RESUMEN
Experiments on rats showed that injection of propranolol into the medulla oblongata increased the contents of epinephrine, norepinephrine, dopamine, and L-DOPA by 3.76, 1.4, 2.0, and 1.7 times, respectively. These propranolol-induced changes in the levels and ratio of neurotransmitters were not accompanied by variations in serotonin content. Propranolol had no significant effects on the content of excitatory amino acids, except marked increase in aspartate content. The level of inhibitory amino acids increased mainly due to an increase in GABA content. The balance between excitatory and inhibitory amino acids was shifted towards inhibitory compounds.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Antagonistas Adrenérgicos beta/farmacología , Catecolaminas/metabolismo , Bulbo Raquídeo/fisiología , Propranolol/farmacología , Sistema Nervioso Simpático/efectos de los fármacos , Glándulas Suprarrenales/metabolismo , Aminoácidos/metabolismo , Animales , Masculino , Bulbo Raquídeo/efectos de los fármacos , Distribución Aleatoria , Ratas , Serotonina/metabolismo , Sistema Nervioso Simpático/fisiología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Local injection of verapamil into ventrolateral region of the medulla oblongata triggered the release of epinephrine. Verapamil increased the total content of norepinephrine and epinephrine by 560% and decreased the content of serotonin by 46%. Verapamil had no effect on norepinephrine/epinephrine and norepinephrine/(norepinephrine+epinephrine) ratios in normal rats. Blockade of K+-channels in the medulla oblongata by local injection of 0.001 mg amiodarone did not change the levels of epinephrine and norepinephrine and norepinephrine/epinephrine and norepinephrine/(norepinephrine+epinephrine) ratios. In the medulla oblongata, verapamil proportionally increased the levels of norepinephrine, dopamine, and L-DOPA. Similarly, amiodarone increased the levels of L-DOPA and dopamine by 2.6 and 3.2 times, respectively. Amiodarone shifted the ratio of neuroactive amino acids towards inhibitory transmitters.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Amiodarona/farmacología , Antagonistas de Aminoácidos Excitadores/metabolismo , Aminoácidos Excitadores/metabolismo , Bulbo Raquídeo/metabolismo , Sistema Nervioso Simpático/metabolismo , Verapamilo/farmacología , Glándulas Suprarrenales/efectos de los fármacos , Animales , Bloqueadores de los Canales de Calcio/farmacología , Dopamina/metabolismo , Epinefrina/metabolismo , Levodopa/metabolismo , Masculino , Microinyecciones , Norepinefrina/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Distribución Aleatoria , Ratas , Ratas Endogámicas , Serotonina/metabolismo , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
In investigation were included 33 children with mild and moderate bronchial asthma of atopic geneses, average duration of the disease 3,5+/-1,9 years, average frequency of asthma attacks was less then once per month (night attacks 2-3 times per week), factors of initiation were dust and sharp smells. It was shown, that in atopic bronchial asthma in children, disbalance in endothelial system is developed, the content of endothelin-1, vasoconstrictor peptide of endotheliocytes, is increased by 64%. At the same time, coefficient of correlation between redox-potential NADP/NADPH and content of IgE decreases from 0,79 (p<0,01) in norm to 0,57 (p<0,05). Obtained data raises the issue of necessity of inclusion in the therapy of bronchial asthma the remedies which prevent bioenergetic failure.
Asunto(s)
Asma/etiología , Asma/metabolismo , Dermatitis Atópica/complicaciones , Dermatitis Atópica/metabolismo , Endotelina-1/metabolismo , Hipoxia/etiología , Hipoxia/metabolismo , Piel/irrigación sanguínea , Piel/metabolismo , Asma/inmunología , Niño , Preescolar , Dermatitis Atópica/inmunología , Femenino , Humanos , Hipoxia/fisiopatología , Inmunoglobulina A/inmunología , Inmunoglobulina E/inmunología , Masculino , Oxidación-Reducción , Piel/fisiopatologíaRESUMEN
Structural and conformational changes in myocardial and erythrocyte actin during cardiac ischemia were studied by the method of fluorescence resonance energy transfer with highly selective fluorescent probes. In contrast to 15-min coronary artery occlusion, 120-min ischemia was accompanied by irreversible structural and conformational changes in the small domain of erythrocyte actin. Posttranslational changes during myocardial ischemia concerned the N- and C-terminal regions of actin and went beyond the allowed conformational fluctuations in the actin molecule without breaking the energy barrier. Our results suggest that under conditions of ischemia, actin of the myocardium and erythrocyte cytoskeleton loses its ability to acquire conformation required for force generation by cardiomyocyte myofibrils and maintenance of elasticity and integrity of the erythrocyte membrane.
