Long-Term Hypoxia Alters Endocrine and Physiologic Responses to Umbilical Cord Occlusion in the Ovine Fetus

Imamura, Toshiko; Umezaki, Hikaru; Kaushal, Kanchan M.; Ducsay, Charles A.

doi:10.1016/j.jsgi.2003.09.006

Cited by 35 publications

(88 citation statements)

References 34 publications

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“…This initial bradycardia is thought to represent a chemoreceptor response that is vagally mediated (Bartelds et al, 1993). Consistent with our data, in chronically hypoxic high altitude-exposed fetal sheep with a comparable reduction in fetal arterial pO 2 and without acidosis, the bradycardic response to umbilical cord occlusion was shown not to be affected (Imamura et al, 2004). As reported by others for partial cord occlusions (Giussani et al, 1997), we observed that following the initial bradycardia fetal heart rate stabilized or even increased slightly only to fall again during the last minute of occlusion.…”

Section: Discussionsupporting

confidence: 90%

Mild chronic hypoxia modifies the fetal sheep neural and cardiovascular responses to repeated umbilical cord occlusion

et al. 2007

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We have shown that five days of mild hypoxia has significant effects on fetal ECoG activity, heart rate and blood pressure. We now studied if mild prolonged hypoxemia had an adverse effect on the fetal cardiovascular and neural responses to repeated cord occlusion and on the magnitude of neuronal damage. Fetal and maternal catheters were placed at 120 days' gestation and animals allocated at random to receive intratracheal maternal administration of nitrogen (n=8) or compressed air in controls (n=7). Five days after surgery, nitrogen infusion was adjusted to reduce fetal brachial artery pO 2 by 25%. After 5 days of chronic hypoxemia the umbilical cord was completely occluded for 5 minutes every 30 minutes for a total of four occlusions. Data are presented as mean ± SEM and were analyzed by Two Way ANOVA or two sample t test. Nitrogen infusion decreased fetal pO 2 by 26% (20.5±1.7 vs. 14.3±0.8 mmHg) without changing fetal pCO 2 or pH. Pre-existing hypoxia fetuses had a greater terminal fall in heart rate in occlusions II, III and IV, and also had a more severe terminal hypotension in the final occlusion. Pre-existing hypoxia was associated with a greater fall in spectral edge frequency during occlussions from 14.4±0.9 Hz to 6.9±0.4 Hz vs. 13.6±1.64 Hz to 10.6±0.77 Hz in controls, p<0.05. In addition, during the three-day post-occlusion period the contribution of theta and alpha band frequencies to total ECoG activity was significantly lower in the pre-existing hypoxia fetuses (p<0.05). These effects were associated with increased neuronal loss in the striatum (p<0.05). In summary, the cardiovascular and neural response indicate a detrimental effect of preexisting mild hypoxia on fetal outcome following repeated umbilical cord occlusions.

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Section: Discussionsupporting

confidence: 90%

Mild chronic hypoxia modifies the fetal sheep neural and cardiovascular responses to repeated umbilical cord occlusion

et al. 2007

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“…Although we previously reported that basal plasma levels of cortisol are not different between LTH and control fetuses (1,23), the potential does exist for lower intra-adrenal concentrations of cortisol in the LTH fetus, as we previously found that the enzymes responsible for cortisol synthesis are lower in the cortex of LTH fetuses (33). It also remained possible that expression of the GR was suppressed in the medulla of the LTH adrenal, thus decreasing the sensitivity to cortisol.…”

Section: Discussionmentioning

confidence: 76%

“…After spending ϳ105-110 days of gestation at high altitude, the animals were transported to Loma Linda University Medical Center Animal Research Facility (elevation: 346 m), where they were implanted with a nonocclusive tracheal catheter (4.0 mm OD) and an arterial catheter. Maternal PO 2 for LTH group was maintained at ϳ60 mmHg (mean PO2 measured in animals at altitude) by adjusting humidified nitrogen (N2) gas flow through the tracheal catheter as previously described (1,21,23). Normoxic, age-matched pregnant ewes were used as controls.…”

Section: Animalsmentioning

confidence: 99%

“…Unfortunately, models of chronic hypoxia often result in a mixed phenotype with effects on such parameters as blood pH and/or fetal growth and metabolism. Our laboratory has developed a model of longterm hypoxia (LTH), in which pregnant ewes are maintained at high altitude (3,820 m) resulting in a sustained, moderate hypoxic state from day 30 of gestation to term without associated fetal growth retardation or fetal acidemia (1,22,23). Using this model, we previously communicated that fetal plasma epinephrine concentrations were significantly attenuated in response to a secondary stressor (superimposed acute hypoxia) compared with control fetuses (26) despite exhibiting similar basal plasma catecholamine levels.…”

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confidence: 99%

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Long-term hypoxia modulates expression of key genes regulating adrenomedullary function in the late gestation ovine fetus

