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The article provides an overview of the literature that focuses on the main types of human adaptation to cold and mechanisms for increasing heat production. It is shown that the studies in recent years, aimed at studying the molecular mechanisms of adaptation to cold, confirmed the results of previous physiological studies have demonstrated that the major contribution to adaptive thermogenesis during cooling made by oxidative fibers in skeletal muscle (birds, marsupials, large placental and people) and brown adipose tissue (small placenta, especially rodents). The main sources of thermoregulatory heat generation are the contractile activity (thermoregulatory shivering and muscle tone), the uncoupling of oxidative phosphorylation and decrease in thermodynamic efficiency of the ATP-powered pumps (ATPase), which are induced by noradrenaline and thyroid hormones and accompanied by an increase in the consumption of oxygen and energy substrates. During long-term adaptation to cold the number and activity of mitochondria increase to provide enhanced ATP consumption.

The possibility of correcting free radical oxidation of lipid membranes by the administration of cytoflavin was experimentally studied in rats. It is established that daily cold exposure for 3 h leads to increase in the level of lipid hydroperoxides, diene conjugates, and malonic dialdehyde on the background of decrease in activity of the antioxidant system in the blood of experimental animals. The introduction of cytoflavin (100 mg/kg, i.p.) for 21 day immediately prior to cold exposure leads to reliable (p < 0.05) decrease in the blood level of lipid hydroperoxides (by 13 - 21%), diene conjugates (by 24 - 25%), and malonic dialdehyde (by 20 - 33%) in comparison to rats of the control group. Analysis of the effect of cytoflavin on activity of the antioxidant system components showed that the level of ceruloplasmin and vitamin E in the blood of animals was reliably (p < 0.05) higher by 10 - 33% than analogous indicator in rats of the control group. Thus, the application of cytoflavin under conditions of long-term influence of cold on the organism of animals leads to stabilization of the processes of lipid peroxidation on the background of increased activity of the blood antioxidant system.

The research of Cortexin and Pinealon within two models of stress, acute hypobaric hypoxia and mild hypothermia, within 18-month aged rats has been held. The peculiarities of peptide preparations' influence on behavior and neurochemical indeces have been identified. Cortexin shows a more pronounced effect on free radical processes and caspase 3 activity in brain than Pinealon. Both preparations forward an accumulation of adrenergic mediator within rats' brains in the model of acute hypobaric hypoxia, as well as serotonin within cerebrum cortex in the model of mild hypothermia, which may underlie their geroprotective effects.

In experiments on rats studied influence of intravenous introduction NazdTA on respiratory function of rats after the full termination of breath at deep hypothermia. It is shown that such method without warming application it is possible to lower on 1.5-2.0 degrees C a temperature threshold of approach full a cold paralysis of respiratory function of an organism. It confirms the hypothesis put forward earlier about an important role of infringement of balance of ions of calcium in cytoplasm of cells in development of a pathology of an organism at deep hypothermia. The received results can be used at resuscitation of victims accidental hypothermia.

The literature data testify the there is an early and delayed hypothermic preconditioning of brain. Neuroprotective effect of early hypothermic preconditioning is a result of activation of adenosine A1 receptors, KATP-channels. Ras protein and predetermined by a decrease in the synthesis of NO*. The infarct-sparing effect of delayed hypothermic preconditioning of brain is depended upon protein synthesis de novo. The presented data demonstrate that hypothermic preconditioning prevents cardiomyocyte necrosis in response to ischemia-reperfusion, improves pump function of the heart during reperfusion period, exerts an antiarrhythmic effect. The hypothermic preconditioning exerts more pronounced cardioprotective effect than ischemic preconditioning. The protective impact of hypothermic preconditioning is depended upon activation of protein kinase C, AMP-activated protein kinase (AMPK) and inhibition of MPT pore. The reactive oxygen species are triggers and mediators of hypothermic preconditioning of heart.

