A new group of unsymmetrical ALM-802 analogs, N1-benzyl-N2-2-[(2,3,4-trimethoxybenzyl)amino]-ethylethane-1,2-diamines of general formula 1, in which one of the aromatic groups was changed, was studied. The anti-ischemic and antiarrhythmic activities of the new compounds were studied. Their ADME characteristics were analyzed. The 2,3,4-trimethoxyphenyl group used as one of the aromatic pharmacophores was shown to play a key role in the activity of compounds of this type. The presence of a second aromatic group was also important since its removal led to the disappearance of cardiotropic activity. However, its structure had significantly less impact on the activity of the corresponding compounds because a rather wide variation of substituents in this group did not change the activity in most arrhythmia and ischemia models.

Purpose of the study. Search for an optimal approach to developing a translational model of endothelial dysfunction (ED).Materials and methods. The experiments were carried out on 58 white male rats, which were randomized into 8 groups: 1st (n = 6) — control for L-methionine (in vitro experiments); 2nd (n = 6) — L-methionine (in vitro experiments); 3rd (n = 6) — control for L-NAME (in vitro experiments); 4th (n = 6) — L-NAME (in vitro experiments); 5th (n = 10) — control for L-methionine (in vivo experiments); 6th (n = 7) — L-methionine (in vivo experiments); 7-a (n = 10) — control for L-NAME (in vivo experiments); 8th (n = 7) — L-NAME (in vivo experiments). In groups 2 and 6, animals were intragastrically administered L-methionine (3 g/kg/day for 7 days), and rats in groups 4 and 8 were administered i.p. with L-NAME (0.025 g/kg/day within 7 days). Control animals received an equivalent volume of solvent. In in vitro experiments, a four-channel myograph (Danish Myo Technology) was used to record the tonic activity of the aortic rings. The contraction strength of the aortic rings caused by norepinephrine (10−7 M) and carbachol (10−5 M) was recorded in isometric mode. In in vivo experiments on anesthetized rats (urethane 1300 mg/kg i.p.), blood microcirculation in the myocardium and skeletal muscle was recorded using laser Doppler flowmetry using a computerized laser analyzer "LAZMA-D" (manufactured by NPP "Lazma", Russia). When assessing microblood flow, the perfusion index (M) was calculated in perfusion units (perf.u.).Results. In vitro experiments have shown that under conditions of hyperhomocysteinemia caused by L-methionine, the vascular response to norepinephrine remains practically unchanged. At the same time, the vasodilating response to carbachol (10−5 M) statistically significantly decreased by 57 % (p = 0.005). In animals treated with L-NAME, not only did the response to carbochol decrease by 55 % (p = 0.009), but also the vasoconstrictor response to norepinephrine increased by 48 % (p = 0.003). Under conditions of ED caused by both hyperhomocysteinemia and L-NAME, blood microcirculation in the myocardium and skeletal muscle is significantly reduced. It has also been shown that in the conditions of the L-NAME-induced ED model, in contrast to the L-methionine-induced ED model, there is no drop in rat body weight and practically no mortality.Conclusion. Thus, ED induced by both hyperhomocysteinemia and L-NAME blockade of endothelial nitric oxide synthase is accompanied by similar changes in blood microcirculation in the myocardium and skeletal muscle. However, taking into account the results of in vitro experiments, we can conclude that the model of ED induced by L-NAME seems more promising, under which, in contrast to ED induced by L-methionine, the vasodilatory response of the vessel to carbachol is not only suppressed, but also the vasoconstrictor reaction to norepinephrine is activated.

We studied the effect of N1-(2,3,4-trimethoxybenzyl)-N2-2-[(2,3,4-trimethoxybenzyl)amino]ethyl-1,2-ethanediamine (compound ALM-802) on the physical performance of mice after acute fatigue. The animals’ performance was assessed on a treadmill. The criterion for assessing exercise tolerance was the length of the distance passed when running on a treadmill until complete fatigue. To assess the actoprotective activity of compound ALM-802, we used a method of stepwise increase in load with an initial running speed of 42 cm/sec and its subsequent increase by 5 cm/sec every 5 min. The maximum speed of movement of the treadmill belt is 77 cm/sec. Animals that received compound ALM-802 (2 mg/kg intraperitoneally), 1 day after acute fatigue, ran a distance to complete fatigue that exceeded that of control mice by 68

