Potential Role of Catecholamine Response to Acute Hypoxia in the Modification of the Effects of Radioprotectors.

Involvement of hormonal response (catecholamine release) to acute hypoxia induced by radioprotectors in modification of their radioprotective properties was studied in experiments on outbred mature female albino mice, female albino rats, and dogs of both sexes. The response intensity was evaluated by the reduction of radioprotective and toxic properties of indralin (a α1-adrenoceptor agonist and a radioprotector). The radioprotective effect of indralin was measured using lethal doses of whole-body γ-irradiation ((60)Co) and its acute toxicity was assessed by LD50. It was found that repeated administration of indralin with 30-60-min intervals was followed by weakening of its radioprotective effect. Similar sensitization effect of indralin was observed after pretreatment with cystamine and epinephrine. Comparison of the severity of sensitization after administration of epinephrine and cystamine in the dose providing radioprotective effect showed that the potential aminothiol-induced release of catecholamines can provide optimal long-term radioprotective effect of epinephrine.

[Radioprotective properties of indralin combined with cystamine and mexamine].

The study of indralin radioprotective properties at its joint application with cystamine and mexamine was carried out in the experiments on inbred mice and rats. The mice and rats were exposed to whole-body y-irradiation at a dose of 9.0 and 9.5 Gy, correspondingly. A combined parenteral administration ofindralin and cystamine at a dose of 25 mg/kg showed ponentiaton of indralin radioprotective properties up to a level of the ED50 effect versus the absence of or a weak radioprotective effect in the case of their separate application. In the experiments on rats, indralin (50 mg/kg) and mexamine (12 mg/kg) injected intraperitoneally almost completely eliminated the animal mortality from the intestinal syndrome of acute radiation sickness amounting in the control radiation group to 60% on the 7th day after exposure to radiation at a dose of 9.5 Gy. However, at the above conditions, radioprotectors at these doses had a low-level radioprotective action at the onset of the bone marrow syndrome of acute radiation sickness. Combined application of indralin and mexamine at the same doses and at the same conditions led to a radiation protection 50% as high as in the case when radioprotectors were applied separately at a double dose.

[Indralin--a novel effective radioprotector during irradiation by high-energy protons].

Experiments with 120 mongrel dogs were aimed at the assessment of radio protective strength of indralin and local shielding of the pelvic marrow from 2.5 Gy, and also their concurrent use for the dogs irradiated by protons (240 MeV) at absolutely lethal and over-lethal 4 Gy and 5 Gy. Clinical observations, hematological investigations and ECG analysis of survived animals were conducted 4.5 years post the irradiation. Dogs that remained healthy following 3.5 to 4.5 years since the irradiation were sacrificed for pathomorphological investigations. The radioprotective effect of local shielding against 4 Gy was weak while this effect of intramuscular indralin (10, 20, 40 mg/kg of body) was significant reaching 50 to 67.7%. The concurrent use of two methods had, apparently, potentiated the 100% radioprotection of the animals irradiated by overlethal 5 Gy. Blood investigations of the survived dogs every 2-4 months evidenced that complete recovery of the total leukocyte count had taken 9 to 13 months. Also, dogs' pregnancy in 9-10 months since the beginning of irradiation pointed to maintenance of fertility and the ability to parturiate 2 or 3 times yielding 5-6 live cubs. Necropsy of the dogs did not reveal gross macroscopic structural changes of visceral organs or tissues. Seven out of 27 sacrificed dogs had benign tumors infrequent in intact dogs at this age.

Field estimation of deformation modulus of the soils by multichannel analysis of surface waves.

The paper presents the processed results of Plate Load Tests and of Multichannel Analysis of Surface Waves for dispersive and semi-rocky soils at the sites with different soil conditions located in the Perm Region, Russian Federation. Unit weight and deformation modulus were calculated from the obtained data. The value of the data lies in their applicability for the prompt preliminary assessment of the site geotechnical situation.

Biological role of gravity: hypotheses and results of experiments on "Cosmos" biosatellites.

