RESUMO
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.
Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Animais , Animais não Endogâmicos , Biomarcadores/metabolismo , Ecocardiografia , Expressão Gênica , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/metabolismo , Hemodinâmica/fisiologia , Humanos , Masculino , Contração Miocárdica/fisiologia , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Pesquisa Translacional Biomédica/métodosRESUMO
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.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Cardiotônicos/farmacologia , Oclusão Coronária/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Morfolinas/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Animais , Animais não Endogâmicos , Ansiolíticos/farmacologia , Biomarcadores/sangue , Oclusão Coronária/genética , Oclusão Coronária/fisiopatologia , Vasos Coronários/cirurgia , Esquema de Medicação , Reposicionamento de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Masculino , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Peptídeo Natriurético Encefálico/antagonistas & inibidores , Peptídeo Natriurético Encefálico/sangue , Ratos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/metabolismoRESUMO
The effects of GK-1, a monomeric dipeptide mimetic of nerve growth factor (NGF) loop 4, on angiogenesis were studied in vitro and in vivo. Experiments on human umbilical vein endothelial cells HUVEC showed that the test compound did not affect tubulogenesis (initial stage of angiogenesis) and prevented realization of the angiogenic effect of NGF and its dimeric dipeptide mimetic GK-2. Experiments on rat hind limb ischemia model demonstrated that GK-1 (1 mg/kg/day intraperitoneally over 14 days) significantly reduced the density of the capillary network in ischemic tissue and increased the number and area of Zenker necrosis in comparison with the control. These data suggest that GK-1 exhibits a pronounced antiangiogenic activity.
Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Fator de Crescimento Neural/química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Animais , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , RatosRESUMO
Effect of trimetazidine (20 and 30 mg/kg) on elevated plus maze behavior of rodents was assessed in the genetic and pharmacological anxiety models. Single intraperitoneal injection of trimetazidine in a dose of 20 mg/kg prevented anxiety development in highly emotional male BALB/c mice and increased the time spent in open arms of the maze. In outbred male rats receiving 10% ethanol solution for 20 weeks, trimetazidine administered intraperitoneally in a dose of 20 mg/kg for 28 days abolished ethanol withdrawal-induced anxiogenesis developed against the background of 4-week alcohol deprivation: it increased the time spent in open arms, the number of entries into open arms, and total locomotor activity in the maze. Anxiolytic properties of trimetazidine were not inferior to those of the non-benzodiazepine anxiolytic Afobazole (fabomotizole) in acute and chronic administration.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Trimetazidina/farmacologia , Alcoolismo/psicologia , Animais , Animais não Endogâmicos , Ansiolíticos/uso terapêutico , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Etanol/efeitos adversos , Masculino , Camundongos Endogâmicos BALB C , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Ratos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/psicologia , Trimetazidina/uso terapêuticoRESUMO
The phenomenon of atypical DNA comets in experiments using DNA comet assay is described and illustrated. The current hypotheses explaining the nature of atypical DNA comets and own vision of the issue are considered. The practical importance of the registration of atypical DNA comets in assessing the genotoxicity is discussed.
Assuntos
Ensaio Cometa/métodos , Dano ao DNA , DNA/química , Animais , DNA/metabolismo , HumanosRESUMO
Dynamic echocardiographic monitoring in rats subjected to forced alcoholization showed the formation of disorders in intracardiac hemodynamics characteristic of ethanol cardiomyopathy formed by the end of 24-week continuous ethanol consumption. The results of echocardiographic monitoring were confirmed by histological and morphometric studies demonstrating fatty infiltration of the myocardium pathognomonic for this condition and bifocal dilatation of cardiac ventricles. These results persuasively demonstrate that echocardiographic studies on small animals are valid and can be used for search for cardiotropic drugs and studies of the mechanisms of their activities.
Assuntos
Cardiomiopatias/patologia , Ecocardiografia/métodos , Miocárdio/patologia , Animais , Cardiomiopatias/induzido quimicamente , Etanol/efeitos adversos , Hemodinâmica , Masculino , RatosRESUMO
Seven-day treatment of rats with experimental myocardial infarction with afobazole (5-ethoxy-2-[2-morpholino)-ethylthio] benzimidasole dihydrochloride) resulted in shrinkage of the ischemic damage area in the heart, stimulation of reparative processes in the myocardium, and prevention of postinfarction remodeling of the left ventricle. Anti-ischemic effect of afobazole in experimental myocardial infarction is presumably due to its interactions with σ(1) receptors.
Assuntos
Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Masculino , Infarto do Miocárdio/patologia , Miocárdio/citologia , Ratos , Receptores sigma/metabolismo , Estatísticas não ParamétricasRESUMO
Preclinical safety investigations of newly synthesized dipeptide compound GB-115 (amide N-phenylhexanoyl-glycyl-L-tryptophan), an antagonist of cholecystokinin receptors, were performed. No animals were lost after GB-115 acute oral administration at a maximum dose of 6000 mg/kg in mice and at 3500 mg/kg in rats. GB-115 administered per os during 6 months in rabbits and rats (both males and females) at the doses of 0.1 and 10 mg/kg induced no irreversible pathological changes in organs and systems studied. The tested dipeptide exhibited no allergenic, immunotoxic and mutagenic activity, and did not affect generative function and the antenatal and postnatal development of progeny. GB-115 at a dose of 10 mg/kg produced suppression of the inflammatory reaction to concanavalin A.
Assuntos
Dipeptídeos/efeitos adversos , Dipeptídeos/farmacologia , Receptores da Colecistocinina/antagonistas & inibidores , Animais , Concanavalina A/efeitos adversos , Concanavalina A/farmacologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Cobaias , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Coelhos , RatosRESUMO
A long-term (21 days) administration of the specific bradycardic agent zatebradine to rats with experimental myocardial infarction led to a decrease in the intensity of necrotic changes in the cardiac muscle as evaluated from the ECG-recorded QS complex incidence rate. Morphological studies provided evidence for reduced intensity of the dystrophic processes in myocardium. Under these conditions, the drug did not affect the pump and contractile heart functions. At the same time, zatebradine normalized the reaction of mean aorta blood flow acceleration to volume load (which was inhibited at myocardial infarction), that is, prevented the development of latent heart failure. Zatebradine restored the infarction-decreased norepinephrine (NE) level in cardiac muscle and increased NE content in hypothalamus and brainstem. Along with that, the ratios of deoxyphenylacetic acid/dopamine and homovanillic acid/dopamine were reduced.
