Fetal responses to long-term hypoxemia in sheep

Kitanaka, Takashi; Alonso, Justo; Gilbert, R. D.; SIu, Bagriantseva; Clemons, Gisela K.; Ld, Longo

doi:10.1152/ajpregu.1989.256.6.r1348

Cited by 59 publications

(80 citation statements)

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“…Kitanaka et al (23) showed that fetuses exposed to 28 days of hypoxemia via high altitude responded by increasing their hemoglobin and hematocrit over time to normalize arterial oxygen contents; these fetuses grew at normal rates, indicative of normal fetal nutrient metabolism. In contrast, our model allowed us to chronically match the mean oxygen content of PI-IUGR fetuses (2.0 mmol/l) (7,28,47).…”

Section: Discussionmentioning

confidence: 99%

Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

Culpepper

Wesolowski

Benjamin

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Wilkening RB, Hay WW Jr, Rozance PJ. Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep. Am J Physiol Regul Integr Comp Physiol 311: R200 -R208, 2016. First published May 11, 2016; doi:10.1152/ajpregu.00037.2016.-Hepatic glucose production (HGP) normally begins just prior to birth. Prolonged fetal hypoglycemia, intrauterine growth restriction, and acute hypoxemia produce an early activation of fetal HGP. To test the hypothesis that prolonged hypoxemia increases factors which regulate HGP, studies were performed in fetuses that were bled to anemic conditions (anemic: n ϭ 11) for 8.9 Ϯ 0.4 days and compared with control fetuses (n ϭ 7). Fetal arterial hematocrit and oxygen content were 32% and 50% lower, respectively, in anemic vs. controls (P Ͻ 0.005). Arterial plasma glucose was 15% higher in the anemic group (P Ͻ 0.05). Hepatic mRNA expression of phosphonenolpyruvate carboxykinase (PCK1) was twofold higher in the anemic group (P Ͻ 0.05). Arterial plasma glucagon concentrations were 70% higher in anemic fetuses compared with controls (P Ͻ 0.05), and they were positively associated with hepatic PCK1 mRNA expression (P Ͻ 0.05). Arterial plasma cortisol concentrations increased 90% in the anemic fetuses (P Ͻ 0.05), but fetal cortisol concentrations were not correlated with hepatic PCK1 mRNA expression. Hepatic glycogen content was 30% lower in anemic vs. control fetuses (P Ͻ 0.05) and was inversely correlated with fetal arterial plasma glucagon concentrations. In isolated primary fetal sheep hepatocytes, incubation in low oxygen (3%) increased PCK1 mRNA threefold compared with incubation in normal oxygen (21%). Together, these results demonstrate that glucagon and PCK1 may potentiate fetal HGP during chronic fetal anemic hypoxemia.glucose; oxygen; PEPCK; glycogen; hepatocyte GLUCOSE IS THE PRINCIPAL ENERGY substrate for the fetus and is essential for normal fetal metabolism and growth. The transport of glucose from the mother to the fetus occurs by facilitated diffusion across the placenta. Therefore, the rate of fetal glucose uptake depends largely on the maternal arterial plasma glucose concentration (19). Normally, transported maternal arterial glucose is the sole source of fetal glucose, and there is no fetal hepatic glucose production (HGP) (20).As part of the transition to extrauterine life, fetal HGP is activated just prior to delivery (13). At birth, infants have a period of reduced glucose intake when they are removed from their placental glucose supply and their mother's milk is being established. Thus, to avoid hypoglycemia, the neonate must rely on endogenous HGP. Fetal sheep at 0.97 gestation have increased endogenous HGP, as well as higher hepatic levels of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK, encoded by PCK1) and glucose-6-phosphatase (G6Pase, encoded by G6PC) compared with 0.95 gestation (11, 13). PEPCK catalyzes the rate-limiting step, and G6Pase catalyzes the final step in gluconeogenesis. Increased perinatal trans...

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Section: Discussionmentioning

confidence: 99%

Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

Culpepper

Wesolowski

Benjamin

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The enhanced blood pressure observed in the preexisting hypoxia during the last two days of the five-day hypoxia period most likely reflects an increase in circulating catecholamines (Kitanaka et al, 1989). An elevation in plasma catecholamines elicited by chemoreceptor mechanisms is also thought to be responsible for the initial hypertension (Boekkooi et al, 1992;Cohn et al, 1974;Giussani et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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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“…There was no effect of either periconceptional or gestational undernutrition on fetal heart rate or on the decrease in fetal heart rate that occurs with increasing gestational age (16,37). The rpp (rpp ϭ systolic BP ϫ heart rate) has been used as a marker of myocardial oxygen consumption and thus of cardiac work in the sheep fetus (14) and human adult (15,29).…”

Section: Discussionmentioning

confidence: 99%

Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep

Edwards

McMillen

2002

American Journal of Physiology-Regulatory, Integrative and Comp

103

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-It has been proposed that fetal adaptations to intrauterine nutrient deprivation permanently reprogram the cardiovascular system. We investigated the impact of restricted periconceptional nutrition and/or restricted gestational nutrition on fetal arterial blood pressure (BP), heart rate, rate pressure product, and the fetal BP responses to ANG II and the angiotensin-converting enzyme inhibitor captopril during late gestation. Restricted periconceptional nutrition resulted in an increase in fetal mean arterial BP between 115 and 125 days gestation (restricted 41.5 Ϯ 2.8 mmHg, n ϭ 12; control 38.5 Ϯ 1.5 mmHg, n ϭ 13) and between 135 and 147 days gestation (restricted 50.5 Ϯ 2.2 mmHg, n ϭ 8; control 42.5 Ϯ 1.9 mmHg, n ϭ 10) as well as an increase in the rate pressure product in twin, but not singleton, fetuses between 115 and 147 days gestation. Mean BP and fetal plasma ACTH were also positively correlated in twin, but not singleton, fetuses. This is the first demonstration that maternal undernutrition during the periconceptional period results in an increase in fetal arterial BP. This increase occurs concomitantly with an increase in fetal ACTH but is not dependent on activation of the fetal renin-angiotensin system. fetus; blood pressure; renin-angiotensin system A WORLD-WIDE SERIES of epidemiological studies has demonstrated associations between low birth weight and poor adult health outcomes, including raised arterial blood pressure (BP) and coronary heart disease (1-3). The reproducibility of these associations across many populations has generated the "fetal origins of adult disease hypothesis." This hypothesis states that fetal adaptations to a period of intrauterine nutrient deprivation result in a permanent reprogramming of the developmental pattern of key organ systems and in subsequent pathological consequences in adult life (3,22). Recent data from the Dutch "Winter Hunger" Famine study provided evidence that the timing of fetal nutrient restriction in pregnancy is important in determining specific pathophysiological outcomes (30,32,33). Individuals exposed to famine in the first trimester only, when the nutrient demands of the conceptus are minimal, had an increased prevalence of coronary heart disease compared with individuals not exposed to the famine during this period (30,32,33). Although adult hypertension was not specifically associated with exposure to maternal malnutrition during any one trimester, it was associated with any level of maternal undernutrition that resulted in reduced fetal growth (33). In experimental studies, rats born to mothers fed a low-protein diet either during the preimplantation period or during mid or late gestation also developed high BP in later life (17,20). It has been proposed that maternal undernutrition may result in exposure of the embryo or fetus to excess glucocorticoids and that this exposure permanently changes the program of structural or functional development of the cardiovascular system (6,18,19,21,35). We previously showed in the sheep that maternal und...

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Fetal responses to long-term hypoxemia in sheep

Cited by 59 publications

References 0 publications

Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

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

Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep

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