In order to reveal the biological significance of gravity, microgravity effects have been studied at the cellular, organism and population levels. The following questions arise. Do any gravity-dependent processes exist in a cell? Is cell adaptation to weightlessness possible; if so, what role may cytoskeleton, the genetic apparatus play in it? What are the consequences of the lack of convection in weightlessness for the performance of morphogenesis? Do the integral characteristics of living beings change in weightlessness? Is there any change in "biological capacity" of space, its resistance to expansion of life? What are the direction and intensity of microgravity action as a factor of natural selection, the driving force of evolution? These problems are discussed from a theoretical point of view, and in the light of results obtained in experiments from aboard biosatellites "Cosmos".

Space radiobiology program in Russia.

The space radiobiology program in Russia is aimed at obtaining fundamental data for developing radiation safety criteria. These criteria are necessary for long-term space missions. This program includes : -substantiation of radiation hazard estimation principles based on the radiation risk conception, -investigation of the radiation affection regularities under the combined influence of the spaceflight factors, -experimental investigation of the HZE-particle delayed effects and acute somatic effects induced by protons and electrons, -individual radiosensitivity investigation, -mathematic modeling of radiobiological effects , -radiobiological basis of control and forecast of radiation influence in space, -development of methods and means of an organism's radioresistance increase.

[Width of radiation protective effects of indralin in comparative studies using different animal species]. / Shirota radiozashchitnogo deistviia indralina v sravnitelnykh issledovaniiakh na razlichnykh vidakh zhivotnykh.

In the experiments on mice, rats, hamsters, guinea pigs, dogs and Macaca Rhesus ED50, the width of radioprotective effect of indralin from alpha-adrenomimetics was investigated. It was made an estimate by ED50, LD50 and therapeutic index (TI): ED50/LD50. ED50 of indralin i.m. on mice is 21.9 (16.2-29.4) mg/kg, on guinea pigs --28.8 (17.0-49.0) mg/kg, on hamsters --50.7 (42.9-59.8) mg/kg and on dogs --6.0 (4.3-8.3) mg/kg. TI of indralin i.m. for same animals is correspondingly equal to 23.7 (15.3-36.5), 25.6 (13.7-47.4), 17.8 (14.8-24.1) and 31.1 (20.6-47.3). TI of indralin p.o. for rats and dogs is close to 18.2 and 23.7. Under the equal conditions TI of cystamine for mice, rats (i.p.) and dogs (i.v.) is respectively 3.3 (2.82-3.70), 2.1 (1.57-2.82) and 1.22. T50 of the elimination of indralin on mice (100 mg/kg i.p. and i.m.) for toxicologic properties measured circa 5-10 min. Under the conditions of repeated application in 30-60 min indralin desensitization to toxic doses happened as the rise of LD50 by 15-30%. T50 of the elimination of indralin in optimum doses for the pharmacodynamic of radioprotective effect is 19.3 (13.3-28.0) min on mice, --19.2 (15.3-25.9) on hamsters, --26.9 (20.4-35.5) on rats and --40.2 (30.5-53.1) min on dogs. In the transition from the experiment on mice to dogs twofold rise of T50 of the elimination of indralin doesn't combine with adequate increase the toxicity of the radioprotector. Pathophysiologic foundation of distinctions between aminothiols and radioprotector realizing the effect through cell receptor in the width of radioprotective effect is discussed.

[The role of cell hypoxia in the effect of radiation protectors]. / Rol' kletochnoi gipoksii v protivoluchevom éffekte radioprotektorov.

In experiment with mice, rats and dogs the intimate relationship has been established between radioprotective efficiency of indraline, cystamine and mexamine and its properties to enhance succinate dehydrogenase (SDG) activity of blood lymphocytes (r = 0.95). In that analysis modifying effect of normobaric hyperoxia has been estimated. Mice and dogs were correspondingly irradiated with gamma-60Co-rays in the dose 8.33 and 3.16 Gy. In the investigation involving mice, dogs and men the effect-dose dependence of aggravating of the SDG activity was linear for indraline, but not for cystamine. In man hypoxic hypoxia with air-hypoxic mixture containing 10% of oxygen has initiated rise of the SDG activity being twice as smaller as the one when indraline in the dose of 100 mg administrated. Hyperoxia suppressed radioprotective properties of indraline, cystamine and mexamine in the ED50 in term of DRF by twice and didn't virtually influenced on that in the optimum radioprotective doses. Hyperoxia and alpha-adrenoblocator tropaphene also suppressed the SDG response to indraline. In vitro experiment cystamine and adrenaline held stimulating action on SDG of blood lymphocytes. The role of pharmacological stimulation of cell respiration and cell hypoxia relating with the one in mechanism of radioprotective effect of the radioprotector of two dissimilar groups was discussed.

