Role of Glutamate in the Mechanisms of Adaptation of the System of Respiratory Control in Rats to Intermittent Hypoxia

In experiments on Wistar rats, we studied the role of changes in the state of glutamatergic transmission in the course of adaptation of the system of respiratory control to intermittent hypoxia. The volume/temporal parameters of respiration were estimated according to characteristics of EMG activity (amplitude, integral intensity of EMG discharges) recorded from the diaphragmatic muscle. Changes in EMG activity of the diaphragm induced by acute hypoxia (breathing a 12% О₂-containing gas mixture) were estimated before and after of a 14-day-long course of intermittent hypoxia trainings and before and after inductions of a blocker of NMDA receptors, МK-801. The results prove that the glutamatergic transmitter system is significantly involved in the reaction of the respiratory system to presentation of a hypoxic stimulus within all stages of formation of the ventilatory response, both before and after the action of intermittent hypoxia. Blocking of NMDA receptors under conditions of adaptation to intermittent hypoxia exerted a more intense influence on the amplitude of respiratory EMG discharges of the diaphragm than on their frequency.     

Adaptation to hypobaric hypoxia involves GABA A receptors in the pons

Survival in low-oxygen environments requires adaptation of sympathorespiratory control networks located in the brain stem. The molecular mechanisms underlying adaptation are unclear. In na?ve 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 GABA(A) receptor expression changes along with the CHH-induced physiological changes. Expression of the GABA(A) receptor alpha4 subunit mRNA increases two-fold in animals conditioned to CHH for 7 days. In addition, de novo expression of delta and alpha6, a subunit normally found exclusively in the cerebellum, is observed after 14 days. Consistent with these changes, diazepam-insensitive binding sites, characteristic of GABA(A) receptors containing alpha4 and alpha6 subunits, increase in the pons. Immunohistochemistry revealed that CHH-induced GABA(A) receptor subunit expression is localized in regions of sympathorespiratory control within the pons. Our findings suggest that a GABA(A) receptor mediated-mechanism participates in adaptation of the sympathorespiratory system to hypobaric hypoxia.     

Modulation of respiration during brain hypoxia

This review is a summary of the effects of brain hypoxia on respiration with a particular emphasis on those studies relevant to understanding the cellular basis of these effects. Special attention is given to mechanisms that may be responsible for the respiratory depression that appears to be the primary sequela of brain hypoxia in animal models. Although a variety of potential mechanisms for hypoxic respiratory depression are considered, emphasis is placed on changes in the neuromodulator constituency of the respiratory neuron microenvironment during hypoxia as the primary cause of this phenomenon. Hypoxia is accompanied by a net increase in neuronal inhibition due to both decreased excitatory and increased inhibitory neuromodulator levels. A survey of hypoxia-tolerant cellular systems and organisms suggests that hypoxic respiratory depression may be a manifestation of the depression of cellular metabolism, which appears to be a major adaptation to limited oxygen availability in these systems.     

低氧预适应的脑机制

A concept ot tissue adaptation to hypoxia( i.e. hypoxic preconditioning) was developed and its corresponding animal models were reproduced in 1966s. The methods of model reproduction in rat, rabbit, and mouse in particular and the main results are brifly introduced in this review. The tolerance to hypoxia o{ preconditioned animals is significantly increased. Regular changes in animals‘ behavior, neurophysiology, respiratory and circulatory physiology, neuromorphology in vivo and {unction of brain and spinal cord in vitro are briefly demonstrated. The protective effects in vivo and in vitro of homogenate extract taken from the brain o{ preconditioned animals, neurochemcals and molecular neurobiolcgical alterations are briefly presented. The essence and significance of tissue adaption to hypoxia/hypoxic preconditioning are discussed in the review in terms of evolution and practical implication.     

Criteria of individual variations in the reactivity of the respiratory system

Individual variations of the respiratory system reactivity have been studied in experiments on rats. It is shown expedient to estimate reactivity of the respiratory system to hypoxic hypoxia by the pattern of changes in the total oxygen uptake. Animals demonstrating no essential changes in the oxygen uptake in response to hypoxia (11% O2) are referred to individuals with high reactivity of the respiratory system; those responding by a drastic decrease in the oxygen uptake--to animals with low reactivity of the respiratory system. A strong correlation is determined between the respiratory system reactivity and individual resistance of organism to acute hypoxic hypoxia.     

