Intermittent hypoxic training as an effective method of activation therapy

Full text

Issue 10. May 2017 | Cardiometry | 93
DOI: 10.12710/cardiometry.2017.9399
Intermittent hypoxic training as an
effective method of activation therapy
Tamara Voronina1*, Nikolay Grechko2, Alla Shikhlyarova3, Natalia Bobkova4
1 London Neurology and Pain Clinic, 4th floor
England, W1G 7JA, London, Harley str. 100
2 Integrated Medical Centre
England, W1U 6BE, London, Crawford str. 121
3 Rostov Research Institute of Oncology
Russia, 344037, Rostov-on-Don, 14th line str. 63
4 Research Laboratory of Cell Mechanisms of Memory Pathology, Institute of Cell
Biophysics Russian Academy of sciences
Russia, 142290, Moscow region, Pushchino, Institutskaya str. 3
* Corresponding author:
phone: +44 (0) 207 935 8416
e-mail: info@tvrejuvenation.com
Abstract
This article considers possibilities of achieving the most effective therapeutic
effect of intermittent hypoxia training (IHT) by initiating an activation and
training reaction. Thanks to IHT the body builds an anti-stress type adapta-
tion which increases the body’s nonspecific resistance to the development
of diseases. It works through a variable functional load which includes a
mechanism for optimizing mitochondrial respiration and is a trigger for syn-
chronizing the performance of the nervous, immune and hormonal systems.
Some biochemical data presented in the article demonstrate the effects of
moderate hypoxia. In addition, laboratory and hardware methods of diag-
nosing for the selection of individual IHT regimes are proposed. IHT is used
to great effect in training of astronauts, pilots, athletes and in the treatment
of diabetes mellitus, trophic ulcers, diseases of the cardiovascular system, the
central nervous system and oncological disorders as well as for rejuvenation
purposes.
Keywords
Intermittent hypoxia training, Activation therapy, Adaptation, Stress, Sport perfor-
mance, Aging diseasses, Lactic acid, Depression, Anorexia, Nitric oxide, Hypoxia
inducible factor – 1 (HIF–1)
Imprint
Tamara Voronina, Nikolay Grechko, Alla Shikhlyarova, Natalia Bobkova. Inter-
mittent hypoxic training as an effective method of activation therapy. Cardio-
metry; No.10 May 2017; p.93–99; DOI: 10.12710/cardiometry.2017.9399; Avai
lable from: www.cardiometry.net/no10-may-2017/intermittent-hypoxic-training
REPORT Submitted: 24.4.2017, Accepted: 15.5.2017, Published online: 25.5.2017
Introduction
Activation therapy is the impact on
the human body of various biologi-
cally active factors, including adapto-
gens, physiotherapy or other stimuli
to obtain a general nonspecific reac-
tion by the body that manifests itself
in an increase in its viability. These
effects have positive impacts, directly
or indirectly, through an increase in
the effectiveness of tissue respiration.
At the present time, much experi-
mental material has been accumulated
on the beneficial effects of natural and
experimental hypoxia on the human
body. A special contribution to the
study was made by N.A. Agadzhanyan
[1–5]; R.B. Strelkov and A.Ya. Chizhov
[6–10]; N.I. Volkov [11], A.Z. Kol-
chinskaya [12–14]; S.G. Krivoshchek-
ov [15, 16] and many others. In recent
years, controlled Intermittent Hypoxic
Training (IHT) is widely used in clini-
cal medicine. IHT is a method of in-
creasing nonspecific resistance of the
body via adaptation to hypoxia which
leads to the effectiveness of mitochon-
drial respiration.
Gas exchange is the fastest metabo-
lism regulator. Oxygen we breathe is
a natural stimulus, an activator that
changes metabolism, expanding the
range of adaptation. By changing the
amount of oxygen in the gas compo-
sition, we directly affect mitochondri-
al respiration. A reduction in oxygen
tension in arterial blood and tissues is
acting as a reflex stimulus of receptive
fields and nerve centers, which regu-
lates physiological processes [17, 18].
