Induction of PGHS-2 mRNA in response to cerebral hypoperfusion in late-gestation fetal sheep

Previous studies have demonstrated that cerebral ischemia stimulated the increased abundance of immunoreactive PGHS-2, but not PGHS-1, in brain tissue homogenates in late-gestation fetal sheep. The goal of the present study was to detect PGHS-1 and PGHS-2 mRNA in specific fetal brain regions, and to semi-quantitatively detect changes in the abundance of the respective mRNA's in response to cerebral hypoperfusion. Fetal brain tissues were collected from control fetuses and from fetuses 30 min and 2 h after cerebral hypoperfusion (produced by brachiocephalic occlusion). Messenger RNA was studied by RT-PCR, and expressed semiquantitatively as a ratio of PGHS-1 or PGHS-2 mRNA abundance to beta-actin mRNA abundance. PGHS-2 mRNA was only detected in the fetal hippocampus, hypothalamus, and brain stem and it was induced by cerebral hypoperfusion. In contrast, PGHS-1 mRNA was detected in all fetal brain tissues but was not induced. We conclude that cerebral hypoperfusion induced PGHS-2 gene expression in hippocampus, hypothalamus, and brainstem, and we speculate that the increased abundance of the enzyme is likely to be important for control of reflex responses to hypotension in the fetus.     

Regulation of cytochrome oxidase redox state during umbilical cord occlusion in preterm fetal sheep

The preterm fetus is capable of surviving prolonged periods of severe hypoxia without neural injury for much longer than at term. To evaluate the hypothesis that regulated suppression of brain metabolism contributes to this remarkable tolerance, we assessed changes in the redox state of cytochrome oxidase (CytOx) relative to cerebral heat production, and cytotoxic edema measured using cerebral impedance, during 25 min of complete umbilical cord occlusion or sham occlusion in fetal sheep at 0.7 gestation. Occlusion was followed by rapid, profound reduction in relative cerebral oxygenation and EEG intensity and an immediate increase in oxidized CytOx, indicating a reduction in electron flow down the mitochondrial electron transfer chain. Confirming rapid suppression of cerebral metabolism there was a loss of the temperature difference between parietal cortex and body at a time when carotid blood flow was maintained at control values. As occlusion continued, severe hypotension/hypoperfusion developed, with a further increase in CytOx levels to a plateau between 8 and 13 min and a progressive rise in cerebral impedance. In conclusion, these data strongly suggest active regulation of cerebral metabolism during the initial response to severe hypoxia, which may help to protect the immature brain from injury.     

Male disadvantage? Fetal sex and cardiovascular responses to asphyxia in preterm fetal sheep

Clinically and experimentally male fetuses are at significantly greater risk of dying or suffering injury at birth, particularly after premature delivery. We undertook a retrospective cohort analysis of 60 female and 65 male singleton preterm fetal sheep (103-104 days, 0.7 gestation) with mean arterial blood pressure (MAP), heart rate, and carotid and femoral blood flow recordings during 25 min of umbilical cord occlusion in utero. Occlusions were stopped early if fetal MAP fell below 8 mmHg or if there was asystole for >20 s. Fetuses that were able to complete the full 25-min period of occlusion showed no differences between sexes for any cardiovascular responses. Similar numbers of occlusions were stopped early in males (mean: 21 min, n = 16) and females (mean: 23 min, n = 16); however, they showed different responses. Short-occlusion males (n = 16) showed a slower initial fall in femoral vascular conductance, followed by greater bradycardia, hypotension, and associated organ hypoperfusion compared with full-occlusion fetuses. In contrast, short-occlusion females (n = 16) showed a significantly more rapid early increase in femoral vascular conductance than the full-occlusion fetuses, followed by worsening of bradycardia and hypotension that was intermediate to the full-occlusion fetuses and short-occlusion males. Among all fetuses, MAP at 15 min of occlusion, corresponding with the time of the maximal rate of fall, was correlated with postmortem weight in males (R(2) = 0.07) but not females. In conclusion, male and female fetuses showed remarkably similar chemoreflex and hemodynamic responses to severe asphyxia, but some males did show impaired hemodynamic adaptation within the normal weight range.     

