RESUMEN
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% (387.9±60.5 and 230.6±29.6 m, respectively, p=0.023). The reference drug trimetazidine (30 mg/kg, intraperitoneally) did not have a significant effect on the distance traveled. Compound ALM-802 helps restore physical performance, i.e. exhibits significant actoprotective activity.
Asunto(s)
Fatiga , Animales , Ratones , Masculino , Fatiga/tratamiento farmacológico , Tolerancia al Ejercicio/efectos de los fármacos , Condicionamiento Físico Animal , Rendimiento Físico Funcional , Diaminas/química , Diaminas/farmacologíaRESUMEN
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.
Asunto(s)
Insuficiencia Cardíaca , Infarto del Miocardio , Disfunción Ventricular Izquierda , Animales , Ratas , Volumen Sistólico , Función Ventricular Izquierda , Infarto del Miocardio/complicacionesRESUMEN
The effect of the compound N1-(2,3,4-trimethoxy)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethane-diamine (code ALM-802) on the amplitude of the Ca2+ response in the cell was studied in in vitro experiments. The concentration of intracellular calcium was assessed using a Fura-2 two-wave probe. The experiments were performed on a culture of isolated rat hippocampal neurons. The effect of compound ALM-802 on the activity of ryanodine receptors (RyR2) was studied on an isolated strip of rat myocardium. The compound ALM-802 (69.8 µM) in hippocampal neurons causes a significant decrease in the amplitude of the Ca2+ response induced by addition of KCl to the medium. Experiments performed on an isolated myocardial strip showed that compound ALM-802 (10-5 M) almost completely blocked the positive inotropic reaction of the strip to the RyR2 agonist caffeine (5×10-5 M). The data obtained indicate that the decrease in the concentration of Ca2+ ions in the cell caused by ALM-802 is due to its ability to block RyR2 located on the membrane of the sarcoplasmic reticulum, which can be associated with the antiarrhythmic activity of the compound.
Asunto(s)
Miocardio , Canal Liberador de Calcio Receptor de Rianodina , Ratas , Animales , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Miocardio/metabolismo , Antiarrítmicos/farmacología , Cafeína/farmacología , Retículo Sarcoplasmático , Calcio/metabolismo , Rianodina/farmacología , Rianodina/metabolismoRESUMEN
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.
Asunto(s)
Fibrilación Atrial , Ratas , Animales , Vacaciones y Feriados , Electrocardiografía , Atrios Cardíacos , Potenciales de AcciónRESUMEN
In in vitro experiments on isolated rat hippocampal neurons, we studied the electrophysiological mechanisms of the antiarrhythmic effects of N-deacetyllappaconitine monochlorhydrate (DALCh), active metabolite of lappaconitine hydrobromide (allapinin). Electrical activity of neurons was recorded by the patch-clamp method in the whole cell configuration. It was shown that DALCh increased the duration of both slow and fast depolarization phases and decreased the amplitude of the action potential. DALCh effectively inhibited transmembrane currents of Na+ ions and partially K+ ions through the corresponding transmembrane voltage-gated ion channels. Thus, DALCh, in contrast to lappaconitine hydrobromide, belongs not to 1C, but to the 1A class of antiarrhythmics according to the Vaughan-Williams classification.
Asunto(s)
Neuronas , Canales de Potasio , Aconitina/análogos & derivados , Potenciales de Acción , Animales , Antiarrítmicos/farmacología , Neuronas/metabolismo , Técnicas de Placa-Clamp , Canales de Potasio/metabolismo , RatasRESUMEN
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.
Asunto(s)
Antiarrítmicos , Neuronas , Ratas , Animales , Antiarrítmicos/farmacología , Potenciales de AcciónRESUMEN
The molecular mechanisms underlying the cardioprotective effect of fabomotizole were studied using the translational rat model of alcoholic cardiomyopathy developed by us. It was shown that intraperitoneal administration of fabomotizole (15 mg/kg) for 28 days to animals with alcoholic cardiomyopathy contributes to normalization of the expression of mRNA of genes of regulatory proteins СаР(p=0.00001), ÐÑаÑ1 (p=0.021), and ÐÑаÑ2 (p=0.018) and receptors RyR2 (p=0.0031) and IP3R2 (p=0.006) in the myocardium of the myocardium of the left ventricle that is enhanced in control animals (p<0.05). These changes were accompanied by echocardiographically documented decrease in the degree of left ventricle remodeling and improvement of its inotropic function.