Asunto(s)
Actinas/química , Eritrocitos/metabolismo , Isquemia Miocárdica/patología , Miocardio/metabolismo , Animales , Vasos Coronarios/patología , Citoesqueleto/metabolismo , Perros , Transferencia Resonante de Energía de Fluorescencia/métodos , Concentración de Iones de Hidrógeno , Isquemia/patología , Miocardio/química , NAD/química , Conformación Proteica , Estructura Terciaria de Proteína , Piridinas/química , Factores de TiempoRESUMEN
Experiments on skinned and hybrid myocardial fibers isolated from normal dogs and animals subjected to 120-min occlusion of the anterior interventricular branch of the coronary artery showed that in contrast to cardiac glycosides, angiotensin-converting enzyme inhibitors suppress contractile ability of myocardial myofibrils in a dose-independent manner within the concentration range of 10(-12)-10(-4)M. This effect is accompanied by a decrease in fiber relaxation rate most pronounced in the presence of captopril. Actin, the major protein of fine filaments is the target for b-acetyldigoxin, K-strophanthin, captopril, enalapril, and trandolapril in myocardial myofibrils. During coronary occlusion, the inhibitors of angiotensin-converting enzyme induce structural and conformational changes in actin that decrease efficiency of contraction. The data obtained cast doubt on advisability of therapeutic use of angiotensin-converting enzyme inhibitors in the therapy of myocardial infarction, especially in its early period.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Glicósidos Cardíacos/antagonistas & inhibidores , Metabolismo Energético , Contracción Miocárdica/efectos de los fármacos , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatología , Miofibrillas/efectos de los fármacos , Actinas/química , Enfermedad Aguda , Animales , Perros , Técnicas In Vitro , Modelos Moleculares , Miocardio/metabolismo , Miocardio/ultraestructura , Miofibrillas/metabolismo , Conformación ProteicaRESUMEN
Experiments on dogs showed that energostim, a directly acting antihypoxant, injected 15 min after occlusion of the upper one-third of the left descending branch of the interventricular coronary artery produced a pronounced cardioprotective effect. The effect was confirmed by electron microscopy (evaluation the necrotic focus), biochemical tests of the heart and blood, and changes in intracardiac hemodynamics (recovery of systolic and diastolic functions). The cardioprotective effect of energostim greatly surpasses that of routine therapy applied during acute myocardium infarction.
Asunto(s)
Antioxidantes/farmacología , Enfermedad Coronaria/prevención & control , Enfermedad Coronaria/terapia , Infarto del Miocardio/prevención & control , Infarto del Miocardio/terapia , Animales , Vasos Coronarios/patología , Perros , Ventrículos Cardíacos/ultraestructura , Hemodinámica , Microscopía Electrónica , Isquemia Miocárdica/tratamiento farmacológico , Miocardio/ultraestructura , Necrosis , Fosfocreatina/metabolismo , Factores de TiempoRESUMEN
The contents of myofibrillar creatine phosphokinase and cytochrome c, the key enzyme of the mitochondrial respiratory chain, increased, while the content of nicotinamide coenzymes and redox potential (NAD/NADH ratio) sharply decreased over the first 6 h of acute myocardial infarction. The contents of norepinephrine and epinephrine increased by 51 and 49%, respectively, 6 h after onset of acute myocardial infarction. By contrast, dopamine concentration decreased by 116% during this period. The increase in the content of cytochrome c directly correlated with the concentration of myofibrillar creatine phosphokinase and Peel index. No correlations were found between norepinephrine/epinephrine and dopamine/(norepinephrine+epinephrine) ratios. The antihypoxant with direct action energostim normalized the content of cytochrome c, increased NAD and dopamine concentrations and NAD/NADH ratio, and decreased the content of norepinephrine and epinephrine to the baseline level in patients with acute myocardial infarction. These results indicate that energostim possesses not only antihypoxic and antioxidant activities, but also pronounced antisympathomimetic properties.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Antioxidantes/farmacología , Infarto del Miocardio/tratamiento farmacológico , Piridinas/química , Catecolaminas/sangre , Creatina Quinasa/sangre , Grupo Citocromo c/sangre , Epinefrina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piridinas/metabolismo , Factores de TiempoRESUMEN
