endogenous glucose occurred at insulin concentrations of 60 microU/ml in arterial plasma. 3. During euglycaemia the MCR of glucose doubled with an increment of about 100 microU/ml of insulin. 4. Hypoglycaemia was associated with a reduction in insulin's suppression of RA of endogenous glucose and hyperglycaemia significantly reduced the increase in MCR due to insulin.     

Preexisting hypoxia is associated with a delayed but more sustained rise in T/QRS ratio during prolonged umbilical cord occlusion in near-term fetal sheep

There is limited information about whether preexisting fetal hypoxia alters hemodynamic responses and changes in T/QRS ratio and ST waveform shape during subsequent severe asphyxia. Chronically instrumented near-term sheep fetuses (124 +/- 1 days) were identified as either normoxic Pa(O(2)) > 17 mmHg (n = 9) or hypoxic Pa(O(2)) < or = 17 mmHg (n = 5); then they received complete occlusion of the umbilical cord for 15 min. Umbilical cord occlusion led to sustained bradycardia, severe acidosis, and transient hypertension followed by profound hypotension in both groups. Preexisting hypoxia did not affect changes in mean arterial blood pressure but was associated with a more rapid initial fall in femoral blood flow and vascular conductance and with transiently higher fetal heart rate at 2 min and from 9 to 11 min of occlusion compared with previously normoxic fetuses. Occlusion was associated with a significant but transient rise in T/QRS ratio; preexisting hypoxia was associated with a significant delay in this rise (maxima 3.7 +/- 0.4 vs. 6.2 +/- 0.5 min), but a slower rate of fall. There was a similar elevation in troponin-T levels 6 h after occlusion in the two groups [median (range) 0.43 (0.08, 1.32) vs. 0.55 (0.16, 2.32) microg/l, not significant]. In conclusion, mild preexisting hypoxia in normally grown singleton fetal sheep is associated with more rapid centralization of circulation after umbilical cord occlusion and delayed elevation of the ST waveform and slower fall, suggesting that chronic hypoxia alters myocardial dynamics during asphyxia.     

The effect of elevation of maternal plasma catecholamines on the fetus and placenta of the pregnant sheep

To study the effects of reduced uterine blood flow on fetal and placental metabolism, adrenaline has been infused at physiological doses (0.5 microgram/min per kg) into the circulation of the pregnant sheep. This gives a reduction of about one third of uterine blood flow at days 120-143 of pregnancy, but causes no significant change in umbilical blood flow. In contrast to the effects of constricting the uterine artery to reduce blood flow to a similar degree, placental oxygen consumption was reduced and that, together with a large increase in lactate production, indicated the placenta became hypoxic. The fetal blood gas status and hence oxygen consumption was not affected significantly. A consistent arterio-venous difference for glucose across the umbilical or uterine circulations was not detected unless the uterine blood flow was comparatively high. Glucose balance across the uterus showed a close linear relationship with uterine blood flow and more particularly with the supply of glucose to the uterus. There was clear evidence for glucose uptake by the placenta and fetus and also glucose output by both. The latter was more common when uterine blood flow was comparatively low or reduced by adrenaline infusion. The results are consistent with the concept that glucose supply has to be maintained to the placenta even at the expense of fetal stores, although lactate can substitute if there is enhanced output because of fetal hypoxia. They indicate that placental mobilisation of glycogen can lead to a net output of glucose to the mother. The manner of communicating to the fetus changes in placental state that occur during maternal adrenaline infusion is not clear. However towards the end of the 60 min infusion, elevation of fetal plasma adrenaline, probably resulting from a breakdown of the placental permeability barrier, may be an important signal.     

Studies on experimental growth retardation in sheep. The effects of maternal hypoxaemia

Intrauterine growth retardation in fetal sheep was caused by removal of endometrial caruncles prior to conception. Such fetuses are chronically hypoxaemic and to establish their ability to withstand additional episodes of hypoxia, the effects of administration of 9% O2 to the pregnant ewe was investigated. Fetuses were studied at 135-140 days. During maternal hypoxia the small fetuses showed a greater tendency to further hypoxaemia and acidaemia, but the differences compared with controls were not large. Whilst the initial response to hypoxaemia was a fall in heart rate in the small fetuses, unlike the controls, the heart rate returned to normal within 15 min. Metabolite responses to hypoxia in the small fetuses were less than normal and the changes in plasma insulin concentrations were uncommonly small. In contrast the plasma cortisol and ACTH responses to hypoxia were larger than normal in the small fetus. The results are discussed in relation to the altered physiological state of the growth-retarded fetal sheep.     

