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Stenosis and occlusion of the common carotid artery (CCA) are one of the main reasons of cerebrovascular pathologies; these factors determine the development of hypoperfusion of the brain. Disorders in the expression of lysyl oxidase (LOX) underlie the development of a number of pathological processes, including vascular and cerebral pathologies. Changes in the activity of this enzyme are assumed to significantly affect the functional state of the mitochondria (MCh). We examined the role of LOX in the regulation of energy metabolism in the rat brain under conditions of experimental unilateral chronic occlusion of the CCA (CCA ChO). Experiments were carried out on Wistar rats with ligated left CCA. Animals of one of the experimental groups received drinking water with 0.2% of a LOX blocker, β-aminopropionitrile (BAPN) during 8 weeks. After such course of BAPN introduction, we estimated the characteristics of energy metabolism in the MCh from tissues of the brain hemispheres using a polarographic technique. Occlusion of the CCA was accompanied by disorders in tissue respiration (oxidative phosphorylation in the MCh); these changes were more expressed in the left hemisphere (P < 0.05), but those in the right one were also quite noticeable. There were indications for the existence of interhemisphere differences in the functioning of the MCh complex 1 in healthy control animals; the respective values were greater in the left hemisphere. Introduction of BAPN promoted partial recovery of the MCh functions; this was manifested in some weakening of the effects of CCA occlusion. Thus, under conditions of unilateral CCA ChO, energy metabolism in both brain hemispheres undergoes negative changes. Changes in the LOX activity are one of the factors responsible for negative shifts in the indices of MCh functioning related to hypoperfusion of brain tissues.

In experiments on Wistar rats, the role of the state of GABAA receptors in the formation of respiratory responses to hypoxic loading was studied under conditions of the norm and experimental mitochondrial dysfunction; the latter was induced by single systemic injections of 3 mg/kg rotenone, a nonselective blocker of complex I in the respiratory chain of the mitochondria. Volume-time parameters of respiration were characterized according to the parameters of respiratory EMG discharges of the diaphragmatic muscle (amplitude, frequency, and integral intensity). Changes in EMG activity of the diaphragm induced by inhalation of a hypoxic gas mixture (12% О2 + 88% N2) were estimated prior to and after injections of the blocker of GABAA and GABAB receptors bicuculline (bicuculline methiodide, 1.0 mg/kg) in control rats and animals with mitochondrial dysfunction. The development of mitochondrial dysfunction was accompanied by suppression of the respiratory reaction to hypoxic loading, which was manifested in a dramatic decrease in the frequency and integral intensity of EMG discharges of the diaphragmatic muscle. These data can be considered an indication of the considerable involvement of GABAA receptors localized at the postsynaptic membranes of peripheral chemoreceptors in the formation of respiratory response to hypoxic stimulation (including the stage of depression of ventilation); this was observed in both control rats and animals with mitochondrial dysfunction. The involvement of a GABA-ergic link in the formation of respiratory activity related to hypoxic stimulation acquires special significance under conditions of experimental mitochondrial dysfunction leading to occlusion of afferent impulsation coming from peripheral chemoreceptors.

This paper reviews the published data of modern studies, which allow one to summarize the accumulated knowledge on the molecular mechanisms underlying the development of some neurodegenerative diseases and the role of disorders of these mechanisms in the pathogenesis of diseases directly related to the impairments of mitochondrial functions.

In experiments on Wistar rats, we studied the role of glutamatergic NMDA-receptor neuronal systems in the mechanisms underlying the control of respiration under conditions of aging- or rotenone-induced deviations of energy metabolism in brainstem neurons. Volume/temporal parameters of breathing were estimated by the characteristics of integrated diaphragmatic EMG activity (amplitude, frequency of volleys, and integral intensity). Changes in the diaphragmatic EMG activity upon hypoxic loading (breathing a 12 % О2-containing gas mixture) were recorded prior to and after injection of the blocker of NMDA receptors МK-801. The obtained data indicate that regulation of the characteristics of respiratory activity formed at the level of brainstem structures can be determined by the mitochondrial energy status in brainstem neurons. It seems possible that such control of the respiratory activity is mediated by ATP-dependent activation of the enzymes responsible for transformation/catabolism of the main neurotransmitters, glutamate and its derivative GABA.

