Continuous Adaptation of Rats to Hypobaric Hypoxia Prevents Stressor Hyperglycemia and Optimizes Mitochondrial Respiration in Acute Hypoxia

Hypoxia poses a stress to cells and decreases mitochondrial respiration, in part by electron transport chain (ETC) complex reorganization. While metabolism under acute hypoxia is well characterized, alterations under chronic hypoxia largely remain unexplored. We followed oxygen consumption rates in THP-1 monocytes during acute (16 h) and chronic (72 h) hypoxia, compared to normoxia, to analyze the electron flows associated with glycolysis, glutamine, and fatty acid oxidation. Oxygen consumption under acute hypoxia predominantly demanded pyruvate, while under chronic hypoxia, fatty acid- and glutamine-oxidation dominated. Chronic hypoxia also elevated electron-transferring flavoproteins (ETF), and the knockdown of ETF–ubiquinone oxidoreductase lowered mitochondrial respiration under chronic hypoxia. Metabolomics revealed an increase in citrate under chronic hypoxia, which implied glutamine processing to α-ketoglutarate and citrate. Expression regulation of enzymes involved in this metabolic shunting corroborated this assumption. Moreover, the expression of acetyl-CoA carboxylase 1 increased, thus pointing to fatty acid synthesis under chronic hypoxia. Cells lacking complex I, which experienced a markedly impaired respiration under normoxia, also shifted their metabolism to fatty acid-dependent synthesis and usage. Taken together, we provide evidence that chronic hypoxia fuels the ETC via ETFs, increasing fatty acid production and consumption via the glutamine-citrate-fatty acid axis.

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DL-3-n-Butylphthalide Improves Physical and Cognitive Performance of Animals with Acute and Chronic Hypobaric Hypoxia

10.21203/rs.3.rs-39309/v1 ◽

2020 ◽

Author(s):

Gang Xu ◽

Yikun Shi ◽

Binda Sun ◽

Lu Liu ◽

Guoji E ◽

...

Keyword(s):

Cognitive Functions ◽

Hypobaric Hypoxia ◽

Chronic Hypoxia ◽

Acute Hypoxia ◽

Redox Homeostasis ◽

Oxidative Capacity ◽

Treadmill Running ◽

Escape Time ◽

Physical Functions ◽

Active Escape

Abstract Background: Studies revealed the protective effect of DL-3-n-butylphthalide (NBP) against ischemic hypoxia diseases. However, the role of NBP in animals with hypobaric hypoxia is elusive. This study investigated the effect of NBP on animals with acute and chronic hypobaric hypoxia.Methods: SD rats and Kunming mice administrated with NBP (90, 180 and 360 mg/kg for mice, and 60, 120, and 240 mg/kg for rats) were located in 10,000 m hypobaric hypoxia chamber. And survival analysis of animals implied that NBP could significantly improve survival percent at 30 min. Then, treated animals were evaluated for exhaustive time and exhaustive distance in forced exercise wheel-track treadmill and treadmill running experiments at 5,800 m for 3 or 21 days, to evaluate physical functions. Rats were also evaluated for times of active escape, average time of active escape, time of passive escape, and average time of passive escape in a shuttle-box experiment at 5,800 m for 7 or 28 days, to evaluate cognitive functions. ATP level was evaluated in the gastrocnemius muscle and maloaldehyde (MDA), superoxide dismutase (SOD), hydrogen peroxide (H2O2), lactate, and glutathione peroxiase (GSH-Px) measurements and routine blood tests were detected.Results: Exhaustive time for rats (NBP, 120 and 240 mg/kg) and exhaustive time and distance for mice (NBP, 90 mg/kg) significantly increased under acute hypoxia. And NBP treatment significantly increased the exhaustive time for rats under chronic hypoxia. Moreover, NBP of 120 and 240 mg/kg significantly increased the average time of passive escape under acute and chronic hypoxia. These results suggested that NBP could improve physical and cognitive functions under acute and chronic hypobaric hypoxia. Furthermore, the levels of MDA and H2O2 decreased but those of SOD and GSH-Px increased under acute and chronic hypoxia. Furthermore, the content of ATP significantly increased, while lactate level significantly decreased. The results presented that NBP could regulate redox homeostasis and improve energy metabolism.Conclusion: NBP could improve physical and cognitive functions under acute and chronic hypobaric hypoxia by increasing anti-oxidative capacity and energy supply.

