Bioenergetic hypoxia: Definition, mechanisms, and methods of correction

Bioenergetic hypoxia is defined as a phasic process starting at the substrate site of the respiratory chain with injury to the mitochondrial enzymatic complex I and involving, as oxygen insufficiency progresses, the terminal cytochrome site of the respiratory chain. Different stages of the process, determined experimentally, are described from a bioenergetic viewpoint. The development of bioenergetic hypoxia in tissues of animals with different resistance to hypoxia is analyzed. Modern concepts of the trigger mechanisms of bioenergetic hypoxia and approaches to correcting the function of the energy system at different stages of hypoxia are discussed. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 9, pp. 244–254, September, 1997     

Individual resistance of the organism and nerve cell to hypoxia

The correlation between the pattern of a neuron's reaction to acute hypoxia and individual resistance to oxygen deficit is studied on ratsin vivo as well as on surviving slices of their cerebellumin vitro. According to the survival time in a pressure chamber simulating an altitude of 11 km all the rats were divided into groups of high resistance, medium resistance, and low resistance to hypoxia. Survival time was 4.2 times longer in the high resistance group than in the low resistance group. In the cerebellar slices of high resistance animals 61.5% high-resistance neurons and 38.5% low-resistance neurons were recorded. On the other hand, in the high resistance animals the percentage of high-resistance neurons and low-resistance neurons was 31.2 and 68.8, respectively. The period of hypoxia development was 4.32 times longer in the high-resistance neurons as compared to low-resistance neurons. It is speculated that individual differences in the resistance to O₂ deficit are of a hereditary nature and manifest themselves not only on the level of the whole organism, but also in the individual nerve cell. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 118, N ^o 11, pp. 454–457, November, 1994     

Role of glycolysis in the maintenance of the energy-synthesizing function of hepatocytes from rats adapted and nonadapted to hypoxia at different oxygen concentrations

It is demonstrated that the lactate-Po₂ dependence is the same in hepatocytes of rats with high and low resistance to hypoxia and does not correlate with phasic changes in the ATP concentration in the 890–50 μM O₂ region. Strong activation of lactate formation against the background of ATP decrease indicates that glycolysis is not the major mechanism determining the steady-state ATP level in the cell and affecting the ATP-Po₂ relationship in a wide range of oxygen concentrations. The intensity of glycolysis in hepatocytes of rats with high resistance to hypoxia is markedly increased after periodic adaptation to hypoxia but remains practically unchanged in the hepatocytes of low-resistance rats. This indicates that fundamentally different compensatory mechanisms are involved in this process in the liver of high- and low-resistance rats. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, N ^o 1, pp. 28–32, January, 1995     

Antihypoxic effects of derivative on the EEG power spectra in rats with different susceptibility to oxygen deficiency

The succinate-containing hydroxypyridine derivative yancarb increases both the altitude tolerated by rats and their survival time at a high altitude, particularly in rats with low resistance to hypobaric hypoxia; it also prevents both phasic changes in the EEG characteristic of hypobaric hypoxia and hemispheric asymmetry and paroxysmal activity in the brain of highly resistant rats in the 5000–10,000 m range and in rats with low resistance in the 5000–11,000 m range. Antihypoxic effects of this substance are more pronounced in low-resistance rats and in the left hemisphere of both high- and low-resistant animals; in altitude range of 10,000–13,000 m these effects are weaker or absent. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 7, pp. 57–62, July, 1997     

Behavioral peculiarities and reactions of brain dopaminergic systems in rats with different resistance to acute hypobaric hypoxia

Locomotor activity in the open field test did not correlate with rat resistance to acute hypobaric hypoxia; there was a correlation between this resistance and rat behavior during acute stress. Immobility was characteristic of rats with low and particularly medium resistance to hypoxia; this reaction can be abolished by antidepressants. By contrast, highly resistant rats were mainly hyperactive. The resistance to hypoxia was associated with extreme parameters of dopaminergic neuron functioning. In low-resistant rats locomotor stereotypia was maximal, while perioral stereotypia was the minimal; highly resistant rats were characterized by an opposite pattern, and medium-resistant rats occupied an intermediate position. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 9, pp. 275–278, September, 2000     

