O pesticida aldrin induz cardiotoxicidade aguda: envolvimento do canal para sódio nav1.5
Data
2023-09-04
Autores
Beserra, Samuel dos Santos 
Orientadores
Campos, Danilo Roman
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A presença do inseticida Aldrin, ou de seus resíduos, acumulados nos lençóis freáticos e em rios onde se extraem a água para consumo doméstico, ou irrigação de cultivos agrícolas, é um grave problema de saúde pública. A bioacumulação deste agrotóxico tem como sintomas: cefaléia, vômitos, tremor muscular, convulsões, as quais são descritos em casos relacionados ao manejo inadequado do agrotóxico ou de elevada ingestão do pesticida. Porém, poucos estudos descrevem sua ação na atividade elétrica cardíaca. Objetivo: Investigar o potencial arrítmico do Aldrin e o papel do canal NaV1.5 Métodos: O ECG, ex vivo, dos corações de camundongo C57Bl/6 foram feitos. Cardiomiócitos isolados do ventrículo esquerdo de camundongos C57Bl/6, e canais NaV1.5 humano foram transitoriamente expressos em células embrionárias de rim humano, linhagem 293 (HEK293), usando um sistema de expressão heteróloga. Cardiomiócitos derivados de células-tronco pluripotentes induzidas de humanos (hiPSC-CMs) foram utilizados para estudar o efeito do aldrin sobre o potencial de ação (PA) cardíaco. As medidas eletrofisiológicas foram realizadas por meio da configuração célula inteira da técnica de Patch-Clamp, na modalidade voltage-clamp para mensuração da corrente de sódio (INa) e current-clamp para registros de PA. Resultados: O aldrin modificou o perfil das ondas do ECG e aumentou a frequência cardíaca nos experimentos in vitro. Além disso, o inseticida promoveu redução da derivada máxima da despolarização (+dV/dt) que corresponde a velocidade máxima da fase 0 do PA, em cardiomiócitos isolados derivados do ventrículo esquerdo de camundongo. Posteriormente foi avaliado o efeito do pesticida sobre o NaV1.5 expresso em célula HEK293, onde há a redução da amplitude de pico da INa, que apresentou dependência da frequência para o efeito. O aldrin promoveu redução significativa da derivada máxima da despolarização (+dV/dt), e também a duração do PA de cardiomiócitos derivados de célula tronco pluripontente induzidas de humanos. Conclusões: Os resultados demostram que o aldrin é capaz de alterar a atividade de condução elétrica do coração, ao modular a corrente de canais NaV1.5 e modificar suas propriedades do PA, o que torna este pesticida um agente arritmogênico e de grande risco à saúde pública.
Introduction: The presence of the insecticide Aldrin accumulated in groundwater and in rivers where water is extracted for domestic consumption or irrigation of agricultural crops, is a serious public health problem. The bioaccumulation of this pesticide has the following symptoms: headache, vomiting, muscle tremors, convulsions, which are described in cases related to inadequate management of the pesticide or high intake of the pesticide. However, few studies describe the action of Aldrin on electrical activity of the heart. Objective: To investigate the arrhythmic potential of Aldrin and the role of the NaV1.5 channel. Methods: Ex vivo ECG of C57Bl/6 mouse hearts were performed. Cardiomyocytes isolated from the left ventricle of C57Bl/6 mice, and human NaV1.5 channels were transiently expressed in human embryonic kidney cells, lineage 293 (HEK293), using a heterologous expression system. Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) were used to study the effect of Aldrin on cardiac action potential (AP). Electrophysiological measurements were performed using the whole-cell configuration of the Patch-Clamp technique, in voltage-clamp mode for measuring sodium current (INa) and current-clamp for AP recordings. Results: Aldrin modified the profile of ECG and increased heart rate in ex vivo experiments. Furthermore, the insecticide promoted a reduction in the maximum derivative of AP depolarization (+dV/dt), which corresponds to the maximum velocity of phase 0 of AP, in isolated cardiomyocytes derived from the mouse left ventricle. Subsequently, the effect of the pesticide on NaV1.5 expressed in HEK293 cells was evaluated. The pesticide caused a reduction in the INa peak amplitude, which showed frequency dependence for the effect. Aldrin promoted a significant reduction in the maximum derivative of depolarization (+dV/dt), and also in the AP duration of human induced pluripotent stem cell-derived cardiomyocytes Conclusions: The results demonstrate that aldrin is capable of altering the electrical activity of the heart, by modulating the NaV1.5 channel current and modifying its PA properties, which makes this pesticide an arrhythmogenic agent and may pose a risk to public health.
Introduction: The presence of the insecticide Aldrin accumulated in groundwater and in rivers where water is extracted for domestic consumption or irrigation of agricultural crops, is a serious public health problem. The bioaccumulation of this pesticide has the following symptoms: headache, vomiting, muscle tremors, convulsions, which are described in cases related to inadequate management of the pesticide or high intake of the pesticide. However, few studies describe the action of Aldrin on electrical activity of the heart. Objective: To investigate the arrhythmic potential of Aldrin and the role of the NaV1.5 channel. Methods: Ex vivo ECG of C57Bl/6 mouse hearts were performed. Cardiomyocytes isolated from the left ventricle of C57Bl/6 mice, and human NaV1.5 channels were transiently expressed in human embryonic kidney cells, lineage 293 (HEK293), using a heterologous expression system. Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) were used to study the effect of Aldrin on cardiac action potential (AP). Electrophysiological measurements were performed using the whole-cell configuration of the Patch-Clamp technique, in voltage-clamp mode for measuring sodium current (INa) and current-clamp for AP recordings. Results: Aldrin modified the profile of ECG and increased heart rate in ex vivo experiments. Furthermore, the insecticide promoted a reduction in the maximum derivative of AP depolarization (+dV/dt), which corresponds to the maximum velocity of phase 0 of AP, in isolated cardiomyocytes derived from the mouse left ventricle. Subsequently, the effect of the pesticide on NaV1.5 expressed in HEK293 cells was evaluated. The pesticide caused a reduction in the INa peak amplitude, which showed frequency dependence for the effect. Aldrin promoted a significant reduction in the maximum derivative of depolarization (+dV/dt), and also in the AP duration of human induced pluripotent stem cell-derived cardiomyocytes Conclusions: The results demonstrate that aldrin is capable of altering the electrical activity of the heart, by modulating the NaV1.5 channel current and modifying its PA properties, which makes this pesticide an arrhythmogenic agent and may pose a risk to public health.