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ULTRASTRUCTURAL PROPERTIES OF THE ADRENAL GLANDS DURING THE ACUTE HYPOXIA

World Science ◽

10.31435/rsglobal_ws/31102019/6719 ◽

2019 ◽

Vol 1 (10(50)) ◽

pp. 41-46

Author(s):

Yagubova Samira Mammadhasan

Keyword(s):

Adrenal Cortex ◽

Adrenal Medulla ◽

Blood Supply ◽

Hypobaric Hypoxia ◽

Adrenal Glands ◽

Acute Hypoxia ◽

Ultrastructural Changes ◽

White Rats ◽

Extracellular Structures

The goal of the study was to study the morphofunctional properties of ultrastructural changes in the cellular and extracellular structures of the adrenal glands during hypobaric hypoxia. The materials of the study were 30 male white rats weighing 180-200 grams. Thus, the results of the conducted studies showed that morphofunctional changes under the effects of acute hypoxia, which develop in different zones of the adrenal cortex, also change the histofunctional state of the adrenal medulla. Morphometric indicators of the adrenal parenchyma increase from the 5th day of hypoxia and are characterized by the increased blood supply to the adrenal glands, which occurs both by the dilatation of capillaries and by an increase in their density.

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DL-3-n-butylphthalide improved physical and learning and memory performance of rodents exposed to acute and chronic hypobaric hypoxia

Military Medical Research ◽

10.1186/s40779-021-00314-7 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Gang Xu ◽

Yi-Kun Shi ◽

Bin-Da Sun ◽

Lu Liu ◽

Guo-Ji E. ◽

...

Keyword(s):

Learning And Memory ◽

Hypobaric Hypoxia ◽

Gastrocnemius Muscle ◽

Chronic Hypoxia ◽

Acute Hypoxia ◽

Treadmill Running ◽

Hypoxia Tolerance ◽

Control Group ◽

Time To Exhaustion ◽

Atp Levels

Abstract Background Studies have revealed the protective effect of DL-3-n-butylphthalide (NBP) against diseases associated with ischemic hypoxia. However, the role of NBP in animals with hypobaric hypoxia has not been elucidated. This study investigated the effects of NBP on rodents with acute and chronic hypobaric hypoxia. Methods Sprague-Dwaley rats and Kunming mice administered with NBP (0, 60, 120, and 240 mg/kg for rats and 0, 90, 180, and 360 mg/kg for mice) were placed in a hypobaric hypoxia chamber at 10,000 m and the survival percentages at 30 min were determined. Then, the time and distance to exhaustion of drug-treated rodents were evaluated during treadmill running and motor-driven wheel-track treadmill experiments, conducted at 5800 m for 3 days or 20 days, to evaluate changes in physical functions. The frequency of active escapes and duration of active escapes were also determined for rats in a shuttle-box experiment, conducted at 5800 m for 6 days or 27 days, to evaluate changes in learning and memory function. ATP levels were measured in the gastrocnemius muscle and malonaldehyde (MDA), superoxide dismutase (SOD), hydrogen peroxide (H2O2), glutathione peroxidase (GSH-Px), and lactate were detected in sera of rats, and routine blood tests were also performed. Results Survival analysis at 10,000 m indicated NBP could improve hypoxia tolerance ability. The time and distance to exhaustion for mice (NBP, 90 mg/kg) and time to exhaustion for rats (NBP, 120 and 240 mg/kg) significantly increased under conditions of acute hypoxia compared with control group. NBP treatment also significantly increased the time to exhaustion for rats when exposed to chronic hypoxia. Moreover, 240 mg/kg NBP significantly increased the frequency of active escapes under conditions of acute hypoxia. Furthermore, the levels of MDA and H2O2 decreased but those of SOD and GSH-Px in the sera of rats increased under conditions of acute and chronic hypoxia. Additionally, ATP levels in the gastrocnemius muscle significantly increased, while lactate levels in sera significantly decreased. Conclusion NBP improved physical and learning and memory functions in rodents exposed to acute or chronic hypobaric hypoxia by increasing their anti-oxidative capacity and energy supply.

