Autonomic control of heart rate differs with electrocortical activity and chronic hypoxaemia in fetal lambs

We aimed to determine the effects of the electrocortical (ECoG) cycle on fetal heart rate and its autonomic control under normoxaemic and hypoxaemic conditions. Heart rate was measured and selective pharmacological blockade was used to quantify sympathetic and parasympathetic tone in low voltage (LV) and high voltage (HV) ECoG. We studied 3 groups of fetal lambs: 6 normal-sized, normoxaemic fetuses (control); 5 growth-retarded, normoxaemic carunclectomy fetuses (carunclectomy-normoxaemic); and 5 growth-retarded, hypoxaemic carunclectomy fetuses (carunclectomy-hypoxaemic). We found slower heart rate in LV compared to HV ECoG in all groups. This was explained by greater parasympathetic tone in LV in all groups, and by a complementary change of sympathetic tone in control fetuses. Hypoxaemic fetuses had slower heart rate than normoxaemic fetuses in both ECoG states. This was due to augmented parasympathetic tone (in LV ECoG) and reduced sympathetic tone (in LV and HV ECoG). We conclude that complementary changes of autonomic tone underly the normal variation of fetal heart rate with the ECoG cycle, with the parasympathetic arm dominant in LV and the sympathetic arm dominant in HV ECoG. In chronic hypoxaemia, complementary changes of autonomic tone contribute to slowing of fetal heart rate. Increased parasympathetic tone and decreased sympathetic tone may enhance cardiac efficiency when the oxygen supply is chronically reduced.     

Effect of thyroidectomy on cardiovascular responses to hypoxia and tyramine infusion in fetal sheep

Fetal sheep were thyroidectomized at 80 days' gestation and reoperated at 118-122 days for insertion of vascular catheters. The effects of hypoxaemia and intravenous tyramine infusion on plasma catecholamine concentrations, blood pressure and heart rate were then determined in experiments at 125-135 days' gestation. Age matched intact fetuses were also studied. Thyroidectomy was associated with increased concentrations of noradrenaline, adrenaline and dopamine in some thoracic and abdominal organs, increased noradrenaline concentrations in the cerebellum, and decreased adrenaline concentrations in the hypothalamus, cervical spinal cord, and superior cervical and inferior mesenteric ganglia. Arterial pressure was significantly lower in the thyroidectomized fetuses (34.0 +/- 0.15 mmHg) than in intact fetuses (44.7 +/- 0.2 mmHg; p less than 0.001). In contrast, plasma noradrenaline concentrations were significantly higher in the thyroidectomized fetuses (2.04 +/- 0.25 ng/ml) compared to the intact fetuses (0.99 +/- 0.08 ng/ml; P less than 0.001). In the intact fetuses there was a significant increase in plasma noradrenaline concentration and blood pressure during hypoxaemia, and bradycardia at the onset of hypoxaemia. In contrast, in the thyroidectomized fetuses hypoxaemia did not cause significant change in plasma catecholamine concentrations, blood pressure or heart rate. Infusion of tyramine produced a 1.9-fold increase of plasma noradrenaline in thyroidectomized fetuses compared to a 9.2-fold increase in the intact fetuses (P less than 0.05). Tyramine infusion caused a similar proportional increase of blood pressure in both thyroidectomized and intact fetuses. Heart rate decreased during the tyramine-induced hypertension in the intact fetus, but increased in the thyroidectomized fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Dose-dependent effects of arginine vasopressin on endocrine and blood gas responses of fetal sheep during the last third of pregnancy