Skinned and hybrid myocardial fibers were studied by methods of tensometry, determination of the ATP hydrolysis intensity, and resonance fluorescent energy transfer between highly selective labels bound to various amino acid residues. It was established that development of the early stage of heart failure in the case of acute myocardial ischemia caused by 15-min coronary artery occlusion (CAO) is related to a reversible damage or adaptive (functional) depression of the contractile protein system. As a result, the system features isolated submolecular post-translational variation in the properties of major proteins in a thin actin filament (myosin is not significantly damaged). This leads to a decrease in the force developed by the hybrid fibers (reconstructed using ghost myocardial fibers taken from ischemic area and normal myosin) and in the ATPase activity of actomyosin (ATP hydrolysis intensity) without any significant change in the Ca-sensitivity, cooperativity of the Ca-response of the actomyosin ensemble, and efficiency of the contractile process. In actin of the ischemic area, CAO results in a serious damage of the Lys61 and Cys374 regions and in a less pronounced damage of the Tyr69 and Cys10 regions. These results suggest that the Lys61 and, probably, Cys374-Lys61 regions are included in the actin monomer as a protomer, without adequate prepolymerization structural-conformational changes necessary to provide for the normal functioning of the filament. In the CAO-induced early stage of heart failure, cardiac glycosides (beta-acetyldigoxin, beta-methyldigoxin, and strophanthin K) produce a direct effect upon the intramolecular structure of myocardial actin, restore the generated force level, and increase the intensity of ATP hydrolysis by actomyosin ensemble. This is achieved by improving or normalizing the structural-conformational state and conformational mobility of the Lys61 and Cys374 region of actin.
Asunto(s)
Glicósidos Cardíacos/farmacología , Enfermedad Coronaria/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Contracción Miocárdica/efectos de los fármacos , Actinas/química , Actinas/efectos de los fármacos , Enfermedad Aguda , Animales , Glicósidos Cardíacos/uso terapéutico , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/fisiopatología , Perros , Evaluación Preclínica de Medicamentos , Colorantes Fluorescentes , Corazón/efectos de los fármacos , Corazón/fisiopatología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/fisiología , Contracción Miocárdica/fisiología , Conformación Proteica/efectos de los fármacosRESUMEN
Experiments conducted on an isolated contractile apparatus, myocardial fibers (MF) in cardiac insufficiency (CI) caused by toxico-allergic myocarditis of 10 days duration (TAM10dd) showed that cardiac glycosides (CG), beta-acetyldigoxin (beta AD), beta-methyldigoxin, and strophanthin K (SK) increase the capacity of the actomyosin ensemble (AME) for generation of force, hydrolization, and economic use of the free energy of ATP hydrolysis. The mechanism of the effect of these CG in the phase of contraction differs from that of their effect on the AE of a normal myocardium. For instance, in severe CI induced by TAM10dd beta AD, in distinction from its action on the AME of a normal myocardium, can increase contractility economy, particularly in the phase of highest energy capacity, the phase of force generation, and exceed the level encountered in normal conditions, it also increases significantly the rate and reduces the time of MF relaxation as in the case of MF of a normal heart.
