The inhibitory effect of daily s.c. administration of cca 50 micrograms kg-1 17-beta-estradiol on liver alanine aminotransferase activity of adult female rats, the absence of this effect after bilateral adrenalectomy and its reappearance after gluccorticoid substitution is described.

The effects exposing rats to space flights of various lengths in a series of COSMOS satellites are reported based on an evaluation of plasma hormone levels and several enzyme activities in the tissues. The results after space flights are compared with those obtained from rats exposed to acute or repeated stress. Space flight induced selective morphological responses in the corticotrophs and gonadotrophs of the pituitary. Plasma levels of ACTH did not change, but plasma growth hormone and TSH levels decreased after longer space flights (>14 days), while prolactin in the plasma increased after short flights (5-7 days). Plasma corticosterone was higher after all flights. Catecholamine levels in plasma increased only after long space flights. These changes in plasma hormone levels affected the activities of enzymes involved in the amino acid metabolism of the liver and lipolysis in the adipose tissues. Norepinephrine level and catecholamine synthesizing enzyme activity in the hypothalamus did not change in flight rats. The norepinephrine content, however, decreased in several nuclei selected from the hypothalamus of flight rats. Increases in plasma insulin and glucose were noted in rats after space flight. Glucagone values in plasma remained unchanged. Comparing these results from flight rats against rats exposed to acute or repeated stress indicate that long stays in microgravity do not represent intensive stressogenic stimulus of the adrenocortical and sympathetic adrenomedullar systems, and hormone alterations observed after space flight may be due primarily to acute stressor activity resulting from a return to Earth's gravity (gravitational stress).

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.

The aim of present experiment was to study the changes of corticosterone, insulin and glucose levels in plasma, of the activity of enzymes involved in aminoacid metabolism in liver and the binding of insulin to specific receptors of cell membrane from liver and also of adipose tissue of rats exposed to space flight for 14 days on biosatellite Cosmos 2044. Adult male Wistar rats (body mass 300-370 g) were divided into five groups: intact control rats (AC), rats exposed to space flight (F), animals in synchronous model experiment (S), rats in antiorthostatic hypokinesia (A) and so called operated control group (C). Half of all groups (5 animals) except the intact control were operated 3 days before the experiment (fibulas on both hind legs were broken). The flight animals were sacrificed 5-6 hours after landing. It was observed that plasma insulin levels are increased in rat exposed to 14-day space flight and in synchron experiments. A significant increase of plasma glucose levels was found in flight rats in spite of high insulin concentrations suggesting that in rats exposed to 14-day space a deterioration of tissue sensitivity to insulin could by present. No significant differences of specific insulin binding to liver plasma membrane fraction in flight and intact control animals were observed. A decrease of insulin binding capacity in liver was found in rats in antiorthostatic hypokinesia (A). However in the membrane of adipocytes an important increase of insulin receptors was noted in rats subjected to space flight. These results suggest, that the liver and adipocyte insulin receptors of flight rats did not respond to the increased plasma insulin levels by "down regulation". The determination of plasma corticosterone levels showed that in flight rats and animals exposed to antiorthostatic hypokinesia the plasma hormone levels are significantly elevated. A significant increase of tyrosine aminotransferase and tryptophan pyrrolase activities in liver of flight rats and those exposed to hypokinesia was observed. Also the elevation of alanine amino-transferase in liver was observed in flight rats, while, the activity of aspartate aminotransferase in liver was similar in control and flight animals. These results showed that the changes in liver enzyme activities in rats after 14-day space flight are in agreement with the results observed in previous experiments after a shorter space flight (7 days).

Growth hormone secretion after L-dopa administration (1000 mg p.o.) was investigated in young adult normal and blind volunteers. The average increment of plasma growth hormone after L-dopa stimulation in the blind was below the criterion for a positive response (less than 5 ng ml-1). The control volunteers showed normal response. After L-dopa stimulation there was a significantly diminished growth hormone response in the young adult blind compared to control volunteers.

Adult rats of both sexes were injected an aqueous suspension of progesterone in a dose of 12.5 mg i.p. + 12.5 mg i.m. and 50% of the animals were subjected to immobilization stress for 150 minutes either immediately after the hormone administration or at various time intervals after that. Non injected rats served as controls. After decapitation the plasma corticosterone level and the activity of tyrosine aminotransferase and tryptophan pyrrolase in the liver was determined. It was found that in non immobilized animals all three parameters investigated were increased to a minor degree 3 hours after progesterone injection. In stressed rats the stimulatory effect of stress induced hypercorticosteronaemia on the activity of both enzymes was decreased at 14 and/or 20 hours after progesterone administration, no sex differences being observed. The potential usefulness of progesterone as inhibitor of exaggerated stress is underlined.

Infusion of 0.5 ml kg-1 min-1 20% glucose i.v. failed to suppress the stimulatory effect of 0.25 microgram kg-1 min-1 epinephrine dissolved in and infused together with the above glucose solution on the activity of liver glycogen phosphorylase in adult male rats. However, 40% glucose solution administered in the same way abolished the effect of the epinephrine infusion completely. An i.v. pulse of 1 g kg-1 glucose in the form of a 40% solution immediately before the infusion of the same dose of epinephrine in saline had only a temporary inhibitory effect on epinephrine induced increase of phosphorylase activity. Finally, i.p. administration of 10 mg kg-1 phentolamine 60 min before epinephrine infusion in saline completely blocked the increasing effect of the latter on both liver phosphorylase and serum glucose, while that of 4 mg propranolol 30 min before the hormone failed to exert any influence. This reconfirmed the well known mediation of the glycogenolytic effect of catecholamines in adult male rats by alpha type adrenergic receptors.