Comparison of lipid peroxidation parameters in the heart,liver, and brain of rats with different degrees of resistance to hypoxia

The relationship between the intensity of lipid peroxidation and the activity of the antioxidant system in the heart, liver, and brain is studied in male Wistar rats with low and high resistance to hypoxia tested by being “raised” to an altitude of 11.5 km and in intact outbred rats. It is found that in all groups of rats the content of lipid peroxidation products is highest in the liver, lower in the heart, and lowest in the brain. In all groups, the rate of the ascorbate-induced lipid peroxidation is highest in the brain, lower in the liver, and lowest in the heart. The activity of the antioxidant system is highest in the brain, lower in the liver, and lowest in the heart of low-resistance and outbred rats, while in high-resistance rats it is the same in all the organs. Thus, the difference in the parameters of lipid peroxidation and, particularly, of the antioxidant system in the studied organs is most pronounced in rats with a low resistance to hypoxia. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, N ^o 2, pp. 138–143, February, 1996 Presented by A. I. Archakov, Member of the Russian Academy of Medical Sciences     

Effects of adaptation to intermittent hypoxia on oxidative phosphorylation in brain mitochondria of rats with different sensitivities toward oxygen deficiency

After long-term adaptation to intermittent hypoxia, rats with an initially low resistance to acute oxygen deficiency were 2 to 4 times more resistant to it, while highly resistant rats did not show a significant change in resistance. The adaptation was accompanied by weakening of the electron-transporting function of the respiratory chain and increasing efficiency of oxidative phosphorylation in the brain mitochondria oxidizing NAD-dependent substrates, indicating that energy was produced in a more economical way. The succinate oxidase pathway of oxidation was found to be utilized to only a limited extent as a compensatory mechanism in animals exposed to intermittent hypoxia over a prolonged period. The effects of adaptation were more marked in the brain mitochondria of rats initially highly sensitive to oxygen deficiency. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N ^o 12, pp. 572–575, December, 1995     

Blood corticosterone and resistance to hypoxia during operant conditioning and development of learned helplessness

Operant conditioning under conditions of uncertain behavioral environment was accompanied by a significant elevation of blood corticosterone, high exploratory activity, and increased resistance to hypoxia. The blood content of corticosterone and exploratory activity significantly decreased in rats developing learned helplessness, but their resistance to hypoxia increased in comparison with that during learning. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No.7, pp. 29–31, July, 1999     

Effects of adaptation to periodic hypoxia on kinetic parameters of respiratory chain enzymes in rat brain

A study of kinetic parameters of brain respiratory enzymes revealed that the maximal velocity and the Michaelis apparent constant for NADH-cytochrome C-reductase are significantly lower in low-resistant rats than in rats with a high resistance to hypoxia. Adaptation to periodic hypoxia increases total resistance only in low-resistant rats. It is accompanied by an increase in the values of kinetics parameters for NADH-cytochrome C-reductase and cytochrome oxidase. Kinetic parameters for these enzymes in the brain of high-resistant rats are either unaltered or even decreased. It is suggested that the first enzymatic complex of the respiratory chain is one of the limiting or regulating links in energy metabolism determining the brain's resistance to hypoxia. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, N ^o 3, pp. 252–255, March, 1996.     

Lipid peroxidation parameters in the internal organs of rats with different degrees of resistance to hypoxia

Lipid peroxidation and the antioxidant system of the heart, liver, and brain are studied in adult male Wistar rats with high and low resistance to hypoxia tested by “raising” to an altitude of 11.5 km and in intact outbred rats. These parameters are found to be the same in the brain of low- and high-resistance rats, while the brain content of lipid peroxidation products is higher in both groups of Wistar rats compared with outbred rats. The heart and liver parameters are coupled to the resistance to hypoxia. Antioxidant activity prevails over lipid peroxidation in the hearts and livers of high-resistance rats, confirming that oxidation plays a major role in the damaging and lethal effects of acute hypoxia. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, N ^o 1, pp 26–29, January, 1996 Presented by A. I. Archakov, Member of the Russian Academy of Medical Sciences     