Arginine vasopressin (AVP) is released in fetal sheep in response to various intrauterine stresses such as hypoxaemia, hypotension, and haemorrhage. We have examined the effects of exogenous AVP injected at two doses (200 ng and 2 micrograms) on the plasma concentrations of ACTH and cortisol, and on arterial blood PO2, PCO2, and pH in chronically catheterized fetal sheep at d110-115, d125-130, and at d135-140 of pregnancy. AVP (2 micrograms) provoked a significant elevation in the plasma ACTH and cortisol concentration at all three stages of gestation, whereas the administration of 200 ng AVP raised plasma ACTH and cortisol only at d110-115 and at d125-130. The increment in plasma cortisol after 200 ng AVP at the two earlier stages of pregnancy was similar to that after 2 micrograms AVP, despite a dose-dependent difference in the change in ACTH concentration. AVP stimulated a rise in PaO2 at each time of study, although the time course of response was shorter at d135-140 than at the previous stages of pregnancy. The effect of AVP on PaCO2 was more variable, showing a transient decrease at +5 min after injection in the two oldest groups of fetuses. pH fell after AVP at d110-115 and at d125-130, but it rose transiently in the oldest fetuses. We conclude that at high concentrations systemic administration of AVP provokes endocrine and blood gas changes in fetal sheep. ACTH was consistently elevated by AVP. PaO2 also rose at each stage of pregnancy, but the effects on PaCO2 and pH varied as a function of fetal age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of hypoxaemia and hypercapnia on breathing movements and sleep state in sinoaortic-denervated fetal sheep

The role of the systemic arterial chemoreceptors in regulating breathing movements was determined in 7 chronically catheterized fetal sheep with carotid denervation and vagal section. Fetal hypoxaemia (delta PaO2 = -11.4 +/- 0.6 mmHg) decreased significantly the incidence of rapid-eye-movements (control = 26 +/- 1.5 min/h; hypoxia = 12 +/- 2.6 min/h, P less than 0.001) and breathing activity (control = 18 +/- 1.0 min/h; hypoxia = 8 +/- 1.1 min/h, P less than 0.001). However, the lag in onset of inhibition (approximately 8 min) was significantly greater (P less than 0.05) than for normal fetuses. The incidence of low voltage electrocortical activity was not affected. Hypercapnia (delta PaCO2 = 9.5 +/- 1.1 mmHg) increased significantly the incidence of rapid-eye-movements and breathing activity. Hypercapnia also increased the mean amplitude of breathing activity and reduced the average breath interval. Rapid-eye-movements and breathing activity were depressed significantly by hypoxaemic hypercapnia. These observations suggest that hypoxic inhibition does not require afferent activity from the aortic or carotid bodies nor from other chemoreflexes mediated by the vagus. However, such peripheral input may be responsible for a more rapid onset of inhibition in normal fetuses.     

Right ventricular function in the hypoxaemic fetal sheep

Right ventricular function was investigated in seven fetal sheep (125-130 days gestation) hypoxaemic at a mean of 5 days postoperation, and were compared to nine normoxaemic fetal sheep of the same gestation. Arterial O2 and CO2 tensions, pH, and haematocrit values for the hypoxaemic and normoxaemic fetuses were 15.6 +/- 1.0 vs. 20.6 +/- 1.8 torr, 49.4 +/- 4.1 vs. 46.1 +/- 1.6 torr, 7.38 +/- 0.02 vs. 7.39 +/- 0.02, and 29 +/- 7.5 vs. 31 +/- 5.3%, respectively. Right ventricular output and stroke volume were similar in the two groups, 241 +/- 57 vs. 247 +/- 75 ml X min-1 X kg-1 and 1.5 +/- 0.4 vs. 1.5 +/- 0.4 ml X kg-1, respectively. Filling and afterload pressures were also similar in the hypoxaemic and normoxaemic fetuses with right atrial pressure of 3.0 +/- 1.0 vs. 3.7 +/- 1.2 mmHg, and arterial pressure of 42 +/- 5 vs. 43 +/- 4 mmHg, respectively. Ventricular function curves were produced by rapid withdrawal and re-infusion of fetal blood producing curves with a steep ascending limb and a plateau phase. The breakpoint joining the limbs of the control function curve for the hypoxaemic and normoxaemic fetuses were right atrial pressure 2.9 +/- 1.0 vs. 3.4 +/- 1.2 mmHg and a stroke volume of 1.5 +/- 0.5 vs. 1.5 +/- 0.4 ml X kg-1, respectively. Linear regression of stroke volume against arterial pressure from 30-90 mmHg during infusions of nitroprusside and phenylephrine at right atrial filling pressures greater than breakpoint was stroke volume = 0.018 ml X kg-1 X mmHg-1 arterial pressure +/- 2.25 ml X kg-1. This equation is not different from that calculated in normoxaemic fetuses, and demonstrates that the fetal right ventricle is quite sensitive to changes in arterial pressure. These data indicate that reduction in fetal oxygen content by an estimated 40% does not affect fetal right ventricular function.     

