Catecholamines,nitrogen oxide,and resistivity to stressor lesions: effect of adaptation to hypoxia

Pronouncement of stress-induced disturbance of searching behaviour (using "open field" test) and stomach ulceration were compared for the first time with activity of the catecholamine system in hypothalamus and striatum and also with activity of the stress-limiting system of nitric oxide (NO) in the rats of two strains August and Wistar, which differ in their resistance against stress-induced cardiovascular disorders. The effect of prior adaptation to hypobaric hypoxia on these disorders was also studied. August rats appeared to be more resistant than Wistar rats against stress-induced disturbance of the searching behaviour and stomach ulceration. Results of measuring the content of catecholamines in brain structures and the content of NO stable metabolites nitrate/nitrite in plasma suggested that these differences could be due to the stress activation of the nigro-striatal dopaminergic system in August rats, which was not observed in Wistar rats, and also to the higher production of NO in August than in Wistar rats. Adaptation to hypoxia considerably restricted these stress disorders in rats of both strains. Importantly, the protective effects were associated with activation of the nigro-striatal dopaminergic system in all the animals. In the result, adapted Wistar rats, as distinct from non-adapted Wistar rats, displayed a stress activation of this system. The protective effects of adaptation were also accompanied by an increased NO synthesis. Taken together, the data suggest an important role of the responsiveness of the brain dopaminergic system and NO system in the mechanism of resistance against stress-induced disturbances.     

Prevention of arrhythmia in acute ischemia in conscious animals using a serotonin analog

The state of the serotonergic system was studied in adaptation of rats to short-term non-damaging stress actions along with the possibility of protecting the heart of conscious animals against arrhythmias in acute ischemia with the serotonin analogue 4-nitro-5-methoxytryptamine. It was shown that the adaptation resulted in a significant increase in rat midbrain serotonin by 70%. Preliminary administration of the serotonin analogue 3 fold reduced the total duration of arrhythmias and approximately 5 fold--the heart fibrillation rate and the death rate of animals in acute ischemia. The data obtained are in agreement with the idea on the role of stress-limiting systems in prevention of stress-induced and ischemic damages of the organism. They show that protective effects of metabolites of these systems can be successfully reproduced with their synthetic analogues or activators.     

Oxidative phosphorylation and ion transport in the mitochondria of two strains of rats varying in their resistance to stress and hypoxia

The role of mitochondria in the inherited or ontogenetically acquired reactions of organism to stress is not studied enough. In the present work, we examined the functional state of the coupled respiratory chain, potassium and calcium transport and rate of hydrogen peroxide production on two rat lines: August and Wistar—which possess different resistance to emotional stress and hypoxia. It was established that the respiration rate and efficiency of oxidative phosphorylation were higher in August rats than in Wistar ones. In August rats, the rate of potassium transport and ATP-dependent mitochondrial swelling as well as the concentration of the ion in the mitochondrial matrix were almost twice as higher comparatively to those parameters in Wistar rats. The rate of H₂O₂ production was found to be decreased in the mitochondria of August rats. It was also demonstrated that the two rat lines differed by their resistance to the opening of the palmitate/Ca²⁺-induced pore and by their ability to retain calcium within mitochondria. The paper discusses the involvement of the mitochondrial ATP-dependent potassium channel in the adaptation of animals to adverse effects.     

Stress-limiting nitric oxide system

The work substantiates a concept of the nitric oxide (NO) system as a universal transmitter and controller of physiological functions and as a new stress-limiting system. The NO system can be activated by a stress, restrict release and/or production of stress hormones, restrict the stress damage to the organism, enhance the organism's resistance against stress, can be activated in adaptation to repeated exposure to environmental factors. Some specifics of the NO system differing it from other stress-limiting systems, are discussed.     

Stability of the cardiovascular functions of different genetic strains of rats subjected to emotional stress

The level of catecholamines was measured in various brain parts in rats of August and Wistar lines, characterized by different stability of cardio-vascular functions in emotional stress. In norm, the August line has a higher content of dopamine (DA), in the mid-brain in particular; the Wistar line has a higher content of noradrenaline (NA) in the hypothalamus. In susceptible animals, which showed different cardio-vascular disorders during 30 hours of immobilization (48% of the Wistar line and 90% of the August), and in animals resistent against emotional stress, the changes in the initial level of catecholamines were observed, both common and specific for two lines. An assumption is made that the stability of cardio-vascular functions in the emotional stress is provided for by an intensive metabolism of the NA-synthesizing neurones in the brain isthmus, and by a moderate activity of the DA-synthesizing neurones of the mid-brain; the susceptibility to cardio-vascular disorders in the emotional stress is due to increase in the activity of the DA-synthesizing mid-brain neurones, the decrease in the activity of the DA-hydroxilase and the exhaustion of NA in the hypothalamus.     

