Effects of adaptation to periodic and continuous hypoxia in disorders of electrical stability of the heart in postinfarction cardiosclerosis

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.     

Significance of ATP-sensitive K(+)-channel in the mechanism of antiarrhythmic and cardioprotective effect of adaptation to intermittent hypobaric hypoxia

Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (5000 m, 6 h/day, 6 weeks). It has been found that such mode of adaptation increased cardiac tolerance to arrhythmogenic action of a 45-min coronary artery occlusion but did not change an infarct size/area at risk (IS/AAR) ratio. In a separate series, rats were exposed to stronger intermittent hypobaric hypoxia (7000 m, 8 h/day, 6 weeks) and subjected to 20-min coronary artery occlusion and 3-h reperfusion on the day after the last hypoxic exposure. It has been established that in this case adaptation decreased the IS/AAR ratio, increased cardiac tolerance to arrhythmogenic action of reperfusion but had no effect on the incidence of ventricular arrhythmias occurred during ischemic period. We found that cardioprotective and antiarrhythmic effect of adaptation to the "altitudes" of 7000 m and antiarrhythmic effect of adaptation to the "altitude" of 5000 m is mediated via K(ATP)-channel activation.     

Effects of adaptation to intermittent high altitude hypoxia on ischemic ventricular arrhythmias in rats

We compared the effects of adaptation to intermittent high altitude (IHA) hypoxia of various degree and duration on ischemia-induced ventricular arrhythmias in rats. The animals were exposed to either relatively moderate hypoxia of 5000 m (4 or 8 h/day, 2-3 or 5-6 weeks) or severe hypoxia of 7000 m (8 h/day, 5-6 weeks). Ventricular arrhythmias induced by coronary artery occlusion were assessed in isolated buffer-perfused hearts or open-chest animals. In the isolated hearts, both antiarrhythmic and proarrhythmic effects were demonstrated depending on the degree and duration of hypoxic exposure. Whereas the adaptation to 5000 m for 4 h/day decreased the total number of premature ventricular complexes (PVCs), extending the daily exposure to 8 h and/or increasing the altitude to 7000 m led to opposite effects. On the contrary, the open-chest rats adapted to IHA hypoxia exhibited an increased tolerance to arrhythmias that was even more pronounced at the higher altitude. The distribution of PVCs over the ischemic period was not altered by any protocol of adaptation. It may be concluded that adaptation to IHA hypoxia is associated with enhanced tolerance of the rat heart to ischemic arrhythmias unless its severity exceeds a certain upper limit. The opposite effects of moderate and severe hypoxia on the isolated hearts cannot be explained by differences in the occluded zone size, heart rate or degree of myocardial fibrosis. The proarrhythmic effect of severe hypoxia may be related to a moderate left ventricular hypertrophy (27 %), which was present in rats adapted to 7000 m but not in those adapted to 5000 m. This adverse effect can be overcome by an unknown protective mechanism(s) that is absent in the isolated hearts.     

Increase of alpha 1-adrenoreactivity of the rat heart in adaptation to periodic hypoxia]

There is a possibility that the cardioprotective effect of adaptation to intermittent hypoxia is due to changes in receptors apparatus of the heart. In this connection the effect of preliminary adaptation to intermittent hypoxia (4 hours per day at the altitude of 4000 m during 40 days) on the state of beta-receptors-adenylate-cyclase system and same other receptors of the heart were studied. It was shown that at the end of the course of adaptation the number of beta-adrenoceptors in the heart was increased with simultaneous decrease in basal adenylate-cyclase activity, accompanied by the diminution of its response to beta-agonist. The number of beta-adrenoceptors was increased by 48% and their affinity to ligand was increased by almost 2 times. The revealed decrease in the reactivity of beta-receptor-adenylate-cyclase system and increase of alpha 1-adrenoreactivity can play a certain role in the mechanism of cardioprotective effect of adaptation to hypoxia.     

