Ketamine Attenuates the ACTH Response to Hypoxia in Late-Gestation Ovine Fetus

Chang, Eileen I.; Wood, Charles E.

doi:10.1159/000369374

Cited by 11 publications

(36 citation statements)

References 25 publications

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“…These values are a subset of previously reported values (Chang & Wood, ). Statistical significance between groups was declared at P ≤ 0.05 (two‐way ANOVA), and Duncan's test was performed to determine differences between groups (different letters are statistically significantly different from each other, P < 0.05).…”

Section: Methodsmentioning

confidence: 98%

Ketamine suppresses hypoxia‐induced inflammatory responses in the late‐gestation ovine fetal kidney cortex

Chang

Zarate

Rabaglino

et al. 2015

The Journal of Physiology

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Key pointsr The fetus responds to decreases in arterial partial pressure of oxygen by redirecting the blood flow mainly to the brain and the heart, at a cost to other peripheral organs like the kidneys.r Renal hypoxia and ischaemia stimulate inflammatory and apoptotic responses. r Ketamine, an NMDA receptor antagonist, is able to reduce renal immune and inflammatory gene expressions stimulated by hypoxia.r Ketamine may have therapeutic potential for protection against ischaemic renal damage in fetuses subjected to acute hypoxia.Abstract Acute fetal hypoxia is a form of fetal stress that stimulates renal vasoconstriction and ischaemia as a consequence of the physiological redistribution of combined ventricular output. Because of the potential ischaemia-reperfusion injury to the kidney, we hypothesized that it would respond to hypoxia with an increase in the expression of inflammatory genes, and that ketamine (an N-methyl-D-aspartate receptor antagonist) would reduce or block this response. Hypoxia was induced for 30 min in chronically catheterized fetal sheep (125 ± 3 days), with or without ketamine (3 mg kg −1 ) administered intravenously to the fetus 10 min prior to hypoxia. Gene expression in fetal kidney cortex collected 24 h after the onset of hypoxia was analysed using ovine Agilent 15.5k array and validated with qPCR and immunohistochemistry in four groups of ewes: normoxic control, normoxia + ketamine, hypoxic control and hypoxia + ketamine (n = 3-4 per group). Significant differences in gene expression between groups were determined with t-statistics using the limma package for R (P ࣘ 0.05). Enriched biological processes for the 427 upregulated genes were immune and inflammatory responses and for the 946 downregulated genes were metabolic processes. Ketamine countered the effects of hypoxia on upregulated immune/inflammatory responses as well as the downregulated metabolic responses. We conclude that our transcriptomics modelling predicts that hypoxia activates inflammatory pathways and reduces metabolism in the fetal kidney cortex, and ketamine blocks or ameliorates this response. The results suggest that ketamine may have therapeutic potential for protection from ischaemic renal damage.

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Section: Methodsmentioning

confidence: 98%

Ketamine suppresses hypoxia‐induced inflammatory responses in the late‐gestation ovine fetal kidney cortex

Chang

Zarate

Rabaglino

et al. 2015

The Journal of Physiology

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“…As in the previous report the tissues were obtained 24 h after a 30-minute period to hypoxia in pregnant ewes 4, 5 . Maternal and fetal arterial oxygen tensions were reduced from 98 ± 2 to 56 ± 2 and from 17 ± 1 to 10 ± 1 mm Hg, respectively.…”

Section: Induction Of Inflammatory Pathways In Fetal Brainmentioning

confidence: 99%

Post-hypoxia Invasion of the fetal brain by multidrug resistant Staphylococcus

Zarate

Rodriguez

Chang

et al. 2017

Sci Rep

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Herein we describe an association between activation of inflammatory pathways following transient hypoxia and the appearance of the multidrug resistant bacteria Staphylococcus simulans in the fetal brain. Reduction of maternal arterial oxygen tension by 50% over 30 min resulted in a subseiuent significant over-expression of genes associated with immune responses 24 h later in the fetal brain. The activated genes were consistent with stimulation by bacterial lipopolysaccharide; an influx of macrophages and appearance of live bacteria were found in these fetal brains. S. simulans was the predominant bacterial species in fetal brain after hypoxia, but was found in placenta of all animals. Strains of S. simulans from the placenta and fetal brain were equally highly resistant to multiple antibiotics including methicillin and had identical genome sequences. These results suggest that bacteria from the placenta invade the fetal brain after maternal hypoxia.

