38 research outputs found
The possibility of using echocardiography in small laboratory animals for acute pharmacological tests
No full textResume. The purpose of this investigation is to study the adequacy of the echocardiography method in small laboratory animals for performing acute pharmacological tests. In experiments on white mongrel male rats, a nonselective ß-adrenoreceptor agonist isoproterenol (20 μg /kg, i.v.) reduces the end-systolic and end-diastolic dimensions and volumes of the heart left ventricle, measured by echocardiography, and increases the shortening and ejection fractions, i.e. has a positive inotropic effect. Cardioselective ß1-adrenoblocker metoprolol (1 mg / kg, i.v.), on the contrary, increases the left ventricle sizes and reduces the shortening and ejection fractions, i.e. has a negative inotropic effect. Thus, the method of echocardiography in small laboratory animals can be used to conduct acute pharmacological tests
Study of the relationship between the severity of alcoholic cardiomyopathy and the level of alcohol consumption in male and female rats in the model of “home drinking”
No full textBackground. 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 cardiotropic properties of ZMEI-3 compound – a potential inhibitor of Epac proteins
No full textIntroduction. It is known that the allosteric effector of cAMP, in addition to protein kinase A, is the Epac regulatory proteins, which in cardiomyocytes play a key role in the electromechanical coupling control and their rhythmic activity. However, under pathological conditions, abnormal activity of Epac proteins is responsible for the hypertrophy and fibrosis of cardiomyocytes and the initiation of cardiac arrhythmias. Objective. To study the cardiotropic activity of the compound N,2,4,6-tetramethyl-N-(pyridin-4-yl)benzolsulfonamide (code ZMEI-3), which potentially has the properties of Epac protein antagonists, in models of cardiac arrhythmias and alcoholic cardiomyopathy ( ACMP).Materials and methods. Experiments were carried out on outbred male rats. The antiarrhythmic activity of the ZMEI-3 compound was assessed in models of aconitine and reperfusion arrhythmias, and the cardioprotective activity in a translational model of ACM, which is formed after 24 weeks of forced intake of 10 % ethanol.Results. Using a model of reperfusion arrhythmias in rats, it was shown that the ZMEI-3 compound (2 mg/kg/day for 7 days i.p.) reduces the incidence of life-threatening arrhythmias, including ventricular fibrillation. In conditions of formed ACMP, the studied compound (2 mg/kg/day for 28 days i.p.) increased the inotropic function of the heart, which was judged by the value of the left ventricular ejection fraction. Histological analysis showed that in conditions of formed ACMP, the ZMEI-3 compound reduces the severity of morphological signs of alcoholic heart damage.Conclusions. Compound ZMEI-3, when used in a course, has a pronounced antiarrhythmic effect and reduces the severity of alcohol-related heart failure
Delayed Results of Experimental Afobazole Therapy in Rats after Acute Myocardial Infarction
No full text
Study of the antiarrhythmic activity of linear alkoxyphenylazalkanes in the model of reperfusion arrythmias in rats
No full textThe 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
Features of the compound ALM-802 antiarrhythmic action
No full textIntroduction. Cardiovascular diseases (CVD) remain one of the leading causes of death worldwide, claiming over 17 million lives annually. This highlights the urgent need to develop innovative drugs to combat CVD. One potential target for such drugs is type 2 ryanodine receptors (RyR2), as they play an important role in maintaining ion homeostasis in cardiomyocytes, and their abnormal activity plays a key role in the genesis of cardiac arrhythmias.Research objective is to study the mechanisms underlying the antiarrhythmic action of ALM-802.Methods. In the first stage, in vivo experiments were performed using models of aconitine, calcium chloride, barium chloride arrhythmia, and reperfusion arrhythmias to evaluate the antiarrhythmic effect of the compound ALM-802. The second stage of the study involved electrophysiological experiments performed on hippocampal cells of newborn rats to evaluate the effect of the compound on voltage-gated transmembrane Na+, K+, and Ca2+ ion channels, as well as its effect on intracellular ion concentration of Ca2+. Experiments performed on an isolated myocardial strip evaluated the effect of the compound ALM-802 on the activity of RyR2.Results. In in vivo experiments, the compound ALM-802 (2 mg/kg, iv) exhibits