Asunto(s)
Cardiomiopatía Alcohólica , Animales , Cardiomiopatía Alcohólica/tratamiento farmacológico , Cardiomiopatía Alcohólica/metabolismo , Ventrículos Cardíacos/metabolismo , Miocardio/metabolismo , ARN Mensajero/metabolismo , Ratas , Canal Liberador de Calcio Receptor de Rianodina/metabolismoRESUMEN
The cardioprotective activity of ALM-802 compound was demonstrated in model experiments simulating postinfarction chronic heart failure in rats forming in 90 days after anterior transmural myocardial infarction. ALM-802 decreased the left ventricle and improved its inotropic function (p=0.038). This effect was observed in case of systematic administration of ALM-802 over 28 days (starting from day 91 after infarction modeling). This is apparently the minimum time for the cardioprotective effect of ALM-802 to prevent or treat the resulting heart failure, because short-term systematic therapy (15 days) produced no positive effect.
Asunto(s)
Ventrículos Cardíacos/metabolismo , Infarto del Miocardio/metabolismo , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Masculino , Infarto del Miocardio/genética , RatasRESUMEN
In vitro experiments performed on an isolated human endothelial HUVEC cell culture showed that the anxiolytic fabomotizole, which, in addition to the anxiolytic effect, has neuroprotective and cardioprotective activities largely associated with its agonistic action on sigma-1 receptors and shows a pronounced angiogenic activity. Fabomotizole angiogenic activity is realized in the range concentration from 10-5 to 10-8 M and is doze-dependent. In the literature, data on the presence of angiogenic activity in sigma receptor agonists have not been previously reported.
Asunto(s)
Ansiolíticos/farmacología , Bencimidazoles/farmacología , Morfolinas/farmacología , Movimiento Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Receptores sigma/metabolismo , Receptor Sigma-1RESUMEN
Social isolation stress was modeled by long-term isolation of 12-month-old rats in individual cages over 28 weeks. It was found that sensitization of blood vessels to the vasoconstrictor action of serotonin due to overexpression of 5HT2A-type receptor genes, as well as an imbalance in the expression level of endothelin ETA- and ETB-receptors (55 and 153%, respectively) are the early signs of vascular aging. A significant contribution to the development of age-related changes in the contractile properties of blood vessels is made by the stress component, which is manifested at the level of glucocorticoid-dependent mechanisms of regulation of gene expression. The decrease in the expression of glucocorticoid receptors caused by isolation stress leads to a decrease in the expression of the genes responsible for the synthesis of V1A-R and ATII-R and to the development of vascular hyporeactivity to the vasoconstrictor action of ATII and AVP. In the aorta of stressed rats, the α1-AR mRNA level increases by 3 times. At the same time, stress did not affect the dynamics of age-related changes in the expression of genes encoding 5HT2A-R and ETA/ETB-R.
Asunto(s)
Aorta/metabolismo , ARN Mensajero/metabolismo , Receptores de Endotelina/metabolismo , Aislamiento Social , Animales , Aorta/efectos de los fármacos , Dexametasona/farmacología , Masculino , Ratas , Vasoconstrictores/farmacologíaRESUMEN
The mechanisms underlying cardioprotective activity of compound ALM-802 were studied in experiments on rats with chronic post-infarction heart failure. Real-time PCR showed that compound ALM-802 (daily intraperitoneal injections in a dose of 2 mg/kg for 28 days starting from day 91 after myocardial infarction modeling) restored the expression of genes encoding ß1- (p=0.00001) and ß2-adrenoreceptors (p=0.01) and type 2 ryanodine receptors (p=0.008) in the myocardium that was reduced in control animals. These effects can serve as the basis for the ability of the compound to reduce the intensity of remodeling and increase the inotropic function of the left heart ventricle shown earlier in this model.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Receptores Adrenérgicos/metabolismo , Animales , Cardiotónicos/uso terapéutico , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Miocardio/metabolismo , ARN Mensajero/metabolismo , Ratas , Canal Liberador de Calcio Receptor de Rianodina/metabolismoRESUMEN
In the study of the sequence of depolarization of the atrial subepicardium of rats in the short-term alcohol consumption model (the "Holiday heart" syndrome), the localization of the sources of atrial arrhythmias was determined for the first time. The difference in the excitation of the right and left atria was discovered: the right atrium is activated anterogradely from the sinoatrial node, whereas the left atrium is activated retrogradely from the ectopic focus located in the left auricular appendage.