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“…These two methods of hypoxia produce contrasting changes in P a CO 2 and pH a . In HH, the hyperventilation of the ewe reduces P a CO 2 and increases pH a in both fetus and mother (Chang and Wood ). In UCO, P a CO 2 is dramatically increased and pH a is dramatically decreased because of reduced perfusion and gas exchange across the placenta.…”

Section: Discussionmentioning

confidence: 99%

“…; Giussani et al. ; Chang and Wood ), asphyxic hypoxia (Roelfsema et al. ), ischemic hypoxia (Powers and Wood ), acidemia (Wood and Chen ), and hypercapnia (Chen and Wood ) stimulate fetal ACTH and cortisol secretion.…”

Section: Introductionmentioning

confidence: 99%

“…We have reported that ketamine, a clinically useful drug that blocks N‐methyl‐D‐aspartate (NMDA) receptors (Mishra et al. ), partially inhibits the fetal ACTH response to hypoxic hypoxia (Chang and Wood ), and almost completely inhibits the fetal ACTH response to brachiocephalic artery occlusion (a model of brain and carotid body ischemic hypoxia) (Powers and Wood ). Furthermore, we have demonstrated that intravenous injection of NMDA stimulates fetal ACTH secretion, and that the effect is partially dependent on prostaglandin biosynthesis (Knutson and Wood ).…”

Section: Introductionmentioning

confidence: 99%

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Ketamine modulates fetal hemodynamic and endocrine responses to umbilical cord occlusion

et al. 2016

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Umbilical cord occlusion (UCO) is a hypoxic insult that has been used to model birth asphyxia and umbilical cord compression in utero. UCO triggers vigorous neural and endocrine responses that include increased plasma ACTH and cortisol concentrations, increased blood pressure (BP), and decreased heart rate (HR). We have previously reported that ketamine, a noncompetitive N‐methyl‐D‐aspartate receptor antagonist, can modify the fetal hemodynamic and ACTH responses to ventilatory hypoxia and cerebral ischemia‐reperfusion. We performed the present experiments to test the hypothesis that ketamine has similar effects on the neuroendocrine and cardiovascular responses to UCO. Fetal sheep were chronically catheterized at gestational day 125. Ketamine (3 mg/kg) was administered intravenously to the fetus 10 min prior to the insult. UCO was induced for 30 min by reducing the umbilical vein blood flow until fetal PaO2 levels were reduced from 17 ± 1 to 11 ± 1 mm Hg. UCO produced an initial increase on fetal BP in both control and ketamine groups (P = 0.018 time), followed by a decrease in the control group, but values remained higher with ketamine. HR decreased after UCO (P = 0.041 stimulus*time) in both groups, but the reduction was greater initially in control compared to ketamine groups. Fetal Pa CO 2 levels increased after UCO (P < 0.01 stimulus*time), but values were higher in the control versus ketamine groups. UCO significantly decreased fetal pH values (P < 0.01 stimulus*time) with a greater effect on the control versus ketamine group. Ketamine delayed the cortisol responses to UCO (P < 0.001 stimulus*time), and UCO produced a robust increase in ACTH levels from 19 ± 2 to 280 ± 27 pg/mL (P < 0.001 stimulus*time), but there were no differences in ACTH levels between UCO groups. We conclude that ketamine augmented the cardiovascular response to UCO, but did not alter the ACTH response to UCO.

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Ketamine Attenuates the ACTH Response to Hypoxia in Late-Gestation Ovine Fetus

Cited by 11 publications

References 25 publications

Ketamine suppresses hypoxia‐induced inflammatory responses in the late‐gestation ovine fetal kidney cortex

Ketamine suppresses hypoxia‐induced inflammatory responses in the late‐gestation ovine fetal kidney cortex

Post-hypoxia Invasion of the fetal brain by multidrug resistant Staphylococcus

Ketamine modulates fetal hemodynamic and endocrine responses to umbilical cord occlusion

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