Heat production of fetal sheep brain in utero

Thermojunctions were implanted in the brains of 10 near term fetal sheep in utero under halothane anesthesia. Brief total occlusion of fetal brachiocephalic artery was followed immediately by an increase in brain temperature (mean +/- SE) of 0.130 +/- 0.014 degrees C-min-1. Occlusion of main pulmonary artery and ascending aorta, simultaneously, led to a brain temperature increase of 0.144 +/- 0.018 degrees C-min-1. Specific heat of three fetal brains was determined to be 0.898 +/- 0.014 cal-g-1. degrees C-1 or 3.76 +/- 0.059 J-g-1. Rate of fetal brain heat production, computed as the product of the higher rate of temperature change and brain specific heat, was 0.129 +/- 0.014 cal-g-1-min-1 or 9.00 +/- 0.98 mW-g-1.

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Glutamate Release from the Ovine Fetal Brain during Maternal Hemorrhage

Anesthesiology ◽

10.1097/00000542-199502000-00022 ◽

1995 ◽

Vol 82 (2) ◽

pp. 521-530 ◽

Cited By ~ 20

Author(s):

Donald H. Penning ◽

David H. Chestnut ◽

Franklin Dexter ◽

James Hrdy ◽

Dan Poduska ◽

...

Keyword(s):

Parietal Cortex ◽

Glutamate Release ◽

Recovery Period ◽

Fetal Brain ◽

In Utero ◽

Extracellular Glutamate ◽

Microdialysis Probe ◽

Fetal Sheep ◽

Near Term ◽

Ovine Fetal

Background Glutamate has been implicated in the pathophysiology of neuronal injury associated with cerebral hypoxia-ischemia. A model using chronic in utero microdialysis was developed to sample the extracellular space of the fetal brain. Using this model, we tested the hypothesis that glutamate efflux from the parasagittal parietal cortex of near-term fetuses would increase during maternal hemorrhage. Methods Twelve near-term fetal sheep were instrumented with vascular catheters, and a microdialysis probe(s) was implanted into the parasagittal parietal cortex. After a 3-day recovery period, the animals were subjected to maternal hemorrhage until either the fetal pH was < 7.00 or the fetus died. The extracellular glutamate concentration in the collected dialysate was determined by high pressure liquid chromatography (HPLC). Results Maternal hemorrhage resulted in an 80-90% decrease in uterine blood flow, a decrease fetal po2, and a mixed metabolic and respiratory fetal acidosis. There were two groups of fetuses, survivors (n = 5) and nonsurvivors (n = 7). The nonsurvivor group showed a large increase (10-30-fold) in peak glutamate release (P = 0.0015). Survivors demonstrated a small (threefold) increase that was not statistically significant (P = 0.065), unless one animal with very low probe recovery was excluded (P = 0.0048). Conclusions Extracellular glutamate release from the fetal brain can occur during maternal hemorrhage with fetal acidemia. The pathophysiologic role (if any) of glutamate release in the survivors remains to be elucidated. Our results are consistent with the hypothesis that in utero release of glutamate occurs during periods of fetal asphyxia. This experimental preparation of chronic fetal brain microdialysis can be used to monitor the brain extracellular concentration of any dialyzable substance in response to stress, including maternal hemorrhage.

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Novel method for in vivo hydroxyl radical measurement by microdialysis in fetal sheep brain in utero

Journal of Applied Physiology ◽

10.1152/japplphysiol.00617.2004 ◽

2005 ◽

Vol 98 (6) ◽

pp. 2304-2310 ◽

Cited By ~ 41

Author(s):

Edwin B. Yan ◽

Jessica K. Unthank ◽

Margie Castillo-Melendez ◽

Suzanne L. Miller ◽

Steven J. Langford ◽

...