[The role of the vasoconstrictor effect in realizing the radioprotective properties of indralin in experiments on dogs]. / Rol' vazokonstriktornogo éffekta v realizatsii protivoluchevykh svoistv indralina v opytakh na sobakakh.

In the experiments on dogs, the role of a pharmacological circulatory hypoxia in the mechanism of radioprotective effect of indraline and mexamine was studied. Angiography revealed 20-40% vasoconstriction of major arteries of legs of animals, of pelvis and abdomen caused by mexamine (10 mg/kg) and the absence of a significant effect of indraline. Disruption of a regional blood circulation in the marrow and spleen (40-50% and 70-80%, respectively) was caused by indraline to the same extent as by mexamine. For indraline, a decrease in pO2 in the marrow was about 50%. With these hemodynamic disturbances, indraline showed 80 to 100% radioprotective effect, while mexamine was inefficient. Acute hypoxic hypoxia (5-7% O2) increased a post-radiation survival rate for dogs by 40%. The radioprotective effect of indraline was blocked by tropaphen and reduced in cases of breathing with pure oxygen. Splenectomy has no effect on radioprotective properties of indraline. Thus, a hypothesis of the mechanism of a radioprotective effect of alpha-adrenomimetics was proposed.

[Mechanism of the radiation-protective effect of indralin]. / K mekhanizmu protivoluchevogo deistviia indralina.

Pharmacological test demonstrated that radioprotective activity of indralin occurs by interaction with alpha-adrenoreceptor. Radioprotective effect of indralin decreased by alpha-adrenoblocker, aminazine and theophylline. Normobaric hyperoxia during irradiation reduced radioprotective effect of indralin in doses about ED50. In experiment with mice and rats it was shown that indralin induced acute hypoxia, impaired oxygen consumption and heat production by 30-46%, spleen bloodflow to 26.3% of control level, rectal temperature by 1.5-2 degrees C (mouse). After 30-min indralin raised resistance of mice to hypoxic hypoxia that is believed due to rapid development of biochemical adaptive process in hypoxic cells.

[Studies of the radiation-protective effects of indralin on the hematopoietic system of different species of animals]. / Issledovanie radiozashchitnogo éffekta indralina na krovetvornoi sisteme u razlichnykh vidov zhivotnykh.

The experiments were made on mice, guinea pigs and dogs. Radioprotector indraline increased radioresistant state of hematopoietic stem cells in vivo and in vitro, decreased the amount of post-radiation chromosome aberrations in marrow, induced more early and intensive post-radiation proliferative repair of marrow and spleen, faster regeneration of the initial amount of leukocytes, thrombocytes and erythrocytes in blood of mice, guinea pigs and dogs. Antiradiation efficiency of indraline in hematopoietic system is equal to 1.5-2 by FMD. Radioprotective mechanism of indraline effect on hematopoietic system is discussed.

[Effect of indralin on genetic disruption induced by radiation in mice]. / Vliianie indralina na geneticheskie narusheniia, indutsirovannye radiatsiei u myshei.

The effect of indralin on frequency of mutations induced by radiation in germ cells, reciprocal translocations, and testicle weight of male mice. The level of protective effect against genetic damage varied depending on the radiation dose and spermatogenesis stage. The values of the defense coefficient ranged from 0.16 to 0.35.

[Problems of variability in weightlessness]. / Problemy izmenchivosti v nevesomosti.

The genetic (cytogenetic) effects of microgravity have been under study for about 30 years. This line of research developed through three periods. Initially, biologists raised the question whether microgravity may act as a lethal factor or a strong mutagen. Many flight experiments gave a negative answer to it. The major goal of the second period was to identify the effects of microgravity at the chromosomal and cellular levels. Such effects, statistically significant although small in value, were detected in Tradescantia paludosa and Drosophila melanogaster microspores. These findings were confirmed by American and--later--by European investigators. The third period addresses the entire problem of variability in microgravity. This approach can be implemented on the basis of a comprehensive program of research that will include experiments at different levels: from the gene to the population level. The basic objective of the program is to clarify the role of the genetic apparatus in the adaptation of living systems to microgravity and, consequently, to determine the role of gravity in the evolution of life on the Earth.

