Avaliação dos efeitos do azul de metileno sobre as arritmias cardíacas e letalidade em ratos normotensos e hipertensos submetidos à isquemia e reperfusão cardíaca

• Ano de defesa: 2024
• Autor(a) principal: Araújo, Erisvaldo Amarante de [UNIFESP]
• Orientador(a): Rodrigues, Francisco Sandro Menezes [UNIFESP]
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• dARK ID: ark:/48912/001300001chs3
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo
• Palavras-chave em Português: Isquemia cardíaca; Reperfusão cardíaca; Azul de metileno; Arritmias cardíacas; Letalidade
• Link de acesso: https://hdl.handle.net/11600/71188

Introduction: Methylene blue (MB) has been proposed in some studies as an important pharmacological tool in ischemia and reperfusion experiments of various organs, such as kidneys, liver, and lungs, in addition to its use in the treatment of cardiovascular diseases such as Vasoplegic Syndrome, due to its activity as a blocker of Nitric Oxide (NO)-activated Guanylate Cyclase (GC) and additional reduction in the production of free radicals. The cellular and molecular mechanisms involved in these effects are still under investigation. Objective: To evaluate the effects of MB on the hearts of normotensive Wistar rats (NWR) and genetically hypertensive Wistar rats (SHR) subjected to cardiac ischemia and reperfusion (IRC), and also to investigate, using computational methods, the possible pharmacological targets of MB in cardiomyocytes. Materials and Methods: Male rats, NWR and SHR (12 to 16 weeks old), were anesthetized and kept under mechanical ventilation for a stabilization period of 15 minutes, cardiac ischemia (IC) for 10 minutes, and cardiac reperfusion (RC) for 75 minutes. The cardiac activity of the animals was monitored and recorded throughout the experimental protocol by electrocardiogram (ECG) to assess the incidence of ventricular arrhythmias (AV), atrioventricular block (BAV), and lethality (LET). Blood samples were collected and processed to determine the serum concentration of biochemical markers of cardiac injury, creatine kinase MB fraction (CK-MB), and troponin I (TnI). The NWR and SHR animals were distributed into 3 experimental groups: (1)SS+IRC group: treated with 0.9% saline solution (SS) administered (i.v) before IRC; (2)MB+IRC group: treated with MB (2 mg/kg, i.v) before IRC; (3)MB+RC group: treated with MB (2 mg/kg, i.v) before RC. To evaluate possible pharmacological targets of MB in cardiomyocytes, the computational method of molecular docking (DMol) was used. Results: In the NWR animal groups, those treated with SS before IRC showed high incidences of AV (90%), BAV (70%), and LET (60%). Treatment with MB before IRC caused a significant increase in the incidences of BAV (100%) and LET (100%), while MB before reperfusion significantly reduced the incidences of AV (50%), BAV (28.5%), and LET (21.4%). In SHR, the SS-treated group showed low incidences of AV (40%), BAV (30%), and LET (20%). Administration of MB before IRC significantly increased the incidences of AV (100%), BAV (85.7%), and LET (78.5%), while the group treated with MB before RC showed incidences of AV (42.8%), BAV (28.5%), and LET (21.4%) similar to the control. No significant differences were observed in the serum concentrations of the studied cardiac injury markers in NWR and SHR, except for the CK-MB levels in NWR animals treated with MB before IRC. DMol showed classified binding from good to excellent for MB with Monoamine Oxidase-B (MAO-B), Calmodulin (CaM), Muscarinic M2 Receptor (M2), and Guanylate Cyclase (GC). Conclusion: These results showed that the administration of MB before RC reduced or prevented the increase in the incidences of AV, BAV, and LET resulting from IRC in both NWR and SHR. In contrast, the administration of MB before IRC significantly increased the incidences of AV, BAV, and LET resulting from IRC in both NWR and SHR, suggesting that this cardiotoxic effect may severely compromise cardiac function in response to IRC.