Adaptation to periodic hypoxia decreases ethanol consumption and abstinence-related damages to the internal organs during withdrawal in chronically alcoholized animals]

Adaptation to intermittent hypoxia in a hypobaric altitude chamber reduced two-fold ethanol consumption in chronically alcoholized rats and limited or eliminated abstinence syndrome. The effect of the adaptation was evident from prevented development of abstinence analgesia, enhanced alcohol consumption following deprivation, abstinence activation of lipid peroxidation in the liver, and release of hepato-specific enzymes fructose monophosphate and gamma-glutamyl transpeptidase into blood. At the same time adaptation prevented the fall of cardiac fibrillation threshold and pronounced disturbance of ventricular contraction and relaxation. The problem is discussed of using adaptation to intermittent hypoxia in the treatment for those forms of alcoholism in which abstinence plays the key role.     

Differences in adaptive stabilization of structures in response to stress and hypoxia relate with the accumulation of hsp70 isoforms

The phenomenon of adaptive stabilization of structures (PhASS) develops during adaptation of the organism to intermittent restraint stress. The PhASS manifests itself in a considerably increased resistance of the heart to a broad spectrum of harmful factors. In the present work, the content of hsp70 and their role in the development of PhASS during adaptation to intermittent restraint stress and to intermittent hypoxia were studied. In adaptation to restraint stress, five hsp70 isoforms with pI ranging from 5.7 to 6.3 were accumulated in the myocardium. The heart simultaneously became strikingly resistant to reperfusion paradox and heat shock. In adaptation to hypoxia, only two hsp70 isoforms with pI about 5.8 were accumulated. The resistance to reperfusion paradox was not increased and the resistance to heat shock was increased only moderately. These data suggest a role of different hsp70 isoforms in the mechanism of PhASS as well as adaptive protection of the heart.Abbreviation hsp70 heat shock proteins - PhASS Phenomenon of Adaptive Stabilization of Structures - CK Creatine Kinase     

间歇性低氧防止缺血再灌注损伤引起的线粒体结构损伤和mtDNA片段缺失

本文用离体Ｌａｎｇｅｎｄｏｒｆｆ灌流大鼠心脏造成急性心肌缺血／再灌注损伤模型,观察间歇性低氧暴露保护心肌线粒体的作用。以聚合酶链式反应（ＰＣＲ）方法和电子显微镜技术,观察线粒体ＤＮＡ（ｍｔＤＮＡ＾４８３４）片段缺失和超微结构的变化。大鼠暴露于模拟海拔５０００米低氧环境（６ｈ／ｄ,２８ｄ）明显降低ｍｔＤＮＡ＾４８３４缺失的发生率（２８．５７％,ｖｓ常氧对照组８７．５％ Ｐ〈０．０５）;而且能够明显减     

Glutathione system adaptation to acute stress in the heart of rats during different regimes of hypoxia training

The intensity of lipid peroxidation (LPO), reduced and oxidized glutathione (GSH and GSSG) contents, glutathione reductase, glutathione peroxidase, glutathione-S-transferase, glucose-6-phosphate dehydrogenase (G-6-PDH), and NADP-isocitrate dehydrogenase (NADP-IDH) activities were studied in the heart of male rats exposed to two modes of intermittent hypoxic training (IHT): I-breathing in normobaric chamber with 7% O2 gas mixture for 5 min with 15 min normoxic intervals 4 times daily during 3 weeks; II-breathing by 12% O2 gas mixture in the same manner). After adaptation to hypoxia, the rats were subjected to 6h-immobilization stress. It has been shown that stress action after IHT (regime I) caused the increase in LPO and the shift of GSH/GSSG to disulfides. A disbalance in antioxidative defense system was determined by the decrease in glutatione peroxidase, G-6-PDH activities, and GSH content. The support of glutathione reductase activity under stress in this group with simultaneous decrease of enzyme activity in the pentose phosphate pathway was realized through the participation of NADP-IDH. Hypoxic training in regime II induced LPO decrease in the heart tissue after stress. The increase in the heart GSH content, optimal balance of glutathione-related enzymes in this group evidences for the dependence of adaptation effects on the vigor of hypoxic exposition. Our results suggest the active participation of glutathione system in the formation of adaptation reactions under the extreme factor influences through the action on intracellular red/ox potential as well as effectiveness of antioxidant defense.     

