Disorders of cerebral circulation are a leading cause of neurological morbidity, disability and death. However, there is currently no promising drug therapy or prevention for these disorders. Non-pharmaceutical therapies might provide new opportunities for protection of brain from hypoxia and ischemia induced by tissue hypoperfusion. Intermittent hypoxic conditioning (IHC) has been studied as a potential therapy. Experimental studies showed that IHC was neuroprotective in hemorrhagic stroke induced by epileptiform seizure and reduced the size of infarct, inflammation, and increased blood-brain barrier permeability after transient middle cerebral artery occlusion. In experimental Alzheimer’s disease (AD), which is considered “a cerebrovascular disorder with neurodegenerative consequences”, IHC exerted pronounced beneficial effects on cerebral circulation. In rats with experimental AD, IHC almost completely prevented endothelial dysfunction of both cerebral and extracerebral blood vessels, rarefaction of brain vascular net and the loss of neurons in the brain cortex. Due to these protective effects, IHC eventually prevented the impairment of memory and development of experimental AD. In spontaneously hypertensive rats, IHC also prevented rarefaction of arterioles and capillaries in brain, which is, interestingly, considered a possible mechanism for the antihypertensive effect of IHC. Despite promising preclinical data, the translation of preclinical hypoxic/ischemic conditioning protocols to a clinical application has been difficult, and clinical studies using this non-pharmacological approach are still scarce. In healthy human subjects, repetitive normobaric IHC significantly diminished variations of ce- rebral perfusion in response to hypercapnia and hypocapnia without compromising cerebral tissue oxygena- tion. This mechanism may be protective in sleep apnea. Paradoxically, elderly people with moderate sleep ap- nea have a survival advantage. Perhaps apneas during sleep may activate adaptive pathways in the elderly. IHC was successfully used for treatment of encephalopathy due to improvement of oxidative homeostasis. Several clinical studies have used repetitive bilateral arm ischemic preconditioning, which reduced stroke recurrence in patients with intracranial arterial stenosis. The ability of the brain to produce an endogenous response to a conditioning stimulus that leads to subsequent protection against future injury has been observed in clinical settings. Patients with previous spontaneous, transient ischemic attacks before cerebral infarction had a more favorable outcome than those without such previous attacks. Deleterious effects of hypoxia are strikingly pronounced during prenatal development and asphyxia at birth resulting in anomalous brain development, schi zophrenia, cerebral palsy, and mental retardation. On the other hand, it appears that moderate IHC in early life accelerates brain development, leading to greater learning and memory capacity. IHC-increased learning capacity is associated with increased brain DNA concentrations, increased neurogenesis, and expression of proteins involved in synaptic plasticity. IHC treatment of mothers at risk of eclampsia resulted in more su- ccessful delivery, less frequent occurrence of nephropathy, fetal hypoxia, premature labor, and better physical condition of newborns. More translational research is needed to more completely utilize beneficial effects of IHC on cerebral circulation.

Previously we have shown that adaptation to hypoxia (AH) is cardio- and vasoprotective in myocardial ischemic and reperfusion injury and this protection is associated with restriction of nitrosative stress. The present study was focused on further elucidation of NO-dependent mechanisms of AH by identifying specific NO synthases (NOS) that could play the major role in AH protection. AH was performed in a normobaric hypoxic chamber by breathing hypoxic gas mixture (9.5-10% O2) for 5-10 min with intervening 4 min normoxia (5-8 cycles daily for 21 days). Expression of neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) protein was measured in the left ventricular myocardium using Western blot analysis with respective antibodies. AH educed iNOS protein expression by 71% (p < 0.05) whereas eNOS protein expression tended to be reduced by 41% compared to control (p < 0.05). nNOS protein expression remained unchanged after AH. Selective iNOS inhibition can mimic the AH-induced protection. Therefore protective effects of AH could be at least partially due to restriction of iNOS and, probably, eNOS expression.