[Combined action of vibration and ionizing radiation on the body]. / Kombinirovannoe deistvie vibratsii i ioniziruiushchego izlucheniia na organizm.

The effect of vibration on the development and outcome of radiation injury was studied and the efficacy of pharmacochemical and local protection was measured. The biological effect of the combined exposure was estimated by radiobiological and hematological methods. The animals were exposed to vibration with a frequency of 70, 700, 1500 Hz (during single and repeated exposures) and irradiation with X-rays, gamma-rays and protons at different doses. Vibration may exert a significant effect on the development and outcome of radiation injury of animals. The effect was that this factor was capable either of increasing or decreasing responses of the animal body to ionizing radiation. The direction and level of changes depended on the pattern and force of stimulation, time and sequence of action of factors, etc. The lymph tissue showed high sensitivity to vibration. The findings indicate that vibration may both enhance and diminish the efficacy of antiradiation pharmacochemical drugs.

[Dynamics of morphologic changes in joint innervation during hypokinesia--a space flight model factor]. / Dinamika morfologicheskikh izmenenii nervnogo apparata sustavov pri gipokinezii--model'nom faktore kosmicheskogo poleta.

Using statistical treatment, a neuromorphological examination of the joint capsule of rats exposed to hypokinesia for 7, 15, 20, 30, 40, and 60 days was carried out. The exposure to 7 days caused an increase in the number of reactively changed nerve fibers and receptors. The exposure to 15 days resulted in a significant increase of the number of nerve fibers with destructive changes that involved mostly large-caliber fibers. However, 20- and, especially, 30-day hypokinesia was followed by a significant reduction of destructive changes. After 40- and 60-day exposure they again became very distinct. This suggested a wave-like pattern of structural changes. At every stage of experimental hypokinesia all the compartments of the joint nervous apparatus showed adaptive-compensatory reactions.

[Species-specific reactions of succinate dehydrogenase of lymphocytes in animals to acute hypoxic hypoxia and its relation to the radiation resistance of the body]. / Vidovye osobennosti reaktsii suktsinatdegidrogenazy limfotsitov u zhivotnykh na ostruiu gipoksicheskuiu gipoksiiu i ee sviaz' s radiorezistentnost'iu organizma.

Experiments on rats and dogs showed that acute hypoxic hypoxia caused an increase of succinate dehydrogenase (SDH) in blood lymphocytes. The rate of SDH increase (VSDH) depended on the oxygen concentration in the breathing hypoxic mixture (BHM) and the animal species. In dogs it proved to be lower than in rats. Experiments on mice, rats and dogs were carried out to study the correlation between the level of the dose decrease factor (DDF) of the BHM and the animal species. The radiation resistance of the animal body in a hypoxic environment was evaluated with respect to the severity of the hypoxic state. A formula has been developed that can help determine ionizing radiation resistance of the animal in a hypoxic state. The formula based on the lymphocyte VSDH is as follows: DDF of BHM = 0.97 + 0.215 VSDH. By calculating the radioprotective effect of the BHM as a function of oxygen consumption, the applicability of the formula to such animal species as rats and dogs has been verified.

Heat stress in microwave irradiation.

In experiments on 159 sexually mature dogs with an average weight of 6.5 + 0.71 kg, a study was made of the dynamics of physiological indices (rectal temperature, respiration and heart activity) of heat stress and various (%) effects of damage depending on power density (500, 300, 100 mV/cm2) and duration of microwave irradiation (2400 MHz). On the basis of the data obtained, it was established that the relationship between power density and duration of microwave irradiation with an equally probable (0.1%) effect of damage may be interpolated (100 < power density < 500) by an exponential equation of the type y = 1416 x-0.8156, where y = power density, mV/cm2, and x is the time of irradiation in minutes. The probability characteristic of adaptation possibilities of functionally critical values of damage not exceeding the indeterminate probability is obtained.