Plasma vasopressin levels are closely associated with fetal hypotension and neuronal injury after hypoxia-ischemia in near-term fetal sheep.

BACKGROUND: Sensitive biomarkers are needed to rapidly identify high-risk infants after hypoxia-ischemia for neuroprotective treatment. Hypotension is a key determinant of hypoxic-ischemic neural injury, and a potent stimulus of humoral pressors including angiotensin-II and arginine vasopressin. We therefore aimed to quantify the relationship between vasopressin and angiotensin-II levels in the latent phase after hypoxia-ischemia induced by umbilical cord occlusion (UCO) with both the severity of preceding hypotension and subsequent neuronal injury. METHODS: Chronically instrumented near-term fetal sheep underwent sham-UCO or UCO for either 15 min or until mean arterial pressure was <8 mmHg. Neuronal injury was assessed after 72 h recovery. RESULTS: Umbilical cord occlusion was associated with severe hypotension that recovered after UCO; two fetuses developed profound secondary hypotension within 6 h and died. Vasopressin levels but not angiotensin-II were significantly elevated 1-3 h after UCO and were closely associated with the severity of hypotension during UCO and the subsequent severity of neuronal loss in the parasagittal and lateral cortex, caudate nucleus and putamen. The Youden cut-point for vasopressin at 1 h was 180.0 pmol/L, with sensitivity 100% and specificity 92.3% for severe neuronal injury or death. CONCLUSION: Vasopressin levels shortly after moderate-severe hypoxia-ischemia may be a useful early biomarker to guide the timely implementation of neuroprotective treatment. IMPACT: It can be difficuIt to rapidly identify infants who might benefit from therapeutic hypothermia. We investigated whether increases in plasma pressor hormones early after hypoxia-ischemia were biomarkers for neonatal hypoxic-ischemic encephalopathy using near-term fetal sheep. Arginine vasopressin levels were elevated at 1-3 h after hypoxia-ischemia and were predictive of the severity of preceding hypotension and subsequent risk of severe neuronal injury or death after hypoxia-ischemia. Arginine vasopressin may help identify neonates at high risk of hypoxic-ischemic encephalopathy early within the therapeutic window for hypothermia.

Blockade of PGHS-2 inhibits the hypothalamus-pituitary-adrenal axis response to cerebral hypoperfusion in the sheep fetus.

Decreases in fetal blood pressure stimulate homeostatic stress responses that help return blood pressure to normal levels. Fetal hypothalamus-pituitary-adrenal (HPA) axis responses to hypotension are mediated by chemoreceptor and baroreceptor reflexes and ischemia of the fetal central nervous system. Indomethacin, a nonselective inhibitor of prostaglandin endoperoxide synthase (PGHS)-1 and -2, attenuates the HPA response to hypotension in the fetus. The present study was designed to test the hypothesis that selective inhibition of PGHS-2 also inhibits the HPA response to cerebral hypoperfusion. We studied 13 chronically catheterized fetal sheep (126-136 days gestation). Five fetal sheep were subjected to intracerebroventricular infusion of nimesulide (0.01 mg/day), a specific inhibitor of PGHS-2, and eight were treated with vehicle (DMSO in water) for 5 days. Each fetus was subjected to a 10-min period of brachiocephalic occlusion, which decreased carotid arterial pressure approximately 75% and reflexively increased fetal plasma concentrations of ACTH, POMC, cortisol, and femoral arterial pressure, and decreased fetal heart rate. Nimesulide significantly inhibited the ACTH response to the BCO, while significantly augmenting the reflex cardiovascular response and altering fetal heart rate variability consistent with increased sympathetic nervous system activity. The results of this study demonstrate that the activity of PGHS-2 in the brain is a necessary component of the fetal HPA response to cerebral hypoperfusion in the late-gestation fetal sheep. These results are consistent with those of recent study, in which we demonstrated that the preparturient increase in fetal ACTH secretion depends upon PGHS-2 activity within the fetal brain.

Oestrogen augments the fetal ovine hypothalamus- pituitary-adrenal axis in response to hypotension.