Changes in hypoxia resistance in rats during daytime

The resistance to acute hypoxia in male Wistar rats was evaluated by the period of survival after exposure to high-altitude hypoxia (11.5 km above see level). The study was performed during daytime (13.00–21.00) in autumn. The fatal rat population was characterized by the log-normal distribution of survival periods. The rats with low and moderate resistance to hypoxia exhibited similar diurnal variations in it with gradual decrease by the end of daytime more pronounced in low-resistant rats. The rats with high resistance showed relatively constant resistance to hypoxia which decreased only at 21:00. All groups revealed a relatively stable resistance to hypoxia from 16:00 to 18:00. These variations in the resistance to hypoxia should be taken into consideration when planning experimental research. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 127, No. 3, pp. 256–260, March 1999     

Effect of the season on lipid peroxidation in the myocardium of rats with different resistance to hypoxia

Lipid peroxidation and the antioxidant system of the myocardium of adult male Wistar rats with low and high resistance to acute hypoxia tested by “raising” to an altitude of 11.5 km are studied in winter and in summer. It is found that the winter season is a mild stressor inducing changes in the myocardial antioxidant system and lipid peroxidation which are similar to those observed at the early stages of catecholamine stress in the summer season. In both cases alterations are more pronounced in low-resistance than in high-resistance rats. In winter, in low-resistance rats the intensity of lipid peroxidation and the activity of the antioxidant system are lower, while the ratio of their parameters (chemiluminescence data) is higher. At the same time, the levels of thiobarbituric acid-reactive substances are higher in winter in both groups. The relationship between the studied parameters and the resistance of rats to hypoxia is more obvious in winter than in summer, i.e., it is season-dependent and is also more pronounced in catecholamine stress. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N^olo 7, pp. 87–90, July, 1995 Presented by N. A. Agadzhanyan, Member of the Russian Academy of Medical Sciences     

Effect of various oxygen concentrations on the ATP content in isolated hepatocytes of rats adapted and nonadapted to hypoxia

It is shown that isolated hepatocytes are capable of perceiving slight changes in the envioronmental oxygen concentration. A complicated phase dependence exists between adenosine triphosphate and partial oxygen pressure, which differs in cells from animals with high and low resistance to hypoxia, the former showing a more stable and resistant energy-synthesizing function than the latter. After long-term adaptation to periodic hypoxia, the resistance of the energy-synthesizing function rises in hepatocytes from high-resistant animals, and falls in low-resistant animals suggesting a fundamentally different organization of the emergency compensatory mechanisms of the energy-synthesizing function in hepatocytes of animals of these two types. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 118, N ^o 12, pp. 576–581, December, 1994     

Effect of hypoxia of increasing severity on the dynamics of cerebral cortex EEGs in rats with different resistance to acute oxygen deficiency

EEGs recorded from the cerebral cortex of rats with high and low resistance to hypoxia during “elevation” in a pressure chamber differ in the dynamics of the EEG power spectra. EEGs of highly resistant rats show phasic changes in biopotentials correlating with the severity of hypoxia: primary increase in the absolute power of all frequency ranges is followed by normalization and a secondary increase with predominance of the slow-wave component, inhibition of the β₂ range and the emergence of interhemispheric differences, and terminal inhibition of the power of all frequency ranges. In rats with low resistance to hypoxia, phases of relative normalization of EEG spectra and their depression during terminal period are not observed, all changes being represented by a continuous increase in the power of the α and δ ranges with progressive inhibition of the β₂ range and then of the β₁ range. Interhemispheric asymmetry is significant throughout the period of power increase. A high amplitude burst activity is recorded in rats of both types starting from an altitude of 8000 or 9000 m. The pattern of EEG changes in rats exposed to hypoxia of growing severity consistently reproduces those observed in patients with ischemic stroke. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 122, No. 9, pp. 262–267, September, 1996     

Effect of electroacupuncture on systemic hemodynamics in rats with postinfarction cardiosclerosis

Electroacupuncture decreased total peripheral vascular resistance and increased cardiac output in 12-week-old postinfarction rats without cardiac insufficiency, while opposite changes were observed in rats with cardiac insufficiency. After the electroacupuncture course, norepinephrine decreased cardiac output in the rats with cardiac insufficiency, while acetylcholine increased it to a much higher extent than in the control rats that were not subjected to physiotherapy. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 127, No. 1, pp. 29–34, January, 1999     

