[Neuroendocrine factors in pathogenesis of motion sickness and the protective effect of drugs]. / Neiroéndocrinnye faktory v patogenenze bolezni dvizheniia i zashchitnom deistvii lekarstvennykh veshchestv.

The paper presents a generalization of many-year complex investigations performed at various departments of the Institute of Medico-Biological Problems (Moscow) and various laboratories and institutes of the Ministry of Public Health and the Russian Academy of Medical Sciences, devoted to the pathogenesis of motion disease (sea sickness, vestibulo vegetative syndrome, various forms of kinetosis). The main attention is given to interpretation of the mechanisms of therapeutic and prophylactic action of drugs used for the treatment of such disorders. In particular, the role of a hormonal component of the system of regulation of physiological functions is considered as manifested in the models of the vestibulovegetative syndrome and in the pharmacotherapy of the motion disease.

Endocrine responses to space flights.

Simultaneously with human space flights several series of observations were performed by using experimental animals--mainly rats--exposed to space flights on board of special satellites BION-COSMOS or in Shuttle Transportation Systems (STS). The aims of these experiments were to study in more details: the mechanisms of the changes in bones and skeletal muscle, the alterations of the function of immune system, the radiation effects on organism, the mechanism of the changes of endocrine functions, the evaluation of the role of hormones in alteration of metabolic processes in organism. The advantages of these animal experiments were the possibilities to analyze not only the plasma samples, but it was possible to obtain samples of organs or tissues: for morphological and biochemical analysis for studies of the changes in enzyme activities and in gene expressions, for measurement of metabolic processes and for investigation of the hormone production in endocrine glands and estimation of the response of tissues to hormones. It was also possible to compare the endocrine response to spaceflight and to other stress stimuli. These animal studies are interesting for verification of some hypothesis in the mechanism of adaptation of human organism to the changes of gravity. The disadvantage was, however, that the animals in almost all experiments could be examined only after space flight. The actual inflight changes were investigated only in two SLS flights. In this short review it is not possible to evaluate all hormonal data available on the response of endocrine system to the conditions of space flights. Therefore we will concentrate on the response of pituitary adrenocortical system, pituitary thyroid and pituitary gonadal functions.

Changes of hormones regulating electrolyte metabolism after space flight and hypokinesia.

The changes of hormones in plasma involved in the body fluid regulation were studied in human subjects during and after space flights in relation to redistribution of body fluids in the state of weightlessness. Since hypokinesia was used as a model for simulation of some effects of the stay in microgravity the plasma hormone levels in rats exposed to hypokinesia were also investigated. Plasma aldosterone values showed great individual variations during the first inflight days, the increased levels were observed with prolongation of space flights. The important elevation was found in the recovery period, however it was interesting to note, that in some cosmonauts with repeated exposure to space flight, the postflight plasma aldosterone levels were not elevated. The urine excretion of aldosterone was increased inflight, however in postflight period the decrease or increase were found in the first 1-5 days. The increase of plasma renin activity was observed in flight and postflight period. The rats were exposed to hypokinesia (forced restriction of motor activity) for 1, 7 and 60 days and urine was collected during last 24 hours. The animals were sacrificed and the concentration of electrolytes and of levels of corticosterone, aldosterone (A), ANF and plasma-renin activity (PRA) were determined in plasma. In urine excretion of sodium and potassium were estimated. An important increase of plasma renin activity and aldosterone concentration was found after short-term hypokinesia (1 day). These hormonal values appear to decrease with time (7 days) and are not significantly different from controls after long-term hypokinesia (60 days). A decrease of values ANF in plasma was observed after 1 and 7 days hypokinesia. After prolonged hypokinesia a decrease of sodium plasma concentration was observed. The excretion of sodium in urine was higher in long-term hypokinetic animals. There were no significant changes of plasma potassium levels in rats exposed to hypokinesia, however the urinary excretion of potassium was elevated. In rats exposed to hypokinesia for 7 and 60 days an increase of urine osmolality was observed. The results of hormone and electrolyte determination in plasma of cosmonauts after space flight and in experimental animals after hypokinesia suggested that in evaluation of relations between the changes of hormone levels and electrolyte in plasma and urine other factors like emotional stress working load; altered diurnal cycles should be considered in interpretation of homeostatic response of fluid and electrolyte metabolism to space flight conditions.

Effect of space flights on plasma hormone levels in man and in experimental animal.

