Efeitos do tratamento com digitoxina sobre a atividade vasomotora simpática na insuficiência cardíaca congestiva experimental
Data
2015-04-30
Autores
Fardin, Nubia Mantovan 
Orientadores
Campos Junior, Ruy Ribeiro de
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A Insuficiência Cardíaca Crônica (ICC) é um estado patológico no qual o coração tem o comprometimento da função do ventrículo esquerdo e/ou do ventrículo direito acompanhado de alterações na regulação neuro-humoral da circulação. Um dos tratamentos ofertados a pacientes com ICC são os digitálicos que estão associados à redução de hospitalizações, sem impacto na mortalidade. Entretanto, os mecanismos subjacentes a estes efeitos ainda não são totalmente conhecidos. A presente tese teve como objetivo verificar as alterações nos reflexos cardiovasculares periféricos e em núcleos centrais envolvidos no controle cardiovascular, além da participação do estresse oxidativo, em um modelo animal de ICC, tratado ou não com digitoxina. Para isso, foram utilizados ratos Wistar, divididos em quatro grupos experimentais: Sham (foram submetidos a cirurgia fictícia); Sham+DIG (foram submetidos a cirurgia fictícia e foram tratados com digitoxina por 60 dias); ICC (foram submetidos a cirurgia de indução de infarto por ablação); ICC+DIG (foram submetidos a cirurgia de indução de infarto por ablação e receberam tratamento por 60 dias). Ratos ICC apresentaram um aumento da atividade nervosa simpática renal (ANSr), comparados a animais Sham. A digitoxina no grupo ICC promoveu normalização da ANSr, porém, essa melhora na simpatoexcitação não foi acompanhada de aumento na sensibilidade dos barorreceptores e receptores cardiopulmonares. Os animais ICC também apresentaram um aumento da resposta a microinjeção de L-glutamato na região rostroventrolateral do bulbo (RVLM) quando comparados a animais Sham. Em animais ICC+DIG houve normalização dessa resposta comparada a animais ICC. Além disso, o grupo ICC+DIG apresentou menor resposta a microinjeção de GABA e bicuculina quando comparado a animais ICC e Sham, sem no entanto, apresentar alterações na expressão proteica de receptores GABA A. Os animais ICC apresentaram um aumento no estresse oxidativo observado pela diminuição da atividade das enzimas antioxidantes e pelo aumento da peroxidação lipídica, e neste caso, o tratamento com digitoxina nos animais ICC+DIG reverteu estes parâmetros, diminuindo a peroxidação lipídica no soro. Os resultados nos levam a acreditar que os efeitos benéficos do digital, em diminuir a ANSr e melhorar a sobrevida, sejam independentes da melhora dos reflexos periféricos e que essa ação, possivelmente, seja devido a ações dos digitálicos em núcleos centrais responsáveis pelo controle cardiovascular e redução do estresse oxidativo sistêmico.
Chronic heart failure (CHF) is a pathological state in which the heart is impaired function of the left and / or right ventricle accompanied by changes in the neurohumoral regulation of the circulation. One of the treatments used are digitalis, which is associated with reduced hospitalizations, with no impact on mortality. However, the mechanisms underlying these effects are not totally understood. Thus, this thesis aimed to investigate changes in peripheral cardiovascular reflexes, and central brain nuclei involved in cardiovascular control, in addition to the involvement of oxidative stress in an animal model of CHF, treated or not with digitoxin. For this, Wistar rats were divided into four experimental groups: Sham (sham surgery suffered); Sham+DIG (sham surgery suffered and treated with digoxin for 60 days); CHF (surgery to induce myocardial ablation); CHF+DIG (surgery to induce myocardial ablation and received digitoxin treatment for 60 days). CHF rats showed an increase in renal sympathetic nerve activity (rSNA), compared to Sham animals. Treatment with digitoxina in CHF-DIG normalize rSNA. However, decrease in rSNA was not accompanied by an increase in the sensitivity of baroreceptors and cardiopulmonary receptors. The CHF animals also showed an increased response to L-glutamate microinjection in rostralventralateral medulla (RVLM) compared to Sham animals, and CHF+DIG animals showed normalization of this response compared to CHF group. In addition, treatment with digitoxin in CHF+DIG promoted a lower response microinjection of GABA and bicuculline when compared to Sham and CHF animals without, however, changes in protein expression of GABA A receptors. Additionally, CHF animals show increased oxidative stress characterized by a reduction of antioxidant enzymes and increase in lipid peroxidation, and in this case, the treatment with digitoxin in CHF+DIG animals reversed this state, reducing lipid peroxidation in serum. The results together lead us to believe that the beneficial effects of digital, to reduce rSNA and improved survival, are independent of the improvement of peripheral reflexes, and that such action is probably due to changes in central nuclei responsible for cardiovascular control, or even by reducing systemic oxidative stress present in this pathology.
Chronic heart failure (CHF) is a pathological state in which the heart is impaired function of the left and / or right ventricle accompanied by changes in the neurohumoral regulation of the circulation. One of the treatments used are digitalis, which is associated with reduced hospitalizations, with no impact on mortality. However, the mechanisms underlying these effects are not totally understood. Thus, this thesis aimed to investigate changes in peripheral cardiovascular reflexes, and central brain nuclei involved in cardiovascular control, in addition to the involvement of oxidative stress in an animal model of CHF, treated or not with digitoxin. For this, Wistar rats were divided into four experimental groups: Sham (sham surgery suffered); Sham+DIG (sham surgery suffered and treated with digoxin for 60 days); CHF (surgery to induce myocardial ablation); CHF+DIG (surgery to induce myocardial ablation and received digitoxin treatment for 60 days). CHF rats showed an increase in renal sympathetic nerve activity (rSNA), compared to Sham animals. Treatment with digitoxina in CHF-DIG normalize rSNA. However, decrease in rSNA was not accompanied by an increase in the sensitivity of baroreceptors and cardiopulmonary receptors. The CHF animals also showed an increased response to L-glutamate microinjection in rostralventralateral medulla (RVLM) compared to Sham animals, and CHF+DIG animals showed normalization of this response compared to CHF group. In addition, treatment with digitoxin in CHF+DIG promoted a lower response microinjection of GABA and bicuculline when compared to Sham and CHF animals without, however, changes in protein expression of GABA A receptors. Additionally, CHF animals show increased oxidative stress characterized by a reduction of antioxidant enzymes and increase in lipid peroxidation, and in this case, the treatment with digitoxin in CHF+DIG animals reversed this state, reducing lipid peroxidation in serum. The results together lead us to believe that the beneficial effects of digital, to reduce rSNA and improved survival, are independent of the improvement of peripheral reflexes, and that such action is probably due to changes in central nuclei responsible for cardiovascular control, or even by reducing systemic oxidative stress present in this pathology.
Descrição
Citação
FARDIN, Nubia Mantovan. Efeitos do tratamento com digitoxina sobre a atividade vasomotora simpática na insuficiência cardíaca congestiva experimental. 2015. Tese (Doutorado em Farmacologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2015.