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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.

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

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.

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.

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.

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.