Адаптация к факторам среды, таким как холод, физические нагрузки, гипоксия в горах, высокие температуры, дозированный стресс и т.д., эмпирически использовалась для повышения резистентности организма к повреждающим факторам задолго до начала систематических исследований ее защитных эффектов и механизмов. После открытия Ф.З.Меерсоном перекрестных защитных эффектов адаптации особое внимание привлекла адаптация к периодической гипоксии (АПГ), обладавшая наибольшим количеством таких эффектов. Адаптация к гипо - и нормобарической гипоксии в настоящее время особенно успешно применяется в клинике для профилактики и лечения сердечно-сосудистых заболеваний и модификации факторов риска. В частности, АПГ устойчиво уменьшает ишемические и неишемические аритмии, улучшает липидный профиль у пациентов с гиперхолестеринемией и повышает толерантность к физическим нагрузкам. У пациентов улучшается субъективное самочувствие и уменьшается количество и продолжительность эпизодов депрессии сегмента ST . В ряде клинических исследований было показано, что АПГ способствует потере массы тела у пациентов с ожирением. Важным терапевтическим эффектом АПГ является ее антигипертензивный эффект, который вначале казался неожиданным в свете хорошо известных данных о том, что периодическая гипоксия, сопровождающая апноэ во сне, напротив, способствует повышению артериального давления. Однако к настоящему времени уже убедительно доказано, что главными детерминантами направленности эффекта периодической гипоксии являются ее интенсивность и продолжительность, и поэтому в зависимости от режима периодической гипоксии ее эффекты могут быть прямо противоположными. Недавние исследования показали, что не только АПГ, но и адаптация к ишемии миокарда обладает выраженным кардиопротекторным эффектом и способствует повышению толерантности к физическим нагрузкам у кардиологических пациентов. Экспериментальные исследования на животных позволили выявить основные механизмы кардиопротекторных эффектов АПГ, среди которых ключевыми являются активация антиоксидантной защиты за счет периодической умеренной активации свободнорадикальных процессов, повышение эффективности энергопродукции в клетках, ограничение Са-перегрузки, предупреждение дисфункции эндотелия коронарных и некоронарных сосудов за счет активации синтеза и депонирования оксида азота, усиление экспрессии белков теплового шока и увеличение плотности микрососудистой сети в скелетных мышцах, головном мозге и миокарде. Таким образом, АПГ является перспективным нефармакологическим средством, которое может использоваться у кардиологических пациентов в качестве дополнения к лекарственной терапии, а в некоторых случаях, возможно, и самостоятельно.