Using a polarographic technique, we studied the peculiarities of energy metabolism in neurons of the rat brainstem structures related to normal physiological aging. Experiments were carried out under in vitro conditions on mitochondrial (MCh) suspensions prepared from the brainstem cells of young and old rats. In addition, we examined, using the same technique, the parameters of oxidative phosphorylation in analogous MCh suspension under conditions of experimental MCh dysfunction induced by single systemic injection of rotenone into young animals. In the case where we used a succinate + rotenone mixture as the substrate for oxidation, the intensity of ADP-stimulated respiration (V3) in preparations from brainstem neurons of old animals was significantly smaller (against the background of a decrease in the efficacy of respiration control, V3/V4). If a mixture glutamate + malate was used as the substrate for oxidation, the V3 and the efficacy of phosphorylation (ADP/O) decreased significantly. The experimental MCh dysfunction resulted in the lowering of practically all parameters of oxidation and phosphorylation under conditions of oxidation of glutamate + malate, as well as V3, V3/V4, and ADP/O, in the case where we used succinate + rotenone as the substrate for oxidation. Less expressed changes in the recorded indices upon oxidation of succinate + rotenone were indicative of activation of the succinate oxidase pathway; this preserved the electrotransport function of the respiratory chain in the MCh on a certain level and the ability of the latter to provide oxidative phosphorylation.

This review deals with modern concepts on the mechanisms of involvement of main central excitatory and inhibitory neurotransmitters, glutamate and GABA, in the control of the respiratory function.

We studied the content of mRNA of a glycoprotein, erythropoietin, in structures of the rat brainstem; the animals were adapted to intermittent hypoxia at different contents of oxygen in hypoxic gas mixtures (12 or 7% О2, a 2-week-long course with five sessions per day). Under conditions of such adaptation, the content of erythropoietin in the brainstem demonstrated a clear trend toward a decrease after a course of moderate hypoxic trainings (12% О2), and a more than twofold drop after a “stronger” course (7% О2). We suppose that the decrease in the intensity of synthesis of this glycoprotein

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.

Results of a comparative study of the sensitivity of the system of respiratory control to increases in the CO2 concentration and the intensity of free-radical processes in young and elderly subjects are described. It is shown that normal (natural) aging is accompanied by a decrease in the sensitivity of the respiratory system to hypercapnic stimulation and a parallel significant decrease in the activity of catalase in the blood of examined subjects. Mechanisms responsible for the modifications of the sensitivity of the system of respiratory control to hypercapnia are discussed; these shifts can be at least partly related to changes in the intensity of production of free radicals observed in elderly subjects.

Data on changes in the function of external respiration induced by Parkinson’s disease (idiopathic Parkinsonism) obtained by various research groups (including results of the author’s own studies) are compared. Probable neurochemical and other mechanisms that influence the system controlling respiratory activity and parameters of lung ventilation are discussed.

In this review, modern concepts on molecular mechanisms underlying reception of the oxygen level in natural O2-sensory structures and cellular in vitro models are considered and discussed.

We describe the results of a study of the relations between the control of the respiratory function in isocapnic increasing hypoxia and the intensity of free-radical processes in groups of healthy young and aged subjects. It is known that aging is accompanied by some weakening of the response of the respiratory system to hypoxia with no considerable changes in the indices of ventilation in the resting state. Aged subjects, as compared with young tested persons, are characterized by a decrease in the activity of catalase, the absence of significant differences in the activity of superoxide dismutase, and a trend toward an increase in the content of products of lipid peroxidation in the blood. We discuss possible mechanisms mediating age-related modifications in the system of control of respiration and consider shifts in the system of pro/antioxidant balance and intensification of peroxidation processes against the background of a decreased activity of catalase primary changes responsible for the above modifications. These effects lead to modifications of the sensitivity of chemoreceptors responding to a drop in O2 tension in the blood.

Based on the published data, the authors analyze in detail events resulting in the death of neurons in the substantia nigra (according to the apoptosis scenario) and in the development of Parkinson's disease (idiopathic parkinsonism).

A study of the functioning of the respiratory system and sympathoadrenal system (SAS) after adaptation to intermittent hypoxia in humans of different ages is described. Considering our own findings and published data, the author discusses the possible mechanisms mediating modifications of the respiratory function and regulating the SAS activity during adaptation to hypoxia. A key role of the carotid glomuses in the modulation of the functional parameters of external respiration and SAS under conditions of hypoxic adaptation is emphasized.