In this case, the stimulus itself is habit-
ual for the organism and, within cer-
tain limits, does not cause inadequate
reactions [19,20]. That is why hypnot-
ic training proved to be a successful
tool for increasing the resistance of the

94 | Cardiometry | Issue 10. May 2017
human body to factors in aviation and
space flights [21-23], to achieve max-
imum sports results [1] and increase
the overall resistance of the body to
adverse effects.
Materials and methods
Under clinical conditions, hypoxic
training with alternating breathing
of ambient air is most often encoun-
tered with a mixture of 10–14% oxy-
gen (O2) and about 86–90% nitrogen
(N2) at normal atmospheric pressure
(through a mask for 3-5 minutes), 6–9
cycles, with pauses between cycles of
3–5 minutes (respiration air at sea lev-
el, i.e. 20.9% O2). The duration of the
session is 45–90 minutes. Adaptation
develops as a result of breathing a hy-
poxic gas mixture, in a discontinuous
mode, which leads to the repeated
shift,"swing", of oxygen saturation in
blood (SpO2) from 100–94% to 86–
78%. We are alternating tension and
rest.The oxygen content in the inhaled
air varies from 20.9% (room air) to
10–14% (through the mask). Rocking
mode, "swing", is the main key to suc-
cessful treatment and training.
Youth is the flexibility in providing
compliance with external influences.
Old age and degenerative diseases are
the rigidity in physiology and psychol-
ogy. From our point of view, due to the
"swing regime" of oxygen tension in
the arterial blood and tissues, which
we estimate by oxygen saturation,
adaptive reactions develop. Monitor-
ing and evaluation of efficacy shows
that the greater the difference (ampli-
tude) between SpO2 tension(breath-
ing with a hypoxic mixture) and SpO2
of rest (20.9% O2) during the session,
then the more effective the training.
Of course, the limits of these oscilla-
tions are determined.
Oxygen gives life, oxygen takes it.
Without oxygen cells die. With too
much oxygen cells die even fast-
er. Mitochondria determine a cell’s
choice between life and death.With a
high energy consumption by the cell,
i.e. with greater delivery of glucose
and oxygen, the mitochondria do not
work efficiently and generate more
superoxide (O-2). Superoxide is one
of the active forms of oxygen (reac-
tive oxygen species further referred
to as ROS). ROS, under conditions
of cellular stress, trigger and intensi-
fy the sequence of reactions that ul-
timately leads to cell death.The me-
tabolism of all eukaryotes is based on
the reduction of oxygen to water (O2
to H2O). This reduction of O2 to H2O
can occur only with the formation of
reactive oxygen species (ROS). ROS
as "the signal for life" occurs under
low concentrations of H2O2. A super-
oxide radical stimulates the division
of normal cells in various tissues. On
the other hand, H2O2 ROS and oth-
er ROS trigger the mechanism of cell
death, the transformation of normal
cells into malignant cells.
IHT, taking into account the doses
which we use, can be called activa-
tion hypoxia, since it manifests itself
as a physiological stimulus, and shows
many well-known beneficial effects.
What are the key biochemical chang-
es which stimulate the entire body
system into giving a general response
to moderate hypoxic effects? In a state
of hypoxia, the body tends to produce
the required amount of energy from
a smaller amount of available oxygen.
This is the main generalized, sum-
ming effect of this method.
First, there is an immediate synthe-
sis of Hypoxia Inducible Factor (HIF-
1), which allows the cells to adapt to
hypoxic conditions. HIF–1 initiates
many reactions aimed at improving
the body's use of oxygen. HIF–1, a
transcription factor that increases the
expression of vascular endothelial
growth factor (VEGF) and VEGF re-
ceptors, alters the expression of genes
controlling glucose transport and gly-
colysis, leads to an increase in the ex-
pression of erythropoietin (EPO) ge-
nes, glycolytic enzymes, such as aldo-
lase A, lactate dehydrogenase A ge-
ne, phosphofructokinase L gene and
pyruvate kinase M gene. [24, 25].
HIF–1a is synthesized in various tis-
sues, including nervous tissue [26].