Effect of adaptation to hypoxia on the antioxidant enzyme activity in the liver in animals that have undergone stress

It was shown in experiments on rats that emotional-painful stress resulted in a rapid increase in malonic dialdehyde (MDA) and in a decrease in the activity of superoxide dismutase (SOD) in liver. Adaptation to moderate intermittent hypoxia in altitude chamber did not affect MDA and increased hepatic SOD by 65%. Stress exposure caused no change in SOD and MDA, but abruptly reduced the fall of SOD in adapted animals. These data are in accordance with the well-known idea that adaptation to hypoxia prevents the activation of lipid peroxidation and the hepatic damage in stress.     

Effects of adaptation to periodic hypoxia on bioelectric activity of cardiomyocytes of isolated heart in ischemia and reperfusion

Experiments on isolated Wistar rat heart perfused according to Langendorff showed that preliminary adaptation of rats to intermittent hypobaric hypoxia limited the fall of values of the resting potential and the amplitude and duration of action potential characteristic for ischemia. Under similar conditions, adaptation considerably reduced the increased time of impulse conduction along the myocardium. In reperfusion, the parameters enumerated restored much more efficiently in hearts from adapted animals than in controls. The role of these changes in the antiarrhythmic effect of adaptation to intermittent hypoxia is under discussion.     

Pretreating rats with hyperoxia attenuates ischemia-reperfusion injury of the heart

Oxidative stress may precondition the heart. The present study investigated whether hyperoxia elicits a preconditioning-like response. Rats were kept in a hyperoxic (>95% O2) environment for 60 or 180 minutes. Hearts were Langendorff-perfused immediately or 24 hours after hyperoxia, and exposed to 25 minutes of global ischemia and 60 minutes of reperfusion. Whole blood was sampled after 60 and 180 minutes of hyperoxia for oxidative stress markers. Hearts were sampled immediately or 24 hours after hyperoxia for measurement of antioxidants, lipid peroxidation products, heat shock protein 72 and endothelial nitric oxide synthase. At the end of reperfusion after 1 h hyperoxia, infarct size was determined by tetrazolium staining. Hyperoxia increased serum levels of conjugated dienes, reduced serum antioxidative protection, reduced reperfusion arrhythmias in most groups, and improved myocardial function. Infarct size was reduced from 45% of myocardial tissue in controls to 22% in treated animals. The myocardial activity of antioxidant enzymes, content of heat shock protein 72, and endothelial nitric oxide synthase in myocardial tissue were not influenced. In conclusion, hyperoxia induces a low-graded systemic oxidative stress, improves postischemic cardiac function and reduces infarct size. The mediators of protection remain to be determined.     

Effect of intermittent high altitude hypoxia on the structure and enzymatic activity of cardiac myosin

The time course of structural and enzymatic changes in cardiac myosin was studied in the right and left ventricle of rats exposed to intermittent high altitude (IHA) hypoxia. In the controls, ATPase activity and myosin structure in both ventricles was the same. After the third exposure to simulated high altitude (2 600 m), myosin enzymatic activity rose significantly in the left ventricle and a significant right-left difference appeared. In the next phase of adaptation (11 exposures, 6 000 m), myosin ATPase activity fell in both ventricles and the right-left difference disappeared. After the 16th exposure (7 000 m), enzymatic activity increased again in both ventricles and attained control values. IHA also produced significant structural changes in cardiac myosin, particularly in the rigaht ventricle. The changes were characterized by the formation of myosin aggregates with significantly lower ATPase activity that the myosin monomer. The time course and localization of structural and enzymatic changes in cardiac myosin corresponded to the morphological damage to the heart fibres.     

Effects of arginine on properties of the erythrocyte membrane in hypoxia]

The antioxidant effect of arginine evident from stabilization of membrane structure and properties and activation of oxygen-toxicity-protecting enzymes was demonstrated in hypoxia. The intraperitoneal injection of L-arginine-HCl in a dose of 120 mg per 100 g body mass prevented the increase of microviscosity, membrane permeability and lipid peroxidation products level in hypoxia. At the same time the activity of the antioxidant enzymes--superoxide dismutase and catalase--was increased in red blood cells by 64 and 46%, respectively.     