Increased myometrial contracture frequency at 96-140 days accelerates fetal cardiovascular maturation

Fetal cardiovascular responses to an altered intrauterine environment of increased myometrial contractures induced by oxytocin (OT) pulses to the ewe over the final 50 days of gestation were studied in chronically instrumented sheep. Ewes received saline (Cntl) or long-term OT treatment (LTOT, 600 microU x kg(-1) x min(-1) in 5-min pulses every 20 min) from 96 days gestational age. Fetal baroreflex responses to sodium nitroprusside (SNP) and phenylephrine (PE) were studied at 133 days gestation. OT increased contractures in LTOT ewes. Fetal blood pressure (FBP) was higher, and fetal heart rate (FHR) and slope of daily change in FBP and FHR were lower in LTOT fetuses. Fetal SNP-induced hypotension resulted in a narrow R-R interval variation range in LTOT fetuses; Cntl fetuses showed early breakdown in compensation. Baroreflex response slope during PE-induced fetal hypertension was lower in LTOT than in Cntl fetuses. Although the cortisol-to-ACTH ratio was lower in LTOT fetuses, fetal plasma ACTH and cortisol changes were similar in control and LTOT fetuses. We hypothesize that contracture-induced alterations in the intrauterine environment accelerate fetal cardiovascular development through mild hypoxemia, repetitive fetal pituitary-adrenal stimulation, and/or physical stimulation.     

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)     

Suprarenal aortic flow reduction versus angiotensin I infusion in fetal sheep

In the unanaesthetized fetal sheep, long-term suprarenal aortic blood flow reduction will cause upper body arterial blood pressure to increase. To see if the response to this procedure was entirely due to the concomitant increase in plasma renin activity, we gave an angiotensin I infusion of several days to 7 fetal sheep and compared their responses to those of 4 fetal sheep undergoing partial occlusion of the aorta above the renal arteries. Both protocols caused upper body arterial blood pressure to increase to comparable levels. Angiotensin I infusion had no effect upon venous blood pressure while suprarenal aortic blood flow reduction caused a significant increase in venous blood pressure as early as 1 day after blood flow reduction. Haematocrits were unchanged in the fetuses with flow restriction but increased in the infused fetuses. We conclude that long-term angiotensin I infusion in the fetus does not mimic the entire complex of responses to suprarenal aortic blood flow reduction.     

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 ontogeny of hemodynamic responses to prolonged umbilical cord occlusion in fetal sheep.

There is evidence that preterm fetuses have blunted chemoreflex-mediated responses to hypoxia. However, the preterm fetus has much lower aerobic requirements than at term, and so moderate hypoxia may not be sufficient to elicit maximal chemoreflex responses; there are only limited quantitative data on the ontogeny of chemoreflex and hemodynamic responses to severe asphyxia. Chronically instrumented fetal sheep at 0.6 (n = 12), 0.7 (n = 12), and 0.85 (n = 8) of gestational age (GA; term = 147 days) were exposed to 30, 25, or 15 min of complete umbilical cord occlusion, respectively. At all ages, occlusion was associated with early onset of bradycardia, profoundly reduced femoral blood flow and conductance, and hypertension. The 0.6-GA fetuses showed a significantly slower and lesser fall in femoral blood flow and conductance compared with the 0.85-GA group, with a correspondingly reduced relative rise in mean arterial blood pressure. As occlusion continued, the initial adaptation was followed by loss of peripheral vasoconstriction and progressive development of hypotension in all groups. The 0.85-GA fetuses showed significantly more sustained reduction in femoral conductance but also more rapid onset of hypotension than either of the younger groups. Electroencephalographic (EEG) activity was suppressed during occlusion in all groups, but the degree of suppression was less at 0.6 GA than at term. In conclusion, the near-midgestation fetus shows attenuated initial (chemoreflex) peripheral vasomotor responses to severe asphyxia compared with more mature fetuses but more sustained hemodynamic adaptation and reduced suppression of EEG activity during continued occlusion of the umbilical cord.     

Local regulation of the uterine blood flow by the umbilical circulation.

Observations were made of the responses of the uterine blood flow in the near-term pregnancy to occlusion of the umbilical circulation to a few cotyledons of the near-term sheep placenta and in one placenta of the multiparous rabbit pregnancy. It was found that the uterine blood flow declined to 67% of its predicted value 1 day after umbilical ligation in the sheep placenta and to 61% of its predicted value 1 day after the death of one of the fetuses of the rabbit pregnancy. The change in the uterine blood flow in response to the occlusion of the umbilical blood supply to the adjacent area is a local response and is similar in its time course and magnitude to the response of the whole placenta which has been previously observed by Raye et al. (9). This local response of the uterine blood flow is considered to be evidence that the uterine blood flow is in part determined and controlled by the structural or chemical nature of the adjacent fetal compartment.     