Нарушения мозгового кровообращения являются ведущей причиной неврологической заболеваемости, инвалидизации и смертности. Однако в настоящее время эффективной лекарственной терапии и профилактики этих нарушений не существует. Новые возможности защиты мозга от гипоксии и ишемии, обусловленной гипоперфузией мозговой ткани, могут открыть нефармакологические методы лечения. В качестве одной из таких возможностей изучается адаптация к периодической гипоксии (АПГ). Экспериментальные исследования показали, что АПГ обладает нейропротекторным действием при геморрагическом инсульте, вызванном эпилептиформными судорогами, а также уменьшает размер инфаркта мозга, ограничивает воспаление и повышает проницаемость гематоэнцефалического барьера после транзиторной окклюзии средней мозговой артерии. АПГ оказывает выраженное благоприятное действие на мозговое кровообращение при экспериментальной болезни Альцгеймера (БА), которая рассматривается как «цереброваскулярное расстройство с нейродегенеративными последствиями». У крыс с экспериментальной БА АПГ почти полностью предупреждала дисфункцию эндотелия церебральных и внецеребральных сосудов, изреживание сосудистой сети и утрату нейронов в коре мозга. Благодаря этим защитным эффектам АПГ в конечном счете предупреждала нарушения памяти и развитие экспериментальной БА у животных. У крыс со спонтанной гипертензией АПГ также предупреждала изреживание артериол и капилляров в мозге, что рассматривается как один из возможных механизмов антигипертензивного эффекта АПГ. Несмотря на многообещающие доклинические данные, переход от экспериментальных протоколов адаптации к гипоксии/ишемии к клиническому применению труден, клинические исследования с использованием этого нефармакологического подхода все еще немногочисленны. Тем не менее на здоровых добровольцах показано, что повторная нормобарическая гипоксия значительно уменьшает изменения перфузии мозга, возникающие в ответ на гипер - и гипокапнию, не нарушая при этом оксигенации мозговой ткани. Этот механизм может оказаться протективным при апноэ сна. Парадоксальным образом обнаружилось, что пожилые люди, страдающие умеренным апноэ сна, обладают преимуществом по продолжительности жизни. Возможно, апноэ сна способно активировать адаптивные механизмы в пожилом возрасте. АПГ успешно применялась для лечения энцефалопатии благодаря улучшению окислительного гомеостаза. В нескольких клинических исследованиях использовалось повторное билатеральное ишемическое преконционирование рук, что снижало частоту рецидивов инсульта у пациентов со стенозом внутричерепных артерий. В клинических условиях отмечалась способность мозга формировать реакцию на адаптирующий стимул, которая обеспечивает защиту от последующих повреждений. Исходы инфаркта мозга были более благоприятными у пациентов, ранее перенесших спонтанные транзиторные ишемические атаки, чем у пациентов без предшествующих атак. Повреждающие эффекты гипоксии особенно ярко выражены при эмбриональном развитии и асфиксии у новорожденных, приводя к аномалиям развития мозга, шизофрении, корковому параличу и задержке умственного развития. С другой стороны, оказалось, что умеренная АПГ в ранний период жизни ускоряет развитие мозга и улучшает функции обучения и запоминания, что связывают с увеличением концентраций ДНК в мозге, стимулированием нейрогенеза и экспрессии белков, вовлеченных в синаптическую пластичность. АПГ беременных женщин в группе риска эклампсии приводит к более успешным родам, снижению частоты нефропатии, гипоксии плода, преждевременных родов и улучшает физическое состояние новорожденных. Для более эффективного использования благоприятного действия АПГ на мозговое кровообращение требуется проведение новых трансляционных исследований.

Adaptation to hypoxia is known to be cardioprotective in ischemic and reperfusion (IR) injury of the myocardium. This study was focused on investigating a possibility for prevention of endothelial dysfunction in IR injury of the rat heart using adaptation to intermittent hypoxia, which was performed in a cyclic mode (5-10 min of hypoxia interspersed with 4 min of normoxia, 5-8 cycles daily) for 21 days. Endothelial function of coronary blood vessels was evaluated after the in vitro IR of isolated heart (15 min of ischemia and 10 min of reperfusion) by the increment of coronary flow rate in response to acetylcholine. Endothelium-dependent relaxation of isolated rat aorta was evaluated after the IR myocardial injury in situ (30 min of ischemia and 60 min of reperfusion) by a relaxation response of noradrenaline-precontracted vessel rings to acetylcholine. The following major results were obtained in this study: 1) IR myocardial injury induced endothelial dysfunction of coronary blood vessels and the aorta, a non-coronary blood vessel, remote from the IR injury area; and 2) adaptation to hypoxia prevented the endothelial dysfunction of both coronary and non-coronary blood vessels associated with the IR injury. Therefore, adaptation to hypoxia is not only cardioprotective but also vasoprotective in myocardial IR injury.