It is found in all cells of the brain,
but its expression in neurons is max-
imal. The synthesis of HIF-1a leads
to an increase in the fowwlong: nitric
oxide (NO), the synthesis of cyto-
chrome-450, dopamine and serotonin,
gamma-aminobutyric acid, thyroxine,
insulin and improves the transport of
glucose. IHT increases the stress-pro-
tein (caperone, shock protein) level in
the cell [27]. There is an intensifica-
tion of production and rejuvenation
of mitochondria (a cell concentrator
for the production of aerobic energy)
and mitochondrial enzymes, which
allows for more efficient use of oxygen
for energy production and excellent
enzymatic antioxidant protection.
Oxidative damage to mitochondrial
DNA, mtDNA, is a recognized mech-
anism responsible for pathogenesis of
aging in mammals. Progressive deg-
radation of mitochondria underlies
oxidative stress, which leads to an
accumulation of molecular damage,
genome instability, reduction of telo-
meres, metabolic disturbances, hor-
monal disorders and acceleration of
glycosylation of proteins. Continuous
renewal of mitochondria in somat-

Issue 10. May 2017 | Cardiometry | 95
ic cells can reduce oxidative stress,
increase the efficiency of oxidative
metabolism, slow down the aging pro-
cess and prevent and/or retard the de-
velopment of age-related pathologies.
The natural mechanism of mitop-
tosis, discovered in the mammalian
organism, promotes the continuous
purification of the mitochondrial ba-
sin in the body from damaged, old
mitochondria. This actively produces
free radical oxidation Reactive Oxy-
gen Species (ROS). ROS include ox-
ygen ions, free radicals and peroxides
both of inorganic and organic origin.
Oscillations of oxygen delivery elimi-
nate the destroyed mitochondria and
stimulate mitoptosis, which is the key
to longevity [28]. Mitoptosis facili-
tates purification of the mitochondri-
al basin thus ensuring the spread of
unmutated mtDNA.
IHT improves blood circulation and
oxygen delivery to tissues due to the ef-
ficient operation of the ATP-K + pump.
It was discovered that the ATP-K chan-
nels of intact ventricular cardiomy-
ocytes blocked by intracellular ATP
under normoxic ambient conditions
begin to open in 20–25 minutes un-
der moderate hypoxia. The dynamics
of this activity has a periodic/cyclical
rhythm [29].
One of the most effective factors of
the biochemical environment of the
body is nitric oxide (NO). NO acts on
the smooth muscle walls of the ves-
sels relaxing them. Nitric oxide also
promotes the inhibition of the prolif-
eration of smooth muscle cells. There
is a decreased aggregation of platelets,
leukocytes and erythrocytes; and re-
duction of adhesion of leukocytes to
the endothelium. Nitric oxide induc-
es neurogenesis and angiogenesis.
Vascular growth occurs only where
there is smooth musculature. This
fact is important for solving the prob-
lem of the use of IHT in patients with
cancer. As known, the vessels of can-
cerous tumors do not have smooth
muscle tissue lining them. The syn-
thesis of nitric oxide (NO) and its
accessibility activates the expression
of other protective factors, including
the following: heat shock proteins
[30], antioxidants, prostaglandins of
H-synthase [31]. An adaptation to
hypoxia prevents both NO overpro-
duction and NO deficiency, resulting
in an improvement in blood pressure
[10, 11, 33]. IHT optimizes concen-
trations of nitric oxide by stimulat-
ing its synthesis, and also limiting its
overproduction [32]. Understanding
the role of NO in the mechanisms of
the adaptation to hypoxia will help
to substantiate the program for the
prevention and treatment of hypox-
ia or ischemic damage to organs and
tissues.
Hyperglycemia inhibits the forma-
tion of nitric oxide (NO) and weakens
its effect. The lack of sufficient syn-
thesis of NO under diabetes mellitus
gives rise to a dysfunction of the en-
dothelium, which in its turn leads to
vasospasm, smooth muscle prolifera-
tion, activation/aggregation of plate-
lets, and adhesion of leukocytes to the
endothelium [34]. IHT is more effec-
tive when it is used for an organism
under the conditions of normoglyce-
mia or in a state of hunger. During
and after fasting periods, sensitivity of
receptors is increasing. Even morning
fasts can play a positive role.