In the fetal sheep, parturition is triggered by an increase in the activity of the fetal hypothalamus- pituitary-adrenal (HPA) axis which, in turn, augments the biosynthesis of oestrogen by the placenta. Parturition can be prevented or delayed by destruction of the paraventricular nucleus (PVN), pituitary or adrenal, or stimulated by infusions of adrenocorticotropin (ACTH) or glucocorticoids. We have previously reported that physiological increases in fetal plasma concentrations of oestradiol have a neuroendocrine effect to increase both basal and hypotension-stimulated ACTH secretion. The present study was performed to test the effect of oestradiol on the central baroreceptor and chemoreceptor reflex pathways. We used immunohistological techniques to identify various neuroanatomical regions which are activated by hypotension and, subsequently, those areas modified by oestrogen's action and baroreceptor and chemoreceptor denervation. We assessed cellular activation in these brain regions by immunostaining for Fos, the protein product of c-fos, an immediate early response gene. We found that oestradiol increased Fos abundance in nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM), and PVN, and augmented the increase in Fos in these regions in response to a 10 min period of brachiocephalic arterial occlusion (BCO). Carotid sinus denervation blocked the Fos response to BCO, but not to oestrogen alone, in these regions. In contrast, the hippocampus responded to BCO with increase Fos in intact fetuses, but did not respond to oestrogen treatment. None of the treatments altered Fos expression in cerebral cortex or in cerebellum. We conclude that oestradiol augments the activity of the central baroreceptor and chemoreceptor reflex pathways, and that it may influence fetal ACTH secretion via this site of action.

Delayed hypotension and subendocardial injury after repeated umbilical cord occlusion in near-term fetal lambs.

OBJECTIVE: This study was undertaken to determine whether myocardial injury occurs after repeated intrauterine asphyxia. STUDY DESIGN: Near-term fetal sheep with implanted instrumentation underwent either sham occlusions (n = 8) or repeated brief umbilical cord occlusions (n = 12) continued until the onset of severe (<20 mm Hg) or sustained hypotension. After 3 days of recovery, the fetal hearts were perfusion fixed. RESULTS: Repeated umbilical cord occlusions led to a severe metabolic acidosis (pH, 6.84 +/- 0.09; lactate concentration, 14.1 +/- 1.5 mmol/L) with increasing hypotension during occlusions, which were terminated after 128 +/- 38 minutes. After the occlusions, the mean arterial pressure showed a delayed fall, which resolved after 12 hours. Ultrastructural examination showed evidence of subendocardial injury, with dilatation of sarcoplasmic reticulum, margination and clumping of nuclear chromatin, and mitochondrial swelling. The most severe morphologic changes, including electron-dense mitochondrial inclusions, were found in the fetuses with delayed recovery of the fetal heart rate after the final occlusion. CONCLUSION: Subendocardial injury occurs after severe repeated intrauterine asphyxia in the late-gestation fetus, and this may contribute to cardiovascular compromise and the development of late decelerations.

Central nervous system regulation of reflex responses to hypotension during fetal life.

The ability of the fetus to survive, grow, and successfully complete the transition from fetal to neonatal life is critically dependent on the appropriate regulation of fetal blood pressure, blood volume, and fluid dynamics. This is a short review of the physiological mechanisms controlling the fetal cardiovascular system, focusing mainly on the neural and endocrine elements in the schema of cardiovascular function and control. The fetal cardiovascular system is arranged anatomically to provide for perfusion of the umbilical-placental circulation, the organ of gas exchange of the fetus, and to largely bypass the lungs. Fetal blood volume and pressure, maintained at levels that are appropriate for this function, are influenced by neural and endocrine control mechanisms, which are similar to, but quantitatively different from, the adult animal. Baroreceptors and chemoreceptors located in the carotid sinuses and aortic arch sense changes in blood pressure and blood gases and comprise the afferent limb of the major reflexes that maintain normal fetal blood pressure and volume. Fetal hypotension stimulates reflex decreases in fetal heart rate, which are apparently mediated by chemoreceptor input. Arginine vasopressin responses to hypotension are most likely mediated by baroreceptor input. Recent evidence suggests that the reflex responses to hypotension in the fetus are modulated by paracrine or endocrine factors. For example, baroreceptor or chemoreceptor reflex pathways are modulated by the endogenous production of prostanoids and by the preparturient changes in fetal plasma estrogen concentration.

Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice.