The intercellular connection of axons-capillaries in the light of genetically determined resistance to emotional stress

Genetic factor is one of the main factors of systemic organization of animal resistance to emotional stress. This notion served as a basis for comparing ultrastructural specific of connections between nervous and vascular systems in catecholamine-synthesizing areas of different lines of Wistar and August rats. Quantitative difference has been observed in the structure of cell junctions. This difference may determine different level of adaptive reactions of animals to stress.     

Learning in rats with differing emotional responsiveness and its relation to brain monoamines

The ability for learning was studied in two groups of Wistar line rats divided by susceptibility to the audiogenic stress-stimulation as compared with the monoamines level in various brain structures. The best ability to learn avoidance reaction in a shuttlebox was shown by animals non-resistant to the stress stimulus as compared with the resistant rats, which correlated positively with the exploratory activity in "the open field". The distinct feature of the animals non-resistant to the stress stimulation consisted in a higher reactivity of the monoamine systems, mainly of the noradrenergic system. This group of animals was also characterized by a higher dopamine content and a lower noradrenaline content in the brain-stem. Decreased activity of the brain dopamine-beta-hydroxylase in animals non-resistant to the stress stimulus, has been suggested.     

Sex-related patterns of body tolerance to repeated acute hypobaric hypoxia

The individual differences in the response of male and female rats to repeated exposure to acute hypobaric hypoxia were experimentally studied. The time of attitudinal reflex maintenance and recovery in a rotating decompression chamber as well as the value of hypoxic hypothermia after decompression to a simulated altitude of 11200 m were used to evaluate the tolerance to hypoxia. Males demonstrated a slightly higher reactivity than females. At the same time, a more efficient adaptation to hypoxia conserved the body’s compensatory capacity and rapidly restored the functions affected by repeated exposure to the extreme factor. Such long-term adaptation was observed in initially low-resistant females, which could increase their resistance to repeated exposures to the stress factor.     

Variability of hemodynamic parameters and resistance to stress damage in rats of different strains

Total power of heart rate variability and baroreflex sensitivity were significantly smaller in the August rats than in the Wistar rats, but adrenal and plasma catecholamine contents were considerably higher in the former ones. 1 hour after stress (30 min in cold water), plasma catecholamine was increased 2-fold in Wistar rats, while in August rats the adrenaline concentration increased only by 58% and the were no changes in noradrenaline content. At the same time, activation of catecholamine metabolism in the adrenal glands was similar in both groups. The oxidative stress induced by hydrogen peroxide depressed the contractile function of isolated heart in the August rats to a smaller extent as compared to Wistar rats, control ones and after the cold-water stress. This effect correlated with more pronounced stability ofantioxidant enzymes in the August rats. It seems that the greater resistance to stress damage in the August rats is mediated by enhanced power of defense mechanisms both at systemic and cellular levels.     

Characteristics of the behavior and adaptive reactions of amygdalectomized rats

The results are considered of the analysis of rats behaviour in tests of the open field, hot plate and passive avoidance, as well as data of temperature measurement and motor activity during repeated animals placing in conditions of moderate cold. It is shown, that in amygdalectomized rats the extinction of motor and vegetative reactions at their repeated placing in the open field and in cold is disturbed in comparison with the intact and partially with hippocampectomized animals. In contrast to intact and hippocampectomized rats, the amygdalectomized ones did not improve thermoregulatory stability at repeated cold exposures. Disturbance of activity of emotiogenic brain mechanisms modulating memory processes, is suggested as one of important causes of derangements of physiological functions adaptation after amygdalectomy. Existence of common mechanisms is postulated of emotiogenic regulation of adaptive transformations of behaviour and some physiological reactions to natural stimuli.     

