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Metabolic effects of physical countermeasures against deficient weight-loading were studied in three groups of 21-30 y.o. volunteers for 7-d dry immersion. Blood serum was investigated for 38 biochemical parameters that characterize myocardium, skeletal musculature, hepatobiliary system, kidney, pancreas, GI tract, prostate, and protein-nucleic, carbohydrate, electrolyte and mineral metabolism. Seven-day DI w/o countermeasures (n = 5) increased concentration of conjugated bilirubin, suppressed activities of muscular (creatine phosphokinase MM) and myocardial enzymes (CPK MB, OBDH), and caused an upward trend in cholesterol, its atherogenic LDP fraction and triglycerides. Mechanic sole stimulation (n = 6) intensified, within the physiological norm, erythrocyte hematolysis raising total bilirubin and potassium. Despite the stimulation, activity of muscle and myocardial enzymes made a decrease. Blood creatinine decreased to a less extent than in the immersed group w/o stimulation, however, lipid parameters did not rise. High-frequency stimulation of the lower leg and hip muscles in the course of immersion (n = 5) was noted to heighten the activity of muscle enzymes and potassium level in blood beyond the physiological norm. Change in creatinine did not reach a statistical significance and lipid metabolism parameters were not different from baseline values. Application of these physical methods of counteracting deficiency of weight bearing did not interfere with redistribution of body liquids due to immersion. Values of the parameters under study were mostly within the normal limits throughout the experimental exposure suggesting absence of pathological developments during DI or in consequence of physical stimulation. Therefore, the reactions were obviously of normal adaptive character.

Simulation of microgravity for cultivated multipotent mesenchymal stromal cells (MSCs) from human marrow changes transiently expression of genes associated with actin cytoskeleton; the effect fades away partially in 120 hrs. following microgravity and completely after 24-hr cell readaptation to static conditions. These changes in expression of some cytoskeleton genes seem to predetermine their reaction to simulated microgravity, and therefore inhibition of MSCs differentiation potential.

The system of congenital immunity was studied in 12 essentially healthy males 18 to 26 years of age subjected to 5-day dry immersion without use of countermeasures. Peripheral blood was analyzed for monocytes, granulocytes and lymphocytes expressing the TLR2+, TLR4+, TLR6+, CD11b+, CD14+, CD16+, CD18+, CD24+, CD36+, CD54+, CD56+ and CD206+ receptors. Expression of early activation marker CD69 on lymphocytes-natural killers was studied in unstimulated and interleukin-2 activated mononuclear cell cultures. The negative shifts in the congenital immunity system in some volunteers at the end of immersion and during recovery can be considered as warnings about depletion of the system reserve and increase of the risk of infectious diseases such as caused by normal microflora which typically does not provoke pathological reactions of the host.

To understand the tail-suspension model to simulate weightlessness better, this study was to investigate the relationship of the amount of body weight supported by forelimbs between the tilt angles of rat in the model. Normal rat had at least two basic postures. One was standing or walking, in which the forelimbs bear 44.6% of the body weight; the other one was resting, in which 23.9% of body weight was placed on the forelimbs. As for tail-suspended rat, body-weight distribution on forelimbs was linearly related to tilt angle. The linear relationship was y = -0.7423x + 70.849, R2 = 0.9269. The tilt angle should be approximately 35 degrees if normal standing load of 44.6% body weight was placed on the forelimbs. On the other hand, it should be approximately 63 degrees if normal resting load of 23.9% of body weight was placed on forelimbs. Furthermore, the body load on forelimbs in tail-suspension model became much larger if the period of different postures was considered. Therefore, it should be careful if forelimbs are used to be as convenient internal control in tail-suspended rats.

The results of extended comparative investigations into the hypogravity effects on the human motor system in space flight and ground-based experiments evidenced that dry immersions (DI) is the most adequate model of microgravity as time of development, degree and depth of structural and functional motor disorders in DI are very close to what is observed in real microgravity. High intensity and speed of the hypogravity effects during immersion as compared with bed rest hypokinesia the only difference from which is the level of support removal provided insight into the leading (trigger) role of support removal in genesis of the microgravity-induced syndromes of muscular deconditioning and hypogravitational ataxia. Involvement and paths of support afferentation within the muscular system were experimentally studied and verified. Much less understood are processes changing the system mechanisms. These issues as well as some nontrivial approaches to elimination of the negative effects of hypogravity were the subject of the multisided immersion experiment the results of which are presented in this book of the journal.