Effects of naloxone on the breathing, electrocortical, heart rate, glucose and cortisol responses to hypoxia in the sheep fetus

Continuous infusions of naloxone HC1 (0.5 mg/kg or 3.8 mg/kg) or saline were given intravenously to fetal sheep at 119 to 137 days of gestation during a one hour period of air administration and a one hour period of hypoxia induced by having ewes breathe 9% O2, 3% CO2 and 88% N2. Fetal carotid PaO2 fell to 13.0 +/- 0.5 mmHg during hypoxia with no change in pH. During hypoxia, plasma cortisol concentration increased significantly more in naloxone-infused fetuses than controls. Ewes, whose fetuses received naloxone, showed a significant increase in cortisol during hypoxia whereas no increase was observed in controls. There were no significant differences between saline and naloxone-infused fetuses during hypoxia in fetal breathing incidence, amplitude, frequency, number of deep inspiratory efforts per hour, heart rate, electrocortical activity or in the rise in plasma glucose caused by hypoxia. Results suggest that endogenous opiates may have a role in modulating cortisol production in the ewe and fetus during hypoxia but do not have a role in mediating the decrease in incidence of breathing activity or rise in plasma glucose. During air administration, naloxone significantly increased fetal breath amplitude, fetal and maternal plasma glucose, fetal heart rate, and the number of electrocortical changes per hour. This suggests endogenous opiates may have a more important role in the normoxic pregnant ewe and fetus.     

Early fetal hypoxia leads to growth restriction and myocardial thinning

Hypoxia is necessary for fetal development; however, excess hypoxia is detrimental. Hypoxia has been extensively studied in the near-term fetus, but less is known about earlier fetal effects. The purpose of this study was to determine the window of vulnerability to severe hypoxia, what organ system(s) is most sensitive, and why hypoxic fetuses die. We induced hypoxia by reducing maternal-inspired O2 from 21% to 8%, which decreased fetal tissue oxygenation assessed by pimonidazole binding. The mouse fetus was most vulnerable in midgestation: 24 h of hypoxia killed 89% of embryonic day 13.5 (E13.5) fetuses, but only 5% of E11.5 and 51% of E17.5 fetuses. Sublethal hypoxia at E12.5 caused growth restriction, reducing fetal weight by 26% and protein by 45%. Hypoxia induced HIF-1 target genes, including vascular endothelial growth factor (Vegf), erythropoietin, glucose transporter-1 and insulin-like growth factor binding protein-1 (Igfbp-1), which has been implicated in human intrauterine growth restriction (IUGR). Hypoxia severely compromised the cardiovascular system. Signs of heart failure, including loss of yolk sac circulation, hemorrhage, and edema, were caused by 18-24 h of hypoxia. Hypoxia induced ventricular dilation and myocardial hypoplasia, decreasing ventricular tissue by 50% and proliferation by 21% in vivo and by 40% in isolated cultured hearts. Epicardial detachment was the first sign of hypoxic damage in the heart, although expression of epicardially derived mitogens, such as FGF2, FGF9, and Wnt9b was not reduced. We propose that hypoxia compromises the fetus through myocardial hypoplasia and reduced heart rate.     

Chronic hypoxia increases insulin-stimulated glucose uptake in mouse soleus muscle

People living at high altitude appear to have lower blood glucose levels and decreased incidence of diabetes. Faster glucose uptake and increased insulin sensitivity are likely explanations for these findings: skeletal muscle is the largest glucose sink in the body, and its adaptation to the hypoxia of altitude may influence glucose uptake and insulin sensitivity. This study tested the hypothesis that chronic normobaric hypoxia increases insulin-stimulated glucose uptake in soleus muscles and decreases plasma glucose levels. Adult male C57BL/6J mice were kept in normoxia [fraction of inspired O? = 21% (Control)] or normobaric hypoxia [fraction of inspired O? = 10% (Hypoxia)] for 4 wk. Then blood glucose and insulin levels, in vitro muscle glucose uptake, and indexes of insulin signaling were measured. Chronic hypoxia lowered blood glucose and plasma insulin [glucose: 14.3 ± 0.65 mM in Control vs. 9.9 ± 0.83 mM in Hypoxia (P < 0.001); insulin: 1.2 ± 0.2 ng/ml in Control vs. 0.7 ± 0.1 ng/ml in Hypoxia (P < 0.05)] and increased insulin sensitivity determined by homeostatic model assessment 2 [21.5 ± 3.8 in Control vs. 39.3 ± 5.7 in Hypoxia (P < 0.03)]. There was no significant difference in basal glucose uptake in vitro in soleus muscle (1.59 ± 0.24 and 1.71 ± 0.15 μmol·g?1·h?1 in Control and Hypoxia, respectively). However, insulin-stimulated glucose uptake was 30% higher in the soleus after 4 wk of hypoxia than Control (6.24 ± 0.23 vs. 4.87 ± 0.37 μmol·g?1·h?1, P < 0.02). Muscle glycogen content was not significantly different between the two groups. Levels of glucose transporters 4 and 1, phosphoinositide 3-kinase, glycogen synthase kinase 3, protein kinase B/Akt, and AMP-activated protein kinase were not affected by chronic hypoxia. Akt phosphorylation following insulin stimulation in soleus muscle was significantly (25%) higher in Hypoxia than Control (P < 0.05). Neither glycogen synthase kinase 3 nor AMP-activated protein kinase phosphorylation changed after 4 wk of hypoxia. These results demonstrate that the adaptation of skeletal muscles to chronic hypoxia includes increased insulin-stimulated glucose uptake.     

