Signaling Role of Mitochondrial Enzymes and Ultrastructure in the Formation of Molecular Mechanisms of Adaptation to Hypoxia

This study was the first comprehensive investigation of the dependence of mitochondrial enzyme response (catalytic subunits of mitochondrial complexes (MC) I-V, including NDUFV2, SDHA, Cyt b, COX1 and ATP5A) and mitochondrial ultrastructure in the rat cerebral cortex (CC) on the severity and duration of in vivo hypoxic exposures. The role of individual animal’s resistance to hypoxia was also studied. The respiratory chain (RC) was shown to respond to changes in environmental [O2] as follows: (a) differential reaction of mitochondrial enzymes, which depends on the severity of the hypoxic exposure and which indicates changes in the content and catalytic properties of mitochondrial enzymes, both during acute and multiple exposures; and (b) ultrastructural changes in mitochondria, which reflect various degrees of mitochondrial energization. Within a specific range of reduced О2 concentrations, activation of the МС II is a compensatory response supporting the RC electron transport function. In this process, MC I develops new kinetic properties, and its function recovers in hypoxia by reprograming the RC substrate site. Therefore, the mitochondrial RC performs as an in vivo molecular oxygen sensor. Substantial differences between responses of rats with high and low resistance to hypoxia were determined.

Features of hypoxic resistance in children with bronchial asthma who have undergone a new coronavirus infection

Aim. To study the characteristics of resistance/sensitivity to normobaric hypoxia in 50 children with bronchial asthma (BA) from 9 to 12 years old, 24 of them after a previous coronavirus infection СOVID-19. Materials and methods. A normobaric hypoxic test (HT) was carried out by creating hypoxemia (threshold level SpO2 80%) during mask inhalation of a gas mixture with 1011% O2 by a child using a ReOxy Cardio apparatus (Ai Mediq S.A., Luxembourg). The data obtained were compared with the results in a group of healthy children the same age. Results. It was found that the integral level of hypoxic resistance of children with BA was generally lower in comparison with the group of healthy children, which was manifested in lower values of the hypoxic index (3.11.4, in the group of healthy children 4.92.8, p=0.005), a significantly increased level of tachycardia and a hypotonic response to dosed hypoxia. Conclusion. When typing reactions to HT, it was found that in children with BA, the type of low resistance to hypoxia is more common (to a greater extent in children with BA after a coronavirus infection), which confirms the need to involve such children in comprehensive rehabilitation programs.

Endotheliumprotectiv and antihypoxic properties of quercetin in elderly patients with metabolic syndrome

Aim: To investigate the effectiveness of course quercetin in improving functional state of the microvascular endothelium and to determine the possibility of using quercetin to increase body resistance to hypoxia in the elderly. Materials and methods. The effectiveness of quercetin in improving the functional state of the endothelium and increasing body resistance to hypoxia was studied in 110 elderly patients with metabolic syndrome, who were divided equally into the main and control groups. Patients in the main group received quercetin at a daily dose of 240 mg for 3 months, and patients in the control group received placebo for the same period. Before and after treatment, the microvascular endothelial function was studied by laser Doppler flowmetry using the post-occlusive hyperemia test. Acute hypoxic test was performed under isocapnicnormobaric hypoxia, during which the followings were recorded: blood saturation (SpO2), heart rate and diastolic blood pressure (BP). Results. In the group of patients receiving quercetin, there was an improvement in blood flow to the skin, as evidenced by a statistically significant increase in the maximum volumetric rate of cutaneous blood flow and the duration of the recovery period of OSHSK to baseline in the post-occlusive hyperaemia. The course of quercetin also led to a less significant decrease in SpO2 during hypoxic test and to a decrease in the absolute values of systolic and diastolic blood pressure, while reducing an increase of the systolic blood pressure on the 20th min of the hypoxic test. Conclusions. In elderly patients with metabolic syndrome (within a 3 month course) the use of quercetin has improved the microvascular endothelium functional status and increased the resistance to hypoxia.