State of the free-radical oxidation system in normobaric hypoxia]

The experiments on the rats have revealed that 7-hour action of 10% hypoxic gas mixture (HGM-10) exerts no effect on the parameters of Fe(2+)-induced chemiluminescence and rate of accumulation of TBA-active products in the heart, liver, kidney, brain tissues and blood plasma. Two-week adaptation to intermittent effect of HGM-10 causes some activation of free-radical oxidation recorded in blood plasma and the more pronounced increase in power of the endogenic antioxidant system. It is assumed that the revealed changes in the state of the homeostatic system of free-radical oxidation and antiradical protection of the organism are of importance in the mechanism of the known preventive and curative action of intermittent normobaric hypoxia.     

Hypoxia-induced lipid peroxidation in the brain during postnatal ontogenesis

Reactive oxygen species (ROS) are common products of the physiological metabolic reactions, which are associated with cell signaling and with the pathogenesis of various nervous disorders. The brain tissue has the high rate of oxidative metabolic activity, high concentration of polyunsaturated fatty acids in membrane lipids, presence of iron ions and low capacity of antioxidant enzymes, which makes the brain very susceptible to ROS action and lipid peroxidation formation. Membranes of brain cortex show a higher production of thiobarbituric acid-reactive substances (TBARS) in prooxidant system (ADP.Fe(3+)/NADPH) than membranes from the heart or kidney. Lipid peroxidation influences numerous cellular functions through membrane-bound receptors or enzymes. The rate of brain cortex Na(+),K(+)-ATPase inhibition correlates well with the increase of TBARS or conjugated dienes and with changes of membrane fluidity. The experimental model of short-term hypoxia (simulating an altitude of 9000 m for 30 min) shows remarkable increase in TBARS in four different parts of the rat brain (cortex, subcortical structures, cerebellum and medulla oblongata) during the postnatal development of Wistar rat of both sexes. Young rats and males are more sensitive to oxygen changes than adult rats and females, respectively. Under normoxia or hypobaric hypoxia both ontogenetic aspects and sex differences play a major role in establishing the activity of erythrocyte catalase, which is an important part of the antioxidant defense of the organism. Rats pretreated with L-carnitine (and its derivatives) have lower TBARS levels after the exposure to hypobaric hypoxia. The protective effect of L-carnitine is comparable with the effect of tocopherol, well-known reactive species scavenger. Moreover, the plasma lactate increases after a short-term hypobaric hypoxia and decreases in L-carnitine pretreated rats. Acute hypobaric hypoxia and/or L-carnitine-pretreatment modify serum but not brain lactate dehydrogenase activity. The obtained data seem to be important because the variations in oxygen tension represent specific signals of regulating the activity of many specific systems in the organism.     

Lipid peroxidation rate and the antioxidant protection system during a three-day dry immersion experiment

The content of lipid peroxidation products (diene conjugates, malondialdehyde, Schiff bases) and antioxidant defense system indices (the main lipid antioxidant tocopherol and the level of general antioxidant activity) were measured in the blood serum of five male volunteers aged 25?C40 years in a three-day dry immersion experiment. During the immersion test, no deviations of indices from the background values were found. An increase in the tocopherol concentration within 2 h after the beginning of the experiment was the only exception. A significant increase in the concentration of lipid peroxidation products, particularly, diene conjugates, was observed 2 h after immersion completion during the reconditioning period. However, the tocopherol content was significantly lower than the background values. It is concluded that the subjects?? adaptation to simulated microgravity conditions displays no pronounced stress component, whereas bringing back to normal vital functions after exposure to immersion induces a pronounced stress reaction illustrated by a significant increase in the lipid peroxidation product levels against a background of a decrease in the functional activity of the antioxidant defense system.     

