The insecticide beta-Cyfluthrin induces acute arrhythmic cardiotoxicity through interaction with NaV1.5 and ranolazine reverses the phenotype

Author(s)

da Silva, Maria Vitoria ; Santos-Miranda, Artur ; Joviano-Santos, Julliane, V ; Souza, Diego Santos ; Marques, Leisiane Pereira ; Sarmento, Jaqueline Oliveira ; Beserra, Samuel Santos ; Roman-Campos, Danilo

• Document type: Journal article
• Source: Clinical Science; v. 136, n. 5, p. 15-pg., 2022-03-01.

Abstract

3-Cyfluthrin, a class II Pyrethroid, is an insecticide used worldwide in agriculture, horticulture (field and protected crops), viticulture, and domestic applications. 3-Cyfluthrin may impair the function of biological systems; however, little information is available about its poten-tial cardiotoxic effect. Here, we explored the acute toxicity of 3-Cyfluthrin in isolated heart preparations and its cellular basis, using isolated cardiomyocytes. Moreover, 3-Cyfluthrin effects on the sodium current, especially late sodium current (INa-L), were investigated us-ing human embryonic kidney cells (HEK-293) cells transiently expressing human NaV1.5 channels. We report that 3-Cyfluthrin raised INa-L in a dose-dependent manner. 3-Cyfluthrin prolonged the repolarization of the action potential (AP) and triggered oscillations on its duration. Cardiomyocytes contraction and calcium dynamics were disrupted by the pesti-cide with a marked incidence of non-electronic-stimulated contractions. The antiarrhyth-mic drug Ranolazine was able to reverse most of the phenotypes observed in isolated cells. Lastly, ventricular premature beats (VPBs) and long QT intervals were found during 3-Cyfluthrin exposure, and Ranolazine was able to attenuate them. Overall, we demon-strated that 3-Cyfluthrin can cause significant cardiac alterations and Ranolazine ame-liorated the phenotype. Understanding the insecticides' impacts upon electromechanical properties of the heart is important for the development of therapeutic approaches to treat cases of pesticides intoxication. (AU)

• FAPESP's process: 21/05584-7 - Assessment of acute and chronic toxicity of the heart and brain exposed to pesticides found in potable water in Brazil
• Grantee: Danilo Roman Campos
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 19/18918-0 - Role of nitric oxide in cardiac arrhythmias during Hypothyroidism
• Grantee: Diego Santos de Souza
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/20777-3 - Genetic variants of the Nav 1.5 sodium channel and its therapeutic implications.
• Grantee: Julliane Vasconcelos Joviano dos Santos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/22830-9 - Involvement of the Ca2+/ Calmodulin/CAMKII signaling axis in the electrical and contractile dysfunctions of the heart in the chronic phase of Chagas Disease
• Grantee: Artur Santos Miranda
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/09403-4 - Hydroxychloroquine action on sodium Nav 1.5 from humans: implications for the treatment of COVID-19
• Grantee: Jaqueline Oliveira Sarmento
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 19/21304-4 - Arrhythmogenic mechanisms in right heart diseases
• Grantee: Danilo Roman Campos
• Support Opportunities: Regular Research Grants