Renin-angiotensin and autonomic mechanisms in cardiovascular homeostasis during haemorrhage in fetal and neonatal sheep.

The present study examined the roles of the renin-angiotensin and autonomic nervous systems in cardiovascular homeostasis during slow progressive haemorrhage (20% of measured blood volume over 1h) in fetal (128-132 and 143-148 days gestation) and neonatal (5-9 and 12-20 days post-natal) sheep. Basal plasma renin activity (PRA) was not significantly different in the 4 sheep groups and increased to a similar degree (approximately 2 to 3-fold) during haemorrhage. Mean arterial pressure (MAP) exhibited modest falls in response to haemorrhage in all sheep groups and while heart rate (HR) was well maintained in the fetal groups there was a tendency to bradycardia in neonates. None of these responses was significantly different in age-matched fetal sheep subjected to bilateral vago-sympathectomy, cervical cord transection or bilateral nephrectomy, with the exception of PRA in the latter group which was close to zero throughout. Treatment with the angiotensin II (AII) antagonist, (Sar1-Ala8) AII (Saralasin), significantly increased basal PRA in both fetal and neonatal sheep (approximately 5 to 7-fold). The PRA response to haemorrhage was absent in neonatal sheep treated with Saralasin but significantly increased in fetal sheep. Saralasin significantly reduced resting MAP in both sheep groups and increased the hypotensive and bradycardic effects of haemorrhage in neonatal (approximately 3 to 5-fold) but not fetal sheep. It is concluded that in the perinatal period studied, fetal and neonatal sheep are equally well able to maintain cardiovascular homeostasis in response to moderate haemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of hypoxia on the initiation of secondary wool follicles in the fetus

The development of secondary wool follicles in single fetal sheep subjected to hypobaric hypoxaemia was studied. One group of pregnant ewes were exposed to 57.1 kPa from 30 to 135 days gestation. Fetal weights (mean +/- s.d.) for the hypoxaemic group (3.35 +/- 0.53 kg; n = 4) were significantly lower than for the controls (4.19 +/- 0.31 kg; n = 3, P less than 0.05). At 110 days gestation, a second group had arterial and venous catheters surgically implanted into the ewe and fetus and skin samples were taken from the fetus. At 120 days gestation (10 days after surgery) these animals were subjected to hypoxia for 20 days, at a level to maintain fetal carotid pO2 between 1.47 and 1.87 kPa (mean carotid pO2 for the control fetuses was 2.84 +/- 0.28 kPa). Fetal weight at 140 days was not significantly different in the hypoxaemic and control groups. Morphometric analysis revealed that the secondary to primary follicle ratio (S:P) was less in both groups of hypoxaemic fetuses than in their respective controls. Although hypoxia for 20 days did not significantly alter fetal weight, it produced a low S:P ratio similar to the longer-term hypoxaemic animals. It is concluded that hypoxia has a marked effect in reducing the initiation of secondary follicles in the last third of gestation.     

In vivo regulation of adrenocorticotrophin secretion in the immature ovine fetus. Modulation by ovine corticotrophin releasing hormone and arginine vasopressin

This study investigates the in vivo regulation of ACTH secretion in the immature ovine fetus by AVP and oCRH. Previously we have demonstrated that whilst AVP-containing neurones are present from 42 days, oCRH-containing neurones cannot be detected in the fetal paraventricular nucleus or median eminence until after 90 or 100 days respectively. In acutely exteriorized fetuses aged between 64-90 days (n = 5), a haemorrhagic stress elicited a significant increase (P less than 0.01) in ACTH values. There was also a significant correlation between plasma ACTH and AVP concentrations in these fetuses. In chronically cannulated fetuses less than 100 days (n = 6) injection of AVP (200 ng) significantly elevated fetal plasma ACTH values at 10 min (P less than 0.01) post injection. Simultaneous injection of AVP (200 ng) and oCRH (10 micrograms) into these fetuses produced a plasma ACTH value that was significantly greater at 10 min (P less than 0.05) than the summed response obtained with separate injection of oCRH and AVP. When AVP and oCRH were injection in equimolar amounts to fetuses between 101-118 days, AVP (2 micrograms) was found to have a greater effect on ACTH than was oCRH (2 micrograms). Pretreatment with a specific vascular antagonist of AVP-d(CH2)5Tyr(Me)AVP failed to significantly inhibit the increase in mean arterial pressure associated with AVP (2 micrograms) injection but partially antagonized (P = 0.04) the decrease in fetal heart rate. The antagonist however completely abolished any effect of AVP on fetal plasma ACTH values. This study suggests that AVP most likely acts through receptors in the fetal pituitary with V1 characteristics.     

