[The influence of mexidol on post-radiation recovery of hemopoietic system].

The purpose of this work was the study in experiments on mice of influence of mexidol on current and outcome of an acute radiation sickness. At an irradiation in a dose 6.0 Gy was studied a condition of hemopoietic system, and at an irradiation in a dose 7.7 Gy a survival rate of animals. In all experiments mexidol applied in two circuits of introduction. The first circuit - once per day with 1 for 8 day after the irradiation. The second circuit of introduction: with 1 for 5 day--two times per day and on 6-8 day once per day. The introduction of mexidol after influence of ionizing radiation reduces a degree of radiative defeat of bone marrow and promotes the activization post-radiation recovery of an erythropoiesis, neutrophilopoiesis in an bone marrow and lymphopoiesis in a thymus gland. This effect is more expressed at introduction mexidol two times per day. At influence of ionizing radiation in a dose 7.7 Gy has survived 56% of mice. The introduction of mexidol two times per day was enlarged by survival rate animal up to 94%. The application of mexidol once per day essentially did not influence on the survival rate of the irradiated mice. The received data show, that the introduction of mexidol with 1 for 8 day after an irradiation, frameing a favorable metabolic background, stimulates recovery processes in hemopoietic system, reduces gravity of a acute radiation sickness and by that enlarges the survival rate of the irradiated animals.

[Effect of energostim on myocardial damage during coronary artery occlusion]. / Vliianie énergostima na porazhenie miokarda pri okkliuzii koronarnoi arterii.

In contrast to traditional therapy (beta-adrenoblocker and nitrates), energostim improves the systolic and diastolic functions of myocardium during 120-min occlusion of the left descending coronary artery. The energostim-induced improvement in the central hemodynamics is correlated with an adaptive increase in activity of the antioxidant system enzymes in response to the ischemic production of reactive oxygen species, which is evidence of the mobilization of reserves of the enzymatic link in the antioxidant defense system of cardiomyocytes. Analogous pattern is observed in the blood. In the control group of traditional therapy, a decrease in the superoxide dismutase (SOD) activity and the redox potential (NAD/NADH) in myocardium are correlated with a decrease in the maximum rate of pressure increase in the left ventricle (R 6.4, p < 0.01) observed 2 h after the coronary occlusion. In the energostim treated group, there is a correlation between the SOD activity and the content of cytochrome C in mitochondria (R 6.1, p < 0.01): a change in the level of cytochrome C during 2-h acute ischemia is correlated with the decrease in redox potential (NAD/NADH) and in the ratio of glutathione peroxidase to Mn-dependent SOD (r 0.64, p < 0.01). Thus, disturbances in the antioxidant defense system of both myocardium and blood plasma of the patients with acute myocardium infarction are correlated with inability of the energy supply system to utilize oxygen in the process of glycolysis and oxidative phosphorylation in mitochondria. Stable adaptive increase in activity of the antioxidant defense system enzymes and a decrease in the content of cytochrome C in the blood plasma are probably the independent indications of beneficial prognosis and high efficacy of the proposed treatment of the ischemic damage of myocardium.

[A disorder of myocardial contractile function in acute experimental coronary failure: the submolecular mechanisms and the action of cardiac glycosides]. / Narushenie sokratitel'noi funktsii miokarda pri ostroi éksperimental'noi koronarnoi nedostatochnosti: submolekuliarnye mekhanizmy, deistvie serdechnykh glikozidov.

Skinned and hybrid myocardial fibers were studied by methods of tensometry, determination of the ATP hydrolysis intensity, and resonance fluorescent energy transfer between highly selective labels bound to various amino acid residues. It was established that development of the early stage of heart failure in the case of acute myocardial ischemia caused by 15-min coronary artery occlusion (CAO) is related to a reversible damage or adaptive (functional) depression of the contractile protein system. As a result, the system features isolated submolecular post-translational variation in the properties of major proteins in a thin actin filament (myosin is not significantly damaged). This leads to a decrease in the force developed by the hybrid fibers (reconstructed using ghost myocardial fibers taken from ischemic area and normal myosin) and in the ATPase activity of actomyosin (ATP hydrolysis intensity) without any significant change in the Ca-sensitivity, cooperativity of the Ca-response of the actomyosin ensemble, and efficiency of the contractile process. In actin of the ischemic area, CAO results in a serious damage of the Lys61 and Cys374 regions and in a less pronounced damage of the Tyr69 and Cys10 regions. These results suggest that the Lys61 and, probably, Cys374-Lys61 regions are included in the actin monomer as a protomer, without adequate prepolymerization structural-conformational changes necessary to provide for the normal functioning of the filament. In the CAO-induced early stage of heart failure, cardiac glycosides (beta-acetyldigoxin, beta-methyldigoxin, and strophanthin K) produce a direct effect upon the intramolecular structure of myocardial actin, restore the generated force level, and increase the intensity of ATP hydrolysis by actomyosin ensemble. This is achieved by improving or normalizing the structural-conformational state and conformational mobility of the Lys61 and Cys374 region of actin.