Purpose of the study. Studying the blood microcirculation characteristics in the brain and heart of rats with ACM.Materials and methods. The study was carried out on white outbred male rats. The animals were randomized into 2 groups: 1st (n = 7) — control (intact) rats that received a normal diet and free access to water; 2nd (n = 6) — animals that received a normal diet and a 10 % ethanol solution as the only source of liquid. After 24 weeks of alcoholization in animals, the size and inotropic function of the heart were assessed using echocardiography. The next day, in anesthetized rats (urethane 1300 mg/kg i.p.), blood microcirculation in the heart and brain was recorded using a computerized laser analyzer “LAZMA-D” (manufactured by NPP “Lazma”, Russia) using the LDF 3.0.2.396 program. Using spectral wavelet analysis, the amplitudes of endothelial, neurogenic, myogenic, pulse and respiratory oscillations of microblood flow and the shunting index were determined.Results. According to echocardiography data, in rats that consumed a 10 % ethanol solution for 24 weeks, ACM is formed, which is accompanied by a decrease in blood microcirculation in the brain and myocardium. Thus, if in control animals the indicator of blood microcirculation in the myocardium was 36.60±2.19 perf. u., then in rats with ACM it was equal to 26.88±1.50 perf. u. units (p = 0.004). In the myocardium of rats with ACM, compared with control animals, the amplitude of both active and passive oscillations of microblood flow was significantly greater.Conclusion. In rats with ACM, the level of blood microcirculation in the heart muscle is significantly reduced, which, according to the results of spectral wavelet analysis, is prognostically unfavorable.

The body surface potential mapping of the heart during the period of ventricular depolarization and the inotropic function of the ventricles were studied in rats under conditions of a translational model of post-infarction chronic heart failure developed by us. We revealed a statistically significant (p<0.001) correlation between the left-ventricular ejection fraction and the values of the maximum positive and negative extrema of the cardioelectric field on the body surface of rats with post-infarction chronic heart failure caused by anterior transmural myocardial infarction. The calculated linear regression equations have high predictive efficiency, which makes it possible to use the amplitude characteristics of the heart cardioelectric field as a marker of the development of chronic heart failure.

Purpose of the study. Studying the features of microcirculation, functional state and anatomy of the heart using the “Holiday Heart” syndrome model in rats we developed.Materials and methods. Experiments were carried out on white outbred male rats. The “Holiday Heart” syndrome was modeled as follows: animals received a 10 % aqueous ethanol solution as the only source of fluid for the first 10 days, then tap water for 10 days, and again a 10 % aqueous ethanol solution for the next 10 days. One day after the end of the repeated intake of alcohol, the animals were taken into the experiment. Animals that received free access to tap water served as control. Some rats in the experimental group (n = 10) had an echocardiogram recorded before the start of the experiment, and on the 31st day of the experiment, after which the level of microcirculation of blood and lymph in the brain and heart was measured using laser Doppler flowmetry. In the remaining animals (n = 10), microcirculation of blood and lymph in the brain and heart was assessed on the 3rd day of alcohol deprivation.Results. Analysis of the obtained data showed that in the conditions of the “Holiday Heart” syndrome model, significant changes occur in the anatomy, functional activity and geometry of the heart: there is a significant thinning of the anterior wall of the left ventricle heart (LV), an increase in systolic and diastolic volumes and sizes of the LV and a significant (p = 0.0018) decrease in its inotropic function. These changes occur against the background of a significant (p = 0.0081) decrease in the level of blood microcirculation in the myocardium, however, on the 3rd day of deprivation, blood flow in the microvessels of the heart increases statistically significantly (p = 0.0285).Conclusion. In model experiments reproducing the “Holiday Heart” syndrome, it was shown for the first time that ethanol causes significant changes in the microcirculation, anatomy, functional activity and geometry of the left ventricle of the heart, which, apparently, can play a key role in the formation of myocardial electrical instability pathognomonic for this syndrome.

Senescence — cellular aging — is a special form of cell death, characterized by the cell’s irreversible loss of its proliferation potential and the development of resistance to apoptosis. Senescence is based on the attrition (shortening) of telomeres that occurs with each subsequent cell division, which ultimately leads to sustained DNA damage and subsequent activation of the cellular aging program. Senescent cells have a unique so-called senescence-associated secretory phenotype (SASP), i.e. the ability of aging cells to secrete into the extracellular environment a large number of pathogenic factors that act paracrine on undamaged cells and transfer them to a state of senescence. The literature review examines the known mechanisms responsible for the formation of various types of senescence, describes the features of senescence-related cardiac damage, and provides a detailed description of biologically active compounds and drugs with senolytic (apoptosis activators) and/or senostatic (SASP inhibitors) activity.