Effect of hypothermia on the fatty acid composition of rat and souslik blood phospholipids is studied. Different reaction of these animals to cooling is revealed: in rats no changes were observed in the fatty acid composition of blood phospholipids, whereas in the hibernating there were significant changes in the content of individual fatty acids (FA). The content of monoenic acids in sousliks decreased almost by 50%, while the content of saturated acid (C18) and of polyenic acids C18 : 2omega6 and C20 : 4omega6 rose significantly. Such changes seem to be the mechanism that promotes maintenance of the organism viability under conditions of a decreased level of metabolism, heart rhythm, and body temperature and is evolutionarily acquired. At the same time, the observed changes in the content of individual FA do not lead to sharp changes in such integrative parameters as the total non-saturation of phospholipids, which determines liquid properties of chylomicrons and other lipolipoprotein transport particles of the souslik blood. There are studied absorption spectra of blood lipid extracts of rats and sousliks under effect of light as well as effect of light upon the FA composition of lipid extracts of these animals. The FA composition of lipid extracts has been established to remain practically constant, whereas the character of changes of spectra under action of light indicates the presence in the extracts of oxidation-reduction reactions. The obtained data allow suggesting that in the lipid extract there occurs cooperation both of the phospholipid molecules themselves and of them with other organic molecules, which makes it possible for fatty acids to participate in processes of transport both of electrons and of protons. This novel role of FA as a participant of the electron transfer might probably be extrapolated to chemical reactions (processes) occurring inside the membrane.

Hibernation is a natural model of Tolerance of hypometabolism, hypothermia, hypoxia, bradycardia, and longterm hypophagia. Here, we review recent advances in the isolation and identification of some natural endogenous regulators from hibernating and cold-adapted animals: proteins, peptides, and nonpeptide substances. We also discuss the employment of molecular, biochemical, and physiological bases of natural hypobiosis in ecology, cryomedicine, and the cryopreservation of genetic material from rare and endangered species. We suppose that our approaches can be extensively used (i) in medicine, when there is a need to slow down or suspend life processes for a short time; (ii) for the adaptation of humans to cold; and (iii) in long-term space flights.

This investigation was aimed at the study of lipid-containing and lipid-producing structures of human integument under normal conditions and in death caused by freezing. The skin of interscapular and epigastral areas was studied in 105 cadavers of individuals of both sexes aged 19-83 years, who died as a result of freezing. In the control group, the skin of 10 cadavers of people killed in the car accidents and those who died by the reasons, not associated with the effect of cold, was studied. Paraffin sections were stained with hematoxylin and eosin. To demonstrate lipids, unfixed cryostat sections were stained with sudan III. The following structures are producing the skin lipids: fat cells of adipose tissue, which is localized not only in subcutaneous fat tissue (hypodermis), but forms the pads, that surround the vascular networks, secretory portions of the gland, hair follicles; keratinocytes, producing lipids as a result of terminal differentiation; a sebaceous glands containing cells (sebocytes) which transform into the sebum as a result of holocrine secretion. The lipids produced by this structures are localized either in situ or are transported to the epidermal surface. Lipid-containing structures of the skin are stratum corneum and a superficial lipid film, which is formed from the secretion of the sebaceous glands--sebum. In people who died as a result of general cooling, the content and distribution of lipids in the skin are significantly changed. In the adipose tissue, the adipocyte dimensions and number is decreased, cells without lipids are found. The thickness of the superficial lipid film was decreased as compared to that in the control group; in some areas it could be absent. In the orifices of hair follicles significant amounts of lipids are deposited.

The influence of extremal cryoeffects on the state of prooxidant and antioxidant systems in the blood serum and heart tissues was studied in young and old rats. It is shown that kinematic parameters of chemiluminescence after cold effects are less expressed in the blood serum of old animals than in young ones. The level of TBA-active products in the blood of young rats was lower than in old ones. After the 6th and 9th cold effect the content of TBA-active products in old animal appoaches such indices in young animals. Three weeks after the cold effects the content of TBA-active products in the myocardium of old rats corresponded to control indices, while in the young ones they were considerably lower. The fermentative link state was investigated in the antioxidant protection system. After the extremal cryoeffects glutathione reductase and glutathione peroxidase activity in old animals approaches its indices in intact rats, while catalase activity increases. Three weeks after cryoeffects one can observe a stable increase of fermentative activity of heart tissues both in old and young animals compared with the control that can evidence for the increase of the organism cold resistance.

White rats were cooled until cessation of their breathing (about 17.6 degrees C) and then transferred to a 19-20 degrees C room. The breathless rats were administered EDTA (experimental group) and saline (control groups). Within 6 min., warming of the brain stem to 18.6 degrees C caused restoration of breathing in experimental rats whereas the control rats remained breathless. The EDTA binds calcium ions in the cells' cytosol and thus restores the normal regulation of metabolism in the brain cells.

