Effect of acute alloxan diabetes on ischemic and reperfusion arrhythmias in rats with different activity of nitric oxide system.

Similar degree of glycemia (28-31 mmol/liter) and similar mortality (37-42%) were revealed in August rats exhibiting enhanced activity of NO system and in Wistar rats 3 weeks after alloxan treatment. Under conditions of myocardial ischemia caused by 10-min coronary artery ligation, the intensity of arrhythmias did not differ from the control in Wistar rats with diabetes mellitus and increased in August rats. Under conditions of reperfusion, diabetes produced an antiarrhythmic effect in Wistar rats and did not affect arrhythmia in August rats. Plasma concentrations of nitrates and nitrites in Wistar and August rats increased by 82 and 143%, respectively, compared to the control. The level of hemoxygenase-1 (hsp32) in the myocardium remained unchanged in Wistar rats and decreased by 26% in August rats. Thus, the absence of antiarrhythmic effect of acute diabetes in August rats is probably related to elevated NO content and reduced antioxidant activity.

Adaptation of the cardiovascular system to postinfarction cardiosclerosis in rats with congenital adrenoreactivity of the myocardium.

Three months after myocardial infarction the severity of heart failure and size of postinfarction scars in August rats with inherently reduced adrenoreactivity of the myocardium were similar to those in Wistar rats. The mortality rate in August rats was 2.5-fold lower than in Wistar rats. During the postinfarction period, myocardial adrenoreactivity in August rats remained lower, while the efficiency of cardiac function was 62% higher than in Wistar rats. The incidence of epinephrine-induced arrhythmias in August rats was much lower than in Wistar rats.

Heart resistance to oxidative stress in rats of different genetic strains.

In August rats reperfusion after regional myocardial ischemia in situ or intracoronary administration of hydrogen peroxide less significantly suppressed contractile activity of the heart compared to Wistar rats. Activities of catalase and superoxide dismutase in the myocardium during reperfusion remained unchanged in August rats. In Wistar rats a profound inhibition of cardiac function was accompanied by a decrease in enzyme activity.

Genetically determined differences in the resistance to myocardial infarction in Wistar and August rats.

In intact August rats, the cardiac contractile function at rest was by 76% higher than in Wistar rats, while their hearts, both intact and after acute myocardial infarction, were more resistant to isometric load than the hearts of Wistar rats. Postinfarction mortality in August rats was 18% vs. 70% in Wistar rats. Adrenoreactivity of the myocardium in August rats was decreased compared to that in Wistar rats. These peculiarities can determine high resistance of August rats to myocardial infarction.

Production and storage of nitric oxide in adaptation to hypoxia.

Adaptation to hypobaric hypoxia is known to exert multiple protective effects related with nitric oxide (NO). However the effect of adaptation to hypoxia on NO metabolism has remained unclear in many respects. In the present work we studied the interrelation between NO production and storage in the process of adaptation to hypoxia. The NO production was determined by the total nitrite/nitrate concentration in rats plasma. The volume of NO store was evaluated in vitro by the magnitude of isolated aorta relaxation to diethyldithiocarbamate. It was shown that both the nitrite/nitrate level and the NO store increased as adaptation to hypoxia developed. Furthermore, the NO store volume significantly correlated with plasma nitrite/nitrate. Therefore, adaptation to hypoxia stimulates NO production and storage and these effects can potentially underlie NO-dependent beneficial effects of adaptation.

[The production and deposition of nitric oxide during adaptation to hypoxia]. / Produktsiia i deponirovanie oksida azota pri adaptatsii k gipoksii.