IHT improves oxygen delivery to tis-
sues due to a change in hemoglobin,
an increase in tissue affinity for oxy-
gen. During IHT, hemoglobin binds
to 2,3-DPG (2,3 diphosphoglycerate),
which greatly facilitates the release of
oxygen from hemoglobin into the tis-
sue [35].
The uniqueness of hypoxic stimu-
lation is that during IHT there is an
improvement in blood circulation in
that part of the body that is in the state
of hypoxia. Affected or inflamed tis-
sues and organs or parts of them have
much lower pH, since they are in the
state of hypoxia. IHT stimulates cap-
illary dilation faster in tissues and or-
gans where is much lower pH and an
increased concentration of lactic acid
(lactate) as compared to non-acidi-
fied, healthy ones. Thus, blood cir-
culation improves primarily in the
affected tissues and organs, including
the brain. Therefore, the uniqueness of
IHT stimulation makes it possible to
treat not only wounds, trophic ulcers,
lung abscesses, but also degenerative
brain diseases: epilepsy, complex par-
tial seizures, hyperkinesis symptoms,
phantom pain syndrome, anorexia
nervosa, depression, Parkinson's and
Alzheimer's diseases [32].
The therapeutic effect can be achieved
by improving oxygen delivery to the
subcortical structures and, first at all,
the nuclei of the visual hillock (medi-
an center, ventrolateral nucleus), or,
in other cases, has the protective and
therapeutic effect in survival of nigral
dopaminergic neurons and in substan-
tia nigra and striatum. As mentioned
above, nitric oxide (NO) production
plays an important role, and it is stim-
ulated in the brain by erythropoietin.
IHT as an activation method acts on
the whole organism and undoubtedly
has much more advantages in achiev-
ing a quick and lasting result in in-
creasing the overall resistance of the
organism than the methods of action
of individual adaptogenes. The im-

96 | Cardiometry | Issue 10. May 2017
pact of IHT immediately involves the
brain changing its blood circulation
and biochemical status. It is known
that even ordinary anxiety changes
the blood circulation and biochem-
ical status of the brain in a mosaic
manner and/or locally [36], and it
may be enough to have one IHT ses-
sion to delete it. Practice showed this.
Patients with diseases such as epi-
lepsy, depression, anorexia and many
others, have a dominant, individ-
ual pathological mosaic pattern in
the brain. These individual patterns
demonstrate altered (insufficient) tis-
sue respiration and altered nervous
excitability, excessively accumulate
certain metabolites, such as lactate
(lactic acid). Undoubtedly, the same
mechanisms work in the prevention
and treatment of the consequences of
strokes and heart attacks. Outstanding
neurophysiologist Natalya Bekhtereva
stressed that leaving the state of the
brain unchanged we cannot cure a
disease. The condition of a disease or
a stable pathological condition, as Na-
talia Bekhtereva called it, is the "inter-
connected complex memory matrix"
[37]. The mechanisms of its "erasure"
and "re-education" are the improve-
ment of blood circulation and tissue
respiration, as well as the "cleaning" or
removal of accumulated metabolites.
Modes of "swinging" by the action of
sparing point electrostimulation of
the brain in the treatment of schizo-
phrenia by Heath R.G. [38] are de-
scribed in the 50's. Natalia Bekhtereva
practiced treatment with electrical
stimulation (TES) of the brain in case
of hyperkinesis and phantom-pain
syndrome, describing the treatment
as "swinging". TES was effective if
stimulation led initially to destabiliza-
tion of painful manifestations, which
was mentioned by V.M. Smirnov [39].
The repeated destabilization seems to
be an activator and a trainer expand-
ing the reserves of adaptation.
The "swing" with oxygen suggests a
repeated shift in the amount of ROS,
which, apparently, play not the least
role in repetitive destabilization and
subsequent adaptation.The metabolic
shift occurs due to repeated changing
in oxygen transport and leads to im-
provment of all the biochemical chains
of oxygen delivery to the cells. An ad-
aptation is a re-setting of the body in
a new mode of operation, more sensi-
tive, suppler and more flexible.