Increased enzymatic activity of antioxidant protection of the heart in the adaptation of rats to short-term stress exposure

It has been shown that adaptation to short-term emotional-painful stresses leads to an increase in antioxidant enzyme activities but does not change vitamin E content in the myocardium. The most labile enzyme was catalase (35% increase). During stress in nonadapted animals the enzyme activity decreased, as compared to the control, while in the group of adapted animals with subsequent stress the activity was even higher than in the control. During initiation of lipid peroxidation in the heart homogenates in vitro there was a 3-fold increase and a 1%-fold decrease in the oxidation intensity in rats exposed to stress and in adapted animals, respectively. The role of adaptation activation of cardiac antioxidant system in the prevention of stress-induced heart damage is discussed.     

Synthesis of chroman analogues of lipoic acid and evaluation of their activity against reperfusion arrhythmias

Novel hybrids of lipoic acid and trolox connected through triamine spacers as well as analogues in which the lipoic acid was attached at different positions of the chroman moiety of vitamin E through an amide bond, were synthesized and exhibited strong inhibition of the microsomal lipid peroxidation. Moreover, the new molecules, at 1 microM concentration, reduced reperfusion arrhythmias and MDA content on isolated rat heart preparations, with the 2- and 5-subtituted chromans possessing the better cardioprotective activity.     

Changes in the expression and/or activation of regulatory proteins in rat hearts adapted to chronic hypoxia

Chronic intermittent high altitude (IHA) hypoxia results in long-term adaptation protecting the heart against acute ischemia/reperfusion injury; however, molecular mechanisms of this phenomenon are not completely elucidated so far. The present study was aimed at investigation of a modulating effect of IHA hypoxia on the expression and/or activation of selected regulatory proteins, with particular emphasis on differential responses in the right ventricle (RV) and left ventricle (LV). Adult male Wistar rats were exposed to IHA hypoxia of 7000 m simulated in a hypobaric chamber (8 h/day, 25 exposures), and protein contents and activities in myocardial fractions were determined by Western blot analysis. In markedly hypertrophic RV of hypoxic rats, gelatinolytic activity of MMP-2 and protein levels of carbonic anhydrase IX (a marker of hypoxia) were significantly enhanced. Study of mitogen-activated protein kinases (MAPKs) revealed no differences in the contents of total p38-MAPK in both ventricles between the IHA and normoxic control rats, whereas activation of p38-MAPK was decreased in the RV and moderately increased in the LV of IHA rats as compared to controls. Extracellular signal regulated kinase-2 (ERK-2) was partially up-regulated in the RV of IHA rats, and, in addition, expression of acidic fibroblast growth factor (aFGF), a potential activator of ERK cascade, was also significantly increased. In contrast, expression of ERKs in the LV as well as their activities in both ventricles, were not affected by IHA hypoxia. Differential effects of IHA hypoxia on c-Jun-N-terminal protein kinases (JNKs) in the RV and LV were also observed. As compared with the controls, total content of JNKs was increased in the RV of the IHA rats, while expression of JNKs in the LV was down-regulated. IHA hypoxia changed neither total levels of Akt kinase in both RV and LV, nor Akt kinase activity in the RV. However, increased levels of activated phospho-Akt kinase were found in the LV of IHA rats. The results demonstrate that adaptation of rat hearts to chronic IHA hypoxia is associated with disctinct changes in the levels and/or activation of several regulatory proteins in two ventricles. The latter could be attributed to both myocardial remodeling and cardioprotection induced by chronic hypoxia.     

Molecular mechanisms of cardiac protection by adaptation to chronic hypoxia

Effective protection of the heart against ischemia/reperfusion injury is one of the most important goals of experimental and clinical research in cardiology. Besides ischemic preconditioning as a powerful temporal protective phenomenon, adaptation to chronic hypoxia also increases cardiac tolerance to all major deleterious consequences of acute oxygen deprivation such as myocardial infarction, contractile dysfunction and ventricular arrhythmias. Although many factors have been proposed to play a potential role, the detailed mechanism of this long-term protection remains poorly understood. This review summarizes current limited evidence for the involvement of ATP-sensitive potassium channels, reactive oxygen species, nitric oxide and various protein kinases in cardioprotective effects of chronic hypoxia.