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Arritmias Cardíacas/etiología , Modelos Cardiovasculares , Nodo Sinoatrial/fisiopatología , Trastornos Relacionados con Alcohol/patología , Trastornos Relacionados con Alcohol/fisiopatología , Animales , Arritmias Cardíacas/patología , Arritmias Cardíacas/fisiopatología , Simulación por Computador , Modelos Animales de Enfermedad , Corazón/efectos de los fármacos , Corazón/fisiopatología , Atrios Cardíacos/fisiopatología , Masculino , RatasRESUMEN
Cardioprotective effect of 1-({4 [(4 chlorobenzoyl)amino]phenyl}sulfonyl-L-proline (compound AL-828) was studied in rats with modeled acute myocardial infarction. The test compound was administered intragastrically in a dose of 30 mg/kg/day for 3 days prior to infarction modeling. Metalloproteinase inhibitor antibiotic doxycycline served as the reference drug and was administered in a dose of 40 mg/kg/day by the same schedule. It was shown that AL-828 similar to doxycycline significantly reduced the intensity of myocardial remodeling and maintained the inotropic function of the myocardium in the acute phase of myocardial infarction. By the 20th minute of ischemia, the end-systolic dimension of the left ventricle in control animals increased from 1.98±0.12 to 3.84±0.16 mm, while in animals treated with AL-828, this increase was significantly (p=0.007) less pronounced (from 1.84±0.07 and 2.87±0.21 mm, respectively). The ejection fraction characterizing the inotropic status of the left ventricle in animals treated with AL-828 was significantly higher (p=0.02). By its cardioprotective activity, AL-828 was not inferior to the reference drug doxycycline. It can be assumed that the cardioprotective activity of compound AL-828 is related to suppression of MMP-9 expression and/or inhibition of its activity as was previously demonstrated by us.
Asunto(s)
Cardiotónicos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Infarto del Miocardio/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Masculino , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Ratas , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiologíaRESUMEN
A translational rat model of chronic heart failure was employed to examine the cardioprotective effect of fabomotizole hydrochloride. Fabomotizole therapy for 28 days (15 mg/kg/day intraperitoneally) restored inotropic function of the left ventricle and increased ejection fraction from 54±3 to 65±3% (p=0.001). The inotropic function returned to normal against the background of significantly reduced myocardial expression of angiotensin (p=0.01) and glucocorticoid (p=0.03) receptors and significant increased expression of sigma-1 receptors (p=0.04). Inhibition of abnormal expression of angiotensin and glucocorticoid receptors responsible for activation of the pathological cascades underlying the postinfarction remodeling of the left ventricle as well as activation of the expression of cytoprotective sigma-1 receptors are viewed as the key features of the cardioprotective action of fabomotizole hydrochloride.
Asunto(s)
Bencimidazoles/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Angiotensinas/metabolismo , Animales , Ecocardiografía , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ratas , Receptores de Glucocorticoides/metabolismo , Receptores sigma/metabolismo , Receptor Sigma-1RESUMEN
Anti-ischemic activity of fabomotizole hydrochloride was studied on the model of subendocardial ischemia in rats with endothelial dysfunction. Endothelial dysfunction was modeled by intragastric administration of methionine (3 g/kg, once a day for 7 days). Acute subendocardial ischemia was induced in narcotized rats by intraperitoneal injection of isoproterenol (20 µg/kg/min over 5 min). Fabomotizole hydrochloride (intraperitoneally, 15 mg/kg) significantly reduced isoproterenol-induced ST segment depression in animals with endothelial dysfunction and with intact vasculature.
Asunto(s)
Bencimidazoles/farmacología , Cardiotónicos/farmacología , Endocardio/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Morfolinas/farmacología , Isquemia Miocárdica/prevención & control , Animales , Animales no Consanguíneos , Modelos Animales de Enfermedad , Endocardio/fisiopatología , Endotelio Vascular/fisiopatología , Isoproterenol/efectos adversos , Isoproterenol/antagonistas & inhibidores , Masculino , Metionina/efectos adversos , Metionina/antagonistas & inhibidores , Isquemia Miocárdica/inducido químicamente , Isquemia Miocárdica/fisiopatología , Ratas , Resultado del TratamientoRESUMEN
We created a translational model of chronic heart failure in rats that developed in 3 months after reproducing experimental anterior transmural myocardial infarction. The model simulated the basic clinicodiagnostic criteria of this disease: impaired contractility and dilatation of heart ventricles, signs of venous congestion, elevated plasma content of biochemical markers, and abnormal overexpression of AT1aR and ß-adrenoceptors.