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Ventilatory response to acute hypoxia in transgenic mice over-expressing erythropoietin: Effect of acclimation to 3-week hypobaric hypoxia

Respiratory Physiology & Neurobiology ◽

10.1016/j.resp.2007.06.010 ◽

2007 ◽

Vol 158 (2-3) ◽

pp. 243-250 ◽

Cited By ~ 12

Author(s):

Francisco C. Villafuerte ◽

Rosa Cárdenas-Alayza ◽

José Luis Macarlupú ◽

Carlos Monge-C ◽

Fabiola León-Velarde

Keyword(s):

Transgenic Mice ◽

Hypobaric Hypoxia ◽

Ventilatory Response ◽

Acute Hypoxia

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Potentiation of the hypoxic preconditioning effect by antihypoxants

Reviews on Clinical Pharmacology and Drug Therapy ◽

10.17816/rcf17137-44 ◽

2019 ◽

Vol 17 (1) ◽

pp. 37-44

Author(s):

Vasiliy E. Novikov ◽

Olga S. Levchenkova ◽

Elena I. Klimkina ◽

Konstantin N. Kulagin

Keyword(s):

Hypobaric Hypoxia ◽

Carotid Arteries ◽

Acute Hypoxia ◽

Hypoxia Inducible Factor ◽

Experimental Models ◽

Hypoxic Preconditioning ◽

Acute Hypobaric Hypoxia ◽

Hypoxia With Hypercapnia ◽

The Common ◽

Common Carotid Arteries

The development of effective methods to increase the organism resistance to hypoxia is an important task of current medicine. One of such methods is preconditioning, as a result of which, a potent mobilization of the adaptive organism abilities occurs under a preconditioning factor action. Aim. To study the possibility of potentiating of the hypoxic preconditioning effect with help of antihypoxants. Methods. Evaluation of the effectiveness of combined preconditioning (antihypoxants + moderate hypobaric hypoxia) was performed on experimental models of acute hypoxia with hypercapnia, acute hypobaric hypoxia in mice, and bilateral occlusion of the common carotid arteries in rats. Investigated antihypoxants are amtizol, hypoxen, cobazole, metaprot, mexidol, mildronate, substances under the codes VM-606, pQ-4 and pQ-1104. Results. PreC with use of amtizol at dose 25 mg/kg, cobazole at dose 30 mg/kg, VM-606, pQ-4 and pQ-1104 at doses 50 mg/kg in combination with moderate hypoxia increased the lifespan of mice in acute hypoxia with hypercapniamodel and acute hypobaric hypoxia from 57 to 170%. Combined preconditioning with amtizol, cobazole and pQ-4 significantly increased the survival rate of rats in cerebral ischemia, amtizol and pQ-4 reduced neurological deficiency in the post ischemic period as well. Conclusion. Antitipoxants as amtizol, cobazole, VM-606, pQ-4, pQ-1104 potentiate the hypoxic preconditioning effect on acute hypoxia with hypercapnia, acute hypobaric hypoxia and occlusion of the common carotid arteries models, the most significant effect was noted for amtizol and pQ-4. Signal role in the adaptation induction to hypoxia and ischemia by combined preconditioning with use of antihypoxants hypoxia-inducible factor HIF-1α can play.

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Influence of the new tiazoloindole derivative on the organism resistance to hypoxia in the early and late periods of preconditioning

Reviews on Clinical Pharmacology and Drug Therapy ◽

10.17816/rcf12454-57 ◽

2014 ◽

Vol 12 (4) ◽

pp. 54-57

Author(s):

Olga Sergeevna Levchenkova ◽

Vasiliy Egorovich Novikov ◽

Vera Vasil'yevna Marysheva

Keyword(s):

Early Phase ◽

Hypobaric Hypoxia ◽

Acute Hypoxia ◽

Late Phase ◽

Animal Life ◽

Resistance To Hypoxia ◽

Hypoxia With Hypercapnia

The aim of this investigation was to study an ability of tiazoloindole derivative encoded VM-606 to influence the lifespan of mice in experimental acute hypoxia with hypercapnia and hypobaric hypoxia in early and late phase of preconditioning. It was found that the use of VM- 606 in dose of 50 mg/kg leads to significant increase in the duration of animal life in case of subsequent acute hypoxia in early phase of preconditioning, but doesn’t produce effect in the late phase of preconditioning.

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THE COMPARATIVE STUDYING OF ANTI-HYPOXEMIC ACTIVITY OF COMPLEX OF ZINC ACETATE WITH N-PROPARGYLIMIDAZOLE AND 3-HYDROXYPYRIDINE

Medical Journal of the Russian Federation ◽

10.18821/0869-2106-2017-23-3-148-151 ◽

2017 ◽

Vol 23 (3) ◽

pp. 148-151

Author(s):

S. A Shakhmardanova ◽

P. A Galenko-Yaroshevsky ◽

L. N Parshina ◽

B. A Trofimov ◽

V. V Tarasov ◽

...