The surfactant system and structure of the respiratory portion of the lungs during de-adaptation following a single exposure to acute pressure chamber hypoxia

The effect of acute pressure chamber hypoxia on the surfactant system and respiratory segment structure of the lungs were studied in rats by physical, fluorescent microscopic and morphometric methods. Acute hypoxia decreases surface activity, induces changes in cellular and extracellular surfactant fluorescence and causes the development of diffuse vesicular emphysema. On the first day of adaptation atelectatic foci dominate over emphysema, and the pulmonary structure normalizes afterwards. During de-adaptation, surface activity and cellular surfactant fluorescence are higher than the control levels. Surface activity and extracellular surfactant fluorescence recover steadily by the fifth day of adaptation. The amount of phagocytized surfactant in alveolar macrophages is increased, with the changes being opposite to those characteristic of extracellular surfactant.     

Human Systemic Reactions to a Dosed Exposure to Hypoxia: A Multiparameter Study

Human physiological reactions to acute hypoxic hypoxia were studied. Analysis of simultaneously recorded parameters of various physiological systems showed the following: activation of the general antihypoxic defense system is based on the formation of an intricate structure of intra- and intersystemic relations of specific and nonspecific elements of adaptation that support vital body functions during environmental oxygen deficit. These specific elements become more important in more severe hypoxia, which suppresses metabolism in some organs and tissues because of redistribution of blood flow. These factors allow the body to function at a lower oxygen tension in its tissues owing to an increased efficiency of mitochondria as a result of changes in the kinetics of enzymes of the mitochondrial respiratory chain. In acute hypoxia, the structure of intra- and intersystemic relations is rather intricate; its functional hierarchy is maintained by stronger individual amplitude-related controlling factors and by modulation of their phase- and time-related links. Advanced stages of hypoxia are associated with disintegration of central regulatory mechanisms, which is manifested by disturbances in amplitude-frequency and spatiotemporal parameters of the brain bioelectrical activity, changes in phasic interactions between elements of regulatory mechanisms, and signs of deregulation and decompensation of vital functions. The interpretation of the results is based on the general theory of adaptation, Medvedev's idea of adaptation as a successive involvement of genetically predetermined and newly-formed regulatory programs of the brain, Anokhin's theory of functional systems, and modern concepts of molecular and biochemical mechanisms of hypoxia. It was concluded that artificial normobaric hypoxia is a unique, biologically adequate model that makes it possible to study the rearrangements in systemic and autonomic regulatory mechanisms in response to strictly determined changes in the environmental concentration of oxygen as a principal factor supporting life.     

Activation of Respiratory Chain Complex II as a Hypoxia Tolerance Indicator during Acute Hypoxia

Activation of respiratory chain complex II during acute hypoxia is an adaptive response that facilitates electron transfer in the respiratory chain when complex I is blocked. Stress induced by acute oxygen deficiency in the body stimulates epinephrine and norepinephrine release into the bloodstream. As a result, compensatory metabolic flows and succinate dehydrogenase and succinate oxidation are activated in the cell. Succinate dehydrogenase activation associated with acute hypoxia exhibits characteristic fluctuations; moreover, stronger stimulation results in oscillations with a shorter period and a higher amplitude. These fluctuations are a consequence of the reciprocal relationship between the sympathetic and parasympathetic systems. In subjects who developed adaptation to hypoxia following repeated sessions of breathing a hypoxic gas mixture, no activation of the succinate–ubiquinone-reductase shunt under hypoxic load was observed. The blood lymphocyte reaction can serve as an indicator of tolerance to acute hypoxia.     

Redox Proteomic Analysis Reveals Oxidative Modifications of Proteins by Increased Levels of Intracellular Reactive Oxygen Species during Hypoxia Adaptation of Aspergillus fumigatus

Aspergillus fumigatus faces abrupt changes in oxygen concentrations at the site of infection. An increasing number of studies has demonstrated that elevated production of intracellular reactive oxygen species (ROS) under low oxygen conditions plays a regulatory role in modulating cellular responses for adaptation to hypoxia. To learn more about this process in A. fumigatus, intracellular ROS production during hypoxia has been determined. The results confirm increased amounts of intracellular ROS in A. fumigatus exposed to decreased oxygen levels. Moreover, nuclear accumulation of the major oxidative stress regulator AfYap1 is observed after low oxygen cultivation. For further analysis, iodoTMT labeling of redox‐sensitive cysteine residues is applied to identify proteins that are reversibly oxidized. This analysis reveals that proteins with important roles in maintaining redox balance and protein folding, such as the thioredoxin Asp f 29 and the disulfide‐isomerase PdiA, undergo substantial thiol modification under hypoxia. The data also show that the mitochondrial respiratory complex IV assembly protein Coa6 is significantly oxidized by hypoxic ROS. Deletion of the corresponding gene results in a complete absence of hypoxic growth, indicating the importance of complex IV during adaptation of A. fumigatus to oxygen‐limiting conditions.     