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.     

Modulation of the responses of fetal sheep to adrenergic stimulation by adrenal demedullation and chemical sympathectomy

The responses to sympathetic stimulation of fetal sheep adrenal-demedullated or sympathectomised by infusion of guanethidine sulphate have been studied. Sympathetic responses in such denervated or sympathectomised fetuses was studied by intravenous infusion of adrenaline or noradrenaline at about 0.4 micrograms/min per kg. This infusion increased plasma concentration 100-200 fold and there was no significant difference between the control fetuses and those in the vasrious treatment groups. Catecholamine infusions at these rates normally have little effect upon fetal blood gas and pH values, but in adrenal-demedullated fetuses adrenaline infusion drepressed fetal arterial PO2 by 4-6 mmHg (P less than 0.05). The heart rate and blood pressure responses to catecholamine infusion in sympathectomised fetuses was, as expected, much increased. Similar observations were made on adrenal-demedullated fetuses, an unexpected finding, and this is taken to illustrate loss of the adrenal medulla is associated with enhanced responsiveness to adrenergic stimulation in peripheral tissues. The majority of the endocrine and metabolic responses, as reflected in fetal plasma concentrations of ACTH, cortisol, insulin, glucose, lactate and fatty acids, to catecholamine infusion were similarly much enhanced by adrenal-demedullation and chemical sympathectomy. Of particular note was a substantial increase in the responsiveness of the fetal adrenal, as reflected in plasma cortisol, to stimulation by ACTH, a change that usually induces labour, but not so in the present sheep. The results on increased sensitivity in adrenal-demedullated fetuses are discussed in relation to likely tissue mechanisms mediating the changes.     

Changes to metabolite concentration in fetal sheep subjected to prolonged hypobaric hypoxia

The effect of hypobaric hypoxaemia on the concentration of metabolic substrates in the ovine fetus and pregnant ewe with implanted vascular catheters, was investigated. At 120 to 141 days of gestation sheep were subjected to hypobaria (mean fetal carotid PO2 12.7 +/- 0.7 torr; n = 9) or normobaria (mean fetal carotid PO2 22.7 +/- 0.7 torr; n = 11; P less than 0.001). At 141 days gestation mean fetal weight was 3.46 +/- 0.72 kg in the hypobaric group compared to 4.15 +/- 0.51 in the normobaric group (P less than 0.05). Concentrations of glucose in maternal and fetal plasma and fructose in fetal plasma were similar in hypobaric and normobaric fetuses. The concentration of lactate in fetal plasma rose from 1.68 +/- 1.34 to 8.79 +/- 5.8 mmol/l (P less than 0.001) within 24 h of onset of hypoxia, but fell to 3.36 +/- 1.13 mmol/l by day 3 of treatment, though still significantly above the concentration of lactate in the control fetuses (1.47 +/- 0.47; P less than 0.001). There was no significant effect of hypoxia on the concentration of lactate or alanine in maternal plasma. Alanine concentration in the plasma of fetuses subjected to hypoxia significantly increased within 24 h of exposure (0.28 +/- 0.10 vs 0.58 +/- 0.39 mmol/l; P less than 0.01) and remained elevated for the duration of the study. There was no significant effect of gestational age on the concentration of metabolic substrates in either the control or experimental groups. Hypoxia is associated with a sustained rise in the concentration of plasma lactate and alanine in the fetus.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of prolonged hypobaric hypoxia on growth of fetal sheep