Adaptation to intermittent hypoxia can enhance a hypoxic ventilatory response (HVR) in healthy humans. Naturally occurring oscillations in blood dopamine (DA) level may modulate these responses. We have measured ventilatory response to hypoxia relative to blood DA concentration and its precursor DOPA before and after a 2-week course of intermittent hypoxic training (IHT). Eighteen healthy male subjects (mean 22.8 ± 2.1 years old) participated in the study. HVRs to isocapnic, progressive, hypoxic rebreathing were recorded and analyzed using piecewise linear approximation. Rebreathing lasted for 5-6 min until inspired O2 reached 8 to 7%. IHT consisted of three identical daily rebreathing sessions separated by 5-min breaks for 14 consecutive days. Before and after the 2-week course of IHT, blood was sampled from the antecubital vein to measure DA and DOPA content. The investigation associated pretraining high blood DA and DOPA values with low HVR (r = -0.66 and -0.75, respectively), elevated tidal volume (r = 0.58 and 0.37) and vital capacity (r = 0.69 and 0.58), and reduced respiratory frequency (r = -0.89 and -0.82). IHT produced no significant change in ventilatory responses to mild hypoxic challenge (PetO2 from 110 to 70-80 mmHg; 1 mmHg = 133.3 Pa) but elicited a 96% increase in ventilatory response to severe hypoxia (from 70-80 to 45 mmHg). Changes in HVRs were not accompanied by statistically significant shifts in blood DA content (24% change), although a twofold increase in DOPA concentration was observed. Individual subject's changes in DA and DOPA content were not correlated with HVR changes when these two parameters were evaluated in relation to the IHT. We hypothesize that DA flowing to the carotid body through the blood may provoke DA autoreceptor-mediated inhibition of endogenous DA synthesis-release, as shown in our baseline data.Key words: hypoxic ventilatory response, dopamine, intermittent hypoxia.

Under clinical conditions, we studied the interaction between dopamine (DA) metabolism and hypoxia stimulationrelated ventilatory responses (HVR) before and after adaptation to periodical hypoxic episodes. Thirty-seven young and elder persons were tested; among elder tested subjects there were patients with Parkinson’s desease treated or not treated with DOPA-DA precursor-containing drugs (levoDOPA/carbiDOPA). We measured the HVR indices and DA and DOPA contents in the venous blood of tested persons before and after a 14-day-long hypoxic training. The highest indices of the ventilation sensitivity to hypoxia together with the lowest above-mentioned chemical indices were observed in young persons. An increase in the DA and DOPA levels in the venous blood were observed concurrently with suppression of the ventilation responses to hypoxic episodes. After a course of periodical hypoxic sessions, we observed in all groups opposite dynamics of DA and DOPA metabolism. An increase in the DA level in young persons and a trend toward its decrease in older healthy persons and parkinsonian patients was nevertheles accompanied by an HVR increase in all groups. Possible relations between the DA metabolism indices and peripheral mechanisms of respiratory control are discussed.

The data obtained during a rather long period of time and reported in the literature suggest that dopamine plays an independent role in the organism, being involved in regulation of the most important functions. The question about the place of dopamine in reception of the oxygen level in the peripheral and central mechanisms that regulate respiration needs further investigation. This question possibly is tightly related to the different sensitivity of various groups and subgroups of dopamine receptors, their spatial distribution and their ability to change their affinity for ligands depending on the environment. This determines a dose-dependent pattern of the effects of dopamine receptor activation and strong dependence of the effects on other experimental conditions.

Background: Short-term exposure to high-altitude hypoxia increases hypoxic ventilatory sensitivity (HVS) in healthy humans. Dopamine (DA) is the implicated neurotransmitter in carotid body (CB) chemoreceptor response, and the microenvironmental conditions in CB tissue are comparable to blood. Continuous DA infusion affected ventilation in animals and humans. Age-related oscillations in blood DA levels may influence peripheral chemoreflexes. Objective: Hypoxic ventilatory responses (HVR) relative to blood DA concentration and its precursor, dihydroxyphenylalanine (DOPA) was measured in young and elderly men during short-term altitude adaptation. Methods: Nine elderly climbers (group 1: 61 ± 1.4 years) and 7 young healthy subjects (group 2: 23 ± 2 years) were tested at sea level on day 0, on day 3 after passive transport to 2,200 m, and on day 14 after climbing to 4,200 and 5,642 m. Results: Sea level HVR in group 1 was 47% lower than in group 2, accompanied by higher blood DOPA (300%) and DA (37%) content. Initial DA and DOPA concentrations showed a negative correlation with initial HVR but a positive correlation with age. Passive transport to middle altitude (2,200 m) increased HVS, doubling HVR slopes in groups 1 and 2 and producing increased maximum expired minute ventilation during isocapnic rebreathing (29 and 28%, respectively). Day 3 2,200-meter blood DOPA content decreased by 22% in group 1 and increased by 300% in group 2. DA increased in both groups. Conclusion: The relationship between HVR and the reciprocal DA and DOPA values seen in both groups is associated with age, producing decreased DA receptor sensitivity and enhanced DA reuptake during adaptation to high altitude.