Evidence that hyperglycaemia per se does not inhibit hepatic glucose production in man

The effect of hyperglycaemia on hepatic glucose production (Ra) was investigated in nine healthy men using sequential clamp protocols during somatostatin infusion and euglycaemia (0-150 min), at plasma glucose levels of 165 mg x dl-1 (9.2 mM, 150-270 min) and during insulin infusion (1.0 mU x kg-1 x min-1, 270-360 min) in study 1 or during hypo-insulinaemia and plasma glucose levels of 220 mg x dl-1 (12.2 mM; 270-390 min) in study 2. Somatostatin decreased Ra and glucose disposal rate (Rd) but increased plasma free fatty acids (FFA) and lipid oxidation during euglycaemia. Increasing plasma glucose to 165 mg x dl-1 (9.2 mM) and hypo-insulinaemia increased Rd, but no suppressive effects on Ra, plasma FFA and lipid oxidation were observed. By contrast hyperinsulinaemia (study 1), as well as a further increase in plasma glucose (study 2), both decreased Ra. However, more pronounced hyperglycaemia increased insulin secretion despite somatostatin resulting in a fall in plasma FFA and lipid oxidation. Our data questions the accepted dogma that hyperglycaemia inhibits Ra independently of insulin action.     

Studies on experimental growth retardation in sheep. The effects of a small placenta in restricting transport to and growth of the fetus

Fetal and placental growth rate in sheep has been manipulated by removal of endometrial caruncles prior to conception. This produced two groups of fetuses, one in which prenatal growth rate was similar to normal and a second group in which the fetuses were about half of the normal size. The mortality in the latter group was high, particularly after catheterisation, and there was evidence of early intra-uterine death and fetal reabsorption. Prior to 125 days the relationship between fetal and placental size was poor, but after 126 days a close correlation between the two was apparent. The small fetuses had comparably small placentas and in all cases there was a close relationship between fetal and placental weight. The experimental growth retardation was associated with hypoglycaemia, hypoxia and hypoinsulinaemia. Plasma T3, T4 and particularly prolactin were very low in the small fetuses whilst levels of cortisol and alanine were high. In contrast to the controls these fetuses showed little evidence of net glucose, alanine or lactate consumption. Infusion of 50% glucose into the pregnant ewe, sufficient to elevate maternal plasma glucose concentrations 2 to 3 fold, caused a comparable increase in the plasma concentrations of normal fetuses but only a 50% rise in the concentration in small fetuses. In contrast administration of 50% O2 to the ewes sufficient to cause a 2 to 3-fold increase in maternal PO2 caused only a small increase of arterial PO2 of normal fetuses but doubled that to normal levels in small fetuses. The results are discussed in relation to the effect of reduced placental size causing a fall in placental and transport and transport capacity and significance of this to the associated fetal growth retardation.     

Use of liposomes to aid intestinal absorption of entrapped insulin in normal and diabetic dogs

The effectiveness of liposomes in aiding intestinal absorption of entrapped insulin was studied in normal and diabetic dogs. Intraduodenal administration of free insulin (490 and 1630 U) or free insulin (88 U) plus empty liposomes to normal conscious dogs produced no change in plasma immunoreactive insulin or glucose Administration of 40–80 U insulin entrapped in liposomes composed of either phosphatidylcholine, distearoylphosphatidylcholine, or dipalmitoylphosphatidylcholine with cholesterol and dicetylphosophate ( in the ratio 10:2:1 by weight) to normal dogs produced substantial rises in peripheral plasma immunoreactive insulin after 45–60 min. However, the magnitude of these rises was neither reproducible nor dose-dependent. No fall in plasma glucose was observed. Intraduodenal administration of 50–100 U insulin entrapped in liposomes to diabetic dogs also produced rises in plasma immunoreactive insulin levels after 45–60 min but again these rises were not dose-related. However, unlike the results in normal dogs, a small fall in plasma glucose followed the plasma immunoreactive insulin rise in diabetic dogs. This glucose fall was not dose-dependent nor was it related to the magnitude of the rise in plasma immunoreactive insulin. In conclusion, it seems that administration of insulin in liposomes may allow absorption of partially degraded insulin into the circulation but the rise in plasma immunoreactive insulin observed in normal and diabetic dogs and the fall in plasma glucose in diabetic dogs are not influenced by the dose of insulin entrapped nor the lipid composition of the liposomes.     