During the recent 25-30 years, sophisticated experiments and mathematical simulation significantly changed the generally accepted theory of oxygen transport in tissue, which was based on two major postulates, namely: 1) Blood flows in capillaries continuously at uniform velocity, 2) Gas circulation between blood and tissue takes place exclusively in capillaries. As was shown by modern research techniques, blood flow in microvessels has irregular sharp velocity fluctuations in very short time intervals (seconds). In addition, mean velocity of blood flow in microvessels of the same caliber and the same micro-region of tissue may differ several times. Therefore, efficiency of microcirculation reactions may be assessed exclusively witH mean blood velocity in capillaries of the whole micro-region, and with complicated changes of the histogram of mean velocity distribution in capillaries. It was shown that arteriolas and venulas of inactive muscles and brain account for 30 to 50% of gas circulation between blood and tissue. This resulted in fundamental change of the previous postulates in the area of tissue gas circulation physiology, and, in effect, in replacement of oxygen transport paradigm created by A. Krog. This study is an attempt to present a new modern concept of oxygen transport in tissue, to show its research significance, and possible applications.

Using of isolated hepatocytes for investigation of the effects of hypothermia, it has been demonstrated that sucrose-base solution provides of maintenance of the energetic parameters (level of ATP, glucose synthesis, rate of gluconeogenesis) within 48 hrs of storage at 4 degrees C. It efficiency was compared with effect on the energetic status of isolated hepatocytes widely used preservation solution--solution of University Wisconsin (UW). After long-term of cold storage of isolated hepatocytes (72 hrs) at 4 degrees C in both solutions, it has been shown sharp decrease of ATP level (on two time). Viability of the liver cells (in both cases) was practically without change.

Beta-carotene, essential, and the heteropolysaccharide of chamomile racemes reduce the manifestation of the antioxidant status and immunological reactivity caused by air and immersion (water) cooling. The effect of the drugs is mediated by various fractions of the erythrocytes.

After a deep prolonged hypothermia, fast warming up of experimental rats (0.26 degree C/min) to the body temperature 35-36 degrees C entailed recovery of the heart rate, blood pressure, 1-min blood volume, oxygen consumption in rats. However, in the process of warming up, cardiac output, function of the left ventricle, oxygen consumption and the CO2 production were decreased. Acidosis and haemoconcentration following a 3 hr prolonged hypothermia were reversible.

The rate of lipid peroxidation was studied in rat brain, liver, skeletal muscles and myocardial tissues in dynamics of hypothermia. Cooling of the animals down to 30 degrees induced lipid peroxidation, which was markedly expressed within 3-hour continuation of the treatment. Profound hypothermia (20 degrees) increased levels of malonic dialdehyde in the tissues studied by 30-160%, while prolongation of the impairment up to 3 hrs resulted in normalization of the lipid peroxidation parameters studied. The artificial hexapeptide dalargin, similar to leu-enkephalin, inhibited the rate of lipid peroxidation in profound hypothermia both in vivo and in vitro.

Ultrastructure of the serotonin-producing (EC) duodenum cells of a hibernant in euthermia (in summer and winter) and hypothermia has been studied. It has been found that EC cells of an active summer and spontaneously arousal animals belong to active population. This cells have protein-synthetic activity. The winter cells are characterized by the deficiency of the synthetic processes and the secretory granules disintegration. The results support the hypothesis that ES cells are an important element in the regulation of the hibernation.

Index of phospholipids saturation was increased in myocardium within 90 min reperfusion after hypothermic (8-12 degrees) ischemia. Content of oleic, linoleic and arachidonic acids was decreased in all the phospholipid fractions studied thus suggesting that phospholipase mechanism was involved in cardiomyocyte membranes impairment. However, mechanisms of adaptation-protective reactions were maintained as synthesis of prostaglandins from these fatty acids was possible and amount of polyenic acids (eicosapentaenic, decasatetraenoic acids) was increased in some phospholipids. Data of literature corroborated this suggestion.

The effect of cooling of animals on phosphorylation of proteins in hypothalamus, pituitary gland and adrenals, was studied in white mice. The regulation of protein phosphorylation in cells during hypothermia was carried out via the adenylate cyclase system in all these structures. The calcium-calmodulin system took part in this process in hypothalamus and adrenals.

Pathomorphological changes in the lungs of patients dying from supercooling were studied. The material included patients who died immediately after the cessation of the etiological factors, those who underwent reanimation and those who died after long-term hospitalization.

A comparative study is conducted for the effect of one-, three- and six-hour artificial deep (20-19 degrees C) hypothermia on the content of free amino acids in the blood serum, tissue, nuclei and mitochondria of the rat brain. It is found out that the content is the highest in the blood serum after a three-hour cooling. In the brain tissue the amount of amino acids lowers, especially under conditions of a six-hour hypothermia. In nuclei a three-hour effect of hypothermia decreases sharply the content of free amino acids and the six-hour one increases the amount of most of them. Under hypothermia the content of nearly all amino acids in the brain mitochondria is higher than in the intact animals.