Such diseases as epilepsy, depression,
anorexia and many others have of
course their own individual patterns
of altered blood circulation and bio-
chemical state. The method of "re-ed-
ucation" for patients with epilepsy with
the help of electrostimulation [16] can
be completely replaced by IHT.
What studies confirm the antitumor
effect of IHT on the body? IHT ac-
tivates p53, a tumor suppressor. P53
(protein p53) functions as a suppres-
sor of the formation of malignant
tumors, respectively, the gene TP53
is an anti-oncogene. Mutations of
gene TP53 are found in cells in about
50% of cancerous tumors. Often it is
called the "guardian of the genome"
[40]. Hypoxia regulates telomerase
[41]. IHT improves blood circula-
tion in organs and tissues by relaxing
smooth muscles in capillaries, but not
in cancerous tumors. Cancer does
not contain smooth muscles in the
vessels, so there is no embolization
of the capillaries or improvement in
blood circulation in tumors. Also,
VEGF does not cause proliferation of
smooth muscle cells (as well as cor-
neal endothelial cells, lens epithelial
cells, fibroblasts and adrenal cortex
cells) [42,43].
What reactions can be observed in
the patient’s body immediately after
IHT?
A positive response appears upon
expiration of 15-30 minutes, the state
of general calm manifests itself, of-
ten accompanied by relaxation and
drowsiness, slowing down of breath-
ing and heart rate. Some patients
improve their color vision dramati-
cally. Cheeks appear pink, limbs are
warmed. After one or two sessions,
sleep and mood improve. In some pa-
tients, long-term depression is cured.
There is a comfortable feeling of re-
laxation in the stomach, “the lump in
the throat or chest" often accompanies
stress is gone. Digestion improves,
and the nonspecific resistance of the
body as a result of integral changes in
the body increases.
Breathing gas mixtures with differ-
ent oxygen content causes hypoxia of
different levels and leads to various
reactions by the body. A weak stim-
ulus causes a training reaction, which
leads to the accumulation of some
substances (proteins, cells, tissues).
A stronger stimulus induces the re-
action of activation, which has some
temporary destructive properties, but
further leads to a more intensive syn-
thesis of proteins and repair. A very
strong stimulus initiates stress, which
leads to a noticeable destruction and
hinders the development of an adap-
tive response.
Strong, intense hypoxia, like other
strong stimuli, causes stressful reac-
tions of anxiety, resistance and op-
pression within 3 phases. Stressful re-
actions are accompanied by profound
changes in the central nervous system,
including the pituitary gland and its

Issue 10. May 2017 | Cardiometry | 97
hypersecretion of ACTH, suppression
of the activity of the thymic-lymphatic
system, metabolic disorders and high
energy expenditure. As the founder
of stress Hans Selye said, "protecting
the body from a strong stimulus is
achieved at a high price – at the cost
of breakage and high costs." Stress is
the nonspecific basis of any pathologi-
cal process.
IHT makes it possible to purpose-
fully dose the strength of stimuli and
the amplitude of fluctuations of the
hypoxic mixture. The purpose of
IHT is to cause the development of
general nonspecific reactions,which
correspond to the symptom complex
of an integral nonspecific adaptation
activation or training reaction de-
scribed and studied by Rostov scien-
tists. [44–47]. It is important to take
into account the individual sensitiv-
ity and subjective sensations of the
individual (sleep, appetite, motor ac-
tivity, efficiency, emotional state) and
compare them with objective indica-
tors.One of these can be a morpho-
logical blood test that classifies the
strength of the impact and identifies
the archetype of the reaction (train-
ing, activation, or stress) [48]. Mon-
itoring heart rate variability (HRV)
and studyingthe thermography of
the body, an electroencephalogram
(EEG) before the session and after it,
dynamics of SpO2 and breath-hold-
ing time may be utilized as valuable
indicators for the assessments of
treatment efficacy.