Keyword(s):

Hydroxyl Radical ◽

High Performance ◽

Fetal Brain ◽

In Utero ◽

In Vivo Studies ◽

Fetal Sheep ◽

Low Concentrations ◽

Sheep Brain

Hydroxyl radical (·OH) is a reactive oxygen species produced during severe hypoxia, asphyxia, or ischemia that can cause cell death resulting in brain damage. Generation of ·OH may occur in the fetal brain during asphyxia in utero. The very short half-life of ·OH requires use of trapping agents such as salicylic acid or phenylalanine for detection, but their hydroxylated derivatives are either unstable, produced endogenously, or difficult to measure in the small volume of microdialysis samples. In the present study, we used terephthalic acid (TA), hydroxylation of which yields a stable and highly fluorometric isomer (excitation, 326 nm; emission, 432 nm). In vitro studies using ·OH generated by the Fenton reaction showed that hydroxylated TA formed quickly (<10 s), was resistant to bleaching (<5% change in fluorescence), and permitted detection of <0.5 pmol ·OH. In vivo studies were performed in fetal sheep using microdialysis probes implanted into the parasagittal cortex. The probe was perfused at 2 μl/min with artificial cerebrospinal fluid containing 5 mM TA, and samples were collected every 30 min. Fluorescence measured in 10 μl of dialysate was significantly greater than in the efflux from probes perfused without TA. High-performance liquid chromotography analysis showed that the fluorescence in dialysis samples was entirely due to hydroxylation of TA. Thus this study shows that it is possible to use TA as a trapping agent for detecting low concentrations of ·OH both in vitro and in vivo and that low concentrations of ·OH are present in fetal brain tissue and fluctuate with time.

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Adrenal glands are essential for activation of glucogenesis during undernutrition in fetal sheep near term

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00205.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. E94-E102 ◽

Cited By ~ 17

Author(s):

A. L. Fowden ◽

A. J. Forhead

Keyword(s):

Adrenal Glands ◽

Metabolic Response ◽

Glucose Production ◽

Oxygen Metabolism ◽

In Utero ◽

Endogenous Glucose Production ◽

Hepatic Glycogen ◽

Fetal Sheep ◽

Glucose Levels ◽

Near Term

In adults, the adrenal glands are essential for the metabolic response to stress, but little is known about their role in fetal metabolism. This study examined the effects of adrenalectomizing fetal sheep on glucose and oxygen metabolism in utero in fed conditions and after maternal fasting for 48 h near term. Fetal adrenalectomy (AX) had little effect on the rates of glucose and oxygen metabolism by the fetus or uteroplacental tissues in fed conditions. Endogenous glucose production was negligible in both AX and intact, sham-operated fetuses in fed conditions. Maternal fasting reduced fetal glucose levels and umbilical glucose uptake in both groups of fetuses to a similar extent but activated glucose production only in the intact fetuses. The lack of fasting-induced glucogenesis in AX fetuses was accompanied by falls in fetal glucose ultilization and oxygen consumption not seen in intact controls. The circulating concentrations of cortisol and total catecholamines, and the hepatic glycogen content and activities of key gluconeogenic enzymes, were also less in AX than intact fetuses in fasted animals. Insulin concentrations were also lower in AX than intact fetuses in both nutritional states. Maternal glucose utilization and its distribution between the fetal, uteroplacental, and nonuterine maternal tissues were unaffected by fetal AX in both nutritional states. Ovine fetal adrenal glands, therefore, have little effect on basal rates of fetal glucose and oxygen metabolism but are essential for activating fetal glucogenesis in response to maternal fasting. They may also be involved in regulating insulin sensitivity in utero.

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α7 nicotinic acetylcholine receptor signaling modulates the inflammatory and iron homeostasis in fetal brain microglia

10.1101/097295 ◽

2017 ◽

Cited By ~ 1

Author(s):

M. Cortes ◽

M. Cao ◽

H.L. Liu ◽

C.S. Moore ◽

L.D. Durosier ◽

...

Keyword(s):

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Iron Homeostasis ◽

Fetal Brain ◽

In Utero ◽

Α7 Nicotinic Acetylcholine Receptor ◽

Fetal Sheep ◽

Nicotinic Acetylcholine ◽

Microglial Phenotype

ABSTRACTNeuroinflammation in utero may result in life-long neurological disabilities. Microglia play a pivotal role, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of microglia. We hypothesized that agonism on α7 nicotinic acetylcholine receptor (α7nAChR) in fetal microglia will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of α7nAChR will achieve the opposite. Using an in vivo - in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep microglia cultures re-exposed to LPS in presence of a selective α7nAChR agonist or antagonist. Our RNAseq and protein level findings show that a pro-inflammatory microglial phenotype acquired in vitro by LPS stimulation is reversed with α7nAChR agonistic stimulation. Conversely, antagonistic α7nAChR stimulation potentiates the pro-inflammatory microglial phenotype. Surprisingly, under conditions of LPS double-hit an interference of a postulated α7nAChR - ferroportin signaling pathway may impede this mechanism. These results suggest a therapeutic potential of α7nAChR agonists in early re-programming of microglia in neonates exposed to in utero inflammation via an endogenous cerebral cholinergic anti-inflammatory pathway. Future studies will assess the role of interactions between inflammation-triggered microglial iron sequestering and α7nAChR signaling in neurodevelopment.

