Physical Fatigue and Morphofunctional State of the Myocardium in Experimental Chronic Stress.

The relationship between the development of skeletal muscle fatigue of a specific type in male Wistar rats and morphofunctional alterations in the myocardium in the posttraumatic stress disorder (PTSD) model has been investigated for the first time. The aggravation of oxidative stress in the cardiomyocytes and the related transformation of the cell structural components and the depletion of energy reserves in PTSD has been identified as one of the main factors that accelerate the onset of musculoskeletal fatigue.

Behavioral Activity and Some Markers of Posttraumatic Stress Disorder among Serotoninergic System Indicators and Glucocorticoid Metabolizing Enzymes in Rats with Different Duration of Hexenal Sleep.

Post-traumatic stress disorder was imitated in rats with long and short hexenal sleep by exposure to cat odor. Rats with long hexenal sleep demonstrated the highest sensitivity to posttraumatic stress disorders and developed anxiety and depressive disorders. The duration of hexenal sleep correlated with changes in markers of post-traumatic stress disorder, e.g. activity of 11ß-hydroxysteroid dehydrogenase-2 in the liver of non-stressed animals and serotonin and monoamine oxidase A activity in the brain of stressed animals.

[CHRONIC UNPREDICTABLE STRESS OF PREGNANT RATS AND HEALTH OUTCOMES OF THEIR OFFSPRING].

It was established that chronic unpredictable stress, which was reproduced by repeated exposure of adverse factors on the pregnant rats (food deprivations during one day, immobilization in the water of room temperature and contact with Felis excrements) results in the stable and sex-specific offspring's behavioural changes in the «open field¼ test, disorders of motor and coordinator functions and the increased sensitivity to pain at the age of both 1 and 3 months. Male and female rats, which were exposed to the prenatal stress, demonstrate elevated blood pressure. Enhanced lipoperoxidation in the blood serum of male rats after prenatal stress was indicated. Thus, prenatal stress leads to the stable alteration of the reactivity, which may favour persistent social maladjustment and the development of different pathologies.

[A MODULATORY INFLUENCE OF THE iNOS ON THE FUNCTIONAL ACTIVITY OF THE KATP-CHANNELS IN CORONARY VESSELS OF RATS ADAPTED TO THE STRESS].

In the experiments carried out on the isolated by Langendorff's method hearts which were perfused at the constant coronary flow it was studied influence of iNOS-derived NO on the functional activity of the KATP-channels in the coronary vascular smooth muscle cells following formation of the adaptation to the stress. As an adaptation to the short stress as a 6-hours immobilization stress result in increase of NO production and rise of expression of gene iNOS; however, adaptation in contrast to the stress leads to moderate accumulation of iNOS against the background unchanged systemic activity of еNOS and in the absence of systemic low-grade inflammation. After an adaptation to the short stress or after 6 hours of immobilization the functional glybenclamid-inhibiting activity of the KATP-channels was suppressed. Nevertheless, after prolonged immobilization suppressed activity of the channels was abolished after blockage of iNOS, whereas iNOS blockage in adapted animals leads not only to the recovery but even to the hyperactivation of the KATP-channels. Hence, increase in NO production which is typical for the adaptation, limits activation of the KATP-channels thus creating a strong link between these channels activity and NO produced by iNOS.

Changes in the profile of NO synthases affect coronary blood flow autoregulation and myocardial contractile activity during restraint stress in rats.

The efficiency of autoregulation of the coronary blood flow and contractile activity of the myocardium in the presence of inhibitors of constitutive and inducible NO synthases was studied in rats exposed to 6-h restraint stress. Intracoronary administration of S-methylisothiourea (10 µmol/liter), but not L-NAME (60 µmol/liter) fully prevented post-stress increase in the volume coronary blood flow rate, intensity of heart perfusion, and reduction of ventricular developed pressure at all levels of perfusion pressure. Real-time PCR showed 6-fold increased expression of inducible NO-synthase mRNA in the heart tissue against the background of unchanged expression of neuronal and endothelial NO synthases and 2-3-fold elevated content of transcripts of stress-inducible genes Hspa1a and Hspbp1. It was shown that the hypotension of coronary vessels and reduced contractile function of the myocardium are related to NO production by inducible NO synthase in endotheliocytes of coronary vessels and cardiomyocytes.

