Ketamine inhibits fetal ACTH responses to cerebral hypoperfusion

Powers, Michael E.; Wood, Charles E.

doi:10.1152/ajpregu.00300.2006

Cited by 20 publications

(44 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies showed that blockade of N-methyl-D-aspartate (NMDA) receptors with ketamine blunts the fetal reflex bradycardic response to hypoxia (2). We subsequently demonstrated that NMDA blockade dramatically reduces the HPA axis response to BCO (18). While we have good evidence that although NMDA-mediated neurotransmission and PGHS-2-mediated prostaglandin biosynthesis are involved in the HPA axis response to cerebral hypotension in fetal sheep, we have not demonstrated that these processes are linked.…”

mentioning

confidence: 55%

“…While fetal central nervous system (CNS)-generated prostaglandins actively modulate the fetal cardiovascular reflexes, the hypothalamus-pituitary-adrenal (HPA) axis response to cerebral hypoperfusion is almost completely dependent on glutamatergic neurotransmission within the fetal brain (18). Previous studies showed that blockade of N-methyl-D-aspartate (NMDA) receptors with ketamine blunts the fetal reflex bradycardic response to hypoxia (2).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis

Knutson

Wood

2010

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

Prostaglandins, generated within the fetal brain, are integral components of the mechanism controlling the fetal hypothalamus-pituitary-adrenal (HPA) axis. Previous studies in this laboratory demonstrated that prostaglandin G/H synthase isozyme 2 (PGHS-2) inhibition reduces the fetal HPA axis response to cerebral hypoperfusion, blocks the preparturient rise in fetal plasma ACTH concentration, and delays parturition. We also discovered that blockade of N-methyl-d-aspartate (NMDA) receptors reduces the fetal ACTH response to cerebral hypoperfusion. The present study was designed to test the hypothesis that PGHS-2 action and the downstream effect of HPA axis stimulation are stimulated by NMDA-mediated glutamatergic neurotransmission. Chronically catheterized late-gestation fetal sheep (n = 8) were injected with NMDA (1 mg iv). All responded with increases in fetal plasma ACTH and cortisol concentrations. Pretreatment with resveratrol (100 mg iv, n = 5), a specific inhibitor of PGHS-1, did not alter the magnitude of the HPA axis response to NMDA. Pretreatment with nimesulide (10 mg iv, n = 6), a specific inhibitor of PGHS-2, significantly reduced the HPA axis response to NMDA. To further explore this interaction, we injected NMDA in six chronically catheterized fetal sheep that were chronically infused with nimesulide (n = 6) at a rate of 1 mg/day into the lateral cerebral ventricle for 5-7 days. In this group, there was no significant ACTH response to NMDA. Finally, we tested whether the HPA axis response to prostaglandin E(2) (PGE(2)) is mediated by NMDA receptors. Seven chronically catheterized late-gestation fetal sheep were injected with 100 ng of PGE(2), which significantly increased fetal plasma ACTH and cortisol concentrations. Pretreatment with ketamine (10 mg iv), an NMDA antagonist, did not alter the ACTH or cortisol response to PGE(2). We conclude that generation of prostanoids via the action of PGHS-2 in the fetal brain augments the fetal HPA axis response to NMDA-mediated glutamatergic stimulation.

show abstract

mentioning

confidence: 55%

mentioning

confidence: 99%

Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis

Knutson

Wood

2010

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

show abstract

“…Throughout each experiment, fetal arterial blood and amniotic fluid pressures were measured as described for study 2. Blood pressure and blood gases from these experiments have been reported previously [20] .…”

Section: Experimental Protocols Study 1: Ontogeny Of Pituitary Hormonmentioning

confidence: 95%

“…3 ). Hemodynamics are shown in figure 3 for comparison, although values of these variables have been reported as a part of a larger study [20] . BCO decreased lingual arterial pressure (downstream from the occlusion) and stimulated reflex increases in femoral arterial blood pressure and heart rate.…”

Section: Ontogeny Of Gonadotropin and Prl Expressionmentioning

confidence: 99%

Influence of Estradiol and Fetal Stress on Luteinizing Hormone, Follicle-Stimulating Hormone, and Prolactin in Late-Gestation Fetal Sheep