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In utero hypoxia altered Ang II-induced contraction via PKCβ in fetal cerebral arteries

Journal of Endocrinology ◽

10.1530/joe-19-0370 ◽

2020 ◽

Vol 244 (1) ◽

pp. 213-222

Author(s):

Hongyu Su ◽

Xueyi Chen ◽

Yueming Zhang ◽

Linglu Qi ◽

Yun He ◽

...

Keyword(s):

Protein Expression ◽

Cerebral Circulation ◽

Cerebral Arteries ◽

Fetal Brain ◽

Calcium Transient ◽

In Utero ◽

Protective Effects ◽

Ang Ii ◽

Voltage Dependent ◽

Near Term

Cerebral circulation is important in fetal brain development, and angiotensin II (Ang II) plays vital roles in regulation of adult cerebral circulation. However, functions of Ang II in fetal cerebral vasculature and influences of in utero hypoxia on Ang II-mediated fetal cerebral vascular responses are largely unknown. This study investigated the effects and mechanisms of in utero hypoxia on fetal middle cerebral arteries (MCA) via Ang II. Near-term ovine fetuses were exposed to in utero hypoxia, and fetal MCA responses to Ang II were tested for vascular tension, calcium transient, and molecular analysis. Ang II caused significant dose-dependent contraction in control fetal MCA. Ang II-induced MCA constriction was decreased significantly in hypoxic fetuses. Neither losartan (AT1R antagonist, 10−5 mol/L) nor PD123,319 (AT2R antagonist, 10−5 mol/L) altered Ang II-mediated contraction in fetal MCA. Phenylephrine-mediated constriction was also significantly weaker in hypoxic fetuses. Bay K8644 caused similar contractions between the two groups. Protein expression of L-type voltage-dependent calcium channels was unchanged. There were no differences in caffeine-mediated vascular tension or calcium transients. Contraction induced by PDBu (PKC agonist) was obviously weaker in hypoxic MCA. Protein expression of PKCβ was reduced in the hypoxic compared with the control, along with no differences in phosphorylation levels. The results showed that fetal MCA was functionally responsive to Ang II near term. Intrauterine hypoxia reduced the vascular agonist-mediated contraction in fetal MCA, probably via decreasing PKCβ and its phosphorylation, which might play protective effects on fetal cerebral circulation against transient hypoxia.

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Transabdominal near infrared oximetry of hypoxic stress in fetal sheep brain in utero

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1735462100 ◽

2003 ◽

Vol 100 (22) ◽

pp. 12950-12954 ◽

Cited By ~ 25

Author(s):

R. Choe ◽

T. Durduran ◽

G. Yu ◽

M. J. M. Nijland ◽

B. Chance ◽

...

Keyword(s):

Near Infrared ◽

In Utero ◽

Hypoxic Stress ◽

Fetal Sheep ◽

Sheep Brain

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Intra-Amniotic LPS Induced Region-Specific Changes in Presynaptic Bouton Densities in the Ovine Fetal Brain

BioMed Research International ◽

10.1155/2015/276029 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Eveline Strackx ◽

Reint K. Jellema ◽

Rebecca Rieke ◽

Ruth Gussenhoven ◽

Johan S. H. Vles ◽

...