An important increase of plasma hormone levels like insulin, TSH and aldosterone was observed in human subjects after space flights, however in the changes of plasma content of ACTH, cortisol, adrenaline and noradrenaline the individual variations were observed in relation to number and duration of space flight. For evaluation of the effects of these changes in plasma hormone levels on metabolic processes also the experiments with small animals subjected to space flights on a board of biosatellite of Cosmos series were running. An elevation of plasma levels of corticosterone, adrenaline, noradrenaline and insulin was found in rats after the space flights of duration from 7 to 20 days. It was demonstrated, that the increase of corticosterone in plasma is followed by the activation of enzymes involved in the amino acid metabolism in rat liver (tyrosine aminotransferase, tryptophanpyrolase, alanine aminotransferase and aspartate aminotransferase). After a short recovery period (2 to 6 days) the plasma corticosterone concentration and also the activity of liver enzymes returned to control levels. The exposition of animals to stress stimuli during this revcovery period showed higher response of corticosterone levels in flight rats as compared to intact controls. The increase of plasma catecholamine levels was not followed by elevation of lipolysis in adipose tissue. This is due to lower response of adipose tissue to catecholamine because a decrease of the stimulation of lipolysis by noradrenaline was observed in animals after space flight. The increase of insulin was not followed by adequate decrease of glucose concentration suggesting a disturbances in glucose utilization similarly as in cosmonauts after a long-term space flight. These results showed that changes in plasma hormone levels, observed after space flight, affected the regulation of metabolic processes in tissues.

[Characteristics of the acidic extract from the epiphysis and its fractions]. / Kharakteristika kislotnogo ékstrakta épifiza i ego fraktsii.

Acid extract of bovine epiphyses was separated by means of gel filtration on Sephadex G-50 into two fractions: high and low molecular preparations. Estimation of biological activity of the acid extract and its polypeptide fractions, which was carried out using the procedure of antigonadotropic effect on preadolescent rat females, showed that the antigonadotropic effect was distinctly higher in the preparation free of high molecular substances.

[Change in carbohydrate metabolism, secretion of insulin and glucagon in normoglycemic rats during administration of various doses of nicotinamide]. / Izmenenie uglevodnogo obmena, sekretsii insulina i gliukagona u normoglikemicheskikh krys pri vvedenii razlichnykh doz nikotinamide.

Development of hypoglycemia, a slight decrease in concentration of glucagon in blood as well as increase in activity of malate-and glucose-6-phosphate dehydrogenases in liver cytosol were detected in rats injected subcutaneously with nicotinamide at a dose of 31.25 mg/kg 6 hrs before decapitation. Increase of the single dose up to 125 mg/kg caused hypoglycemia, distinct increase in concentration of insulin and glucagon in blood plasma simultaneously with a pronounced inhibition of the enzymatic activity in liver tissue. Effect of nicotinamide on carbohydrate metabolism appears to have a dissimilar character depending on the drug dose: its small doses accelerated utilization and oxidation of glucose but did not affect the secretion of insulin and glucagon.

[Neuropharmacology of the autonomic vestibular syndrome]. / Neirofarmakologiia vestibulovegetativnogo sindroma.

It was found during studies on man and experiments on animals that various neuromediator systems of the organism (M-cholinergic, H1-histaminergic, dopaminergic, and opioidergic) are involved in the genesis of VVS. In addition, animal experiments showed that of great importance in the process are different regulatory peptides, in particular, substance P and beta-endorphin. The findings indicate that some neuropeptides may be used in the future in man for VVS prevention. At neuronal level the role of opioid peptides in realization of vestibulovegetative reactions is decoded and a number of possible mechanisms of their action is established. The study of the human hormonal status in VVS revealed complex neuroendocrine changes occurring in the organism. Based on the knowledge of some neurohormonal and neurochemical mechanisms of VVS pathogenesis, a new drug prevention and therapy of seasickness was proposed, efficacy of opioid antagonists naloxone and nalorphine was shown.

[Hormonal response of the bodies of cosmonauts after completion of brief space flights]. / Gormonal'naia reaktsiia organizma kosmonavtov posle zaversheniia kratkovremennykh kosmicheskikh poletov.

After short-term (7-day) space flights the following parameters were measured in blood of cosmonauts: cortisol, ACTH, aldosterone, thyrotropic hormone, thyroxine, triiodothyronine, somatotropic hormone, insulin, testosterone, cyclic nucleotides, prostaglandins, activities of the kallikrein-kinin, fibrinolytic and coagulatory systems, and plasma renin activity; in addition, renal excretion of aldosterone and total 17-oxycorticosteroids was determined. It was demonstrated that after the short-term flights the acute period of adaptation was accompanied by a moderate activation of the renin-angiotensin-aldosterone system, adrenal glucocorticoid function, pancreatic insular apparatus, kallikrein-kinin system as well as increased cyclic AMP which is suggestive of a moderately expressed stress-reaction.