[The action of a number of cardiac glycosides on an isolated system of myocardial contractile proteins in heart failure due to toxic-allergic myocarditis. The molecular mechanism]. / Deistvie riada serdechnykh glikozidov na izolirovannuiu sistemu kontraktil'nykh belkov miokarda pri nedostatochnosti serdtsa, obuslovlennoi toksiko-allergicheskim miokarditom. Molekuliarnyi mekhanizm.

Experiments conducted on an isolated contractile apparatus, myocardial fibers (MF) in cardiac insufficiency (CI) caused by toxico-allergic myocarditis of 10 days duration (TAM10dd) showed that cardiac glycosides (CG), beta-acetyldigoxin (beta AD), beta-methyldigoxin, and strophanthin K (SK) increase the capacity of the actomyosin ensemble (AME) for generation of force, hydrolization, and economic use of the free energy of ATP hydrolysis. The mechanism of the effect of these CG in the phase of contraction differs from that of their effect on the AE of a normal myocardium. For instance, in severe CI induced by TAM10dd beta AD, in distinction from its action on the AME of a normal myocardium, can increase contractility economy, particularly in the phase of highest energy capacity, the phase of force generation, and exceed the level encountered in normal conditions, it also increases significantly the rate and reduces the time of MF relaxation as in the case of MF of a normal heart.

[The subcellular pathophysiology of heart failure due to toxic-allergic myocarditis and the action of refracterin on intracardiac hemodynamics and the functional state of the 3 subcellular cardiomyocyte systems responsible for the act of contraction-relaxation]. / Subkletochnaia patofiziologiia nedostatochnosti serdtsa, obuslovennoi toksiko-allergicheskim miokarditom, i deistvie refrakterina na vnutriserdechnuiu gemodinamiku i funktsional'noe sostoianie trekh subkletochnykh sistem kardiomiotsita otvetstvennykh za akt sokrashchenie--rasslablenie.

It is shown that cardiotropic drug refracterin promotes recovery of cardiac contraction and relaxation, their coordination destroyed in cardiac failure (CF) caused by 10-day toxico-allergic myocarditis (TAM). Pumping capacity of the heart returns to normal after normalization of functional activity of three systems of cardiomyocyte responsible for contraction-relaxation: contractile proteins, energy supply and calcium transport. The key process is refracterin-related reestablishment of normal content and proportion of adenyl nucleotides and creatininephosphate and regulation role of phosphorylation and energy of metabolic processes in the cells and their interaction. Thus, refracterin effectiveness lies in its ability to interfere in intracellular metabolic processes in the myocardium, to reestablish normal homeostasis of the systems responsible for contraction-relaxation function and eventually to remove left ventricular cardiac dysfunction.

[The positive action of refracterin on the reserve potentials and metabolism of the myocardium during its overload in toxic-allergic myocarditis]. / Polozhitel'noe deistvie refrakterina na rezervnye vozmozhnosti i metabolizm miokarda pri ego peregruzke na fone toksiko-allergicheskogo miokardita.

Heart overloading due to pressure as a result of 8 periodic full aortic constriction in heart failure (HF) caused by 10-day toxic-allergic myocarditis (TAM) leads to deterioration of heart contractility (pump function). This is explained by additional decline in functional activity of all three systems of cardiomyocyte responsible for contraction-relaxation. In particular, by a sharp fall of ATP and CP content in the myocardium, a 400% decrease in myofibril power, 200% reduction in efficiency of contraction and marked deterioration of calcium transport. The resultant exhaustion of myocardial reserve brought 70% lethality among the animals. Under the above conditions coordination between the systolic and diastolic cardiac functions, correlation between myocardial functional activity and subcellular systems of cardiomyocyte are impaired. In pressure heart overloading refracterin initiates profound metabolic rearrangements improving metabolism, remodelling of the system of energy supply, reestablishment of systemic homeostasis, normalization of cardiomyocyte and cardiac reserves.

[The comparative efficacy and differences in the molecular mechanism of the inotropic action of cardiac glycosides and nonglycoside cardiotropic agents on the contractile protein system of the myocardium]. / Sravnitel'naia éffektivnost' i razlichiia v molekuliarnom mekhanizme inotropnogo deistviia nekotorykh serdechnykh glikozidov i neglikozidnykh kardiotropnykh sredstv na sistemu kontraktil'nykh belkov miokarda.