Keyword(s):

Motor Cortex ◽

Dentate Gyrus ◽

Somatosensory Cortex ◽

Fetal Brain ◽

Control Group ◽

Fetal Sheep ◽

Increased Risk ◽

Sheep Brain ◽

Presynaptic Density ◽

Ovine Fetal

Rationale. Chorioamnionitis has been associated with increased risk for fetal brain damage. Although, it is now accepted that synaptic dysfunction might be responsible for functional deficits, synaptic densities/numbers after a fetal inflammatory challenge have not been studied in different regions yet. Therefore, we tested in this study the hypothesis that LPS-induced chorioamnionitis caused profound changes in synaptic densities in different regions of the fetal sheep brain.Material and Methods. Chorioamnionitis was induced by a 10 mg intra-amniotic LPS injection at two different exposure intervals. The fetal brain was studied at 125 days of gestation (term = 150 days) either 2 (LPS2D group) or 14 days (LPS14D group) after LPS or saline injection (control group). Synaptophysin immunohistochemistry was used to quantify the presynaptic density in layers 2-3 and 5-6 of the motor cortex, somatosensory cortex, entorhinal cortex, and piriforme cortex, in the nucleus caudatus and putamen and in CA1/2, CA3, and dentate gyrus of the hippocampus.Results. There was a significant reduction in presynaptic bouton densities in layers 2-3 and 5-6 of the motor cortex and in layers 2-3 of the entorhinal and the somatosensory cortex, in the nucleus caudate and putamen and the CA1/2 and CA3 of the hippocampus in the LPS2D compared to control animals. Only in the motor cortex and putamen, the presynaptic density was significantly decreased in the LPS14 D compared to the control group. No changes were found in the dentate gyrus of the hippocampus and the piriforme cortex.Conclusion. We demonstrated that LPS-induced chorioamnionitis caused a decreased density in presynaptic boutons in different areas in the fetal brain. These synaptic changes seemed to be region-specific, with some regions being more affected than others, and seemed to be transient in some regions.

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Cerebrovascular autoregulation during fetal development in sheep

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.3.h1069 ◽

1994 ◽

Vol 266 (3) ◽

pp. H1069-H1074 ◽

Cited By ~ 13

Author(s):

S. Helou ◽

R. C. Koehler ◽

C. A. Gleason ◽

M. D. Jones ◽

R. J. Traystman

Keyword(s):

Perfusion Pressure ◽

Fetal Brain ◽

Blood Gases ◽

Fetal Sheep ◽

Cerebrovascular Autoregulation ◽

Cerebrovascular Resistance ◽

Arterial Blood ◽

Artificial Cerebrospinal Fluid ◽

Near Term

There are scant data regarding the development of cerebrovascular autoregulation in fetuses. We tested the hypothesis that a decrease in cerebrovascular resistance (CVR) at reduced cerebral perfusion pressure (CPP) is absent in midgestation and near-term fetal sheep. Catheters were chronically implanted for microsphere determination of cerebral blood flow (CBF) in 9 fetuses at 92 days and in 10 fetuses at 132 days gestation (full term = 145 days). CPP was reduced by ventricular infusion of artificial cerebrospinal fluid. In 92-day fetuses, CPP was reduced stepwise from 35 to 25 and 18 mmHg and CBF decreased from 52 +/- 5 to 43 +/- 4 and 27 +/- 5 (SE) ml.min-1 x 100 g-1, respectively. Half of the immature fetuses showed some reduction in CVR at moderate reduction in CPP; however, there was no significant change in CVR in the group as a whole (from 0.72 +/- 0.06 to 0.61 +/- 0.04 and 0.89 +/- 0.20 mmHg.ml-1.min.100 g). In 132-day fetuses, CPP was reduced from 45 to 33 and 28 mmHg and CBF was unchanged (from 105 +/- 7 to 97 +/- 11 and 89 +/- 8 ml.min-1 x 100 g-1). CVR decreased from 0.45 +/- 0.05 to 0.41 +/- 0.08 and 0.33 +/- 0.03 mmHg.ml-1.min.100 g. There were no significant changes in arterial blood gases at reduced CPP in either age group. We conclude that cerebrovascular autoregulation at reduced CPP is not well developed at 92 days (0.63 gestation) in fetal sheep but that autoregulatory capacity is evident near term. We speculate that poor autoregulation may place the premature fetal brain at risk for injury.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.6.e1207 ◽

2000 ◽

Vol 279 (6) ◽

pp. E1207-E1215 ◽

Cited By ~ 16

Author(s):

Zhice Xu ◽

Calvario Glenda ◽

Linda Day ◽

Jiaming Yao ◽

Michael G. Ross

Keyword(s):

Fetal Brain ◽

Plasma Osmolality ◽

Ang Ii ◽

Double Labeling ◽

Fetal Sheep ◽

Vasopressin Release ◽

Fetal Plasma ◽

Ovine Fetus ◽

Near Term ◽

Stimulation Of

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.

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