Evolutionary Aspects of Cardioprotection

The review addresses the mechanisms of adaptation of the myocardium and cells of the cardiovascular system to hypoxia and ischemia as well as biochemical mechanisms of cardioprotection in animals of different phylogenetic levels. A special focus is placed on general adaptive strategies developed by evolutionarily distant animals in response to hypoxia and ischemia and on preconditioning and myocardial hibernation phenomena.     

Principles of Physiological Regulation of the Body Functions in Incomplete Adaptation

The main condition of completing the process of adaptation of the body to the effect of an external factor is the return of the homeostatic system parameters to their initial levels or their stabilization at a new level. The article considers the state of incomplete adaptation (IA) based on the process of the stabilization of systemic reactions (respiration and blood circulation) on repeated exposure to extreme environmental factors (hypoxia and cold) associated with the excitation of the central regulatory mechanisms of the respiratory center system performing a compensatory–protective function. It is postulated that a change in the afferent information flows (the thresholds of excitation and reactivity of the peripheral receptor systems) forms the basis of IA. The IA state is supposed to persist for an indefinitely long period of time due to insufficient functional reserves and to be the cause of psychosomatic pathology.     

Effects of hypoxia on respiratory defence reflexes. Effects of thirty hours' oxygen deficiency on cough, the expiration reflex and sneezing in awake cats

The authors studied, in 11 awake adult cats, the parameters of the expiration reflex (ER), tracheobronchial (TB) and laryngopharyngeal (LPh) cough, the respiratory rate (f), tidal volume (VT), the end tidal fractional CO2 concentration (FETCO2), the pH, the blood gases and the heart rate during 30 hours' isobaric hypoxic hypoxia (FO2 = 0.11). During the whole 30 hours the cats developed hypocapnic hypoxemia, f remained unchanged and VT was markedly elevated. In the acute phase (15 min) of hypoxic hypoxia of the same intensity, changes in respiratory parameters were the same and the intensity of respiratory reflexes increased significantly (Tatár et al. 1984). During prolonged hypoxic hypoxia there were no statistically significant changes in the intensity of the ER and of TB and LPh cough. The authors assume that some adaptation of the central mechanisms regulating the defence reflexes of the airways took place; this hypothesis is warranted, because an increase in the susceptibility of the cough centre during constant conditions of the stimulation of cough receptors would not be biologically expedient. The different changes in the intensity of respiratory defense reflexes in the acute and the prolonged phase of hypoxic hypoxia in the presence of identical changes in respiratory parameters are further indirect evidence pointing to the existence of functional differences between the respiratory centre and the cough centre.     

Increase of alpha 1-adrenoreactivity of the rat heart in adaptation to periodic hypoxia]

There is a possibility that the cardioprotective effect of adaptation to intermittent hypoxia is due to changes in receptors apparatus of the heart. In this connection the effect of preliminary adaptation to intermittent hypoxia (4 hours per day at the altitude of 4000 m during 40 days) on the state of beta-receptors-adenylate-cyclase system and same other receptors of the heart were studied. It was shown that at the end of the course of adaptation the number of beta-adrenoceptors in the heart was increased with simultaneous decrease in basal adenylate-cyclase activity, accompanied by the diminution of its response to beta-agonist. The number of beta-adrenoceptors was increased by 48% and their affinity to ligand was increased by almost 2 times. The revealed decrease in the reactivity of beta-receptor-adenylate-cyclase system and increase of alpha 1-adrenoreactivity can play a certain role in the mechanism of cardioprotective effect of adaptation to hypoxia.     

NO-dependent mechanisms of adaptation to hypoxia.

In studying NO-dependent mechanisms of resistance to hypoxia, it was shown that (1) acute hypoxia induces NO overproduction in brain and leaves unaffected NO production in liver of rats; (2) adaptation to hypoxia decreases NO production in liver and brain; and (3) adaptation to hypoxia prevents NO overproduction in brain and potentiates NO synthesis in liver in acute hypoxia. Dinitrosyl iron complex (DNIC, 200 microg/kg, single dose, iv), a NO donor, decreases the resistance of animals to acute hypoxia by 30%. Nomega-nitro-L-arginine (L-NNA, 50 mg/kg, single dose, ip), a NO synthase inhibitor, and diethyl dithiocarbamate (DETC, 200 mg/kg, single dose, iv), a NO trap, increases this parameter 1.3 and 2 times, respectively. Adaptation to hypoxia developed against a background of accumulation of heat shock protein HSP70 in liver and brain. A course of DNIC reproduced the antihypoxic effect of adaptation. A course of L-NNA during adaptation hampered both accumulation of HSP70 and development of the antihypoxic effect. Therefore, NO and the NO-dependent activation of HSP70 synthesis play important roles in adaptation to hypoxia.     