Metabolic peculiarities were studied on the model of prolonged immobilization hypothermia in rats (body temperature +20 degrees C for 24 h). Stress reactions and the state of peripheral catecholaminergic systems were compared in hypo- and normothermia. A direct correlation was established between the intensity of metabolism and the mediator activity in adrenergic nerve structures.

The effect of forced cooling was studied as applied to the contents of ammonia, glutamine, glutaminic, asparaginic and alpha-amino butyric acids in the brain of sousliks woken-from hibernation. The cooling of the woken sousliks to the body temperature of 30, 20 and 25 degrees C decreased to some extent the ammonia content in the brain. A deeper hypothermia (10 degrees C) causes its 60,4% decrease as compared to the ammonia amount in woken animals. The cooling of the animals to 30, 25, 20 and 10 degrees C considerably decreases the contents of glutamine, glutaminic acid and GABA in the brain tissue.

Respiration and phosphorylation were studied on isolated myocardial mitochondria of intact and acute and chronic cold-exposed rats at 25 and 15 degrees C. The data obtained attest to activation of oxidation and phosphorylation of rat myocardial mitochondria in response to cold exposure of different duration and power at constant parameters of energy coupling. Cold adaptation changed the mitochondrial response to short-term hypothermia and subsequent warming up. As the temperature in vitro was reduced, the rates of respiration and phosphorylation diminished, with phosphorylation exhibiting a greater temperature sensitivity than respiration.

In rats were Heren carcinoma at the initial stage of hypothermia (30-31 degrees C) in hepatic tissues there was observed at a greater intensity of protein and nucleic acids synthesis contrary to its marked reduction in tumor tissues. In tumor tissues a cessation of protein synthesis was observed at 20-21 degrees C. while that of nucleic acids at 14-15 degrees C. Under these regimens of hypothermia no complete cessation of protein and nucleic acids synthesis in hepatic tissue occurred. However, their synthesis was markedly suppressed.

The complex of physiological reactions caused by cooling is shown to change nonspecifically the organism's toxicokinetics and sensitivity to poisons resulting in considerably increased intake of inhaled harmful substances and their more rapid, though less significantly, elimination. A redistribution of heavy metals in the organism is possible, for example, prolonged cobalt retention in the adrenals. Cooling slows down association and dissociation rates of carboxyhaemoglobin in acute carbonic oxide poisoning. An increase in the acute toxicity of poisons is characteristic for the initial stages of cooling, although in pronounced hypothermia the acute effect of poisons is progressively reduced.

Cold exposition within 3 days at 2-4 degrees caused destabilization of rat erythrocyte membranes. Content of blood serum hemoglobin, total peroxidase activity and the glucose-6-phosphate dehydrogenase activity were increased. Resistance of the animals against high oxygen pressure was reduced. Administration of arginine within 3 days into the animals led to stabilization of membranes and to elevation of rat resistance towards high oxygen pressure.

After 10 days of swimming (10 min per day, water temperature +20 degrees C) the oxygen consumption in rat liver mitochondria increased via the external pathway of NADH oxidation from 3.6 +/- 0.3 to 4.4 +/- 0,2 nmoles O2 x min-1 x mg-1 protein; when the rats were simultaneously injected with an endogenous immunomodulator T-activin (5 micrograms/100 g body weight) daily, this rate increased up to 6.5 +/- 0.6 nmoles O2 x min-1 x mg-1 protein. In the control group, the uncoupled respiration rate is also higher, while the ascorbate+ +TMPD oxidation rate is lower than in the cold- and cold + T-activin-treated groups. The metabolic states of lymphocyte mitochondria did not differ in the three experimental groups. The respiration rates and delta psi m (monitored by diS-C3-(5) fluorescence) of lymphocyte mitochondria in these three groups were also identical.

Constant heat loss studied by direct calorimetry is decreased during acute hypothermia induced by 30-40 min exposure at -6 degrees C, and body temperature falls by 7-9 degrees. Heat production is restored within 35-40 min. Cooling of the animals at -11.8 degrees leads to a fall in body temperature by more than 10 degrees, and restitution sets in about 25 min. Brain tissue respiration (incubation at 23 and 33 degrees) is increased at the 5th and 45th min after hypothermia with no changes in Q10-respiration. The metabolism of heart and liver tissues and skeletal muscles is increased at 5th, 40th and 105th min of restitution; Q10 of skeletal muscle respiration is decreased after 105-min restitution. Temperature compensation for metabolism as the mechanism of tissue homeostasis obvious during arousal in hibernating animals, is absent in non-hibernating heterothermal animals.