The methods of controlled enhance-
ment of adaptation or activation acting
on the whole body undoubtedly have
many more advantages in achieving a
quick and lasting result than methods
of uncontrolled, blind effect of indi-
vidual adaptogens.
Conclusions
Nature demonstrates that there are
certain resources which can have a
powerful and quick effect on me-
tabolism.They can kill or cure. Con-
sidering them, oxygen is among the
strongest.Our aim is to design, de-
velop and apply the most efficient
IHT methodology to act as a natural
trainer, regulator and activator for
restoration and rejuvenation for the
body and brain.
Statement on ethical issues
Research involving people and/or ani-
mals is in full compliance with cur-
rent national and international ethi-
cal standards.
Conflict of interest
None declared.
Author contributions
The authors read the ICMJE criteria
for authorship and approved the final
manuscript.
Reference:
1. Aghajanyan NA, Mirrahimov MM.
Mountains and resistance of the
body. Moscow: Science, 1970. 182 p.
[in Russian]
2. Agadzhanyan NA, Chizhov AY.
Classification of hypoxic conditions.
Peoples' Friendship University of
Russia. Russian Ecological Academy.
Moscow: KRUK. 1998. [in Russian]
[in Russian]
3. Agadzhanyan NA, Chizhov AY. Hy-
poxic, hypocapnic and hypercapnic
states. Textbooks for students of med-
ical schools. Moscow: Medicine. [in
Russian]
4. Normal-hypoxic therapy (the meth-
od of "Mountain air"); Monograph.
Ed. by Aghajanyan NA, et al. Moscow:
Publishing house of the Peoples Friend-
ship University. 1994. 95 p. [in Russian]
5. Intermittent normoboric hypoxic
therapy. Reports of the Academy of
Problems of Hypoxia. Scientific edi-
tors: Agadzhanyan NA, Strelkov RB,
Chizhov AY. Volume 1. Moscow, 2005
[in Russian]
6. Strelkov RB, Chizhov AY. Anti-ray
protection of animals and humans.
Moscow. 1994. [in Russian]
7. Strelkov RB, Chizhov AY. Inter-
mittent normobaric hypoxia in the
prevention of treatment and reha-
bilitation. Ekaterenburg: The Urals
Worker. 2001. [in Russian]
8. Strelkov RB, ChizhovAY. Normo-
baric hypoxic therapy and hypoxira-
diotherapy. Peoples' Friendship Uni-
versity of Russia. Research Institute
of Ecology and High Technologies at
the PFUR. Academy of Problems of
Hypoxia. Moscow. 1998. [in Russian]
9. Intermittent normoboric hypoxic
therapy. Reports. Ed. by RB Strelkov.
International Academy of Problems
of Hypoxia of the Scientific and Tech-
nical Association "BIO-NOVA". Vol-
ume 4. Moscow, 2005 [in Russian]
10. Chizhov AY, PotievskayaVI. In-
termittent normoboric hypoxia in the
prevention and treatment of hyper-
tension. Moscow: Publishing house
of the Russian University of Peoples'
Friendship. 2002. [in Russian]
11. Volkov NI, SmetaninVY, Smirn-
ov VV. Hypoxia load and interval hy-
poxic training. Monograph. Moscow,
2000. [in Russian]
12. Hypoxia. Automated analysis of
hypoxic conditions of healthy and sick
people. Volume I. Russian Academy of
Sciences. Kabardino – Balkarian Sci-
entific Center Institute of Informatics
and Problems of Regional Manage-
ment. Sanatorium of the Ministry of

98 | Cardiometry | Issue 10. May 2017
the Interior of the Russian Federation
"Nalchik", Moscow – Nalchik 2005 [in
Russian]
13. Hypoxia. Automated analysis of
hypoxic conditions of healthy and
sick people. Volume II. The Russian
Academy of Sciences. Kabardino -
Balkarian Scientific Center Institute
of Informatics and Problems of Re-
gional Management. Sanatorium of
the Ministry of the Interior of the
Russian Federation "Nalchik" Mos-
cow – Nalchik 2005 [in Russian]
14. Hypoxia, automated analysis of
hypoxic conditions of healthy and
sick people. Collection of works ed-
ited by Kolchinskoy AZ, Moscow –
Nalchik, 2005. 358 p. [in Russian]
15. Krivoschekov SG, Divert GM, Di-
vert VE. Extension of the functional
range of respiratory and gas exchange
responses in repetitive hypoxia. Hu-
man Physiology. 2005;31(3):330-6.