The effect of cranioskeletal trauma complicated by blood loss on the functional state of the liver in the early period of traumatic disease in rats with different resistance to hypoxia and their correction

Introduction. Traumatic events are considered to be one of the current problems in modern urban society. Beyond being the immediate cause of the death of the injured, the development of multiple organ failure syndrome is a perilous complication of severe multiple and combined trauma. An experimental cranioskeletal trauma is known to be accompanied by internal organ dysfunction. Nonetheless, the development of organ dysfunction in terms of hypoxia resistance in the presence of cranioskeletal trauma remains insufficiently studied.The objective of research: to establish the dynamics of the functional state of the liver in the presence of cranioskeletal trauma, complicated by blood loss in rats with different hypoxia resistance in the early period of traumatic disease and evaluate the efficacy of Thiocetam in the correction of identified abnormalities.Material and methods: The experimental studies were conducted on 196 white non-linear male rats weighing 180-200g. Initially, an individual resistance to hypoxia of the rats was estimated, and the animals demonstrated high- and low- resistance value to hypoxia (HR and LR, respectively) were selected for the further study. The HR- and LR-rats were separately divided into 4 groups: control and three experimental once. In the first experimental groups the HR-and LR-animals were induced the cranioskeletal trauma under thiopental sodium anesthesia (40 mg·kg-1); the animals of the second experimental groups were inflicted the acute blood loss of 20-22% of circulating blood volume; in the third experimental groups, the HR and LR animals were subjected to an acute blood loss following the cranioskeletal trauma and administered the intraperitoneal injection of the Thiocetam at a dose of 250 mg·кg-1 of body weight once a day for correction. The bile excretion function of the liver was analyzed in the controls and experimental groups of animals 1, 3 and 7 days after trauma.The results and discussion. The conducted studies indicated the higher rate of bile excretion in the control group of LR-rats compared to the control of HR-rats. The rate of bile excretion was occurred decreased in both HR- and LR-rats under the influence of the cranioskeletal trauma. However, the degree of decrease in the studied parameter of the LR-rats was considerably greater than the corresponding value of the HR-rats. An additional blood loss model resulted in more marked abnormalities, particularly in the experimental group of LR-rats. The 7-day administration of Thiocetam led to the significant decrease in the abnormal bile excretion rate in the experimental groups of HR- and LR-rats compared to the animals without corrective medication. The analysis of deviation degree of the studied parameter in the animals administered Thiocetam in relation to the animals without correction evidenced better efficacy of the medication in the experimental group consisted of LR-rats compared to the group of HR-rats, especially under the conditions of additional acute blood loss model. Consequently, Thiocetam is able to compensate less-developed defense mechanisms of LR-rats compared to the HR-rats, which should be taken into consideration in real-life clinical practice settings in the comprehensive treatment of the injured with cranioskeletal trauma complicated by blood loss considering the possibility to determine their resistance to hypoxia.Conclusions. The rate of bile excretion as a basic indicator of the functional state of the liver in the intact LR-rats is found to be substantially higher than in HR-rats. The degree of decrease in the rate of bile excretion is significantly greater in LR-rats after 7 days of the post-traumatic period under the influence of cranioskeletal trauma complicated by acute blood loss. The administration of Thiocetam is accompanied by a marked positive effect on the rate of bile excretion in the HR- and LR-rats, but the degree of increase in the studied parameter is considerably greater in the experimental group of LR-rats.

The effect of free radical stress correction on corticoid signaling in the kidney of rat with different resistance to hypoxia after systemic circulation arrest

Aim. To assess the influence of the pathogenetic action of the succinate-containing drug on corticosteroid regulation in the kidney of rats with different resistance to hypoxia during recovery after systemic circulation arrest. Methods. The object of the study was male non-inbred white rats weighing 200220 g. A week after testing for resistance to hypoxia, a 5-minute systemic circulation arrest was simulated by intrathoracic clamping of the vascular bundle of the heart, followed by resuscitation. In the postresuscitation period, the experimental rats were once daily injected with a solution containing inosine + nicotinamide + riboflavin + succinic acid, and the control rats 0.9% Sodium Chloride solution. The observation period was 35 days. We studied the content of corticosterone, aldosterone in blood plasma, gluco- and mineralocorticoid receptors, carbonylated proteins, dityrosine, and products that react with thiobarbituric acid in homogenates of the kidneys. Statistical data were presented as mean and standard deviation M. Nonparametric KruskalWallis (N) and MannWhitney (U) tests followed by Dunn test, Spearman correlation analysis were used. Differences were considered statistically significant at p 0.05. Results. The use of succinate-containing preparation reduced the intensity of free radical processes in both groups of animals. Against this background, in low-resistance rats, on the 1st day, the concentration of glucocorticoid receptors statistically significantly increased to 117% (p 0.05), and then was comparable to the control; the greatest statistically significant changes in the level of mineralocorticoid receptors occurred on the 1st day (increase by 25%, p 0.001) and at 2135th days (decrease by 2230%, p 0.001). In highly resistant rats, the correction led to a shift in the maximum content of glucocorticoid receptors from the last day (134% of the control level, p 0.01 without therapy) to the 1st (123%, p 0.05 with succinate-containing therapy) and maintaining the receptors level comparable to the initial, in the future. The level of mineralocorticoid receptors in highly resistant rats was lower than in low resistant rats, both in the group without correction and with correction. Conclusion. Correction of the course of the postresuscitation period with a succinate-containing drug in animals with a low resistance to hypoxia against the background of a decrease in the intensity of carbonyl stress and restoration of feedback mechanisms causes stabilization of glucocorticoid receptors level and a decrease in mineralocorticoid receptors to control values by the end of the experiment; in organisms highly resistant to hypoxia, against the background of correction, the activity of lipid peroxidation decreases and the level of both types of receptors are restored.