A short-term cooling of adult rats and gophers up to 30, 25 and 20 degrees C is accompanied by a rise of the glucose level in blood. No dependence is found between lowering the body temperature drop and degree of glycaemia. Prolongation of hypothermia of 30 and 20 degrees C up to 3 h causes (as compared to the control) a decrease in the glucose amount in blood of gophers but not in the rats. The cooling of the eye-opening, month and adult rats up to 20 degrees C is accompanied by a significant increase in the content of glucose in the brain and skeletal muscles. Simultaneously in the eye-opening and adult animals, contrary to the month ones, the level of glucose in the liver and blood rises. The content of glucose in the brain of the normothermal gophers (61.2 mg.) is 3,4 times as high as in the rat brain. At all the studied stages of artificial hypothermia as well as at 15 and 30-day hibernation (5 degrees C) the amount of glucose of the gopher brain remains at a relatively high level (41.6-101.5 mg%).

Male rats weighing 235-350 g were subjected to cooling for 4-6 hours at -20 degrees C. The lungs of the supercooled animals developed interstitial and intraalveolar edema, focal atelectases and local hemorrhages. It was shown that under overall acute hypothermia the following processes occur in the lungs: 1/local impairment of the air-blood barrier integrity due to hydropic dystrophy and degeneration of type I alveolocytes and endotheliocytes; 2/disintegration, aggregation and membrane lysis of the alveolar surfactant which underlie atelectases; 3/accumulation of the surface active material in the interstice of the interalveolar septa both because of elimination of disintegrated surfactant by type I alveolocytes and as a result of phospholipid secretion from the basal side of type II alveolocytes; 4/an increase in functional activity of type II alveolocytes and alveolar macrophages.

Changes in the content of ascorbic acid in the blood, urine and suprarenals and also of glucose and 11-oxycorticosteroids in guinea pigs with different vitamin C allowances under conditions of cold stress were studied. The data obtained suggest that the degree of the vitamin C allowances is essential for adequate reactions of the organism exposed to the action of cold, but the shifts in metabolic transformations point to the need for a more reserved utilization of high ascorbid acid doses.

Acute hypoxic hypoxia ("height" 7000 m) did not cause distinct alterations in content of adenyl and guanyl nucleotides from brain tissue. Negative alterations in the pool of macroergic phosphates occurred in a deficit of oxygen ("height" 8000 m). Short-term training with hypoxia prevented the alterations in nucleotide pool even if the extreme hypoxia was applied ("height" 9000 m). Pre-cooling of animals promoted the maintenance of nucleotide pool at the "height" of 8000 and 9000 m. Hypothermia did not protect against the distinct alterations in content of both adenyl and guanyl nucleotides under conditions of oxygen deficit ("height" 9500 m and 1100 m).

The peculiarities of 24-hour hypothermia were studied in rats during immobilization and a 5-hour recovery period. The levels of glucose in blood and liver, glycogen in liver, skeletal muscles and heart, total lipids in liver and blood, nonesterified fatty acids in blood have shown that the speed of rewarming is limited both by the level of carbohydrate and lipid energy substrates.

The content of ammonia, glutamine, dicarboxylic amino acids and GABA was studied in the brain under 1, 2, 4-fold separate and simultaneous effect of hypothermia (19-20 C) and hyperoxia (3 atm.). A two-fold hypothermia of rats is accompanied by a greater increase of ammonia in the brain than a three-fold one. The content of glutamine under two-fold cooling is unchanged and under three-fold cooling it is twice as low as compared to its content in the brain of the control rats. The content of glutamic acid decreased after two-fold hypothermia is almost unchanged by the third seance of hypothermia. The repeated actions of hyperoxia also cause a considerable increase in the ammonia content but the dynamics of changes in the content of the nitrogenous metabolic products is contary to that in animals subjected to repeated seances of hypothermia. A simultaneous combined action of hypothermia and hyperoxia produces no additive effect on the system ammonia-glutaminic acid.

An increased content of adrenaline was observed in rabbit adrenal glands under the conditions leading to a decrease of rectal temperature. At the same time the activities of aspartate- and alanine aminotransferases in liver hyaloplasm and ornithine carbamoyl-transferase in mitochondria were decreased, while the activity of the transaminases in mitochondria was maintained unaltered. After the recovery of the temperature the content of the hormone still exceeded the normal level; function of the enzymes studied was distinctly intensified in all the subcellular fractions of hepatocyte. Content of 11-hydrocorticosteroid, being unaltered distinctly in overcooling, was markedly decreased within the later period. Membrane and substrate interrelations, apparently responsible for the biochemical alterations observed, are discussed.