Keyword(s):

Zinc Acetate ◽

Hypobaric Hypoxia ◽

Large Range ◽

Narrow Range ◽

Acute Hypoxia ◽

Comparative Investigation ◽

Complex Compounds ◽

Control Groups ◽

Acute Hypobaric Hypoxia ◽

Hypoxia With Hypercapnia

The pharmacotherapy of hypoxia is an important task of modern experimental and clinical pharmacology. The medications with anti-hypoxic effect implemented into clinical practice unfortunately do not meet requirements of physicians due to poor efficiency, narrow range of active dosages and undesirable side effects. The complexes of zinc with N-alkenylimidazole demonstrated anti-hypoxic activity at various models of acute hypoxia within large range of dosage. Therefore, further studying of zinc-contained compounds as possible correctors of hypoxia is of particular interest. The experiments with white nonlinear male mice were used for comparative investigation of ant-hypoxic effect of complex compounds of zinc acetate with N-propargylimidazole and 3-hydroxipyridine, including complexes immobilized on sulfated arabinogalaсtan and also well-known anti-hypoxants and/or anti-oxidants: etomerzol, mexidol, nooglutil and hypoxen. It is demonstrated that anti-hypoxic effect of complex of zinc acetate with N-propargylimidazolein conditions of acute hypobaric hypoxia, acute hypoxia with hypercapnia acute hematic hypoxia by width of active dosages (1-100 mg/kg, intraperitoneally) and degree of expression (19-317% in comparison with control groups of animals) excels the similar effect in well-known anti-hypoxants and/or anti-oxidants: etomerzol (25-100 mg/kg, intraperitoneally), mexidol (100 mk per kg, intraperitoneally), nooglutil (25-100 mg/kg, intraperitoneally) and hypoxen (50-150 mg/kg, intraperitoneally). The protective effect of complex of zinc acetate with 3-hydroxipyridine by width of active dosages (25-100 mg/kg, intraperitoneally) and degree of expression (27-167% in comparison with control groups of animals) in conditions of exogenous hypoxia (acute hypobaric hypoxia and acute hypoxia with hypercapnia) excels similar effect of etomerzol and mexidol ans is comparable with effect of nooglutil and hypoxen. The complexes immobilized on sulfated arabinogalactan were ineffective.

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Adaptation to hypobaric hypoxia involves GABAA receptors in the pons

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00339.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. R549-R557 ◽

Cited By ~ 9

Author(s):

Yee-Hsee Hsieh ◽

Thomas E. Dick ◽

Ruth E. Siegel

Keyword(s):

Brain Stem ◽

Hypobaric Hypoxia ◽

Molecular Mechanisms ◽

De Novo ◽

Acute Hypoxia ◽

Receptor Expression ◽

Dependent Manner ◽

Low Oxygen ◽

Subunit Expression ◽

The Brain

Survival in low-oxygen environments requires adaptation of sympathorespiratory control networks located in the brain stem. The molecular mechanisms underlying adaptation are unclear. In naïve animals, acute hypoxia evokes increases in phrenic (respiratory) and splanchnic (sympathetic) nerve activities that persist after repeated challenges (long-term facilitation, LTF). In contrast, our studies show that conditioning rats to chronic hypobaric hypoxia (CHH), an environment characteristic of living at high altitude, diminishes the response to hypoxia and attenuates LTF in a time-dependent manner. Phrenic LTF decreases following 7 days of CHH, and both sympathetic and phrenic LTF disappear following 14 days of CHH. Previous studies demonstrated that GABA is released in the brain stem during hypoxia and depresses respiratory activity. Furthermore, the sensitivity of brain stem neurons to GABA is increased following prolonged hypoxia. In this study, we demonstrate that GABAA receptor expression changes along with the CHH-induced physiological changes. Expression of the GABAA receptor α4 subunit mRNA increases two-fold in animals conditioned to CHH for 7 days. In addition, de novo expression of δ and α6, a subunit normally found exclusively in the cerebellum, is observed after 14 days. Consistent with these changes, diazepam-insensitive binding sites, characteristic of GABAA receptors containing α4 and α6 subunits, increase in the pons. Immunohistochemistry revealed that CHH-induced GABAA receptor subunit expression is localized in regions of sympathorespiratory control within the pons. Our findings suggest that a GABAA receptor mediated-mechanism participates in adaptation of the sympathorespiratory system to hypobaric hypoxia.

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