Influence of cranioskeltal trauma, complicated with blood loss, on the bile-forming function of liver during the early period of traumatic disease among rats with different resistance to hypoxia and its correction

Introduction. The development of multiorgan dysfunction and insufficiency is one of the serious complications of severe multiple and combined lesions. In their pathogenesis, a key role is played by secondary lesions of organs remote from the site of direct injury, which is caused by the systemic response of the body to inflammation and is a characteristic feature of traumatic disease. As a model of the development of organ damage in experimental polytrauma, the biliary function of liver is often investigated. However, the features of systemic disorders, in particular, the biliary function of liver, in conditions of severe skeletal injury, depending on the resistance to hypoxia, have not been studied enough.Purpose: to determine the dynamics of biliary function of liver in case of cranioskeletal trauma complicated with blood loss among rats with different resistance to hypoxia during the early period of traumatic disease and to evaluate the effectiveness of thiocetam in the correction of identified disorders.Materials and methods. 108 nonlinear white male rats weighing 180-200 g were used in the experiments. Previously, individual resistance to hypoxia was determined, rats were divided into two groups: with high- and low-resistance (HR and LR) animals to hypoxia. Subsequently, HR and LR rats were divided into 4 groups: one control and three experimental. Under conditions of thiopentale sodium anesthesia (40 mg kg-1) the first experimental group HR and LR of rats was had cranioskeletal trauma, the second - acute blood loss in the amount of 20-22% of circulating blood volume, the third experimental group after application of cranioskeletal injuries and acute blood loss in order to correct HR and LR-rats were thrown Thiocetam intraperitoneally, dose 250 mg kg-1 of body weight 1 time per day. Animals of the control and experimental groups in 1, 3 and 7 days after injury were catheterized the common bile duct, collected bile, in which the content of total bile acids was determined.It was found out that laboratory white rats, which are genetically different in resistance to hypoxia, also differ in the intensity of biliary function of liver. Among HR rats, the bile content of total bile acids was higher than that among LR rats. Under the influence of cranioskeletal injury, the bile content of total bile acids decreased among both HR and LR rats. Despite the lower initial content of total bile acids in the bile of LR rats, under the influence of cranioskeletal trauma in this group, the degree of the studied indicator reduction was significantly greater than among HR rats, indicating greater sensitivity of LR rats to pathogens of traumatic disease, which lead to damage to the microsomal monooxygenase system of hepatocytes. Under the conditions of acute blood loss additional modeling, the disorders were more visible, but the result was statistically significant only among LR rats in 3 days of the experiment. In addition, LR rats had a greater degree of reduction of the studied indicator in 3 and 7 days of the experiment. Under the influence of seven-day-usage of Thiocetam in the groups of LR and HR rats with cranioskeletal trauma, the violation of total bile acids content in the bile became significantly lower compared to animals without correction. A similar result was found under conditions of additional acute blood loss. Under these conditions, the degree of increase of total bile acids content in the bile was greater among LR rats than among HR rats, which indicates a higher efficiency of Thiocetam among LR rats.Conclusions: 1. The content of total bile acids in the bile among intact HR-rats is significantly higher than among LR-rats. Under the influence of cranioskeletal trauma, the content of total bile acids in the bile is reduced compared to the control, but the degree of reduction is significantly greater among LR rats after 7 days of the experiment. Complication of cranioskeletal injury with acute blood loss causes a significantly greater reduction in the bile content of total bile acids among LR rats compared with HR rats after 3 and 7 days of the experiment. The use of Thiocetam is accompanied by a decrease of liver biliary dysfunction, which is more visible among LR rats with acute blood loss.