It is common knowledge that adaptation to hypobaric hypoxia provides for a number of protective NO-dependent effects in the organism. However, many aspects of its influence on NO metabolism remain unclear. In this work we studied the relationship between NO production and deposition in the course of adaptation to hypoxia. No production was assayed by the total concentration of nitrates and nitrites in rat serum, while the volume of NO depot was determined from the level of isolated aorta relaxation in response to diethyldithiocarbamate in vitro. In the course of adaptation to hypoxia, nitrate and nitrite concentration increases as well as NO deposition in the vascular wall. The volume of NO depot correlated reliably with the serum concentration of nitrates and nitrites. Hence, adaptation to hypoxia increases NO production and deposition, which can underlie its NO-dependent protective effects.

NO-dependent mechanisms of adaptation to hypoxia.

In studying NO-dependent mechanisms of resistance to hypoxia, it was shown that (1) acute hypoxia induces NO overproduction in brain and leaves unaffected NO production in liver of rats; (2) adaptation to hypoxia decreases NO production in liver and brain; and (3) adaptation to hypoxia prevents NO overproduction in brain and potentiates NO synthesis in liver in acute hypoxia. Dinitrosyl iron complex (DNIC, 200 microg/kg, single dose, iv), a NO donor, decreases the resistance of animals to acute hypoxia by 30%. Nomega-nitro-L-arginine (L-NNA, 50 mg/kg, single dose, ip), a NO synthase inhibitor, and diethyl dithiocarbamate (DETC, 200 mg/kg, single dose, iv), a NO trap, increases this parameter 1.3 and 2 times, respectively. Adaptation to hypoxia developed against a background of accumulation of heat shock protein HSP70 in liver and brain. A course of DNIC reproduced the antihypoxic effect of adaptation. A course of L-NNA during adaptation hampered both accumulation of HSP70 and development of the antihypoxic effect. Therefore, NO and the NO-dependent activation of HSP70 synthesis play important roles in adaptation to hypoxia.

[NO-Dependent mechanisms of adaptation to hypoxia]. / NO-zavisimye mekhanizmy adaptatsii k gipoksii.

Studies of nitrogen oxide (NO)-dependent mechanisms of organism resistance to hypoxia demonstrate that (1) acute hypoxia induces NO hyperproduction in the brain and does not affect NO production in the liver; (2) adaptation to hypoxia decreases NO production in the liver and brain; and (3) adaptation to hypoxia prevents NO hyperproduction in the brain and enhances NO synthesis in the lever during acute hypoxia. An NO donor--dinytrosyl iron complexes (DCI, 200 micrograms/kg, single intravenous (i.v.) introduction)--decreases animal resistance to acute hypoxia by 30%, while introduction of an NO synthase inhibitor--N- nitro-L-arginine (NNA, 50 micrograms/kg, single intraperitoneal (i.p.) introduction)--and an NO trap--diethyldithiocarbamate (DETC, 200 mg/kg, single i.p. introduction)--increases the resistance 1.3 and 2 times, respectively. Adaptation to hypoxia is realized against a background of accumulation of heat shock proteins HSP70 in the liver and brain. Course treatment with DCI reproduces the antihypoxic effect of adaptation to hypoxia. Course treatment with NNA during adaptation to hypoxia prevents both accumulation of HSP70 and development of the antihypoxic effect. Hence, No and NO-dependent activation of HSP70 synthesis play an important role in adaptation to hypoxia.

[The antimutagenic effect of adaptation to stress]. / Antimutagennyi éffekt adaptatsii k stressu.

C57BL mice were adapted to moderate periodic hypoxia and repeated electric pain stresses of limited intensity. These animals adapted to each of the factors and control animals were given the potent mutagen, free radical oxidation activator dioxidine in a single dose of 300 mg/kg. Dioxidine administered to unadapted animals resulted in chromosomal aberrations in 11% of stem bone marrow cells mainly due to the appearance of single and multiple chromosomes. Preadaptation to stress decreased the number of these dioxidine-induced chromosomal aberrations nearly twice. Adaptation to periodic hypoxia had no defensive action. As previously shown, adaptation to repeated stresses leads to the accumulation of heat-shock proteins (HSP) in the cellular nuclei of animals and prevents the degradation of isolated nuclei when single-chain DNA is added. Adaptation to hypoxia does not cause nuclear accumulation of HSP or prevents their degradation when unicellular DNA is supplemented. This suggests that the antimutagenic effect of stress adaptation is likely to be accounted for by the stabilizing action of HSP.