The neuromuscular junctions were investigated in m. soleus of rats subjected to a 3-month tail suspension simulating the microgravity effects. Electron microscopy analysis revealed some ultrastructural signs of atrophy, degeneration and adipose dystrophy of muscle fibers. The aggregate of these findings points to progressive atrophy in m. soleus, while ultrastructural changes in the neuromuscular synapses testify a reduced functional activity of the synapses and partial denervation of the muscle fibers which, probably, underlay the atrophic process in the muscle. Increases in the number of axon terminals found in some neuromuscular synapses as well as of synaptic vesicles in individual axon terminals are likely to reflect formation of a particularly active pool of spinal motoneurons at L5, possibly associated with the growth in the number of fast fibers resulted from transformation.

In an experiment with rats system and intracellular energy metabolism was assessed by cell reactions to chronic injection of beta-guanidine propionic acid (beta-GPA) stimulating AMP-dependent protein kinase (AMPK). Suspension was shown to inhibit the succinate dehydrogenase (SDH) activity, reduce glycogen in both types of muscle fibers, and stimulate the activity of alpha-glycerophosphate dehydrogenase (alpha-GPDH) in fast fibers. Supplementing the rat chow with beta-GPA did not modify these parameters during suspension; however, the blood urea level increased considerably in the suspended and control rats. In the controls, beta-GPA as well as suspension, stimulates growth of the aspartate aminotranspherase activity (AST) in blood. Yet, the suspension and beta-GPA injection had no additive effect. Moreover, their effects were opposite in rats subjected to suspension + beta-GPA. Glucose concentration was observed to become lowered in blood of resting rats treated with beta-GPA. This effect can be associated with a more intensive insulin-dependent glucose transport to muscles. The additional glucose, because of increased demand by fibers, underwent to oxidation and did not replenish the intracellular carbohydrate deposits These data suggest energy metabolism shifting toward activation of the processes of disintegration of substrates for energy production due to a sharp growth of energy demand.

Summarized are the results of comparative analysis of morphological changes in rat's skeletal muscles after microgravity and its simulation. On completion of space flight, hindlimb muscles of rats exhibited atrophy developed in space microgravity in consequence of the lack of weight-bearing loads and changes solely in the slow anti-g muscles due to the hemodynamic disorders appearing after space flight. Immobilization combined with clinostatting cannot be a veridical laboratory model of microgravity, as horizontally positioned animals still possess weight and, besides, experience severe chronic stress of immobilization. Tail suspension with the head-end permanently down and the hind limbs out of use appeared the most demonstrative model of the space microgravity effects. With this model, the hindlimb muscles underwent changes identical to what had been observed in space flown animals. Data of the simulation studies suggest stabilization of muscle atrophy at a certain level and an earlier and stronger reaction to the hindlimb unloading in young rats as compared to old animals. Skeletal muscles in females and males responded to suspension similarly in spite of difference in the hormonal status.

Effectiveness of the countermeasures and methods for mitigation of the unfavorable effects of microgravity on mineral turnover and properties of bones was evaluated in simulation experiments with animals (penal immobilization, suspension) and with participation of human subjects (37 to 120-d head-down bed rest). The experiments with rats were aimed at testing pharmaceutical preparations (bisphosphonates), determining doses, plan and way of administration. Preparations of this group differ considerably in their action on osteogenesis, mostly because of specifics of the chemical structure. Nonetheless, optimization of the course of treatment masked significantly side effects without detriment to the preventive action. Head-down bed rest was used to test effectiveness of physical exercises (PE) as a main countermeasure against the microgravity impacts. Both standard and experimental PE regimens were tested. Several groups of test-subjects combined PE with consumption of xidifon (a bisphosphonate). In addition, mineral supplements (potassium and calcium) were used. The PE + xidifon combination and regulation of mineral intake with foods was found to reduce calcium losses during 370-d bed rest and prevent a material degradation of strength of bone samples, and essentially rehabilitate shifts in the hormonal regulation of calcium turnover and calciuretic function of the kidney.

