PYRETHROIDS IMPAIR HEART FUNCTION AND INDUCE ARRHYTHMIAS THROUGH SODIUM CHANNEL MODULATION

Pyrethroids (PY) are synthetic insecticides and their mechanism of action relies on disrupting the inactivation kinetic of Na_V channels in insects. PY acute or chronic intoxication has been reported; however, there is a shortage of cardiotoxicity assay of PY. Thus, we evaluate the in vitro, ex vivo and in vivo toxicity of Type 1 and Type 2 pyrethroids and the metabolite 3-PBA. The patch-clamp technique was used to study cardiac ion channels in isolated left ventricular cardiomyocytes from rats treated with permethrin (1 mg/Kg) during 28 days. The ex vivo rat heart preparation was deployed to evaluate acute toxic effect. For in vivo cardiotoxicity assay, animals were administered with PY or 3-PBA during 28 days through gavage (1 mg/kg/day). ECG was used to evaluate heart function. To assess susceptibility to arrhythmias, caffeine and dobutamine were administered during ECG monitoring. This work was approved by the Ethic Committee on Animal Use (CEUA 9319131123). Patch-clamp showed that sodium current density increased in cardiomyocytes of permethrin-treated animals, also showed a shift on the activation curve and in the steady-state Na⁺ inactivation curve to more negative membrane potentials in comparison to control. Recovery from inactivation showed no difference. In the ex vivo heart preparation PY caused pronounced increment in the QT interval. In the context of dysrhythmia, cipermethryn (CYP) and permethrin (PER) caused the most severe phenotype of arrythmias. Neither PY type caused a significant change in peak amplitude of contraction. The in vivo experiments showed that deltamethrin, CYP and PER increased both the P wave duration and the QT interval, while CYP only increased the QT interval. For the assessment of susceptibility to arrhythmias, PER demonstrate the most severe phenotype. The metabolite 3-PBA showed no significant difference in the ECG parameters after 28 days of exposure, but did show difference on QT interval after 56 days of exposure. In conclusion, the in vitro, ex vivo and in vivo exposure to PY and 3-PBA disrupt heart function, most likely due to impairment in sodium channel function in the heart, but other mechanism may be involved. This work was supported by FAPESP (2022/07256-0; 2021/05584-7).