Asunto(s)
Glicósidos Cardíacos/farmacología , Insuficiencia Cardíaca/fisiopatología , Corazón/efectos de los fármacos , Proteínas Musculares/efectos de los fármacos , Miocarditis/fisiopatología , Animales , Metabolismo Energético/efectos de los fármacos , Corazón/fisiopatología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Técnicas In Vitro , Proteínas Musculares/fisiología , Contracción Miocárdica/efectos de los fármacos , Miocarditis/complicaciones , Miocarditis/metabolismo , Miocardio/metabolismo , Conejos , Factores de TiempoRESUMEN
It is shown that cardiotropic drug refracterin promotes recovery of cardiac contraction and relaxation, their coordination destroyed in cardiac failure (CF) caused by 10-day toxico-allergic myocarditis (TAM). Pumping capacity of the heart returns to normal after normalization of functional activity of three systems of cardiomyocyte responsible for contraction-relaxation: contractile proteins, energy supply and calcium transport. The key process is refracterin-related reestablishment of normal content and proportion of adenyl nucleotides and creatininephosphate and regulation role of phosphorylation and energy of metabolic processes in the cells and their interaction. Thus, refracterin effectiveness lies in its ability to interfere in intracellular metabolic processes in the myocardium, to reestablish normal homeostasis of the systems responsible for contraction-relaxation function and eventually to remove left ventricular cardiac dysfunction.
Asunto(s)
Acetildigoxinas/farmacología , Fármacos Cardiovasculares/farmacología , Grupo Citocromo c/farmacología , Insuficiencia Cardíaca/fisiopatología , Corazón/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Miocarditis/fisiopatología , Miocardio/ultraestructura , Oxifedrina/farmacología , Acetildigoxinas/uso terapéutico , Animales , Transporte Biológico/efectos de los fármacos , Calcio/metabolismo , Fármacos Cardiovasculares/uso terapéutico , Grupo Citocromo c/uso terapéutico , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Corazón/fisiopatología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Hemodinámica/efectos de los fármacos , Proteínas Musculares/efectos de los fármacos , Proteínas Musculares/fisiología , Contracción Miocárdica/fisiología , Miocarditis/complicaciones , Miocarditis/tratamiento farmacológico , Miocardio/metabolismo , Oxifedrina/uso terapéutico , Conejos , Factores de TiempoRESUMEN
Heart overloading due to pressure as a result of 8 periodic full aortic constriction in heart failure (HF) caused by 10-day toxic-allergic myocarditis (TAM) leads to deterioration of heart contractility (pump function). This is explained by additional decline in functional activity of all three systems of cardiomyocyte responsible for contraction-relaxation. In particular, by a sharp fall of ATP and CP content in the myocardium, a 400% decrease in myofibril power, 200% reduction in efficiency of contraction and marked deterioration of calcium transport. The resultant exhaustion of myocardial reserve brought 70% lethality among the animals. Under the above conditions coordination between the systolic and diastolic cardiac functions, correlation between myocardial functional activity and subcellular systems of cardiomyocyte are impaired. In pressure heart overloading refracterin initiates profound metabolic rearrangements improving metabolism, remodelling of the system of energy supply, reestablishment of systemic homeostasis, normalization of cardiomyocyte and cardiac reserves.
Asunto(s)
Cardiotónicos/uso terapéutico , Corazón/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Miocarditis/tratamiento farmacológico , Miocardio/metabolismo , Animales , Calcio/metabolismo , Cardiotónicos/farmacología , Evaluación Preclínica de Medicamentos , Metabolismo Energético/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Hemodinámica/efectos de los fármacos , Miocarditis/metabolismo , Miocarditis/fisiopatología , ConejosRESUMEN
The in vitro study on an isolated system of myocardial contractile proteins determined optimal concentrations of the positive inotropic action and biological activity ranges of beta-methyldigoxin (beta-MD), strophanthin K, K-strophantozide, beta-acetyldigoxin (beta-AD), milrinone, and amrinone. Optimal concentrations of the beta-MD and strophanthin K (10(-2) and 10(-6) M, respectively) significantly increased qualitatively and quantitatively the economy and thermodynamic efficiency, altered the energy transformation in the contractile protein system under the isometric contraction, whereas the beta-AD produced only the quantitative effect. However, the beta-MD and strophanthin K at concentrations exceeding the optimal one by one order lost the ability to produce the qualitative effect, retaining only the quantitative one in the actomyosin ensemble. The strophanthin K significantly increased the economy of a single actomyosin ensemble in the force generation phase and the beta-MD in the tension maintenance phase. Unlike the strophanthin K, the beta-MD did not slow down (did not worsen) the relaxation process. This provides grounds to conclude that the beta-MD produces most favorable effect on the energy transformation by myocardial contractile proteins.