Wood¹,

Keller‐Wood²

2011

Neonatology

Self Cite

View full text Add to dashboard Cite

Background: Hypotension and reduced cerebral blood flow secondary to brachiocephalic occlusion (BCO) stimulate various homeostatic physiological and endocrine responses. Our previous studies have also suggested a role of estradiol in augmenting the fetal stress response to BCO. Objectives: We tested the hypothesis that gonadotropins and/or prolactin (PRL) are upregulated in fetal pituitary in response to fetal stress and play a role in the response to BCO-induced stress. Methods: We performed 3 studies: one in which we measured ovine fetal pituitary PRL, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) mRNA throughout the latter half of gestation in order to better understand the ontogenetic changes upon which dynamic responses are superimposed; one in which we measured these mRNA abundances in response to BCO and/or estrogen treatment, and one in which we measured plasma LH responses to BCO in chronically catheterized late-gestation fetal sheep. Results: PRL gene expression is increased dramatically in the last 20% of gestation. LH and FSH mRNAs were unchanged except for a transient dip in the expression of LH in the last few days before the normal time of spontaneous parturition. Chronic treatment with estradiol decreased LH and FSH mRNA, but increased PRL mRNA abundance after BCO. In contrast, BCO alone increases the abundance of LH, but not FSH or PRL mRNA in fetal pituitary. Plasma LH concentrations were not increased in response to BCO. Conclusions: We conclude that the late-gestation fetal sheep responds to hypotensive stress with increases in LH mRNA but not LH secretion. LH, FSH and PRL changes are therefore unlikely to contribute to the fetal response to cerebral hypoperfusion.

show abstract

“…Brachiocephalic occlusion stimulates cardiovascular and endocrine responses as direct responses to ischemia/ reperfusion and as reflex responses to carotid chemoreceptor activity (21,39). Glutamate neurotransmission appears to play an important role in mediating the fetal ACTH response to brachiocephalic artery occlusion (BCO) (19). Related to, and perhaps downstream from, N-methyl-D-aspartate (NMDA) neurotransmission is the influence of brain-derived prostaglandins, mediated by cyclooxygenase-2 [prostaglandin-endoperoxide synthase 2 (PTGS2)], which is upregulated in various brain regions after BCO (12).…”

mentioning

confidence: 99%

Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment

Wood

Rabaglino

Richards

et al. 2014

Physiological Genomics

Self Cite

View full text Add to dashboard Cite

Wood CE, Rabaglino MB, Richards E, Denslow N, Zarate MA, Chang EI, Keller-Wood M. Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment. Physiol Genomics 46: 523-532, 2014. First published May 13, 2014 doi:10.1152 doi:10. /physiolgenomics.00186.2013 is a wellknown modulator of fetal neuroendocrine activity and has been proposed as a critical endocrine signal readying the fetus for birth and postnatal life. To investigate the modulatory role of E2 on fetal stress responsiveness and the response of the fetal brain to asphyxic stress, we subjected chronically catheterized fetal sheep to a transient (10 min) brachiocephalic artery occlusion (BCO) or sham occlusion. Half of the fetuses received subcutaneous pellets that increased plasma E2 concentrations within the physiological range. Hypothalamic mRNA was analyzed using the Agilent 8x15k ovine array (019921), processed and annotated as previously reported by our laboratory. Analysis of the data by ANOVA revealed that E2 differentially regulated (DR) 561 genes, and BCO DR 894 genes compared with control and E2ϩBCO DR 1,153 genes compared with BCO alone (all P Ͻ 0.05). E2 upregulated epigenetic pathways and downregulated local steroid biosynthesis but did not significantly involve genes known to directly respond to the estrogen receptor. Brachiocephalic occlusion upregulated kinase pathways as well as genes associated with lymphocyte infiltration into the brain and downregulated neuropeptide synthesis. E2 upregulated immune-and apoptosis-related pathways after BCO and reduced kinase and epigenetic pathway responses to the BCO. Responses to BCO are different from responses to hypoxic hypoxia suggesting that mechanisms of responses to these two forms of brain hypoxia are distinct. We conclude that cerebral ischemia caused by BCO might stimulate lymphocyte infiltration into the brain and that this response appears to be modified by estradiol. cortisol; fetal heart; mitochondria; metabolism; late gestation DURING THE TRANSITION FROM intra-to extrauterine life, birth asphyxia is a common cause of cerebral ischemia (29), commonly resulting in the need for resuscitation of the neonate. Disturbances in cerebral blood flow can result from various manipulations in the neonatal intensive care unit, including hypocarbia secondary to mechanical ventilation (18), continuous positive airway pressure (16, 42), and extracorporeal membrane oxygenation (7). Reduction of cerebral blood flow in the neonate compromises oxygen delivery or, if severe, produces ischemia/reperfusion injury (10) and results in morbidity, including intraventricular hemorrhage (6) and long-term cognitive deficit (14).We have investigated the cardiovascular and endocrine responses to cerebral hypoperfusion in late-gestation chronically catheterized fetal sheep (31,38,39), in this animal model of late fetal development. This model allows us to investigate responses to stress in utero and better understand the native homeostatic mechanisms that promote survival af...

show abstract

Ketamine inhibits fetal ACTH responses to cerebral hypoperfusion

Cited by 20 publications

References 67 publications

Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis

Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis

Influence of Estradiol and Fetal Stress on Luteinizing Hormone, Follicle-Stimulating Hormone, and Prolactin in Late-Gestation Fetal Sheep

Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment

Contact Info

Product

Resources

About