[Formation and reversal development of the local mechanisms of heart protection during adaptation to continuous stress]. / Formirovanie i obratnoe razvitie lokal'nykh mekhanizmov zashchity serdtsa pri adaptatsii k nepreryvnomu stressornomu vozdeistviiu.

Experiments with isolated rat hearts demonstrated that in the course of adaptation to continuous immobilized stress of moderate intensity (1, 5, and 15 days), the heart gradually (at day 15) formed the defense mechanism previously described, that is the adaptive structural stabilization phenomenon (ASSP). ASSP defends cardiac contractile function and has a powerful antiarrhythmic and cytoprotective effect in total ischemia, reperfusion, and under the action of toxic concentrations of calcium and catecholamines. The protective ASSP effect formed over 15 days of continuous stress proved to be steady-state, remaining for 15 days of adaptation cessation. Thus, during adaptation to continuous stress higher regulatory mechanisms determine the gradual development of a highly effective defense mechanism in the heart at the cellular level.

[Contractile function and some parameters of energy metabolism of the myocardium in the process of adaptation to the effect of moderate continuous stress]. / Sokratitel'naia funktsiia i nekotorye pokazateli énergeticheskogo metabolizma miokarda v protsesse adaptatsii k umerennomu nepreryvnomu stressornomu vozdeistviiu.

Experiments were conducted on rats to study the dynamics of changes of the heart contractile function (CF) and some indices of myocardial energy metabolism during adaptation to moderate continuous 15-day stress. After 24 hours of stress a complex of shifts typical of an acute stress syndrome (mobilization of CF, reduction of the content of glycogen and creatine phosphate, increase of phosphorylase activity) was recorded. After 5 days of stress the absolute CF value reduced, particularly at rest (doubled), as a consequence of which the relative values of the maximally developing CF on the 5th second of an isometric load induced by compression of the aorta were 1.5 times those in the controls. The content of glycogen and creatine phosphate and the activity of phosphorylase were reduced by 25-30%. After 15 days the CF and the values of myocardial energy metabolism were normalized. Exclusion of the vagal tonus by atropine on the 5th day of stress showed that the low level of CF and reduced phosphorylase activity are not consequent upon heart exhaustion but are regulatory mechanisms.

[The role of cholinergic regulation and stabilization of myocardial structures in the adaptive protection of the heart]. / Rol' kholinergicheskoi reguliatsii i stabilizatsii struktur miokarda v adaptatsionnoi zashchite serdtsa.

It was found that rat immobilization in small-size cages leb to physiological changes. On day 1 it was a stress-reaction that resulted in decreases of the fibrillation threshold and arrhythmia resistance. On day 5 it was an increase in the vagal tone that caused noticeable atropine-relieved bradycardia. The fibrillation level returned to the baseline. Heart resistance to ischemic and reperfusion arrhythmias increased drastically as compared to the control level. On day 15 the vagal effect declined to reach the baseline; in spite of this heart tolerance to reperfusion arrhythmias further increased. This was followed by enhanced resistance of isolated hearts of the adapted animals to the reperfusion paradox and tonic concentrations of epinephrine and Ca2+, which indicated the formation of the phenomenon of adaptation stabilization of cardiac structures. After termination of the 5-day stressogenic exposure the cholinergic stress-limiting protection of the heart disappeared rapidly, i. e. within 12 hours. The protective effect of the adaptation stabilization phenomenon, which developed during 15 days of the stressogenic exposure, proved to be more stable and persisted during 15 days after its cessation. It is concluded that, based on the coordination of short-term central and long-term cellular mechanisms, the animal body develops optimal adaptation that emerges rapidly and persists for an adequately long period of time. The step-by-step replacement of central mechanisms with cellular ones provides high reliability and efficiency of the protection of the heart and the entire body from extended environmental effects.