The effect of prolonged hypobaric hypoxia on fetal sheep was studied. Pregnant ewes were subjected to an atmospheric pressure of 429 torr from 30 days to 135 days gestation (long-term study). Average fetal weight for the hypoxaemic group (3.35 +/- 0.53 kg; n = 4; mean +/- SD) was significantly lower than for the controls (4.23 +/- 0.29 kg; n = 7; P less than 0.05). A short-term study was undertaken with fetuses (n = 8) which were catheterized at 110 days gestation and whose dams were subjected to hypobaric hypoxia from 120 to 141 days gestation. The mean carotid PO2 of fetuses in the hypoxic group was 12.7 +/- 0.7 torr compared to 22.7 +/- 0.7 torr for the control group (n = 9; P less than 0.001) throughout the period of treatment. Fetal arterial oxygen content fell from 6.5 +/- 1.7 to 4.9 +/- 0.4 ml/dl (P less than 0.05), but rose to control values after 7 days due to an increase in fetal haemoglobin concentration (9.6 +/- 1.1 to 13.0 +/- 1.9 g/dl, P less than 0.001) and packed cell volume (33 +/- 3 to 45 +/- 4%, P less than 0.001). In the hypoxaemic fetuses, pH fell initially from 7.34 +/- 0.02 to 7.28 +/- 0.03 (P less than 0.05) and then recovered to 7.32 +/- 0.03 within 24 h. Mean fetal weight of the short-term hypoxic group was 3.46 +/- 0.72 kg compared to 4.15 +/- 0.51 for the control group (P less than 0.05). Both long- and short-term hypoxia produced a similar reduction in fetal body weight. The adrenal glands were significantly heavier in the hypoxic fetuses than in controls. Placental weight was not effected by hypoxia, but exposure from 30 days gestation reduced the average size of cotyledons (P less than 0.05). It is concluded that the fetal sheep increases its ability to acquire and transport oxygen in response to chronic hypoxia, but this compensation is not sufficient to prevent growth retardation or changes to the pattern of tissue growth.     

Changes in hypoxanthine and lactate during and after hypoxia in the fetal sheep with chronically-implanted vascular catheters

The effect of intra-uterine hypoxia on the hypoxanthine and lactate concentration in fetal sheep with catheters chronically implanted was investigated. Experiments were conducted on five fetuses. Sixty-four blood samples from nine hypoxic and recovery periods were analysed. A significant increase of hypoxanthine and lactate occurred in parallel with the fall of arterial oxygen saturation (SaO2) and arterial oxygen pressure (PaO2) during the first 20 min of hypoxia. The elevations in plasma hypoxanthine and lactate were significantly greater during more severe hypoxia than mild hypoxia, as judged from the amount of low oxygen gas mixture given to the ewe (7 or 9%). There were no difference in PaO2 and only minor difference in SaO2 between the two groups. The increase in lactate over 20 min was the same throughout the one-hour period of hypoxia, while the increase of hypoxanthine was less pronounced at the end of the period. This might be due to the fact that hypoxanthine was cleared from fetal plasma at a fairly rapid rate, half of the excess concentration being eliminated after 25 +/- 21 min compared to 85 +/- 47 min for lactate in six experiments post hypoxia. Linear regression analysis revealed a highly significant correlation between hypoxanthine and SaO2, pH and lactate (P less than 0.001). These three variables explained 77% of the variance of hypoxanthine, when calculated by multiple regression analysis.     

The effect of acute hypoxaemia on ventricular function during beta-adrenergic and cholinergic blockade in the fetal sheep

The effect of acute hypoxaemia on right and left ventricular function was investigated in 8 fetal sheep (137-140 days gestation). Fetuses were instrumented with electromagnetic flow sensors on the ascending aorta and the main pulmonary artery. After 8 days recovery, hypoxaemia was achieved by reducing the maternal ewe's inspired O2 concentration to 13.1 +/- 1.5%. Control and hypoxaemic arterial blood values were pH 7.37 +/- 0.04 (SD) and 7.35 +/- 0.06, PCO2 48.0 +/- 2.8 and 47.6 +/- 5.1 mmHg, PO2 19.9 +/- 2.2 and 11.4 +/- 1.5 mmHg, haematocrit 37.5 +/- 1.2 and 39.5 +/- 2.2, respectively. Arterial pressure increased insignificantly with acute hypoxaemia (50.2 +/- 3.9 to 53.6 +/- 8.1 mmHg). Left and right ventricular performance was assessed by generating biventricular function curves relating stroke volume to mean atrial pressure. All function curves were composed of steep ascending and plateau limbs that intersected at a breakpoint. Comparing control and hypoxaemia function curves, the left ventricular stroke volume breakpoints were 0.79 +/- 0.20 and 0.78 +/- 0.21 ml/kg, respectively, while the right ventricular stroke volume breakpoints were 0.99 +/- 0.11 and 0.88 +/- 0.21 ml/kg (n.s.). In 4 fetuses, acute hypoxaemia was associated with significant increases in arterial blood pressure (P less than 0.05). In these fetuses, the right ventricular function curve was shifted significantly downward compared to the control right ventricular curve. When nitroprusside was given to these hypertensive fetuses to return blood pressure to control levels, the right ventricular function curve returned to baseline. We conclude that even under conditions of extreme hypoxaemia, ventricular function is well preserved in the normotensive fetal sheep. However, when increases in arterial pressure also accompany hypoxaemia, detectable changes in right ventricular function can be accounted for by changes in arterial pressure.     