Asunto(s)
Glicósidos Cardíacos/farmacología , Cardiotónicos/farmacología , Corazón/efectos de los fármacos , Proteínas Musculares/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Animales , Perros , Relación Dosis-Respuesta a Droga , Metabolismo Energético/efectos de los fármacos , Técnicas In Vitro , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/metabolismo , Miocardio/metabolismo , ConejosRESUMEN
Skin assay of dog myocardial fibers showed alterations in free energy of ATP hydrolysis correlated distinctly with the rate of activity generated by the fiber (r = 0.87; P < 0.01). Impairment of chemomechanical coupling occurred in the system of myocardial contractile proteins under conditions of athyreosis and L-thyroxin-induced toxicosis, which is responsible for qualitative and quantitative deteriorations of energy transformation in cardiomyocyte myofibrils. The sites of energy generation and liberation appear to be spatially disconnected in the active actomyosin complex and their coupling and uncoupling is related to properties of actin.
Asunto(s)
Corazón/fisiopatología , Hipotiroidismo/fisiopatología , Tirotoxicosis/fisiopatología , Tiroxina/metabolismo , Adenosina Trifosfato/metabolismo , Animales , ATPasa de Ca(2+) y Mg(2+)/metabolismo , ATPasas Transportadoras de Calcio/metabolismo , Perros , Metabolismo Energético , Hidrólisis , Hipotiroidismo/metabolismo , Contracción Miocárdica , Miocardio/metabolismo , Tirotoxicosis/metabolismoRESUMEN
Active and rigor force generation under the effect of electrostatic charge, the temperature and pCa, was significantly decreased in informational experimental disease. Other significant changes on the molecular level occurred in cardiomyocyte contractile apparatus in conditions of experimental informational disease.
Asunto(s)
Adenosina Trifosfato/metabolismo , Enfermedades Cardiovasculares/metabolismo , Metabolismo Energético/fisiología , Miocardio/metabolismo , Miofibrillas/metabolismo , Trastornos Neuróticos/metabolismo , Fosforilación Oxidativa , Trastornos Psicofisiológicos/metabolismo , Animales , Calcio/metabolismo , Condicionamiento Clásico/fisiología , Modelos Animales de Enfermedad , Perros , Hidrólisis , Masculino , Contracción Miocárdica/fisiología , TemperaturaRESUMEN
In vitro on skinned myocardial fibers (SMF) with extracted or functionally inactivated enzymes and membranes of mitochondria, longitudinal sarcoplasmic reticulum, triads and sarcolemma, new evidence of beta-acetyldigoxin and strophanthin K direct stimulating effects on contractile protein system of myocardium has been obtained. It has been revealed in energy release stimulation and force generation, in quantitative (beta-acetyldigoxin) or quantitative and qualitative (strophanthin K) stimulation of energy transduction, in the increase of contractile process cooperativity and Ca-sensitivity of SMF as well as in the SMF relaxation time extension (in the case of strophanthin K). It is suggested that different effects of beta-acetyldigoxin and strophanthin K are due to the differences in the conformations of actomyosin ensembles formed by strong bound (AMESB), which are induced by the influence of these cardiac glycosides. It has been demonstrated that ouabain (strophanthin K) has no direct effect on functioning of AMESB.
Asunto(s)
Acetildigoxinas/farmacología , Corazón/efectos de los fármacos , Ouabaína/farmacología , Estrofantinas/farmacología , Animales , Técnicas In Vitro , Mitocondrias Cardíacas/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Conejos , Sarcolema/efectos de los fármacos , Retículo Sarcoplasmático/efectos de los fármacosRESUMEN
Energy transduction in purified myocardial myofibrils from normal rabbits and those having toxi-allergic myocarditis (TAM) was compared. In TAM a sharp decrease in the rate and value of ATP hydrolysis enthalpy released during free contraction of myofibrils takes place, and is accompanied by a rise in the amount of energy dissipated as heat. It is concluded that, at the early stages of shrinkage force generation during myofibril contraction in TAM, a breakdown of actin activation of Mg(2+)-ATPase activity for myosin occurs, the character of the bonds is changed, and the efficiency of myosin cross-bridge interaction with the protomeres of the actin thin filaments is decreased. The contractile process becomes wasteful.