Five series of head-down (-10 degrees to -30 degrees, up to 18 hr) tilt tests were performed with participation of 65 healthy male subjects. The ultrasonic technique was used to investigate the liver, spleen, pancreas, kidney, and the main abdominal vessels, i.e. aorta in the abdomen and superior mesenteric artery, interior caval, portal, and splenic veins. A few hours of HDT already brought about a complex of load-deprivation reflexes (the syndrome of stagnant parenchymal organs) characterized by a prolonged venous congestion in the abdominal organs-vessels system, increases in sizes and blood filling of the liver, spleen, pancreas, kidney, and the main arteries and veins in this hemodynamic region. This was the first time when increases in pancreas including its head, body and tail, and the abdominal blood vessels were quantified at the beginning of adaptation to HDT. The load-deprivation reflexes arising in this period were hemodynamic by nature. Considering the significant functional strain of the abdominal organs and vessels and particularly the limited control of excessive blood flow towards the pancreas and kidneys, there is a good reason to look into the ways to improve the existing countermeasures against the consequences of immobilization for humans both in general clinic and preventive medicine, and in short- and long-term space missions.

The histomorphometric method there was used to study effects of ephedrine, strychnine, and support loads on the atrophy of m. soleus and m. gastrocnemius in rats with load-deprived lower extremities (14-day tail-suspension). Deficiency of support loads on the lower extremities led to atrophy of the muscles, especially the slow m. soleus. Injections of ephedrine (0.06 mg/kg), strychnine (0.015 mg/kg) as well as ephedrine and strychnine at one and the same time did not affect the development of atrophy. On the contrary, daily 2-hr support loading of the rear extremities had a favourable effect on the muscle atrophy as it was slowed down. Particularly effective were injections of ephedrine on the background of support loads following which the mass of m. soleus in the suspended rats was close to vivarium control. It is suggested that the preventive effect of ephedrine is associated with stimulating the CNS controllers of the somatotropic function of the pituitary body and eventual enhancement of the somatotropic hormone production.

Double-blind placebo-controlled method was applied to study venoconstrictor agent Dihydroergotamine effects on orthostatic tolerance in 8 healthy male-volunteers after 6-hour exposure to antiorthostatic stress (-6 degrees). The drug was able to induce blood centralization and diuresis additional to those caused by the simulated microgravity per se and failed to prevent the orthostatic intolerance. In 6 subjects the studies were repeated with the occlusive cuffs used in order to prevent venous blood return from the vascular bed of the lower limbs during 0-gravity simulation. The occlusive cuffs were shown to eliminate the additional drug-induced blood centralization and diuresis. Orthostatic tolerance in this case occurred to be less affected than in the case of no countermeasure used or in the case when dihydroergotamine was used alone. Thus, it was shown that mechanical prevention of the drug-induced blood centralization from being realized in 0-gravity simulation must be considered as the requirement necessary to permit the drug to perform its beneficial effect on the orthostatic tolerance after the real or simulated weightlessness.

Microneurography is an electrophysiological method to record impulse traffic in human peripheral nerve in situ. Using this method, not only sensory afferent nerve activity, but also postganglionic sympathetic efferent outflow leading to muscle (muscle sympathetic nerve activity-MSNA) and skin (skin sympathetic nerve activity-SSNA) can be recorded in human subjects. In this paper, the methodology of microneurography and following findings obtained by microneurography on sympathetic nerve responses to environmental stress in humans are reviewed. 1. MSNA is enhanced by gravitational stress, while being suppressed by simulated weightlessness through baroreflex mechanism to maintain hemodynamic homeostasis. 2. MSNA is enhanced by simulated high altitude through chemoreflex mechanism. 3. SSNA, which is composed of sudomotor and vasomotor discharges, plays an essential role in thermoregulation. There exist regional differences between SSNA responses to ambient temperature in the nerves innervating hairy and glabrous skin. The function of the sympathetic nervous system in humans has been so far generally analyzed indirectly by observing the effector organ activity or by measuring the plasma noradrenaline level. Meanwhile, a more direct method to approach the sympathetic nervous function in man, called microneurography, has been developed. By applying this technique, it is possible to investigate how the human sympathetic nervous system responds to different kinds of environmental stress (Mano, 1990, 1994). In this paper, the usefulness of microneurography as a research tool in environmental physiology is shown with a review of microneurographic findings on sympathetic nerve responses to environmental stress in human subjects.