significant antiarrhythmic activity comparable/superior to that shown by the reference drugs procainamide, verapamil, and amiodarone on the models mentioned above. In in vitro experiments, it was shown that ALM-802 (69.8 µM) initiates the inactivation of K+ and Na+ ion channels and does not affect the activity of Ca2+ ion channels. The compound ALM-802 effectively prevents the increase of Ca2+ ion concentration in the cytosol during depolarization of contraction. In addition, experiments on isolated myocardial strips showed that the compound ALM-802 (5x10-5 M) blocks RyR2.Conclusion. Thus, based on the spectrum of its antiarrhythmic activity, the compound ALM-802 combines the properties of antiarrhythmic drugs of class IA or IC and class III according to the E.M. Vaughan Williams classification. In addition, the ALM-802 compound exhibits antagonistic activity towards RyR2. The latter is also considered significant, as it is known that under conditions of myocardial pathology, abnormal activity of RyR2 initiates diastolic leakage of Ca2+ ions from the sarcoplasmic reticulum cysterns, which leads to a decrease in the inotropic function of the left ventricle of the heart and significantly increases the risk of developing malignant cardiac arrhythmias
Study of ALM-802 orto-alkoxi analogues cardiotropic activity
No full textNew ortho-alkoxy analogs of the compound ALM-802 1a (N1-(2-methoxybenzyl)-N2-[2-((2-methoxybenzyl)amino)ethyl]ethane-1,2-diamine trihydrochloride) and 1b (N1-(2-ethoxybenzyl)-N2-[2-((2-ethoxybenzyl)amino)ethyl]ethane-1,2-diamine trihydrochloride), which differ from it by the presence of alkoxy groups in the phenyl rings only in the ortho positions. It was established that these structural changes lead to the disappearance of anti-ischemic activity. At the same time, antiarrhythmic activity was revealed in compound 1b on the models of aconitine and calcium chloride arrhythmias in rats (1 mg / kg, intravenously), which was absent in 1a
Study of methoxy-group position influence on compound alm-802 cardiotropic activity
No full textA new compound ALM-803 (trihydrochloride N1-(3,4,5-trimethoxybenzyl)-N2-{2-[(3,4,5-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine) was synthesized as analog of ALM 802, differing from it by the position of the methoxy groups in the phenyl rings. It is established that this structural change leads to the disappearance of anti-ischemic activity and antiarrhythmic activity on the model of aconitine arrhythmia in rats, but the antiarrhythmic activity on models of chloride-calcium arrhythmia and electrical fibrillation of the heart of rats remained (1 mg/kg, intravenously)
Investigation of the fabomotizol dihydrochloride effect on the morphological picture of the heart left ventricle in rats with the subacute myocardial infarction
No full textThe purpose of the study. Investigation of the effect of the fabomotizol dihydrochloride systematic therapy on the morphological picture of the heart left ventricle (LV) in rats in the subacute period of myocardial infarction. Materials and methods. Myocardial infarction (MI) modeling was carried out using the A.Selye method. Fabomotizol dihydrochloride was administered to rats intraperitoneally 1 time per day from the 15th to the 28th day after MI at a dose of 15 mg/kg. At the end of the experiment, euthanasia and a pathoanatomic autopsy were performed. Samples of hearts after fixation in formalin and standard wiring were poured into paraffin blocks. Histological sections of the hearts were microscoped in transmitted light. Results. Dilation of the LV cavity and thinning of its walls in animals treated with fabomotizol dihydrochloride are less pronounced than in control rats with MI. In the periinfarction zone of the myocardium in rats treated with fabomotizol dihydrochloride, wave-like deformation and fragmentation of cardiomyocytes is less intense, and the transverse striation of myofibrils, on the contrary, is more pronounced than in the control. In animals treated with fabomotizol dihydrochloride, the periinfarction zone is well vascularized. Conclusion. According to the results of morphological studies performed on a model of subacute MI in rats, it was demonstrated that systematic therapy with fabomotizole dihydrochloride contributes not only to a significant reduction in the necrosis zone, but also to a certain extent prevents the development of early postinfarction remodeling. In rats treated with fabomotizol dihydrochloride, in contrast to control animals, reparative processes prevail in the cardiac muscle. These observations indicate the presence of cardioprotective activity in the drug