Effect of preliminary adaptation to short-term stress exposure on the resistance of the spontaneously contracting myocardium to a lipid peroxidation inducer

Contractile function of the isolated right atrium was studied in male Wistar rats adapted to short-term stressor exposures at varying times after adaptation was completed. Adaptation to short-term stressor exposures induced a limited decrease in myocardial contractility immediately after adaptation was over. On the 3d day an additional reduction in the characteristics of contractile function was still observed. However, by the 5th day the characteristics recovered to the control level. At the same time adaptation completely prevented the derangement of myocardial contractility, induced by exposure to a prolonged stress. That protective effect was observed as early as adaptation was completed, on days 3 and 5 after adaptation, and became lessened on the 10th day. It is assumed that on the 5th day after adaptation the animals are in a postadaptation state where the untoward effect of adaptation disappears whereas the protective effect is demonstrable to a full extent. As a result all the characteristics of myocardial contractility following a prolonged stress on the 5th day after completion of short-term stressor exposures differed in no way from the control parameters.     

Nitric oxide storage in rats of various genetic strains and its role in the antistressor effect of adaptation to hypoxia

Adaptation to hypobaric hypoxia induced a gradual increase in the NO production along with a progressive NO storage in vascular wall. Unadapted August rats were more resistant against stress-induced stomach ulceration than the Wistar rats. Following a 6-day adaptation rats of both strains revealed a protective antiulcerogenic effect. A long-term adaptation potentiated the stress damage of the stomach rather than protected against it. A higher basal NO production seems to provide a more efficient antistress defence in the August rats. An intense NO storage may create a relative NO shortage and thus predispose to stress-induced vasoconstriction and ulceration.     

The relationship between glycemia, insulin and oxidative stress in hereditary hypertriglyceridemic rat

The aim of this study was to determine the effects of insulin infusion on oxidative stress induced by acute changes in glycemia in non-stressed hereditary hypertriglyceridemic rats (hHTG) and Wistar (control) rats. Rats were treated with glucose and either insulin or normal saline infusion for 3 hours followed by 90 min of hyperglycemic (12 mmol/l) and 90 min of euglycemic (6 mmol/l) clamp. Levels of total glutathione (GSH), oxidized glutathione (GSSG) and total antioxidant capacity (AOC) were determined to assess oxidative stress. In steady states of each clamp, glucose infusion rate (GIR) was calculated for evaluation of insulin sensitivity. GIR (mg.kg(-1).min(-1)) was significantly lower in hHTG in comparison with Wistar rats; 25.46 (23.41 - 28.45) vs. 36.30 (27.49 - 50.42) on glycemia 6 mmol/l and 57.18 (50.78 - 60.63) vs. 68.00 (63.61 - 85.92) on glycemia 12 mmol/l. GSH/GSSG ratios were significantly higher in hHTG rats at basal conditions. Further results showed that, unlike in Wistar rats, insulin infusion significantly increases GSH/GSSG ratios in hHTG rats: 10.02 (9.90 - 11.42) vs. 6.01 (5.83 - 6.43) on glycemia 6 mmol/l and 7.42 (7.15 - 7.89) vs. 6.16 (5.74 - 7.05) on glycemia 12 mmol/l. Insulin infusion thus positively influences GSH/GSSG ratio and that way reduces intracellular oxidative stress in insulin-resistant animals.     

Effect of chronic stress during prepubertal period of life on development of inherited arterial hypertension

The immediate and long-lasting effects of environmental stress during prepubertal life on arterial blood pressure (AP) were studied in rats with inherited stress-induced arterial hypertension (ISIAH) and normotensive Wistar rats. Two models of chronic stress (the 21st-32nd postnatal days) were used: repeated handling and unpredictable stress of daily exposures to a variety of mild physical or psychoemotional stressors. Chronic prepubertal stress did not affect the basal or stress-induced AP levels in young or adult Wistar rats. In ISIAH rats, chronic stress during the early phase of hypertension development did not accelerate its formation and did not augment its manifestation in adults. Moreover, the basal AP was decreased in young and adult ISIAH rats exposed to prepubertal stress as compared to the age-matched controls. AP elevation under acute stress conditions was lower in young ISIAH rats exposed to unpredictable stress. No long-lasting effect of prepubertal stress on acute stress-induced AP elevation in adults was found. The conclusion was drawn that moderate physical and psychoemotional training at prehypertensive stage can positively affect the development of inherited arterial hypertension.     