The functional state of the sympathoadrenal system and the autonomic regulation of the cardiac rhythm in younger schoolchildren

A comparative analysis of functional states of the sympathoadrenal system (SAS) and its reactions to isometric muscular effort was performed in seven-year-old schoolchildren of both sexes with different types of cardiac regulation. Children with a predominance of sympathetic influences displayed a higher excretion of noradrenaline and a lower excretion of dopamine than their counterparts with normal or vagal tone. A graded isometric exercise changed the functional state of the SAS in a manner dependent on the initial autonomic tone, baseline excretion of catecholamines, and sex. Boys displayed more strained reactions of the SAS than girls did, which was associated with a decrease in its reserve potential, especially pronounced in the states of vagal and normal tones. This suggests imperfect mechanisms of adaptation to static loads.     

Respiratory potential of maize (Zea mays L.) roots exposed to hypoxia

When hypoxia is not too severe, root aerobic metabolism can be partly supported by oxygen delivery via aerenchymateous tissues. In terms of supplying energy, this adaptation is of special importance in plants with a high metabolic demand, such as maize (Zea mays L.). The ability of maize to respond to hypoxia by morphological changes is well documented; however, little is known on the potential for oxidative metabolism in different types of maize roots. In our study, we assessed the root respiratory potential in seminal and adventious nodal roots of maize exposed to mild short-term hypoxia. Plants responded to the treatment with an increased portion of nodal roots per total root length, while there were no changes in the biomass of shoots and roots. Thick nodal roots had much higher respiratory potential (Electron Transport System Activity – ETS) than nodal roots of smaller diameter or seminal roots, irrespective of the aeration rate. The only change in ETS under oxygen deficiency was found for seminal roots where oxygen consumption increased by 25%. Increased root porosity was observed in all roots, the increase was higher in nodal roots. On the basis of ETS data and taking into account changes of root morphology, it can be concluded that large changes of root respiratory potential are not involved in the response of maize to hypoxia. Obviously, maize can cover the respiratory needs with shifts in the growth of different root types which inherently differ in their potential aerobic respiration.     

A redox-silent analogue of tocotrienol inhibits hypoxic adaptation of lung cancer cells

We have previously reported that a redox-silent analogue of α-tocotrienol (T3), 6-O-carboxypropyl-α-tocotrienol (T3E) shows more potential anti-carcinogenic property than T3 in a lung cancer cell (A549 cell). However, the mechanisms by which T3E exerts its potential anti-carcinogenic effect is still unclear. As tumor malignancy is associated with hypoxia adaptation, in this study, we examined whether T3E could suppress survival and invasion in A549 cells under hypoxia. Hypoxia treatment drastically-induced activation of the protein tyrosine kinase, Src, and its regulated signaling required for hypoxia adaptation of A549 tumor cells. The survival and invasion capacity of the tumor cells under hypoxia was suppressed by T3E via the inactivation of Src. More specifically, T3E-dependent inhibition of Src-induced Akt activation contributed to suppression of cell survival under hypoxia, and the reduction of fibrinolytic factors such as plasminogen activator-1(PAI-1) via the decrease of hypoxia-inducible factor-2α by T3E led to inhibition of hypoxic invasion. Overall these results suggest that T3E suppresses hypoxia adaptation of A549 cells by the inhibition in hypoxia-induced activation of Src signaling.     

Regulation of peripheral and systemic blood circulation in rats in conditions of acute nitrite hypoxia

Regulation of the systemic and peripheral hemodynamics in the conditions of acute nitrite hypoxia (doses of NaNO₂ 10, 30, and 50 mg/kg of the body mass) were studied on white male rats. It was shown that NaNO₂ causes a quick dose-dependent decrease in the blood pressure with an intensification of the parasympathetic tonus and development of bradycardia. The hemodynamics was restored as the oxygen capacity of the blood decreased with an increase in the sympathetic tonus and development of tachycardia. The role of intracardial metasympathetic structures and the renin-angiotensin system in cardiovascular adaptation to hypoxia was established. Adaptation to nitrite hypoxia is accomplished by a coordinated interaction of neurogenic and humoral factors. A combination of pharmacological agents, which include separate links of regulator systems of the organism, leads to failure of the adaptation process.