Cortisol inhibits ACTH but not the AVP response to hypoxaemia in fetal lambs at days 123-128 of gestation

During acute hypoxemia in fetal sheep the elevation in ACTH concentration in the fetal circulation at days 125-129 is greater than that at term, but similar rises in AVP occur at both times. To examine whether the diminished ACTH response is due to elevated endogenous cortisol, and if there is differential control of ACTH and AVP release in hypoxemia, we infused either vehicle or cortisol (5 micrograms/min) into fetal sheep at days 123-128 for 5 h before and then during a 2-h period of acute hypoxemia (mean PaO2 decrease 8.2 mmHg) without acidemia. During cortisol infusion, plasma cortisol rose to 40-50 ng/ml, similar to values in term fetuses. In vehicle-infused fetuses, cortisol rose from 2.1 to 7.0 ng/ml at +1 to +2 h of hypoxemia. ACTH rose significantly during hypoxemia in the vehicle-infused fetuses, and this response was attenuated by cortisol infusion. In contrast, fetal AVP rose significantly during hypoxemia both in the presence and absence of cortisol infusion. Fetal breathing movements, and electroocular activity decreased during hypoxemia, and these responses were not altered by cortisol. We conclude that cortisol exerts differential negative feedback on ACTH but not on AVP release during hypoxemia. The maintained AVP response may facilitate cardiovascular adjustments of the fetus to hypoxemia even when endogenous cortisol is elevated, such as near term.     

The effect of hypothalamic paraventricular nuclear lesions placed at 108-110 days gestational age on plasma ACTH concentrations in the fetal sheep

Lesions that completely destroyed the paraventricular nucleus of the hypothalamus were placed in fetal sheep (n = 4) at 108-110 days of gestational age. These fetuses were then subjected to hypotension (50% of initial mean fetal arterial blood pressure), hypoxaemia (a decrease in fetal PaO2 greater than or equal to 5 torr) and bolus injection of corticotropin releasing factor (CRF-1.0 micrograms iv) in random order on successive days. The lesioned fetuses produced significantly less ACTH after hypotension (+10 min: 35.7 +/- 26.9 vs. 358.0 +/- 99.7 and +30 min: 28.2 +/- 12.2 vs. 238.0 +/- 73.0 pg.ml-1) (P less than 0.05), hypoxaemia (+40 min: 23.5 +/- 9.3 vs. 198.3 +/- 75.8 and +60 min: 32.3 +/- 18.8 vs. 295.3 +/- 99.9 pg.ml-1) (P less than 0.05) and intravenous administration of 1 microgram CRF (+15 min: 32.0 +/- 16.8 vs. 145.7 +/- 25.0 and +60 min: 33.0 +/- 23.3 vs. 161.3 +/- 43.1 pg.ml-1) (P less than 0.05). Our experiments suggest an important role for the fetal paraventricular nucleus in control of ACTH secretion. They also indicate that impairment of paraventricular nucleus function at this stage of fetal life may have a detrimental effect on the ability of the anterior pituitary to secrete ACTH in response to exogenous CRF.     

