The aim of the work was to study the primary bioenergetic mechanisms of hypoxia formation in the myocardial tissue of experimental animals depending on the differentiated physical characteristics of vibration (frequency and duration) and their combination. The study of the functional states of native mitochondria in the composition of the tissue homogenate was carried out using the polarographic method and a galvanic-type closed-oxygen sensor in a 1-ml thermostatic cuvette in a salt incubation medium. The metabolic states of the mitochondria of the myocardium of experimental animals were modeled in vitro during the oxidation of endogenous substrates (before and after the administration of inhibitors of different links of the respiratory chain), with varying exogenous energy substrates (before and after the introduction of 2,4-DNP into the cell). In order to ensure synchronism of measurements in a short time, an incomplete cycle of metabolic states “endogenous respiration → rest → activity” was used. The results of multiple comparisons of variations in kinetic parameters revealed a reliable but multidirectional effect of the frequency of vibration on the rate of oxidation of substrates of the mitochondria of the heart of rabbits in different metabolic states. A change in the duration of exposure to vibration showed an increase in the oxidation rate of endogenous substrates and succinic acid at rest to 21–56 sessions by 17% and 24. 4%, respectively, while the oxidation rate of glutamate decreased to 56 sessions by 24. 5%. Comparison of the general variability of kinetic parameters with a combination of frequency and duration of vibration at different levels of variation showed that it was the interaction of factors that made the most important and significant contribution to the intergroup variability of oxidation rates of endogenous and exogenous substrates, identifying signs of the formation of bioenergetic hypoxia and allowing analysis of the primary physical transformation phenomena in the biological effect.
kKeyword:vibration; mitochondria; energy metabolism; heart; liver; kidney; vibration model of hypoxia; dystrophy; rabbit.
AAdsoras:The purpose of the paper was experimental study of activity of energy production of the heart, liver and kidney after harmful action of general vibration with 8 and 44 Hz frequency. The functional state of native mitochondria in tissue homogenates was studied by polarographic method by means of closed oxygen device of halvanic type in thermostated cuvette of 1 ml volume in the salt medium of incubation. Metabolic states of mitochondria of the rabbit heart, liver and kidney were modeled in vitro in oxidation of endogenous substrates (before and after administration of inhibitors of different stages of breath chain) varying exogenous substrates (before and after administration of 2.4-DNP into the cell). In order to synchronize the changes in short time, the incomplete cycle of metabolic states "endogenous breath → rest → activity" was used. The velocity of mitochondrial oxidation of endogenous substrates was determined by tissue
Activity of the energy production system in rabbits myocardium was examined under various conditions of whole-body vibration. The energy-dependent response of native mitochondria from rabbit heart was studied polarographically using a Clark closed membrane electrode. In was established that the energy production system in rabbit myocardium was involved in organism's response to whole-body vibration. Functional changes in myocardial mitochondria were shown to depend on the mode of whole-body vibration (frequency and duration). It manifested in an imbalance between functional activity of FAD- and NAD-dependent components of the respiratory chain. The increase in the frequency and duration of vibration was accompanied by dysfunction of the energy production system in cardiomyocytes. These changes manifested in activation of succinic acid oxidation and inhibition of NAD-dependent components of the mitochondrial respiratory chain. Vibration due to systemic dysregulatory influence can be used as a model for studies of both vibration phenomenon realized at the level of the energy production system in organs and tissues and vibroprotective properties of medicinal products.
Introduction: Thrombopoietin receptor agonists are commonly second-line drugs in immune thrombocytopenia (ITP) pharmacotherapy in children and prescribed for chronic ITP refractory to first-line therapy.
Standard ITP pharmacotherapy in children: includes prescribing glucocorticoids or intravenous immunoglobulins.
Thrombopoietin receptor agonists: Currently Romiplostim and Eltrombopag are used in the Russian Federation pediatrics. Their pharmacodynamic features in comparison with other drugs used in ITP are presented in the paper. Increased thrombocytopoiesis is the dominant, but not the only component of Romiplostim and Eltrombopag mechanism of action. It is relevant to study their effect on immune tolerance in ITP, which may be associated with a persistent platelet response in some patients after drug discontinuation.
Conclusion: The issue of thrombopoietin receptor agonist efficacy and safety as well as the mode of their use in ITP children treatment continues to be studied. The high cost of drugs continues to be a limiting factor to their earlier prescription. Generic drugs – Romiplostim and Eltrombopag partly solve the problem, promote their earlier prescription in ITP, but require additional study of their bioequivalence and therapeutic equivalence in comparison with the original drugs.
Graphical Abstract
This review discusses information about the structure and function of calcium channels in the plasma membrane and mitochondria of the heart, and pharmacological methods for modulating their conductance. Experimental data are presented that characterize the change in the energy metabolism of cardiomyocytes against the background of the transformation of the conductivity of L-type calcium channels of the cell membrane in a non-invasive model of vibration-mediated (56 sessions of total vertical vibration, with a frequency of 44 Hz and an amplitude of 0.5 mm) hypoxia.
It was shown that in animals treated with calcium channel blocker adalat (nifedipine INN) against the background of vibration, the rate of endogenous respiration (Ve), measured by the polarographic method using a closed Clark electrode in native homogenate of rabbit myocardial tissue, remained at the level of intact animals and amounted to 16.3 4.3 ng-O atom/ min mg of protein, amytal sensitivity increased by 39% (p 0.05) compared to the group of vibrated animals, low-natality decreased by 40% (p 0.05). The dynamics of the rate of substrate respiration (Vac and Vglu + mal) in the group with adalat returned to that of intact animals, which indicated the restoration of the physiological predominance of the activity of theNADH CoQ-reductase complex in redox reactions. It was found that the blockade of transport of Ca2+ ions at the level of high-threshold (HVA) voltage-dependent ion channels of the L-type of the cell membrane, normalizing the activity of the I enzyme-substrate complex of the respiratory chain and regulatoryly restraining the hyperactivity of succinate dehydrogenase in zone II of the enzyme-substrate complex, has an energy-protective effect. Adalat prevented a low-energy shift and the development of bioenergetic hypoxia in the myocardial tissue of experimental animals.
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