The in vitro study on an isolated system of myocardial contractile proteins determined optimal concentrations of the positive inotropic action and biological activity ranges of beta-methyldigoxin (beta-MD), strophanthin K, K-strophantozide, beta-acetyldigoxin (beta-AD), milrinone, and amrinone. Optimal concentrations of the beta-MD and strophanthin K (10(-2) and 10(-6) M, respectively) significantly increased qualitatively and quantitatively the economy and thermodynamic efficiency, altered the energy transformation in the contractile protein system under the isometric contraction, whereas the beta-AD produced only the quantitative effect. However, the beta-MD and strophanthin K at concentrations exceeding the optimal one by one order lost the ability to produce the qualitative effect, retaining only the quantitative one in the actomyosin ensemble. The strophanthin K significantly increased the economy of a single actomyosin ensemble in the force generation phase and the beta-MD in the tension maintenance phase. Unlike the strophanthin K, the beta-MD did not slow down (did not worsen) the relaxation process. This provides grounds to conclude that the beta-MD produces most favorable effect on the energy transformation by myocardial contractile proteins.

[Disruption of chemomechanical coupling in cardiomyocyte myofibrils in L-tyroxine toxicosis and athyreosis]. / Narushenie khemomekhanicheskogo sopriazheniia v miofibrillakh kardiomiotsita pri L-tiroksinovom toksikoze i atireoze.

Skin assay of dog myocardial fibers showed alterations in free energy of ATP hydrolysis correlated distinctly with the rate of activity generated by the fiber (r = 0.87; P < 0.01). Impairment of chemomechanical coupling occurred in the system of myocardial contractile proteins under conditions of athyreosis and L-thyroxin-induced toxicosis, which is responsible for qualitative and quantitative deteriorations of energy transformation in cardiomyocyte myofibrils. The sites of energy generation and liberation appear to be spatially disconnected in the active actomyosin complex and their coupling and uncoupling is related to properties of actin.

[The uncoupling of the functioning of the force generation and ATP hydrolysis centers in the myocardial myofibrils in experimental informational disease]. / Razobshchenie funktsionirovanie tsentrov generatsii sily i gidroliza ATF v miofibrillakh miokarda pri éksperimental'noi informatsionnoi bolezni.

Active and rigor force generation under the effect of electrostatic charge, the temperature and pCa, was significantly decreased in informational experimental disease. Other significant changes on the molecular level occurred in cardiomyocyte contractile apparatus in conditions of experimental informational disease.

[Differences in mechanisms of action of beta-acetyldigoxin, strophanthin K and ouabain]. / O razlichii mekhanizmov deistviia beta-atsetildigoksina, strofantina K i uabaina.

In vitro on skinned myocardial fibers (SMF) with extracted or functionally inactivated enzymes and membranes of mitochondria, longitudinal sarcoplasmic reticulum, triads and sarcolemma, new evidence of beta-acetyldigoxin and strophanthin K direct stimulating effects on contractile protein system of myocardium has been obtained. It has been revealed in energy release stimulation and force generation, in quantitative (beta-acetyldigoxin) or quantitative and qualitative (strophanthin K) stimulation of energy transduction, in the increase of contractile process cooperativity and Ca-sensitivity of SMF as well as in the SMF relaxation time extension (in the case of strophanthin K). It is suggested that different effects of beta-acetyldigoxin and strophanthin K are due to the differences in the conformations of actomyosin ensembles formed by strong bound (AMESB), which are induced by the influence of these cardiac glycosides. It has been demonstrated that ouabain (strophanthin K) has no direct effect on functioning of AMESB.

[Interaction of aldolase with thin filaments within I-disks, isolated from skeletal muscles]. / Vzaimodeistvie al'dolazy s tonkimi nitiami v sostave I-diskov, izolirovannykh iz skeletnykh myshts.

Using electron microscopy and optical diffraction, Ca2+-dependent binding of a glycolytic enzyme (aldolase) to thin filaments of isolated skeletal muscle I-disks have been revealed. On the micrographs of negatively stained I-disks the cross-striation determined by troponin-tropomyosin complex distribution has a period of about 38 nm. The width of troponin-tropomyosin stripes is 5-6 nm. On the optical diffraction patterns from isolated I-disks the meridional reflections measuring 38.5, 19.2, 12.8 nm are present. On the micrographs of isolated I-disks, treated with aldolase in the absence of Ca2+ (1 mM EGTA) the width of periodic transverse stripes (period approximately 38 nm) increases from 5-6 nm to 25-28 nm due to the interaction of aldolase with thin filaments. On the optical diffraction patterns from I-disks treated with aldolase in the absence of Ca2+ (1 mM EGTA) the strong meridional reflection equal to 38.5 nm is present, while the reflections equal to 19.2 nm are absent. The optical diffraction patterns from I-disks treated with aldolase in the presence of Ca2+ (greater than or equal to 10(-5) M) do not, as a rule, differ from those obtained from I-disks not treated with aldolase, i.e. they contain the three above reflections. The binding of aldolase to thin filaments in the absence of Ca2+ is the reason of disappearance of meridional reflections equal to 19.2 and 12.8 nm.