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When the right vagus nerve of anesthetized cats was stimulated with repetitive bursts of pulses, decelerated heart rate became synchronized to the rhythm of the vagal bursts. Each burst applied to the vagus was followed by a single heart contraction. Within defined limits an increase in the frequency of vagal bursts evoked a proportional acceleration of the heart, whereas a decreased frequency diminished the heart rate. Therefore, over the range of synchronization the heart rate was precisely controlled by changing the vagal stimulation rate. We concluded that the chronotropic effect evoked by vagal bursts was composed of two functionally different types of influence, namely, inhibitory tonic and synchronizing. The vagotropic influence of intravenously injected regulatory peptides was found to be selective for either the tonic or synchronizing component. For instance, dalargin (D-Ala2-Leu5-Arg6-enkephalin) and neokyotorphin selectively diminished the inhibitory tonic vagal influence, whereas delta sleep inducing peptide and neurotensin potentiated it. The magnitude of synchronizing vagal influence was not modified by these peptides. In contrast, secretin selectively inhibited the synchronizing vagal effect, but the tonic one was not affected. Somatostatin potentiated the synchronizing effect but diminished the tonic one. These data support the hypothesis that certain regulatory peptides can modulate the effects of repetitive vagal bursts on pacemaker activity.

A main issue in pharmacology is the seek for effective agents for the correction of ED. To study the endothelioprotective effects of 2-ethyl-3-hydroxy-6-methylpyridinium (2e3h6m) nicotinate under conditions of L-NAME-induced oxidation. The L-NAME pattern of induced oxide efficiency (25 mg/g) for one week was used. The endothelial and cardioprotective effect of 2e3h6m nicotinate at an amount of 3.75 mg/kg compared to picamilon 10 mg/kg was examined via the coefficient of ED (QED) and a number of exercise tests. Nicotinate 2e3h6m and picamilon exerted a pronounced endothelioprotective impact on the pattern of L-NAME-induced NO deficiency, which manifested itself in a decrease in the coefficient of endothelial dysfunction (ED). At the same time, 2e3h6m nicotinate (7.6 mg/kg) was 2.1 times more effective than picamilon (10 mg/kg). So, 2e3h6m nicotinate was produced itself as an endothelio and cardioprotector.

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Introduction: In this review, the analysis of technologies for obtaining biologically active proteins from various sources is carried out, and the comparative analysis of technologies for creating producers of biologically active proteins is presented. Special attention is paid to genetically modified animals as bioreactors for the pharmaceutical industry of a new type. The necessity of improving the technology of development transgenic rabbit producers and creating a platform solution for the production of biological products is substantiated. The advantages of using TrB for the production of recombinant proteins: The main advantages of using TrB are the low cost of obtaining valuable complex therapeutic human proteins in readily accessible fluids, their greater safety relative to proteins isolated directly from human blood, and the greater safety of the activity of the native protein. The advantages of the mammary gland as a system for the expression of recombinant proteins: The mammary gland is the organ of choice for the expression of valuable recombinant proteins because milk is easy to collect in large volumes. Methods for obtaining transgenic animals: The modern understanding of the regulation of gene expression and the discovery of new tools for gene editing can increase the efficiency of creating bioreactors for animals and help to obtain high concentrations of the target protein. The advantages of using rabbits as bioreactors producing recombinant proteins in milk: The rabbit is a relatively small animal with a short duration of gestation, puberty and optimal size, capable of producing up to 5 liters of milk per year per female, receiving up to 300 grams of the target protein.

Data which were obtained last time allow to re-comprehend ideas concerning mechanisms of cardiac rhythm regeneration and demonstrate existence of rhythm generator in the central nervous system in addition to such in the heart itself. Intracardiac generator is a life-supporting factor which supports pumping function of the heart while central nervous system is in deep inhibition status. Central generator provides adaptive reactions of the heart in natural medium. Integration of the two hierarchic levels of rhythmogenesis provides reliability and functional perfection of cardiac rhythm generation system in the organism.