Evidence of sustained forearm vasodilatation after brief isocapnic hypoxia.

Healthy subjects exposed to 20 min of hypoxia increase ventilation and muscle sympathetic nerve activity (MSNA). After return to normoxia, although ventilation returns to baseline, MSNA remains elevated for up to an hour. Because forearm vascular resistance is not elevated after hypoxic exposure, we speculated that the increased MSNA might be a compensatory response to sustained release of endogenous vasodilators. We studied the effect of isocapnic hypoxia (mean arterial oxygen saturation 81.6 +/- 4.1%, end-tidal Pco2 44.7 +/- 6.3 Torr) on plethysmographic forearm blood flow (FBF) in eight healthy volunteers while infusing intra-arterial phentolamine to block local alpha-receptors. The dominant arm served as control. Forearm arterial vascular resistance (FVR) was calculated as the mean arterial pressure (MAP)-to-FBF ratio. MAP, heart rate (HR), and FVR were reported at 5-min intervals at baseline, then while infusing phentolamine during room air, isocapnic hypoxia, and recovery. Despite increases in HR during hypoxia, there was no change in MAP throughout the study. By design, FVR decreased during phentolamine infusion. Hypoxia further decreased FVR in both forearms. With continued phentolamine infusion, FVR after termination of the exposure (17.47 +/- 6.3 mmHg x min x ml(-1) x 100 ml of tissue) remained lower than preexposure baseline value (23.05 +/- 8.51 mmHg x min x ml(-1) x 100 ml of tissue; P < 0.05). We conclude that, unmasked by phentolamine, the vasodilation occurring during hypoxia persists for at least 30 min after the stimulus. This vasodilation may contribute to the sustained MSNA rise observed after hypoxia.     

Metabolic and hormonal responses to cooling the fetal sheep in utero

The metabolic and hormonal effects of cooling 10 fetal sheep in utero (115-142 days of gestation) for 2h were studied. The fetal core temperature fell by 2.81 +/- 0.14 degrees C while the maternal temperature fell 0.86 +/- 0.15 degrees C. This hypothermia caused a significant rise in the fetal and maternal plasma glucose concentrations (P less than 0.001) and a fall in the fetal insulin concentrations (P less than 0.01). The fetal plasma lactate and cortisol concentrations rose rapidly (P less than 0.01) while the growth hormone fell (P less than 0.01) and remained low until cooling ceased when a rapid rebound occurred. There was no significant change in any of the fetal iodothyronines and no elevation of nonesterified free fatty acid concentrations, in contrast to the rapid rise (P less than 0.01) which occurred when newborn lambs were cooled. These observations demonstrate that appropriate glucose, insulin, lactate and cortisol responses to hypothermia have differentiated by 120 days of gestation. However, neither a thyroid hormone response nor an elevation in free fatty acid levels was observed. Thus not all components of the thermogenic response to hypothermia can be demonstrated in the late gestation fetail sheep in utero.     

Haemodynamic and catecholamine responses to hypothermia in the fetal sheep in utero

Chronically catheterised fetal sheep (117-134 days) were cooled in utero via a tubing coil placed around the fetal trunk through which cold water was circulated for one hour. The fetal core temperature was reduced by 5.51 +/- 0.61 degrees C. This hypothermia was associated with tachycardia (P less than 0.001) and hypertension (P less than 0.001) (n = 12). The tachycardia was abolished by treatment with propranolol (n = 4) and the hypertension by treatment with phentolamine (n = 5). Blood flow in the left umbilical artery was measured by an electromagnetic flow probe in 4 fetuses and rose (P less than 0.001) with fetal cooling. The increase in blood flow was abolished by treatment with either phentolamine or propranolol. These observations are consistent with a redistribution of fetal blood flow from peripheral tissues to placental and thermogenic tissues during cooling. Fetal plasma adrenaline and noradrenaline concentrations rose (P less than 0.01) during fetal cooling (n = 5). These studies demonstrate that catecholamine and cardiovascular responses to environmental hypothermia have differentiated prior to birth in the sheep fetus.