[Effects of adaptation to exposure to short-term stress on indices of resistance of energy metabolism and contractile function of the myocardium to acute hypoxic hypoxia and reoxygenation]. / Vliianie adaptatsii k kratkovremennym stressornym vozdeistviiam na ustoichivost' pokazatelei énergeticheskogo metabolizma i sokratitel'noi funktsii miokarda k ostroi gipoksicheskoi gipoksii i reoksigenatsii.

Effect of preliminary adaptation to immobilization stress with progressive duration from 15 min. to 1 h (every second day, 8 sessions) on the resistance of indices of myocardial energy metabolism and contractile function to acute hypoxic hypoxia and subsequent reoxygenation was studied. It was shown, that adaptation to short-term stress exposure by some way provided the retention of activities of important enzymes like creatine-phosphokinase and phosphorylase under the harmful action of acute hypoxia and subsequent reoxygenation. At the same time, the ATP restoration and the CP super-restoration were observed during reoxygenation. This effect, in its turn, was accompanied by a more pronounced super-restoration of the heart contractile function than in control.

[Effect of the antioxidant ionol on energy metabolic indices and heart function during acute hypoxia and subsequent reoxygenation]. / Vliianie antioksidanta ionola na pokazateli énergeticheskogo metabolizma i funktsiiu serdtsa pri ostroi gipoksii i posleduiushchei reoksigenatsii.

The effect of preliminary administration of antioxidant ionol on the heart energy metabolism and contractile function was estimated in hypoxic hypoxia and subsequent reoxygenation. The protective effect of ionol on the energy metabolism in hypoxia was shown to occur mainly at the level of glycolysis. In reoxygenation, the protective effect of ionol manifested at the level of creatine kinase system to provide a rapid restoration of the CP synthesis rate. This shift correlated with the velocity of restoration of the developed pressure and the velocities of contraction and relaxation. On the whole the data obtained correspond to the notion that creatine kinase system and ATP play an important role in the depression and subsequent restoration on the heart contractile function in acute hypoxia and reoxygenation and ionol provides more effective performance of this system and correspondingly more rapid restoration of the contractile function in reoxygenation.

[Effects of adaptation to periodic and continuous hypoxia in disorders of electrical stability of the heart in postinfarction cardiosclerosis]. / Vliianie adaptatsii k periodicheskomu i nepreryvnomu deistviiu gipoksii na narushenie élektricheskoi stabil'nosti serdtsa pri postinfarktnom kardioskleroze.

The effects of adaptation to intermittent and continuous hypoxia on the electrical stability of the heart were compared in middle altitude conditions and in altitude chamber in Wistar rats with postinfarction cardiosclerosis. It has been shown that both forms of adaptation could restore the heart fibrillation threshold and restrict the ectopic activity in postinfarction cardiosclerosis. Beneficial effects of adaptation to intermittent hypoxia in conditions of the altitude chamber appeared to be more radical.

[Enhanced resistance of the heart to arrhythmogenic factors as affected by adaptation of the body to stress exposures]. / Povyshenie rezistentnosti serdtsa k aritmogennym faktoram pod vliianiem adaptatsii organizma k stressovym vozdeistviiam.

Adaptation to short-term nondamaging stress effects largely limits or prevents cardiac arrhythmias in acute ischemia and reperfusion. The study examines to what extent this anti-arrhythmic effect depends on adaptational shifts of the heart itself. Isolated hearts of animals adapted to stress are shown to possess dramatically increased resistance to arrhythmias induced by local ischemia and reperfusion. The role of activated prostaglandin biosynthesis, adenosine, antioxidant systems, desensitization and other protective control systems functioning at heart level to provide this anti-arrhythmic effect is discussed.