The response of the umbilical and femoral artery pulsatility indices in fetal sheep to progressively reduced uteroplacental blood flow

Fetal artery Doppler velocimetry may provide noninvasive information on the state of fetal oxygenation. It was hypothesized that during decreasing fetal oxygenation, the pulsatility index in the femoral artery will increase, whereas the pulsatility index in the umbilical artery will not change. Decreasing fetal oxygenation was induced in ten chronically-instrumented fetal sheep by progressive occlusion of the maternal common internal iliac artery. The pulsatility index in the umbilical artery was serially measured in six fetuses (group I, n = 6) and the pulsatility index in the femoral artery was serially measured in four fetuses (group II, n = 4). Fetal arterial oxygen content decreased by 72% in group I (P less than 0.0001) and by 79% in group II (P less than 0.0001). Fetal heart rate did not change. Fetal blood pressure increased by 11% in group I (P less than 0.02) and by 15% in group II (P less than 0.005). The umbilical artery pulsatility index (group I) did not significantly change during decreasing fetal oxygenation, whereas the femoral artery pulsatility index (group II) increased by 150% (P less than 0.005). It is concluded that progressively reduced uteroplacental blood flow results in fetal hypoxaemia, which is associated with increased pulsatility index in the femoral artery, while the pulsatility index in the umbilical artery does not change.     

Plasma catecholamines in the hypoxaemic fetal rhesus monkey

To assess the response of the sympathoadrenal system of the primate fetus to oxygen deprivation, we measured plasma catecholamines in 8 chronically catheterized fetal rhesus monkeys. A range of fetal hypoxaemia was produced by having the mother inspire 15, 10, or 9% oxygen mixtures while tranquilized with ketamine. Catecholamines from fetal carotid and maternal femoral arteries were measured by radioenzymatic assay. Fetal plasma norepinephrine and epinephrine concentrations increased significantly at all levels of hypoxaemia, but dopamine increased only at very low fetal oxygen tensions. Norepinephrine levels exceeded those of epinephrine and dopamine under all conditions. Relatively more severe hypoxaemia was necessary to elevate concentrations of epinephrine above baseline as compared with norepinephrine. A negative exponential correlation (P less than 0.001) was found between both fetal arterial PO2 and oxygen content and plasma norepinephrine and epinephrine, which was qualitatively similar to that observed previously in the sheep fetus. Maternal catecholamines were found to increase during hypoxaemia as well, but to a lesser degree than in the fetus.     

Osmotic threshold and sensitivity for vasopressin release and fos expression by hypertonic NaCl in ovine fetus

In adults, hyperosmolality stimulates central osmoreceptors, resulting in arginine vasopressin (AVP) secretion. Near-term fetal sheep have also developed mechanisms to respond to intravascular hypertonicity with stimulation of in utero AVP release. However, prior studies demonstrating fetal AVP secretion have utilized plasma tonicity changes greater than those required for adult osmotically induced AVP stimulation. We sought to examine near-term fetal plasma osmolality threshold and sensitivity for stimulation of AVP secretion and to correlate plasma hormone levels with central neuronal responsiveness. Chronically instrumented ovine fetuses (130 +/- 2 days) and maternal ewes simultaneously received either isotonic or hypertonic intravascular NaCl infusions. Maternal and fetal plasma AVP and angiotensin II (ANG II) levels were examined at progressively increasing levels of plasma hypertonicity. Intravenous hypertonic NaCl gradually elevated plasma osmolality and sodium levels. Both maternal and fetal plasma AVP increased during hypertonicity, whereas ANG II levels were not changed. Maternal AVP levels significantly increased with a 3% increase in plasma osmolality, whereas fetal plasma AVP significantly increased only at higher plasma osmolality levels (over 6%). Thus the slope of the regression of AVP vs. osmolality was greater for ewes than for fetuses (0.232 vs. 0.064), despite similar maternal and fetal plasma osmolality thresholds for AVP secretion (302 vs. 304 mosmol/kg). Hyperosmolality induced Fos immunoreactivity (FOS-ir) in the circumventricular organs of the fetal brain. FOS-ir was also demonstrated in the fetal supraoptic and paraventricular nuclei (SON and PVN), and double labeling demonstrated that AVP-containing neurons in the SON and PVN expressed Fos in response to intravenous NaCl. These results demonstrate that, in the ovine fetus at 130 days of gestation, neuroendocrine responses to cellular dehydration are functional, although they evidence a relatively reduced sensitivity for AVP secretion compared with the adult.