An as yet undescribed biphasic response of liver tyrosine aminotransferase (TAT) activity to a single administration of a microcrystallic watery suspension of 25 mg of progesterone (Agolutin Depot, SPOFA Praha) is described in adult female rats subjected to immobilization stress for 150 min. Exaggeration of the stress induced increase of TAT activity 3 and 8 h after hormone administration and its suppression 20 h after it was observed. The stress induced serum corticosterone increase is not correlated with the described changes, however, in non-stressed animals an increased TAT activity at 3 and 8 h after progesterone injection tightly follows the increased plasma corticosterone values. No statistically significant changes were found with respect to liver tryptophan pyrrolase activity.

The interactions of the effects of i.v. injections of 1.00, 0.50 or 0.25 g kg-1 glucose with those of i.v. administration of 0.5 or 1.0 microgram kg-1 epinephrine applied 10 min after glucose on the activity of liver glycogen phosphorylase and glycogen synthase were studied one minute after the hormone injection in adult male rats which had fasted for 24 h. The administration of 0.5 microgram kg-1 epinephrine failed to influence the activity of either enzyme. After the dose of 1.0 microgram kg-1, however, phosphorylase activity increased, that of synthase decreased. This effect of epinephrine on the activity of both enzymes was counteracted by 1.00 and 0.50 g kg-1 of glucose, that of synthase even by 0.25 g kg-1 of glucose. A stimulatory effect of glucose on synthase a activity was confirmed. A similar effect on total synthase activity is being described both in fed rats and those which had fasted for 24 h. In fed animals a decreased sensitivity of synthase against physiological levels of catecholamines and the paradoxical rebound of the sensitivity after an i.v. glucose load of 1.00 g kg-1 were observed.

In adult male rats anaesthetized with pentobarbital the intravenous infusion of 0.5 micrograms.kg-1.min-1 of epinephrine increased liver phosphorylase a activity within 5 min, whereas later a weakening of the hormone effect was observed. After increasing the infusion rate to 1.0 micrograms.kg-1.min-1 and extending the study to more parameters, the diminishing effect on phosphorylase was confirmed and a similar response was established for liver cAMP. Concomitantly, a decrease and recovery of liver glycogen synthase a activity was observed. In rats with permanent catheters in one of their tail arteries for obtaining blood samples, the plasma epinephrine levels were shown to be permanently increased (from cca 1 pmol.ml-1 before infusion of 1.0 micrograms.kg-1.min-1 to more than 30 pmol.ml-1 during infusion) and remained at steady levels throughout the infusion. Therefore, the weakening of the epinephrine effect should be ascribed to changes at (or beyond) the catecholamine receptor level. A hitherto undescribed decrease of total glycogen synthase activity was observed during the infusions.

In adult male rats anaesthetized with pentobarbital, intravenous infusion of 0.25 microgram kg-1 min-1 of epinephrine increased plasma epinephrine levels to more than 10 pmol ml-1 within 5 min, the values remaining constant during the next 20 min. On the other hand, a maximal increase of liver phosphorylase a was found after 5 min and this response was attenuated at 10 and 20 minutes in the fed rats. Fasting for 24 h extinguished the greatest part of this response. During infusion, a decrease of liver synthase a activity was observed in the fasted and of total synthase activity in both the fed and fasted animals. In fed rats an i.v. bolus of 0.50 microgram.kg-1 or doubling of the infusion rate for 5 min, both immediately after 20 min of infusion, led to maximal phosphorylase a activity again and to a decrease of synthase a activity. The levels of cAMP in the liver were increased by the infusion in one series and unchanged in another.

Endogenous corticosterone released in protracted immobilization stress fails to increase the activity of liver glycogen synthase, perhaps because of the inhibition of synthase phosphatase by phosphorylase a. It was also found, that in rats subjected to acute immobilization stress the stimulation of the activity of both synthase a and total forms by glucose administered i.v. is depressed. Finally, in rats fasting for 24 h a paradoxical augmentation by glucose of the stimulatory effect of glycogenolytic hormones released in acute immobilization stress on phosphorylase a activity was observed.

Glycogen phosphorylase activity was determined in rat livers obtained by laparotomy in thiobarbital (Inactin, PROMONTA) anaesthesia induced by injection of the drug via a polyethylene catheter into a jugular vein as described previously [Németh et al. 1983a]. Intact rats and animals exposed to open field stress without or after i.p. injection of the alpha blocker phentolamine (Regitine, CIBA; 20 mg kg-1, 90 min before stress) or the beta blocker propranolol (Inderal, ICI; 2 mg kg-1, 30 min before stress) were studied. In stressed animals a net increase of phosphorylase activity was observed. This response was abolished after alpha blockade, while after beta blockade it was potentiated. In a further series on animals subjected to the same type of anaesthesia, the activating effect of immobilization stress on phosphorylase activity was confirmed in both fed and fasted animals, the response of the latter issuing from a lower initial level but being of the same extent as in the fed rats.

The release of endogenous corticosterone was stimulated by intraperitoneal administration of ACTH to conscious rats. Corticosterone had no reproducible stimulatory effect either on the activation of synthase or inactivation of phosphorylase. On the other hand, an induction of the synthesis of total synthase enzyme protein was observed which could be blocked by actinomycin D. In Sephadex-filtered liver homogenates, a particularly impaired pattern of phosphorylase inactivation/synthase activation was observed during incubation at 20 degrees C in the ACTH-treated rats.