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.     

Prostaglandin E2 stimulates adrenocorticotrophin and cortisol secretion via a hypothalamic site of action in fetal sheep.

The hypothesis that prostaglandins stimulate fetal adrenocortical activity via a central site of action within the fetal brain was tested in chronically catheterized fetal sheep. At day 120 gestation (term = 145 days) fetal sheep were surgically prepared with catheters in the lateral cerebral ventricle, jugular vein and carotid artery and experiments began five days later. Intravenous (i.v.) infusion of prostaglandin E2 (30 or 120 micrograms.h-1) caused a significant dose-related increase in fetal plasma concentrations of ACTH. Despite this increase in ACTH, cortisol was only stimulated after the highest dose of prostaglandin E2. Intracerebroventricular (i.c.v.) infusion of PGE2 (30 micrograms.h-1) also stimulated ACTH secretion although the peak response was delayed and considerably less compared with the same dose administered intravenously. Prostaglandin F2 alpha administered i.v. or i.c.v. had no effect on circulating concentrations of either ACTH or cortisol. These data provide evidence that prostaglandin E2 can stimulate fetal ACTH secretion by acting in the fetal brain. Furthermore, the greater release of ACTH after i.v. compared with i.c.v. prostaglandin E2 suggests that a site of action other than the brain, such as the pituitary gland, may also be important. These results provide further evidence that during late gestation circulating prostaglandins can act to stimulate fetal pituitary-adrenal maturation.     

Central and peripheral mechanisms underlying gastric distention inhibitory reflex responses in hypercapnic-acidotic rats

We have observed that in chloralose-anesthetized animals, gastric distension (GD) typically increases blood pressure (BP) under normoxic normocapnic conditions. However, we recently noted repeatable decreases in BP and heart rate (HR) in hypercapnic-acidotic rats in response to GD. The neural pathways, central processing, and autonomic effector mechanisms involved in this cardiovascular reflex response are unknown. We hypothesized that GD-induced decrease in BP and HR reflex responses are mediated during both withdrawal of sympathetic tone and increased parasympathetic activity, involving the rostral (rVLM) and caudal ventrolateral medulla (cVLM) and the nucleus ambiguus (NA). Rats anesthetized with ketamine and xylazine or α-chloralose were ventilated and monitored for HR and BP changes. The extent of cardiovascular inhibition was related to the extent of hypercapnia and acidosis. Repeated GD with both anesthetics induced consistent falls in BP and HR. The hemodynamic inhibitory response was reduced after blockade of the celiac ganglia or the intraabdominal vagal nerves with lidocaine, suggesting that the decreased BP and HR responses were mediated by both sympathetic and parasympathetic afferents. Blockade of the NA decreased the bradycardia response. Microinjection of kainic acid into the cVLM reduced the inhibitory BP response, whereas depolarization blockade of the rVLM decreased both BP and HR inhibitory responses. Blockade of GABA(A) receptors in the rVLM also reduced the BP and HR reflex responses. Atropine methyl bromide completely blocked the reflex bradycardia, and atenolol blocked the negative chronotropic response. Finally, α(1)-adrenergic blockade with prazosin reversed the depressor. Thus, in the setting of hypercapnic-acidosis, a sympathoinhibitory cardiovascular response is mediated, in part, by splanchnic nerves and is processed through the rVLM and cVLM. Additionally, a vagal excitatory reflex, which involves the NA, facilitates the GD-induced decreases in BP and HR responses. Efferent chronotropic responses involve both increased parasympathetic and reduced sympathetic activity, whereas the decrease in BP is mediated by reduced α-adrenergic tone.     

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.     

Effect of central naloxone on hormone and blood pressure responses to hemorrhage in conscious sheep

The role of the brain opioid system in the control of hypothalamic-pituitary-adrenal activity was studied in 10 conscious sheep with an indwelling cannula in a cerebral lateral ventricle. On separate days, sheep received infusions of artificial CSF (control) and the opiate antagonist, naloxone (100 micrograms/hr) before and during acute moderate hemorrhage (15 ml/kg over 10 min). Infusion of naloxone before hemorrhage raised plasma ACTH and resulted in a significant increase in cortisol compared to the control infusion. In contrast, ACTH and cortisol responses to hemorrhage tended to be blunted by central naloxone infusion. The responses of vasopressin, aldosterone and the catecholamines remained unaffected by naloxone. The fall in blood pressure and the rise in heart rate accompanying hemorrhage were likewise unaltered. These results suggest that brain opioid peptides have an inhibitory effect on basal ACTH secretion but do not play a major role in modulating the hemodynamic or pituitary-adrenal responses to acute moderate hemorrhage in conscious sheep.     