Ducsay¹,

Hyatt²,

Młynarczyk³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Ducsay CA, Hyatt K, Mlynarczyk M, Root BK, Kaushal KM, Myers DA. Long-term hypoxia modulates expression of key genes regulating adrenomedullary function in the late gestation ovine fetus. Am J Physiol Regul Integr Comp Physiol 293: R1997-R2005, 2007. First published August 15, 2007; doi:10.1152/ajpregu.00313.2007.-We previously communicated that long-term hypoxia (LTH) resulted in a selective reduction in plasma epinephrine following acute stress in fetal sheep. The present study tested the hypothesis that LTH selectively reduces adrenomedullary expression of phenylethanolamine-N-methyltransferase (PNMT), the rate-limiting enzyme for epinephrine synthesis. We also examined the effect of LTH on adrenomedullary nicotinic, muscarinic, and glucocorticoid receptor (GR) expression. Ewes were maintained at high altitude (3,820 m) from 30 to 138 days gestation (dGA); adrenomedullary tissue was collected from LTH and age-matched, normoxic control fetuses at 139 -141 dGA. Contrary to our hypothesis, in addition to PNMT, adrenomedullary expression (mRNA, protein) of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) were reduced in the LTH fetus. Immunocytochemistry indicated that TH and DBH expression was lower throughout the medulla, while PNMT appeared to reflect a reduction in PNMT-expressing cells. Nicotinic receptor alpha 1, 2, 3, 5, 6, 7, beta 1, 2, and 4 subunits were expressed in the medulla of LTH and control fetuses. Messenger RNA for alpha 1 and 7 and beta 1 and 2 subunits was lower in LTH fetuses. Muscarinic receptors M1, M2, and M3 as well as the GR were also expressed, and no differences were noted between groups. In summary, LTH in fetal sheep has a profound effect on expression of key enzymes mediating adrenomedullary catecholamine synthesis. Further, LTH impacts nicotinic receptor subunit expression potentially altering cholinergic neurotransmission within the medulla. These findings have important implications regarding fetal cardiovascular and metabolic responses to stress in the LTH fetus. adrenal; ovine; catecholamine BY LATE GESTATION IN THE DEVELOPING ovine fetus, stress activates the sympathetic nervous system, eliciting the release of both norepinephrine and epinephrine. These catecholamines play an essential role in regulating fetal cardiovascular and metabolic responses to a wide variety of stresses and are fundamental in the adaptation of the neonate to the extrauterine environment postbirth (12,35,36). As observed in the adult, the adrenal medulla is the major source of both basal and stress-induced epinephrine in the circulation and contributes significantly to plasma norepinephrine concentrations in the late-gestation ovine fetus (12,25,34,35). There is evidence that both structural and functional innervation of the adrenal medulla occurs during the final third of gestation as the fetus prepares for birth with synapses between splanchnic cholinergic nerve terminals and adrenal chromaffin cells developing between 100 and 130 days of gestation (dGA; term is ϳ148 dGA) in fetal sheep ...

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“…This would exert an inhibitory effect on basal cortisol production overcoming the low level of stimulation by elevated basal ACTH. Stimulation with high levels of ACTH in vitro (Monau et al 2010) or those observed in vivo in response to a secondary stressor (Adachi et al 2004, Imamura et al 2004 would decrease NO activity, thus enhancing cortisol output. We propose that this can occur through ACTH interaction with the MEK/ERK1/2 and/or the AKT/IP 3 .…”

Section: Potential Indirect Effects On Nomentioning

confidence: 99%

eNOS activation and NO function: Differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia

Ducsay¹,

Myers²

2011

Journal of Endocrinology

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Nitric oxide (NO) plays a role in a wide range of physiological processes. Aside from its widely studied function in the regulation of vascular function, NO has been shown to impact steroidogenesis in a number of different tissues. The goal of this review is to explore the effects of NO on steroid production and further, to discern its source(s) and mechanism of action. Attention will be given to the regulation of NO synthases in specific endocrine tissues including ovaries, testes, and adrenal glands. The effects of hypoxia on generation of NO and subsequent effects on steroid biosynthesis will also be examined. Finally, a potential model for the interaction of hypoxia on NO synthesis and steroid production is proposed.

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Long-Term Hypoxia Alters Endocrine and Physiologic Responses to Umbilical Cord Occlusion in the Ovine Fetus

Abstract: Despite similar ACTH responses to UCO, the cortisol response was greater in the LTH fetuses than in normoxic controls. LTH appears to result in enhanced adrenal sensitivity to a secondary stressor or altered cortisol metabolism.

Cited by 35 publications

References 34 publications

Mild chronic hypoxia modifies the fetal sheep neural and cardiovascular responses to repeated umbilical cord occlusion

Mild chronic hypoxia modifies the fetal sheep neural and cardiovascular responses to repeated umbilical cord occlusion

Long-term hypoxia modulates expression of key genes regulating adrenomedullary function in the late gestation ovine fetus

eNOS activation and NO function: Differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia

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