Effects of adaptation to hypoxia on cytochrome levels in the brain and liver of rats

After a prolonged (for 30 days) adaptation of rats to intermittent hypoxia, their brains contained lowered levels of mitochondrial cytochromes, despite an increase in the number of mitochondria in the brain tissue mass, along with similar levels of high-energy compounds and more protein as compaired to the brains of unadapted controls. A mitochondrial population with novel properties presumably emerged in the brain. These effects were all more strongly marked in rats with an initially low resistance to hypoxia. In the liver of hypoxiaadapted animals, unlike in their brain, cytochrome levels in the mitochondrial and microsomal redox chains were lowered and the biogenesis of mitochondria was much less intensive. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N ^o 12, pp. 576–579, December, 1995     

Effect of acute hypoxia on resistance to hypoxia in rats

The resistance of rats to hypoxia was measured by survival time after exposure to high-altitude (11.5 km) hypoxia. The first exposure to acute hypoxia caused phasic changes in the survival time: short-term in high-resistant rats (about 24 h) and long-term in moderate- and lowresistant rats (38–39 days) starting from 1 h and 6–7 days after the first exposure, respectively. Adaptive reactions were more pronounced in low- and moderate-resistant rats, while disadaptation was typical of high-resistant animals. In all rats, the adaptive effect dominated until days 22–23. Throughout the testing, the initial type of resistance was retained in 79% of high-resistant rats, in 41% of low-resistant and in 33% of moderate-resistant rats, i. e., the initially homogenous groups formed after the first exposure in accordance with the type of resistance became mixed, which reduced the intergroup differences. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 127, No. 6, pp. 625–628, June, 1999     

Activity of liver monooxygenase system in rats with low and high resistance to hypoxia

Rats with low and high resistance to hypoxia are shown to differ in terms of the baseline activity of liver monooxygenases bothin vivo andin vitro. Low-resistance animals are characterized by a significantly higher rate of elimination of antipyrine, hexenal, and nifedipine, as evidenced by shorter half-elimination period and higher urinary concentration of metabolites. The concentration of microsomal cytochromes P-450 and b5 as well as the rates of N-demethylation of amidopyrine, p-hydroxylation of aniline, and hydroxylation of diazepam are considerably higher in rats with low resistance to hypoxia. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 122, No. 9, pp. 291–294, September, 1996     

Impact of twelve-day combined exposure to hypobaric hypoxia and physical exercise on structural and metabolic characteristics of skeletal muscle in rats

This study, in which rats were exposed on 12 successive days to hypoxia in combination with exercise on a treadmill, showed that a reduction in partial oxygen pressure leads to a decrease in the magnitude of the structural component of vascular resistance rather than to improvement in the system of oxygen utilization, and that such combined exposure may cause alterations in protein synthesis and result in early stimulation of capillary growth in muscles, as well as elicit differential changes of enzyme activity in different types of muscle fibers. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, N ^o 6, pp. 602–605, June, 1995 Presented by A. I. Grigor'ev, Member of the Russian Academy of Medical Sciences     

Arguments for revision of classification of hypoxic states

Hypoxia always leads to dysfunction of organs and culminates in the fatal outcome. The principles of classification of the hypoxic states were formulated in 1930-s. The first successful cardiac transplantation posed the problem of dividing of circulatory cardiovascular hypoxia into two subdivisions: hypoxia associated with impaired cardiac contractility (cardiac insufficiency) and hypoxia resulting from vascular smooth muscle cell. Here we attempted to improve classification of hypoxic states on the basis of new medical achievements. The proposed classification considers the following hypoxic states: 1) exogenous hypoxia; 2) respiratory hypoxia; 3) hypoxia resulting from cardiac insufficiency; 4) hypoxia provoked by vascular smooth muscle dysfunction; 5) hemic hypoxia; 6) tissue hypoxia; and 7) combined hypoxia. There are specific and pathogenically substantiated methods for correction of all elements of the “hypoxic chain” that regulate tissue metabolism at the cellular and subcellular level both in the whole organism and in individual organs. These methods open new vistas in biology and medicine, in particular, in transplantology. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 127, No. 2, pp. 146–151, February, 1999