FEATURES OF RESISTANCE TO HYPOXIA IN ELDERLY PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

FEATURES OF RESISTANCE TO HYPOXIA IN ELDERLY PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE E. O. Asanov, Yu. I. Golubova, I. A. Dyba, S. O. Asanova Abstract Aim: to study the features of resistance to hypoxia in elderly patients with COPD. Material and methods. We examined 46 elderly patients with COPD and 18 apparently healthy elderly people. Hypoxia resistance was determined by performing a hypoxic test with inhalation of 12 % O2 for 20 minutes. The state of ventilation and blood saturation were assessed. Results. Hypoxia caused the reduction of SpO2 and the development of arterial hypoxemia in elderly patients with COPD, which were more significant than in healthy elderly people. It was found that among elderly patients with COPD and healthy elderly subjects there were people with preserved and reduced resistance to hypoxia. However, reduced resistance to hypoxia was much more common in elderly patients with COPD. Decreased resistance to hypoxia in elderly patients with COPD was associated with the degree of bronchial obstruction: deterioration of bronchial passability led to reduced resistance to hypoxia. Elderly patients with COPD with reduced resistance to hypoxia had a decrease in the ΔVE/ ΔSpO2 ratio and a slow ventilation response to hypoxic exposure. Conclusions. Among healthy elderly people and elderly patients with COPD there were subjects with reduced and preserved resistance to hypoxia. Decreased resistance to hypoxia was much more common in elderly patients with COPD. Decreased resistance to hypoxia was more common in patients with moderate than mild bronchial obstruction. Elderly patients with COPD with reduced resistance to hypoxia had reduced ventilation response to hypoxia and chemoreflex sensitivity. Key words: COPD, older age, resistance to hypoxia, ventilation, saturation. Ukr. Pulmonol. J. 2021;29(3):36–40:

Bronchial obstruction and resistance to hypoxia in elderly patients with COPD

Background. Age-related morphofunctional changes in the body lead to the development of arterial hypoxemia, tissue hypoxia and hypoxic changes. All this causes a decrease in the body’s resistance to hypoxia and contributes to the development of lung diseases, in particular, chronic obstructive pulmonary disease (COPD) in the elderly. With the development of COPD in the elderly due to bronchial obstruction and disorders of pulmonary gas exchange, age-related hypoxic shifts, arterial hypoxemia, tissue hypoxia and resistance to hypoxia are further reduced. However, the relationship between bronchial obstruction and resistance to hypoxia in elderly patients with COPD has not been studied. Objective. To identify the relationship between bronchial patency and resistance to hypoxia in elderly patients with COPD. Materials and methods. The study included 30 patients with COPD in the elderly (60-74 years), I-II stage, without exacerbation, with a disease duration of 7 to 26 years, risk groups A and B. The type and severity of pulmonary ventilation were assessed indicators of spirometry and the curve “flow/volume” of forced exhalation on the device Spirobank (Mir, Italy). To determine the body’s resistance to hypoxia, a hypoxic test with 12 % oxygen content was performed for 12 min with monitoring of blood saturation using the automated software and hardware complex Hypotron (Ukraine). Results. Researches have shown that under hypoxic exposure, blood saturation in elderly patients with COPD is reduced, on average, by 18.23±0.26 %. This decrease in blood saturation can be regarded as severe arterial hypoxemia. At the same time, in elderly patients with COPD with an increase in bronchial patency disorders, the saturation shifts in hypoxia, on average, also increase. There was a significant correlation (r=0.50; p=0.006) of blood saturation shifts in hypoxia with bronchial obstruction. Conclusions. In elderly patients with COPD, resistance to hypoxia is determined by bronchial obstruction.

CARDIORESPIRATORY SYSTEM AND ANTIHYPOXIC RESISTANCE STATE IN ELDER CORONARY HEART DISEASE PATIENTS

The aim of the study. Evaluation of cardiorespiratory system and microcirculation state in elder CHD patients with different resistance against hypoxia. Methods. The author has carried out a retrospective analysis of 103 CHD 60+-patients, their deaths have occurred due to cardiovascular events. Two patient groups have been formed including patients (68 persons) having kept their resistance to hypoxia (their blood SO2 level was never below 80 %) and patients (35 ones) with decreased resistance to hypoxia, their blood SO2 level having been dropped below 80 %. Results: The life span of patients with decreased hypoxia resistance is lower comparing to ones having kept such resistance. The patients with decreased hypoxia resistance demonstrate decreased ejection fraction, increased mass of left ventricle myocardium as well as increased left ventricle volumes. Such patients show also significant increase of mean daily values of systolic, diastolic, and mean arterial pressure. Generally, the micro-circulation state in patients with decreased anti-hypoxic resistance is lower comparing to persons having kept this resistance. Simultaneously, the endothelial function of persons with decreased anti-hypoxic resistance is significantly worse. The pulmonary ventilation system patency and bronchial patency in these persons are also lowered comparing to these indices in patients with kept anti-hypoxic resistance. Conclusions: The decrease of anti-hypoxic resistance leads to the shorter life span on elderly CHD patients. Such decreased resistance is accompanied by worsened potency of cardio-respiratory system, microcirculation, and endothelial system functioning.