Adaptation to intermittent normobaric hypoxia is cardioprotective and can stimulate nitric oxide (NO) synthesis. However the role of nitric oxide (NO) in prevention of ischemia-reperfusion (IR) injury of myocardium is controversial. This study was focused on evaluating the effect of adaptation to hypoxia and IR on NO production and development of nitrative stress in the myocardium. Adaptation to hypoxia tended to increase NO production, which was determined by the total level of plasma nitrite and nitrate, and prevented IR-induced NO overproduction. The IR-induced NO overproduction was associated with significant 3-nitrotyrosine (3-NT) accumulation in the left ventricle but not in septum or aorta. In hypoxia-adapted rats, 3-NT after IR was similar to that of control rats without IR. IHC induced marked accumulation of HIF-1alpha in the left ventricle. We suggest that HIF-1alpha contributes to NO-synthase expression during adaptation to hypoxia and thereby facilitates the increase in NO production. NO, in turn, may subsequently prevent NO overproduction during IR by a negative feedback mechanism.

The aim of study was to investigate the effect of hypoxia on the macrophage phenotype and phenotypic plasticity and to determine the resistance to acute hypoxia in C57/BL mice, which have the pro-inflammatory M1 macrophage phenotype, and in BALB/c mice, which have the anti-inflammatory M2 macrophage phenotype. The following results were obtained. 1) The response of macrophages to acute hypoxia has two successive phases, the immediate, anti-inflammatory phase, and the delayed, pro-inflammatory phase. This response was more distinctly inverted in C57/BL6 M1 macrophages than in BALB/c M2 macrophages; 2) the effect of acute hypoxia on macrophage phenotypic plasticity depends on the genetically predetermined, original macrophage phenotype. In this process, a clear regularity was observed: hypoxia increased the capability of macrophages for changing into the pro-inflammatory M1 phenotype, while their capability for changing into the anti-inflammatory M2 phenotype remained virtually unaffected. 3) BALB/c mice were more resistant to acute hypoxia than C57/BL6 mice. Taken together, these data expand our understanding of mechanisms for pathogenetic effects of hypoxia.

Background. Latent arterial hypertension (LAH) is a serious health problem and is often underdiagnosed in routine examination. Thus, a sensitive and economical test to detect latent hypertension is needed. Objective. To assess the opportunity of pressure response to voluntary breath holding (30 second breath holding test) to detect masked arterial hypertension in young subjects. Design and methods. 269 young subjects (18-36 years old) with no clinical signs of cardiovascular disease, diabetes mellitus, any chronic diseases including pulmonary diseases, who did not do sports professionally, underwent 30 second breath holding test. Results. The results of breath holding and 24 hour monitoring tests coincided in 250 out of 269 cases (93 %). Latent hypertensions was diagnosed (by 24 hour blood pressure monitoring) in none of the subjects with normal or high normal resting blood pressure and negative breath holding test (negative predictive value - 100 %). For subjects with normal or high normal resting blood pressure, a positive breath holding test (53 subjects) detected latent arterial hypertension in 34 subjects (positive predictive value - 64 %). Conclusions. The breath holding test helps to effectively exclude latent arterial hypertension in healthy subjects and accurately identifies subjects who should be further tested for arterial hypertension.

We report here studies addressing the possibility of preventing neurodegenerative changes in the brain using adaptation to periodic hypoxia in rats with experimental Alzheimer’s disease induced by administration of the neurotoxic peptide fragment of β-amyloid (Ab) into the basal magnocellular nucleus. Adaptation to periodic hypoxia was performed in a barochamber (4000 m, 4 h per day, 14 days). The following results were obtained 15 days after administration of Ab. 1. Adaptation to periodic hypoxia significantly blocked Ab-induced memory degradation in rats, as assessed by testing a conditioned passive avoidance reflex. 2. Adaptation to periodic hypoxia significantly restricted increases in oxidative stress, measured spectrophotometrically in the hippocampus in terms of the content of thiobarbituric acid-reactive secondary lipid peroxidation products. 3. Adaptation to periodic hypoxia completely prevented the overproduction of NO in the brains of rats with experimental Alzheimer’s disease, as measured in terms of increases in tissue levels of stable NO metabolites, i.e., nitrites and nitrates. 4. The cerebral cortex of rats given Ab injections after adaptation to periodic hypoxia did not contain neurons with pathomorphological changes or dead neurons (Nissl staining), which were typical in animals with experimental Alzheimer’s disease. Thus, adaptation to periodic hypoxia effectively prevented oxidative and nitrosative stress, protecting against neurodegenerative changes and protecting cognitive functions in experimental Alzheimer’s disease.