A new group of unsymmetrical ALM-802 analogs, N-1-benzyl-N-2-{2-[(2,3,4-trimethoxybenzyl)amino]-ethyl}ethane-1,2-diamines of general formula 1, in which one of the aromatic groups was changed, was studied. The anti-ischemic and antiarrhythmic activities of the new compounds were studied. Their ADME characteristics were analyzed. The 2,3,4-trimethoxyphenyl group used as one of the aromatic pharmacophores was shown to play a key role in the activity of compounds of this type. The presence of a second aromatic group was also important since its removal led to the disappearance of cardiotropic activity. However, its structure had significantly less impact on the activity of the corresponding compounds because a rather wide variation of substituents in this group did not change the activity in most arrhythmia and ischemia models.

Background . Earlier, on the translational model of alcoholic cardiomyopathy (ACMP) developed by us in outbred white rats, which reproduces the main clinical diagnostic signs of this disease, it was shown that in rats of both sexes under conditions of constant 24/7 alcoholization for 24 weeks, AСMP is formed. This study purpose is a comparative assessment of the features of the ACM formation in male and female rats depending on the level of ethanol consumption in model experiments simulating "domestic drunkenness" with periodic alcoholization 24/2 for 24 weeks. Materials and methods . Experiments were performed on outbred white rats randomized into 4 groups: group 1 — control male rats (n=18), group 2 — control female rats (n = 18), group 3 — alcoholized male rats (n = 39) and group 4 — alcoholized female rats (n = 19). Control animals received a normal diet and free access to water. Animals of the 3rd and 4th groups weekly, for 24 weeks, from Friday 22.00 to Monday 8.00, received a 10 % ethanol solution as the only source of liquid with unlimited access to standard food, and the usual diet on the remaining days. Results . In animals of both sexes, after 24 weeks from the consumption start of the ethanol solution, ACM is formed, as evidenced by an increase in the end-systolic and end-diastolic sizes of the left ventricle of the heart (p = 0.0001) and a decrease in its ejection fraction (p = 0.0001), while the degree of pathological myocardial remodeling is more pronounced in females. According to cluster analysis, by the consumption of ethanol (CET), animals of both sexes are divided into 3 subgroups: low, medium and high CET, however, in males, the subgroup with an average CET prevails — 56 %, and in females with a high CET — 47 % (p = 0.0286), the low CET subgroup is minimal (16 %). At the same time, if in males in all subgroups, starting from the 8th week of alcoholization, CET dynamically decreases, then how in females in subgroups with medium and high CET, starting from the 16th week, it increases. It was found that the degree of left ventricular remodeling in females with high and moderate CET was almost 2 times higher than in males (p < 0.05). Conclusion. In model experiments imitating “domestic drunkenness”, it was shown that in females the intensity of the left ventricle heart remodeling is significantly higher than in males, which, apparently, is determined by the identified gender-dependent multidirectional trends in the formation of alcoholic behavior characterized by dynamic growth. consumption of ethanol in female rats as the duration of alcoholization increases.

The antiarrhythmic activity of bis-alkoxyphenyltriazaalkanes 1 and bis-alkoxyphenyldiazaalkanes 2 was analyzed in a model of reperfusion arrhythmia in rats. It was found that the key requirements for the compounds activity in this model are the use of 2,3,4 trimethoxyphenyl aromatic pharmacophores and the presence of a central nitrogen atom in the linker. The most active compounds were ALM-802 (trihydrochloride N1–(2,3,4-trimethoxybenzyl)-N2– {2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine) and ALM-811 (N1-(2,3,4-trimethoxybenzyl)-N3-{3-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,3-propanediamine trihydrochloride), which significantly prevented the development of ventricular tachycardias and/or ventricular fibrillation.