Acute hyperglycemia induced by ketamine/xylazine anesthesia in rats: mechanisms and implications for preclinical models

The effects of anesthetic agents, commonly used in animal models, on blood glucose levels in fed and fasted rats were investigated. In fed Sprague-Dawley rats, ketamine (100 mg/kg)/xylazine (10 mg/kg) (KX) produced acute hyperglycemia (blood glucose 178.4 +/- 8.0 mg/dl) within 20 min. The baseline blood glucose levels (104.8 +/- 5.7 mg/dl) reached maximum levels (291.7 +/- 23.8 mg/dl) at 120 min. Ketamine alone did not elevate glucose levels in fed rats. Isoflurane also produced acute hyperglycemia similar to KX. Administration of pentobarbital sodium did not produce hyperglycemia in fed rats. In contrast, none of these anesthetic agents produced hyperglycemia in fasted rats. The acute hyperglycemic effect of KX in fed rats was associated with decreased plasma levels of insulin, adrenocorticotropic hormone (ACTH), and corticosterone and increased levels of glucagon and growth hormone (GH). The acute hyperglycemic response to KX was dose-dependently inhibited by the specific alpha2-adrenergic receptor antagonist yohimbine (1-4 mg/kg). KX-induced changes of glucoregulatory hormone levels such as insulin, GH, ACTH, and corticosterone were significantly altered by yohimbine, whereas the glucagon levels remained unaffected. In conclusion, the present study indicates that both KX and isoflurane produce acute hyperglycemia in fed rats. The effect of KX is mediated by modulation of the glucoregulatory hormones through stimulation of alpha2-adrenergic receptors. Pentobarbital sodium did not produce hyperglycemia in either fed or fasted rats. Based on these findings, it is suggested that caution needs to be taken when selecting anesthetic agents, and fed or fasted state of animals in studies of diabetic disease or other models where glucose and/or glucoregulatory hormone levels may influence outcome and thus interpretation. However, fed animals are of value when exploring the hyperglycemic response to anesthetic agents.     

Vagal blockade does not prevent adrenocorticotropin, cortisol, and cardiopulmonary responses to thromboxane A2.

Previously, we reported that thromboxane A2 (TxA2) mediates heart rate, adrenocorticotropin (ACTH), cortisol, and blood gas responses, although the specific site of action was not identified. In the present study, we interrupted vagal nervous transmission in chronically instrumented conscious sheep and infused the TxA2 mimetic U46619 or saline into the carotid artery or U46619 into the vena cava to determine whether TxA2 acts at vagal afferent nerves. Heart rate increased in all three groups during vagal blockade, and responses were not different between groups. Carotid artery and intravenous infusions of U46619 resulted in an increase in blood pressure, but responses were not different between groups. PaO2 decreased in response to vagal blockade in all groups, and responses were not different among groups. Arterial pH increased and PaCO2 decreased during vagal blockade in response to carotid artery U46619 infusions but not in response to vagal blockade alone or combined with carotid artery saline or intravenous U46619. ACTH, cortisol, and hematocrit increased significantly in response to carotid artery infusions of U46619 during vagal blockade but not in response to carotid artery saline or intravenous U46619 infusions. In summary, carotid artery infusions of TxA2 mimetic result in ACTH, cortisol, PaCO2, pHa, and hematocrit responses that are not prevented by vagal blockade. We conclude that these responses are mediated at a site perfused by the carotid vasculature and not at a site innervated by the vagal nerves, findings consistent with the hypothesis that TxA2 acts on the brain to mediate cardiopulmonary and pituitary-adrenal responses.     