Asunto(s)
Modelos Animales de Enfermedad , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Infarto del Miocardio/fisiopatología , Miocardio/patología , Animales , Animales no Consanguíneos , Biomarcadores/metabolismo , Ecocardiografía , Expresión Génica , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/metabolismo , Hemodinámica/fisiología , Humanos , Masculino , Contracción Miocárdica/fisiología , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Investigación Biomédica Traslacional/métodosRESUMEN
Anti-ischemic activity of N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino] ethyl}-1,2-ethanediamine (ALM-802) based on the structure of standard p-FOX inhibitors trimetazidine and ranolazine was studied on the model of endocardial ischemia in intact rats and animals with endothelial dysfunction. Acute endocardial myocardial ischemia was caused by infusion of isoproterenol (20 µg/kg/min intravenously). Endothelial dysfunction in rats was modeled by inducing hyperhomocysteinemia (3 g/kg methionine intragastrically one a day over 7 days). The reference drugs trimetazidine (30 mg/kg, intravenously) and ranolazine 10 mg/kg, intravenously) that were effective only in intact rats. In contrast, ALM-802 (2 mg/kg, intravenously) showed a pronounced anti-ischemic effect in animals with endothelial dysfunction, which suggests that the mechanisms of its cardioprotective action differ from those known for p-FOX inhibitors.
Asunto(s)
Hiperhomocisteinemia/tratamiento farmacológico , Infarto del Miocardio/tratamiento farmacológico , Ranolazina/uso terapéutico , Trimetazidina/uso terapéutico , Animales , Electrofisiología , Hiperhomocisteinemia/inducido químicamente , Isoproterenol/toxicidad , Masculino , Infarto del Miocardio/inducido químicamente , RatasRESUMEN
Using a translation model of alcoholic cardiomyopathy in rats we showed the presence of an additional abnormal excitation focus in the area of the pulmonary vein lacunae in the left atrium and enhanced heterogeneity of the atrium depolarization pattern. These changes can determine electric instability of the myocardium and induce malignant heart rhythm disturbances including, sudden cardiac death.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Arritmias Cardíacas/fisiopatología , Cardiomiopatía Alcohólica/fisiopatología , Etanol/toxicidad , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Animales , Animales no Consanguíneos , Modelos Animales de Enfermedad , Electrocardiografía , Atrios Cardíacos/fisiopatología , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Contracción Miocárdica/efectos de los fármacos , Miocardio/patología , Venas Pulmonares/efectos de los fármacos , Venas Pulmonares/fisiopatología , RatasRESUMEN
Original translational rat model of chronic heart failure provoked by experimental anterior transmural myocardium infarction was employed to examine the preventive action of anxiolytic Afobazole (15 mg/kg/day administered intraperitoneally during the first 15 days after coronary occlusion) on the development of the heart failure assessed in 3 months after infarction. Afobazole prevented the development of pathologic remodeling of the myocardium, maintained its inotropic function, and decreased the plasma level of brain natriuretic peptide known as a biochemical marker of chronic heart failure. In the myocardium, Afobazole down-regulated overexpression of the genes induced in chronic heart failure and assessed by corresponding RNA levels, which code angiotensin (AT1A-R), vasopressin (V1A-R), and glucocorticoid (GR) receptors as well as Epac2 protein. The revealed biochemical changes are consistent with the data on cardioprotective action of Afobazole.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bencimidazoles/farmacología , Cardiotónicos/farmacología , Oclusión Coronaria/tratamiento farmacológico , Insuficiencia Cardíaca/prevención & control , Morfolinas/farmacología , Infarto del Miocardio/tratamiento farmacológico , Animales , Animales no Consanguíneos , Ansiolíticos/farmacología , Biomarcadores/sangre , Oclusión Coronaria/genética , Oclusión Coronaria/fisiopatología , Vasos Coronarios/cirugía , Esquema de Medicación , Reposicionamiento de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Factores de Intercambio de Guanina Nucleótido/antagonistas & inhibidores , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/fisiopatología , Masculino , Infarto del Miocardio/genética , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Péptido Natriurético Encefálico/antagonistas & inhibidores , Péptido Natriurético Encefálico/sangre , Ratas , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Receptores de Vasopresinas/genética , Receptores de Vasopresinas/metabolismoRESUMEN
The expression of Epac proteins (exchange protein directly activated by cAMP) and calmodulin (CaM) was assessed by the content of the corresponding mRNA in biopsy specimens of cardiac atrium, left ventricle, and thoracic aorta of rats with alcoholic cardiomyopathy. In the myocardium, overexpression of Ðpac1, ÐÑаÑ2, and СаРmRNA was found. The content of Epac2 mRNA in the left ventricle was elevated by 2.9 times (p=0.000001), in the left atrium by 3.2 times (p=0.00001), in the right atrium by 3 times (p=0.00001). In contrast to the myocardial tissue, the content of CaM mRNA in the thoracic aorta was not increased, but showed a tendency to decrease, when compared to the control values, while the level of Epac1 and Epac2 mRNA was increased. The assumption is made that regulatory proteins Epac and CaM can play a key role in arrhythmogenesis development under conditions of alcoholic cardiomyopathy.