[Hormonal metabolic status of the human body under the conditions of the Far North]. / Gormonal'no-metabolicheskii status organizma cheloveka v usloviiakh Krainego Severa.

The concentrations of hormones (ACTH, cortisol, aldosterone, thyrotrophin, thyroxine, triiodothyronine, growth hormone, insulin, prolactin and testosterone), electrolytes (Na and K) as well as glucose and triglycerides were measured in 10 athletes who made a 380 km ski expedition in the Far North at ambient temperatures of -32 to -34 degrees C. Human adaptation to the geographic and climatic conditions of high latitudes was accompanied by noticeable changes in the incretory function of the adenopituitary, thyroid gland, adrenals and gonads. The data obtained indicate that a ski trip in the Far North produces a distinct stress with physical and cold components being predominant.

[Effect of long-term space flight on polyamine levels in the rat brain]. / Vliianie dlitel'nogo kosmicheskogo poleta na soderzhanie poliaminov v golovnom mozge krys.

The concentration of polyamines, i.e. putrescine, spermidine and spermine, was measured in different brain compartments of rats flown for 18.5 days on Cosmos-1129. Exposure to space flight led to changes in the polyamine content that were most distinct in medulla oblongata. It is suggested that the changes develop as a result of a chronic stress associated with the effects of weightlessness.

Endocrine response to acute changes of brain blood flow due to lower body negative pressure in man.

The decrease of brain flow due to lower body negative pressure (LBNP) was used to study the role of cerebral glucopenia in the activation of anterior pituitary function in 10 young healthy men. During LBNP with a maximum negative pressure of--50 mm Hg the changes in heart rate, blood pressure cerebral blood flow (with the aid of rheoencephalography) and electrocardiogram were recorded and the levels of hGH, ACTH, hPRL, insulin and cortisol were measured with the aid of radioimmunoassay. During the first investigation an infusion of 20% glucose (1 g per min for first 30 min and 0.5 g per min for next 30 min) was used, while during the second investigation (one week later) the infusion of saline was applied. It was found that the infusion of glucose prevented the increase of hGH which was observed only during the infusion of saline. No differences in the level of ACTH, cortisol and hPRL were observed between the investigations with glucose and saline infusion. The increased level of insulin was related to the level of glucose during the infusion, while no changes were found during saline infusion. It was suggested that the increase of hGH level during LBNP resulted from glucopenia in cerebral tissue.

[Hormone content of the blood plasma of rats after a flight on the Kosmos-1129 biosatellite]. / Soderzhanie gormonov v plazme krovi krys posle poleta na biosputnike "Kosmos-1129".

The concentration of ACTH, insulin, glucagon, glucose, epinephrine, norepinephrine, thyrotrophic hormone, thyroxine, and triiodothyronine was measured in plasma of the rats flown for 18.5 days on Cosmos-1129. As a result of the flight, the concentration of insulin, thyrotrophic hormone, and triiodothyronine increased and that of thyroxine decreased. It is suggested that the above changes have been induced by an acute stress associated with biosatellite reentry and touchdown.

[Effect of space flight aboard "Kosmos-1129" on thyroid hormone content of the blood and thyroid gland of rats]. / Vliianie poleta na biosputnike "Kosmos-1129" na soderzhanie gormonov shchitovidnoi zhelezy v krovi i tkani samoi zhelezy u krys.

Thyrotrophin, thyroxine, triiodothyronine, and reverse triiodothyronine were measured in plasma and thyroxine and triiodothyronine in the thyroid gland of the rats flown for 18.5 days onboard Cosmos-1129. Postflight the plasma content of thyrotrophin and triiodothyronine increased and that of thyroxine decreased and the gland content of thyroxine and triiodothyronine diminished. It is postulated that in the flight animals the functional activity of the thyroid gland declined.

[Biochemical status of adrenocortical dysfunction after space flight]. / Biokhimicheskii status adrenokortikal'noi disfunktsii posle zaversheniia kosmicheskogo poleta.

Renal excretion of 17-HOCS and aldosterone as well as the ratio of excreted glucocorticoids and their precursors was investigated in the Soyuz-31 Commander before and after his 7-day flight. Renal excretion of total 17-HOCS remained unchanged while hydroxylation in positions 11 and 17 in the course of corticosteroid synthesis was relatively deficient.