New compounds of bis(2,3,4-trimethoxyphenyl)azaalkanes differing in the structure of the central atom were obtained. The anti-ischemic and antiarrhythmic activities of the new compounds were studied. Their absorption, distribution, metabolism, and excretion (ADME) characteristics were analyzed. Replacement of the central N atom by other atoms (O, C, S) had practically no effect on their antiarrhythmic and anti-ischemic properties but improved their calculated oral bioavailability. The promising compound ALM-863 {2,2′-oxybis[ N -(2,3,4-trimethoxybenzyl)ethane-1-amine] dihydrochloride} at a dose of 3 mg/kg (i.v.) completely repeated the spectrum of cardiotropic properties of the ALM-802 prototype, was less toxic and surpassed it in terms of calculated pharmacokinetic parameters, and was selected.

In model experiments reproducing the holiday heart syndrome in rats, a discrepancy between the depolarization of the right and left atria has been revealed, which manifested by an atypical arrangement of positive and negative cardiopotentials in the cardioelectric field on the body surface during the P wave and the absence of inversion of the areas of cardioelectric potentials before the onset of P waves in lead II ECG from the limbs.

The mechanisms underlying the antiarrhythmic action of compound trihydrochloride N1-(2,3,4-trimethoxy)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethane-diamine (code ALM-802) were studied in vitro. The experiments were performed on a culture of rat hippocampal neurons. The electrical activity of neurons was recorded by the patch-clamp method in the whole cell configuration. It is shown that the compound ALM-802 effectively blocks potential-dependent Na+ and K+ channels and does not affect the activity of potential-dependent Ca2+ channels. The inhibition of currents through these channels is dose-dependent; the IC50 of Na+ and K+ channels were 94±4 and 67±3 μM, respectively. These findings indicate that compound ALM-802 combines the properties of class I and class III antiarrhythmic agents according to the Vaughan—Williams classification.

Цель исследования – сравнительное изучение антиаритмической активности фабомотизола и производных бензодиазепина (феназепама и диазепама) на модели электрической фибрилляции желудочков сердца у крыс с интактным и денервированным миокардом. Методика. В экспериментах на интактных крысах и крысах с денервированным миокардом в сравнительном аспекте изучена антиаритмическая активность анксиолитиков – производных бензодиазепина (феназепама и диазепама) и бензимидазола (фабомотизола). Результаты. Показано, что феназепам (1,0 мг/кг, в/в) и фабомотизол (7,5 мг/кг, в/в) у интактных животных, в отличие от диазепама (0,5 и 1,0 мг/кг в/в), статистически значимо (р=0,028) повышают порог электрической фибрилляции желудочков сердца. У животных с денервированным миокардом только фабомотизол проявлял противофибрилляторную активность (p<0,05). Заключение. Таким образом, анксиолитики фабомотизол и феназепам проявляют выраженную антиаритмическую активность, однако феназепам реализует свою антиаритмическую активность преимущественно на уровне ЦНС, а фабомотизол – на уровне кардиомиоцитов. Aim. To compare the antiarrhythmic activity of fabomotizole and benzodiazepine derivatives (phenazepam and diazepam) in electrical ventricular fibrillation modeled in rats with intact and denervated myocardium. Methods. In experiments on intact rats and rats with denervated myocardium, the antiarrhythmic activity of the anxiolytics, benzodiazepine (phenazepam and diazepam) and benzimidazole (fabomotizole) derivatives, was compared. Results. It was shown that phenazepam (1.0 mg/kg, i.v.) and fabomotizole (7.5 mg/kg, i.v.) administered to intact animals, in contrast to diazepam (0.5 and 1.0 mg/kg, i.v.), significantly (p=0.028) increased the electrical ventricular fibrillation threshold. In animals with denervated myocardium, only fabomotizole showed an antifibrillatory activity (p<0.05). Conclusion. It can be assumed that phenazepam implements its antiarrhythmic activity mainly at the level of the central nervous system whereas fabomotizole produces it at the level of the myocardium.

We report here the synthesis of novel compounds of the bis-(2,3,4-trimethoxybenzyl)propanediamines group and studies of their anti-ischemic and antiarrhythmic activity. Introduction of a hydroxyl group into the central part of the propane linker was found to produce virtually no change in the spectrum of cardiotropic properties of the unsubstituted compound ALM-851, while introduction of two methyl groups led to the complete disappearance of both antiarrhythmic and antiischemic activities. Compound ALM-850 (1,3-bis((2,3,4-trimethoxy-benzyl)amino)propan-2-oldihydrochloride) at a dose of 3 mg/kg significantly blocked the development of rhythm disturbances and death in animals in the aconitine and calcium chloride arrhythmia models, and also decreased ST segment depression in the isoproterenol ischemia model.