Fibroblast growth factor-2 (FGF-2) has been implicated in various signaling processes which control embryonic growth and differentiation, adult physiology and pathology. To analyze the in vivo functions of this signaling molecule, the FGF-2 gene was inactivated by homologous recombination in mouse embryonic stem cells. FGF-2-deficient mice are viable, but display cerebral cortex defects at birth. Bromodeoxyuridine pulse labeling of embryos showed that proliferation of neuronal progenitors is normal, whereas a fraction of them fail to colonize their target layers in the cerebral cortex. A corresponding reduction in parvalbumin-positive neurons is observed in adult cortical layers. Neuronal defects are not limited to the cerebral cortex, as ectopic parvalbumin-positive neurons are present in the hippocampal commissure and neuronal deficiencies are observed in the cervical spinal cord. Physiological studies showed that FGF-2-deficient adult mice are hypotensive. They respond normally to angiotensin II-induced hypertension, whereas neural regulation of blood pressure by the baroreceptor reflex is impaired. The present genetic study establishes that FGF-2 participates in controlling fates, migration and differentiation of neuronal cells, whereas it is not essential for their proliferation. The observed autonomic dysfunction in FGF-2-deficient adult mice uncovers more general roles in neural development and function.

Effect of pulsatile intravenous oxytocin administration to pregnant sheep over the last third of gestation on fetal ACTH and cortisol responses to hypotension.

OBJECTIVE: To examine the effect of increasing myometrial contractility in the last third of gestation on ovine fetal response to hypotension. METHODS: Oxytocin (600 microU/kg/minute) or saline was infused via the maternal jugular vein as 5-minute pulses every 20 minutes, starting at 97 +/- 1 days of gestational age (mean +/- standard error of the mean) until labor. Fetal hypotension (10 minutes) was induced by intravenous nitroprusside infusion at 133 +/- 1 days' gestation. RESULTS: Ewes from both groups went into labor at the same gestational age. Total fetal body and adrenal gland weights were higher in controls than in the oxytocin-treated group. Maternal arterial pH and blood gas values were normal throughout the study. At 132-136 days' gestation, fetal arterial oxygen pressure was lower in the oxytocin group than in controls (P < .05). Basal fetal ACTH concentrations did not change between 130 and 136 days in both groups. The mean fetal plasma ACTH concentration was not different between the control (40.6 +/- 4.1 pg/mL) and oxytocin groups (32.6 +/- 4.9 pg/mL). Pre-hypotension fetal plasma ACTH was similar in both groups, whereas cortisol was lower in the oxytocin group. Hypotension significantly increased fetal plasma ACTH and cortisol concentrations; however, both ACTH and cortisol responses were smaller in the oxytocin group (P < .05). CONCLUSIONS: Increased myometrial contractility throughout the last third of gestation modifies the normal ACTH and cortisol relation at the critical time of prepartum increase in adrenocortical activity. In addition, fetal ACTH and cortisol responses to hypotension are diminished in fetuses exposed to such a prolonged increase in myometrial contractility. These observations support the hypothesis that myometrial contractility influences fetal neuroendocrine development.

Hypotension in fetal and newborn lambs; different patterns of reflex heart rate control revealed by autonomic blockade.

Reflex heart rate (HR) responses to hypotension were studied in chronically instrumented fetal and newborn lambs. Studies spanned 106-141 days of gestation and 1-22 days after birth. Brief hypotensive stimuli (10 s) were produced by inflation of a cuff implanted around the inferior vena cava; HR and mean arterial pressure (MAP) were recorded from a carotid arterial catheter. Autonomic nervous control of HR was examined using selective sympathetic beta-adrenergic blockade (propranolol 1 mg/kg), cholinergic blockade (atropine 0.2-0.3 mg/kg), and total autonomic blockade (propranolol plus atropine). In newborn lambs (n = 4) HR increased progressively as MAP was reduced in the range 5-50%. Tachycardia during mild hypotension (less than 15% MAP fall) was due to sympathetic activation as it was abolished by propranolol. During severe hypotension (greater than 30% MAP fall) tachycardia was reduced by selective beta-adrenergic blockade and by cholinergic blockade, and totally abolished by total autonomic blockade; thus withdrawal of vagal tone plus augmentation of sympathetic activity contribute to the increase of HR in response to large MAP falls in the newborn. Fetal lambs (n = 4) responded with tachycardia in mild hypotension (less than 15% MAP fall) but this was reversed when hypotension was severe (greater than 30% MAP fall). The primary tachycardia was due to sympathetic activation and was indistinguishable from the newborn response.(ABSTRACT TRUNCATED AT 250 WORDS)