Tetramisole is a new I_K1 channel agonist and exerts I_K1‐dependent cardioprotective effects in rats

Abstract

Cardiac ischemia, hypoxia, arrhythmias, and heart failure share the common electrophysiological changes featured by the elevation of intracellular Ca 2+ (Ca 2+ overload) and inhibition of the inward rectifier potassium (I K1 ) channel. I K1 channel agonists have been considered a new type of anti‐arrhythmia and cardioprotective agents. We predicted using a drug repurposing strategy that tetramisole (Tet), a known anthelminthic agent, was a new I K1 channel agonist. The present study aimed to experimentally identify the above prediction and further demonstrate that Tet has cardioprotective effects. Results of the whole‐cell patch clamp technique showed that Tet at 1–100 μmol/L enhanced I K1 current, hyperpolarized resting potential (RP), and shortened action potential duration (APD) in isolated rat cardiomyocytes, while without effects on other ion channels or transporters. In adult Sprague–Dawley (SD) rats in vivo, Tet showed anti‐arrhythmia and anticardiac remodeling effects, respectively, in the coronary ligation‐induced myocardial infarction model and isoproterenol (Iso, i.p., 3 mg/kg/day, 10 days) infusion‐induced cardiac remodeling model. Tet also showed anticardiomyocyte remodeling effect in Iso (1 μmol/L) infused adult rat ventricular myocytes or cultured H9c2 (2‐1) cardiomyocytes. Tet at 0.54 mg/kg in vivo or 30 μmol/L in vitro showed promising protections on acute ischemic arrhythmias, myocardial hypertrophy, and fibrosis. Molecular docking was performed and identified the selective binding of Tet with Kir2.1. The cardioprotection of Tet was associated with the facilitation of I K1 channel forward trafficking, deactivation of PKA signaling, and inhibition of intracellular calcium overload. Enhancing I K1 may play dual roles in anti‐arrhythmia and antiventricular remodeling mediated by restoration of Ca 2+ homeostasis.

Chronic Propafenone Application Increases Functional KIR2.1 Expression In Vitro

“…Therefore, regulating the IK 1 current can greatly affect the excitability and arrhythmogenesis of cardiomyocytes [ 13 , 14 ]. Recent findings and the development of new compounds may yield new pharmacological IK 1 modulators [ 10 , 15 , 16 , 17 ].…”