[The special role of inducible NO-synthase in the mechanism of rat coronary vessels tone regulation during immobilization stress, combined with diabetes mellitus].

Persistent hyperglycemia after intraperitoneal injection of streptozocin (50 mg/kg) to the rats prevents decrease of coronary vessels myogenic tone and myocardial contractility during subsequent 6-hr immobilization stress. The intensity of these abnormalities in all experimental groups is significantly reduced with the supplement of the perfusate with inducible NO-synthase (iNOS) selective blocker S-methylisothiourea. Similar rise of the NO2-/NO3- concentration in the rats' blood after "stress", "diabetes mellitus" and "diabetes mellitus + stress" combines with an increase of iNOS transcripts in the myocardium to 6, 5.8 and 51 times compared with control. These data testify to a substantial modification of the cells from coronary vessels in the presence of marked and persistent hyperglycemia. Inducible NO-synthase uncoupling caused by excessive formation of the reactive oxygen and nitrogen species in the myocardium may be one of number mechanisms responsible for such phenotypic vascular alteration in the "stress + diabetes mellitus" group.

Functional activity of BK(Ca) channels in coronary vascular smooth muscle cells during combined exposure to hyperglycemia and stress.

The effect of tetraethylammonium in a dose of 1 mM (inhibiting functional activity and preventing opening of BKCa channels) was least pronounced during restraint stress. The influence of this agent was more significant in animals exposed to 14-day hyperglycemia alone or in combination with restraint stress. Therefore, hyperglycemia and stress (individual or combined exposure) significantly inhibit functional activity of BKCa channels in smooth muscles of the coronary vessels. Our results suggest that the development of hyperglycemia is realized via pathogenetic mechanisms of vascular injury in the heart (similarly to stress conditions). Permanent increase in blood glucose level and 6-h immobilization probably induces nonspecific post-stress abnormalities in channel function.

Adaptation to short-term stress exposures prevents poststress dysfunction of calcium-activated potassium channels in coronary vessels.

Adaptation to short-term stress exposures prevents immobilization stress-induced decrease in functional activity of BK(Ca)channels in smooth muscle cells of coronary vessels developing against the background of NO overproduction and increase in the relative content of oxidized glutathione (change in redox state of the glutathione system). The protective antistress mechanisms of adaptation probably include prevention of NO overproduction by inducible NO synthase and maintenance of dependent glutathione redox state functional activity of BK(Ca)channels in smooth muscle cells of coronary vessels.

[Nitrogen monoxide and functional activity of large conductance Ca-activated potassium channels in coronary vessels in rats with limited motor activity].

The study was aimed at the detection of endothelial factors contribution and nitric monoxide produced by constitutional and inducible NO-synthase in regulation of Ca-activated potassium channels activity of high conductivity in immobilization stress. The experiments were conducted in isolated rat-female hearts after retrograde perfusion with Krebs-Henseleit solution bubbled with 95% O2, 5% CO2 at 37 degrees C. To study BK(Ca)-channels role in the regulation of coronary vessels tone and contractile myocardial function BK(Ca)-channel blocker tetraethylammonium (ImM/l concentration) (Sigma, USA) was added in perfused solution. The obtained results justify: firstly, the non-selective blockade of constitutional and inducible NO-synthase L-NAME accompanied by the reduction of coronary flow volume velocity to control values level in the group of animals underwent to stress; second, selective blocker of inducible NO-synthase S-methylisotiourea completely eliminates evoked by stress hypotonia of cardiac vessels and reduction of contractile activity of left ventricle in stressed rats; thirdly, stress reduces the functional activity of Ca-activated potassium channels and the removal of endothelium or blockade of nitric monoxide completely it restores.