Carotid baroreflex pressor responses at rest and during exercise: cardiac output vs. regional vasoconstriction

The arterial baroreflex mediates changes in arterial pressure via reflex changes in cardiac output (CO) and regional vascular conductance, and the relative roles may change between rest and exercise and across workloads. Therefore, we quantified the contribution of CO and regional vascular conductances to carotid baroreflex-mediated increases in mean arterial pressure (MAP) at rest and during mild to heavy treadmill exercise (3.2 kph; 6.4 kph, 10% grade; and 8 kph, 15% grade). Dogs (n = 8) were chronically instrumented to measure changes in MAP, CO, hindlimb vascular conductance, and renal vascular conductance in response to bilateral carotid occlusion (BCO). At rest and at each workload, BCO caused similar increases in MAP (average 35 +/- 2 mmHg). In response to BCO, neither at rest nor at any workload were there significant increases in CO; therefore, the pressor response occurred via peripheral vasoconstriction. At rest, 10.7 +/- 1.4% of the rise in MAP was due to vasoconstriction in the hindlimb, whereas 4.0 +/- 0.7% was due to renal vasoconstriction. Linear regression analysis revealed that, with increasing workloads, relative contributions of the hindlimb increased and those of the kidney decreased. At the highest workload, the decrease in hindlimb vascular conductance contributed 24.3 +/- 3.4% to the pressor response, whereas the renal contribution decreased to only 1.6 +/- 0.3%. We conclude that the pressor response during BCO was mediated solely by peripheral vasoconstriction. As workload increases, a progressively larger fraction of the pressor response is mediated via vasoconstriction in active skeletal muscle and the contribution of vasoconstriction in inactive beds (e.g., renal) becomes progressively smaller.     

Effects of acute acidemia on the fetal cardiovascular defense to acute hypoxemia

In complicated pregnancy, fetal hypoxemia rarely occurs in isolation but is often accompanied by fetal acidemia. There is growing clinical concern about the combined effects of fetal hypoxemia and fetal acidemia on neonatal outcome. However, the effects on the fetal defense responses to acute hypoxemia during fetal acidemia are not well understood. This study tested the hypothesis that fetal acidemia affects the fetal defense responses to acute hypoxemia. The hypothesis was tested by investigating, in the late-gestation sheep fetus surgically prepared for long-term recording, the in vivo effects of acute fetal acidemia on 1) the fetal cardiovascular responses to acute hypoxemia and 2) the neural and endocrine mechanisms mediating these responses. Under general anesthesia, five sheep fetuses at 0.8 gestation were instrumented with catheters and Transonic flow probes around the femoral and umbilical arteries. After 5 days, animals were subjected to an acute hypoxemia protocol during intravenous infusion of saline or treatment with acidified saline. Treatment with acidified saline reduced fetal basal pH from 7.35 +/- 0.01 to 7.29 +/- 0.01 but did not alter basal cardiovascular variables, blood glucose, or plasma concentrations of catecholamines, ACTH, and cortisol. During hypoxemia, treatment with acidified saline increased the magnitude of the fetal bradycardia and femoral vasoconstriction and concomitantly increased chemoreflex function and enhanced the increments in plasma concentrations of catecholamines, ACTH, and cortisol. Acidemia also reversed the increase in umbilical vascular conductance during hypoxemia to vasoconstriction. In conclusion, the data support our hypothesis and show that acute acidemia markedly alters fetal hemodynamic, metabolic, and endocrine responses to acute hypoxemia.     

Effect of baroreceptor activity on ventilatory response to chemoreceptor stimulation.

This study tested the hypothesis that ventilatory responses to chemoreceptor stimulation are affected by the level of arterial pressure and degree of baroreceptor activation. Carotid chemoreceptors were stimulated by injection of nicotine into the common carotid artery of anesthetized dogs. Arterial pressure was reduced by bleeding the animals and raised by transient occlusion of the abdominal aorta. The results indicate that ventilatory responses to chemoreceptor stimulation were augmented by hypotension and depressed by hypertension. In additional studies we excluded the possibility that the findings were produced by a direct effect of changes in arterial pressure on chemoreceptors. Both carotid bifurcations were perfused at constant flow. In one carotid bifurcation, perfusion pressure was raised to stimulate carotid sinus baroreceptors. In the other carotid bifurcation, pressure was constant and nicotine was injected to stimulate carotid chemoreceptors. Stimulation of baroreceptors on one side attenuated the ventilatory response to stimulation of contralateral chemoreceptors. This inhibition was observed before and after bilateral cervical vagotomy. We conclude that there is a major central interaction between baroreceptor and chemoreceptor reflexes so that changes in baroreceptor activity modulate ventilatory responses to chemoreceptor stimulation.     

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.