The study focused on a possibility of preventing brain neurodegeneration by adaptation to intermittent hypoxia (AH) in rats with experimental Alzheimer's disease (AD) modeled by injection of a neurotoxic bert-amyloid peptide fragment (Ab) into n. basalis magnocellularis. AH was produ- ced in an altitude chamber (4.000 m; 4 hours daily; 14 days). The following results were obtained after fifteen days of the Ab injection: (1) AH substantially prevented the memory impairment induced by Ab, which was determined using the conditioned avoidance reflex test; (2) the AH significantly restricted the enhanced oxidative stress, which was determined spectrophotometrically by thiobarbituric acid-reactive substance level in the hippocampus; (3) the AH completely prevented Ab-induced nitric oxide (NO) overproduction in brain, which was measured by tissue level of nitrite and nitrate; (4) pathologically changed and dead neurons (Niessle staining) were absent in the brain cortex of rats exposed to AH before the Ab injection. Therefore AH seems to effectively prevent oxidative and nitrosative stress thereby providing protection of brain against neurodegeneration and preservation of cognitive function in experimental AD.

NO synthesis disturbances play an important role in the development of neurodegenerative damage in Alzheimer disease. We previously showed that adaptation to intermittent hypobaric hypoxia prevents cognitive disturbances in rats with experimental Alzheimer disease [6]. Here we evaluated the role of NO in cognitive disorders and development of adaptive protection during experimental Alzheimer disease. Adaptation to hypoxia in rats was performed in a hypobaric pressure chamber at a simulated altitude of 4000 m (4 h per day for 14 days). Alzheimer disease was simulated by bilateral injections of a toxic fragment of β-amyloid (25–35) into n. basalis magnocellularis. For evaluation of the role of NO in the development and prevention of memory disorders, the rats received intraperitoneally either NO-synthase inhibitor Nω-nitro-L-arginin (L-NNA, 20 mg/kg, every other day for 14 days) or NO-donor dinitrosyl iron complex (200 μg/kg daily for 14 days). NO-synthase inhibitor potentiated the damaging effect of β-amyloid, abolished the protective effect of adaptation to hypoxia, and produced memory disorders in rats similar to those observed during experimental Alzheimer disease. In contrast, the increase in NO level in the body provided by injections of the NO-donor produced a protective effect against memory disorders caused by β-amyloid similar to that induced by adaptation to hypoxia. We concluded that reduced NO production in the organism plays an important role in the development of cognitive disorders produced by injections of β-amyloid, while prevention of NO deficit by administration of NO-donors or nonpharmacological stimulation of NO synthesis can provide a protective effect in experimental Alzheimer disease.

Addition of N-acetylcysteine induced relaxation of the coronary and basilar arteries thus indicating some basilar NO-stores in these vessels. The maximum capacity of the NO-stores was similar in the coronary and the basilar arteries. Following adaptation to hypoxia, however, the depot was much greater in the coronary artery wall. This seems to be connected with different degree of participation of the NO-dependent vasodiatation in implementation of the adaptive response to hypoxia in coronary and cerebral vascular systems.