[in Russian]
16. Krivoshchekov SG, Divert GM, Di-
vert VE. Individual characteristics of
external respiration during intermittent
normobaric hypoxia. Human Physio-
logy. 2006;32(3):301-7. [in Russian]
17. Frolkis VV. Hypoxia as a reflex
stimulus of the cardiovascular system.
Physiology and pathology of respira-
tion, hypoxia, oxygen therapy. Kiev:
Publishing House of the Academy of
Sciences of the Ukrainian SSR, 1958.
Pp. 149–161. [in Russian]
18. Berezovsky VA. Oxygen tension in
the tissues of animals and humans. K.:
Nauk. Dum., 1975. 277p. [in Russian]
19. Barbashova ZI. Acclimatization to
hypoxia and its physiological signifi-
cance. Moscow, Leningrad: Publish-
ing House of the USSR Academy of
Sciences, 1960. – 215 p. [in Russian]
20. Mirrakhimov MM. Treatment of
internal diseases by mountain climate.
Мoscow: Meditsina, 1977. 208 p. [in
Russian]
21. Vasilenko ME, Gazenko OG, Gra-
menitsky PT, et al. Changes in altitude
stability in barocamera training. Func-
tions of the organism in conditions of
gas environment changes. Moscow,
Leningrad: Publishing House of the
USSR Academy of Sciences, 1958; V.
2. 143 p. [in Russian]
22. Vladimirov GE. Influence of low
atmospheric pressure on metabolism.
Fundamentals of Aviation Medicine.
Moscow, 1939. p. 49–52. [in Russian]
23. Vladimirov GYe. The importance
of staying in the mountains to im-
prove the body's resistance to hypox-
ia. Leningrad.1939. p.21. [in Russian]
24. Iyer NV. Cellular and develop-
mental control of O2 homeostasis by
hypoxia-inducible factor 1 alpha.Gen.
Dev. 1998 Jan 15;12(2):149–62.
25. Semenza GL. HIF-1: mediator of
physiological and pathophysiological
responses to hypoxia. J Appl Physiol.
2000;88:1474–1480.
26. Wiener CM, Booth G, Semen-
za GL. In vivo expression of mRNAs
encoding hypoxia-inducible factor 1.
BiochemBiophys Res Common. 1996;
225: 485–488.
27. Meerson FZ. Adaptive Medicine:
mechanisms and protective effects of
adaptation. Monograph. Moscow; 1993:
254–257.
28. Lyamzaev KG, et al. BiochimBio-
physActa. 2008 Jul-Aug; 1777(7–8):
817–25.
29. Babenko AP, Kazantseva ST, Ro-
manova YV, et al. “The Mechanisms
of Activation Of the ATP-Sensitive
Potassium Channels of the Sarcolem-
ma Of Cardiomyocytes In Hypoxia”.
Materials of the VII All-Russian Sym-
posium on Ecological and Physiologi-
cal Problems of Adaptation. M., 1994;
30. Zhong N, et al. Intermittent hypox-
ia exposure-induced heat-shock pro-
tein 70 expression increases resistance
of rat heart to ischemic. ActaPharma-
col Sin. 2000 May; 21(5):467–72.
31. Davidge ST, Baker PN, Laughlin
MK, Roberts JM. Nitric oxide pro-
duced by endothelial cells increases
production of eicosanoids through ac-
tivation of prostaglandin H synthase.
Circ Res. 1995 Aug;77(2):274–83.
32. Manukhina EB. Intermittent hy-
poxia training protects cerebrovascu-
lar function in Alzheimer's disease.
ExpBiol Med (Maywood). 2016 Jun;
241(12): 1351–63.