[Adaptation to short-term stress exposure increases the activity ATP-sensitive potassium channels in the smooth muscle cells of coronary blood vessels].

The study was aimed at the effect of prior adaptation to short-term stress exposure on changes in K(ATP)-channel activity induced by severe stress and the dependence of the changes on the state of endothelium which plays important role in autoregulation of the coronary flow and myocardial contractility. Experiments were conducted on isolation hearts of female rats. At the first step of experiment, the heart was perfused by Krebs-Henseleit solution; at the second step, the heart was perfused with the same solution in which glibenclamide (1 microM), glibenclamide with saponin or N(omega)-nitro-L-arginine (60 microM) methyl ether was added. During the experiment, the perfusion pressure was stepwise elevated from 40 to 120 mm Hg with 20 mm intervals (coronary autoregulation). Adaptation to short-term stress prevented development of stress-specific myocardial hyperperfusion (increased volumetric velocity of coronary flow against the background of decreased myocardial contractility) and the reduction of coronary dilation reserve. In coronary vessels of adapted rats, as distinct from control rats, basal glibenclamide-sensitive functional activity of K(ATP)-channels depended on presence and functional activity of endotheliocytes; it was reduced in presence of endothelium and increased after de-endothelization or NO synthase inhibition. In all experimental groups, the increase in glibenclamide-sensitive functional activity of K(ATP)-channels induced by NO synthase inhibition more than twice as great as after the endothelium denudation. In adapted animals, stress did not decrease the functional activity of K(ATP)-channels and their activity slightly depended on presence of endotheliocytes. In addition, the elevation of their functional activity characteristic of adaptation and evident after endothelium removal has vanished. Therefore adaptation to short-term stress exposure is associated with a potential increase in basal activity of K(ATP)-channels which enhances the potency of vascular dilation system and may apparently reduce the risk of high vascular tone when such important local regulatory system as the NO system is damaged.

[Participation of ATP-sensitive potassium channel in autoregulation of coronary blood flow under the condition of limited motor activity].

The aim of study involved detection of the effect of the K(ATP)-channel blocker glibenclamide on autoregulation of coronary flow, the expression of reactive hyperemia, the value of coronary dilatation reserve, and the myocardial contractile function in isolated rat hearts after a 6-hour immobilization stress. The experiments have been performed on 64 isolated rat hearts (female): into the cavity of left ventricle, a latex balloon connected with electromanometer has been introduced. Every experiment consisted of 2 stages. The heart has been perfused by Krebs-Henseleite solution in the first stage, and in the second stage--by the same solution with glibenclamide (1 mkM) or its combination with verapamile (10(-)6 M) or saponin (44 mcg/ml of coronary flow within 2 minutes) added to it. During the experiment, the perfusion pressure has been elevated step by step from 40 to 120 mm Hg with 20 mm Hg steps (coronary autoregulation). In rats after immobilization, the glibenclamide effect on cardiac vessel tone and expression of maximal hyperemic coronary flow (in contrast to its influence on myocardial contractile function) is lower than in control and depends on endotheliocyte presence which suggests an important role of endothelium in maintaining cardiac vessel smooth cell activity of K(ATP)-channels inhibited under the stress condition. After immobilization stress, the role of endothelium in the reactive hyperemia origin was enhanced, that of the K(ATP)-channels was reduced. The general activity of both mechanisms of tone regulation of cardiac vessels remains the same as in control. This suggests that the K(ATP)-channels as nitric monoxide and eicozanoids are the local system of myogenic tone regulation of the rat cardiac vessels; that the rat immobilization inhibits the activity KATp-channel's smooth cells of coronary vessels and creates a marked dependence of their activity on endothelium presence.