The exploratory behavior in an open field and in a burrowing chamber of rats with different predispositions to stress]

The peculiarities of oriental research behavior and correlation between activities of catecholaminergic and serotoninergic brain systems dependently on their stress resistance degree were investigated in Wistar rats. The experiments showed that resistant (R) to a sound stimulus rats differed from nonresistant (NR) ones by increased research activity under moderate stress in the open field test and by decreased research behavior level in the cell chamber test. The biochemical analysis of biogenic amines in different brain structures revealed increased norepinephrine levels in stress R rats, and increased dopamine and serotonin levels in NR ones. The findings suggest that inborn behavior regulation in animals with different stress resistance is determined by different correlations between serotonin-dopamine and norepinephrine brain systems activities.     

Spike activity of neurons of the ventromedial hypothalamus of the rat during stress

In fixed Wistar line rats, neuronal activity of the ventromedial hypothalamus was studied in conditions of acute emotional stress elicited by electric stimulation of the ventromedial hypothalamus stochastically alternating with electrocutaneous stimuli. Distinctions were revealed in neuronal activity of the animals with different stress resistance. The pattern of neuronal impulse activity proved to be the most informative one.     

Effect of prostaglandin E2 on the development of myocardial damage in rats with various resistance to hypoxia

Experiments conducted on male rats with congenital high and low resistance to hypoxia (HH and LH, respectively) have revealed, that injection of prostaglandin E2 (PHE2) 15 min before the injection of adrenalin essentially decreases the activity of lipid peroxidation in myocardium as compared with animals which have been injected to only adrenalin. This modulative effect (PHE2) on the action of adrenalin was more pronounced in LH-rats. Consequently, the activity of the prostaglandin stress-limiting system determines to a great extent the organism resistance to hypoxia.     

Increase of calcium-dependent activity of phospholipase C in the myocardium in adaptation of animals to short-term stress effects]

The effect of adaptation of rats to repeated short-term stress exposures was studied on the density and the affinity of alpha 1-adrenoceptors in the heart and on the phospholipase C activity and sensitivity to changes in Ca2+ concentration. It was found that adaptation to stress was accompanied by a desensitization of alpha 1-adrenoceptors and also by an increase in Ca(2+)-dependence of phospholipase C activity in the heart. The role of increased activity of phospholipase C and activated inositol triphosphate-diacylglycerol regulatory cascade is discussed as regard to the previously revealed accumulation of heat shock proteins in the myocardium and to the adaptive protection of the heart.     

The physiological reactions to stress in 3 strains of rats]

We have studied the resistance of Wistar, August, Fisher male rats to 2- and 24-hours immobilization by vegetative and behavioral reactions. The difference in the resistance has been observed both between the three lines of rats and within one particular line. The lowest resistance to stress has been demonstrated by Fisher rats, the highest by Wistar rats. The correlation between emotional reactivity of rats and their response to stress has been shown.     

Taurine modulates kallikrein activity and glucose metabolism in insulin resistant rats

Summary. Taurine, a potent antioxidant has been reported to show an antidiabetic effect in streptozotocin-induced diabetes mellitus in which the development of hyperglycemia results from the damage to β cells of pancreas by reactive oxygen species. In addition, taurine also increases the excretion of nitrite and enhances the formation of kinins and would be expected to improve insulin resistance. The effect of taurine on insulin sensitivity was examined in the high fructose-fed rats, an animal model of insulin resistance. Male Wistar rats of body weight 170–190 g were divided into 4 groups: a control group and taurine-supplemented control group, taurine supplemented and unsupplemented fructose-fed group. An intravenous glucose tolerance test (IVGTT) and a steady state plasma glucose level (SSPG) were performed before the sacrifice. The fructose-fed rats displayed hyperglycemia and insulin resistance and they had a greater accumulation of glycogen than did control rats. Hyperglycemia and insulin resistance were significantly lower in the taurine supplemented fructose-fed group than in the unsupplemented fructose-fed group. Urinary kallikrein activity was higher in taurine-treated animals than in the rats fed only fructose. The activity of membrane bound ATPases were significantly lower in fructose-fed rats than in the control rats and were significantly higher in the taurine supplemented group than in the fructose-fed group. Taurine effectively improves glucose metabolism in fructose-fed rats presumably via improved insulin action and glucose tolerance. Received January 5, 2001 Accepted August 21, 2001