33. Manukhina EB, et al. Role of Ni-
tric Oxide in Cardiovascular Adap-
tation to Intermittent Hypoxia. Ox-
ide in Cardiovascular Adaptation to
Intermittent Hypoxia. ExpBiol Med.
April 2006;231(4):343-65.
34. Hyperglycemia impairs the ac-
tivity of nitric oxide, resulting in en-
dothelial dysfunction. Adrie 1996;
Cooke et al. 1997; Federici et al. 2002.
35. Proctor HJ. Increased erythrocyte
2,3-DPG: Usefulness during hypox-
ia. Journal of Surgical Research. June
1974;16(6):569–74.
36. Medvedev SV. The problem of
brain research. Institute of the Human
Brain of the RAS, 2015.
37. Bekhtereva NP. The Magic of the
Brain and the Labyrinths of Life. Mos-
cow, St. Petersburg: SOVA Publishing
House, 2007.
38. Heath RG. 1) Physiological Data-elec-
trical Recording. Studies in Schizophre-
nia. Cambridge,1954. P. 151–156; 2) Elec-
trical Self-Stimulation of Brain in Man.
Amer. J. Psychiat. 1963;120(6):571–7;
Heath RG, Hodes R. Introduction of
Sleep Stimulation of Caudate Nucleus
in Macaque Rhesus and Man. Trans.
Am. Neur. Ass. 1952;77:204–10.

Issue 10. May 2017 | Cardiometry | 99
39. Smirnov V.M. Stereotactic neuro-
logy. Leningrad: Medicine, 1976.
40. Chandel NS, etal.“Redox regulation
of p53 during hypoxia”. Department of
Medicine, Gwen Knapp Center, Com-
mittee on Immunology and the Howard
Hughes Medical Institute, The Univer-
sity of Chicago, Illinois, USA. Oncogene
2000 Aug 10; 19(34): 3840–8.
41. Minamino T., et al. Hypoxia Ex-
tends the Life Span of Vascular Smooth
Muscle Cells through Telomerase Ac-
tivation. Molecular and Cellular Biol-
ogy,May 2001, p. 3336–3342, Vol. 21.
42. Fernandez HA, Kallenbach K, Seghe-
zzi G, Grossi E, Colvin S, Schneider R,
Mignatti P, Galloway A. Inhibition of
endothelial cell migration by gene trans-
fer of tissue inhibitor of metalloprotein-
ases-1. J Surg Res 1999;82:156–62.
43. Gospodarowicz D, Ferrara N, Sch-
weigerer L, Neufeld G. Structural char-
acterization and biological functions
of fibroblast growth factor. Endocr Rev
1987;8:95–114.
44. Garkavi LH, Ukolova MA, Kvak-
ina EB. Regularity of development of
qualitatively different general non-
specific adaptive reactions of the or-
ganism. Diploma for the opening of
the 158 Committee of the Council of
Ministers of the USSR on Inventions
and Discoveries. Discoveries in the
USSR. – Moscow, 1975. No. 3. p. 56-
61. [in Russian]
45. Garkavi LH. Adaptive "Activation
reaction" and its role in the mechanism
of antitumor effect of hypothalamic
stimulation: Author's abstract. Dis. Dr.
Sci. Donetsk, 1969. 30 p. [in Russian]
46. Garkavi LK, Kvakina EB, Kuzmen-
ko TS, Shikhlyarova AI. Anti-stress
reactions and activation therapy. The
activation reaction as a pathway to
health through self-organization pro-
cesses. Ekaterinburg: Philanthropist,
2002. 196 p. [in Russian]
47. Garkavi LK, Kvakina EB, Kuzmen-
ko TS, Shikhlyarova AI. Anti-stress
reactions and activation therapy. The
activation reaction as a pathway to
health through self-organization pro-
cesses. Ekaterinburg: Philanthropist,
2003. 336 p. [in Russian]
48. Shikhlyarova AI, et al. Energetic
criteria of lymphocytes in evaluation of
efficacy of system processes correction
under oncopathology. Cardiometry.
November 2016;9:70–3. DOI:10.12710/
cardiometry.2016.9.7073.