Aim. To evaluate intensity of endothelial dysfunction, processes of apoptosis, state of central and peripheral hemodynamics and to evaluate how these characteristics are influenced by angiotensin II receptors antagonists (ARA II) candesartan (Atacand) and losartan (Cosaar) in patients with chronic cor pulmonale (CCP) at different stages of disease. Material and methods. 100 patients with chronic obstructive pulmonary disease (COPD), complicated by CCP were included into the study. Caspase activity as apoptosis induction marker, von Willebrand factor, production of nitric oxide in blood plasma and condensate of breathing out air were assessed. 70 patients received ARA II (50 patients candesartan 4-8 mg daily, 20 patients losartan 50-100 mg daily), 30 patients received neither ARA II nor angiotensin converting enzyme inhibitors (ACEI). Results. Significant increase in intensity of endothelial dysfunction and activation of apoptosis processes were registered according to growth of CCP severity. After 6 months of therapy von Willebrand factor decreased by 25,2% and 27,7% in candesartan and losartan groups respectively (p

Aim. To evaluate intensity of endothelial dysfunction, processes of apoptosis, state of central and peripheral hemodynamics and to evaluate how these characteristics are influenced by angiotensin II receptors antagonists (ARA II) – candesartan (Atacand) and losartan (Cosaar) in patients with chronic cor pulmonale (CCP) at different stages of disease.Material and methods. 100 patients with chronic obstructive pulmonary disease (COPD), complicated by CCP were included into the study. Caspase activity as apoptosis induction marker, von Willebrand factor, production of nitric oxide in blood plasma and condensate of breathing out air were assessed. 70 patients received ARA II (50 patients – candesartan 4-8 mg daily, 20 patients – losartan 50-100 mg daily), 30 patients received neither ARA II nor angiotensin converting enzyme inhibitors (ACEI).Results. Significant increase in intensity of endothelial dysfunction and activation of apoptosis processes were registered according to growth of CCP severity. After 6 months of therapy von Willebrand factor decreased by 25,2% and 27,7% in candesartan and losartan groups respectively (p<0.01 for both groups). In the control group only 13.2% of von Willebrand factor reduction was seen.Conclusion. ARA II added to common therapy of COPD complicated by CCP improves functional state of endothelium restricting hyperproduction of nitric oxide and its toxic effects and slowing down apoptotic cell death.

Preadaptation of cultured HT22 mouse hippocampal neurons to oxidative stress prevented cell damage induced by severe oxidative stress. This protection manifested in a decrease in metabolic disturbances in neurons. Adaptation of neurons to oxidative stress was accompanied by accumulation of HSP32 and HSP70. HSP synthesis inhibitor quercetin abolished the protective effect of adaptation under conditions of oxidative stress. Activation of HSP70 synthesis in neurons is an important mechanism for adaptive protection of cells.

Low oxygen delivery to organs and tissues is one of the most life-threatening situations. Periodic hypoxic episodes may have not only damaging, but also protective effects on the organism depending on how long and intensive this factor is. In both cases an important role is played by changes in the synthesis and metabolism of NO. The direction of NO synthesis and, finally, the direction of periodic hypoxia effect is determined by the regimen of hypoxic impact. The effect of NO depends on its concentration. Both NO excess and deficit are very unfavorable to the organism. Sleep apnea syndrome and pulmonary hypertension are typical examples of NO-dependent damaging effects of periodical hypoxia. NO-dependent protective effects of adaptation to periodic hypoxia are underlied by moderate stimulation of NO synthesis, which provides both compensation for NO deficit and the limitation of its hyperproduction. In turn, NO may increase the expression of other protective factors, which makes adaptive protection more reliable and durable. Understanding the mechanisms of adaptation to hypoxia will help develop new approaches to the prevention of hypoxia and ischemic lesions and the improvement of adaptive abilities of the organism.

Study on a model of 6-day dosed adaptation to heat in rats showed that this adaptation decreased the severity of cardiac arrhythmias during ischemic and reperfusion injury. The duration of arrhythmias decreased not only in the ischemic period, but also under conditions of reperfusion. Adaptation delayed the development of arrhythmias during ischemia, decreased the number of animals with late reperfusion arrhythmias, and improved recovery of the heart after ischemia and reperfusion.