В. М. покровский, В. В. полищук кубанский государственный медицинский университет, краснодар, Российская ФедерацияThe influence of The precision of The seT respiraTorY rhYThm reproducTion on The parameTers of cardiorespiraTorY sYnchronism pokrovskii V. m., polischuk V. V. Kuban state medical university, Krasnodar, russian federationЦель работы -определение связи между точностью воспроизведения задаваемой частоты дыхания в пробе сердечно-дыхательного синхронизма (СДС) и получаемыми параметрами СДС. Показатель точности воспроизведения задаваемого ритма дыхания оценивался в 93 пробах как процентное отношение количества совпавших отметок стимулятора и максимальной амплитуды на пневмограмме к общему количеству поданных в течение пробы сигналов. Анализ показал независимость параметров СДС от точности воспроизведения задаваемого ритма дыхания. Следовательно, взаимодействие сердечного и дыхательного ритмов зависит от способности нервных центров к адаптации в определенном диапазоне, что позволяет объективно оценивать регуляторно-адаптивные возможности организма. Ключевые слова: сердечно-дыхательный синхронизм, регуляторно-адаптивный статус, сознательный контроль дыхания, частота дыхания, адаптацияThe aim of the study is to determine the presence of the relationship between the accuracy of reproduction of the set respiratory rate in the test of cardiorespiratory synchronism (CRS) and the obtained CRS parameters. The index of the accuracy of the reproduction of the set breathing rhythm was estimated in 93 tests as the percentage of the matched marks number of stimulator and the maximum amplitude on the pneumogram to the total number of signals given during the test. The analysis showed lack of dependence of the CRS parameters from the precision of the set breathing rhythm reproduction. Consequently, the interaction of the heart and respiratory rhythms depends on the ability of the nerve centers to adapt in a certain range, which makes it possible to objectively assess the regulatory and adaptive capabilities of the organism.

α-synuclein is one of the key molecular links in the pathogenesis of Parkinson’s disease. The accumulated data indicate that pathogenic mutations in the Snca gene are associated with the development of neurodegenerative brain damage, indicating the relevance of studying the synuclein neurobiological role.The aim of the study was to create a genetically modified clone of mouse stem cells with a conditional knockout of humanized α-synuclein, which can be used for the reinjection into mouse blastocysts, as well as for basic and applied in vitro research in the field of pathophysiology and neuropharmacology.Materials and methods. To create mouse stem cells with a conditional knockout of the humanized Snca gene, a previously obtained clone with the first Snca exon flanked by LoxP sites, was used. The CRISPR/Cas9-mediated homologous recombination system with donor DNA oligonucleotides of the human sites of the corresponding gene sites was used to humanize the fourth and fifth exons. Cas9 nuclease, single guide RNA, and donor DNA were transfected into mouse cells.Results. An approach to obtaining clones of mouse genetically modified stem cells expressing pathological humanized α-synuclein, has been proposed and implemented. The resulting clones were plated on Petri dishes for propagation and a further genetic analysis. Clone 126-2F4 was found out carrying the necessary genetic modifications. The results obtained are fundamentally important not only for understanding the development of the pathological process in α-synucleinopathies, but which is more important, for the development of new therapeutic approaches that will stop the extension of the human α-synuclein aggregation pathology throughout the nervous system, and the validation of these approaches in preclinical trials.Conclusion. As a result of the study, a strategy for CRISPR/Cas9-assisted homologous recombination in the genome of mouse embryonic stem cells has been developed to create a fully humanized Snca gene encoding α-synuclein, and the clone genome of mouse embryonic stem cells has been edited using a CRISPR technology. The RNA and DNA oligonucleotides necessary for the creation of RNP complexes that carry out a directed homologous recombination in the Snca locus of the mouse genome have been synthesized. The developed cell clone can serve to create a line of genetically modified mice that serve as a test system for pathophysiological and neuropharmacological studies associated with synucleinopathies. Herewith, before the induction of the Cre-dependent recombination, this line is a representative model for studying a biological role of mutant Snca. At the same time, after a Cre-dependent knockout activation, it is possible to imitate the pharmacological inhibition of α-synuclein, which is of particular interest for applied research in neuropharmacology.