Indoxyl Sulfate Induces Ventricular Arrhythmias Attenuated by Secretoneurin in Right Ventricular Outflow Tract Cardiomyocytes

Ventricular arrhythmias (VAs) are major causes of sudden cardiac death in chronic kidney disease (CKD) patients. Indoxyl sulfate (IS) is one common uremic toxin found in CKD patients. This study investigated whether IS could induce VAs via increasing right ventricular outflow tract (RVOT) arrhythmogenesis. Using conventional microelectrodes and whole-cell patch clamps, we studied the action potentials (APs) and ionic currents of isolated rabbit RVOT tissue preparations and single cardiomyocytes before and after IS (0.1 and 1.0 μM). Calcium fluorescence imaging was performed in RVOT cardiomyocytes treated with and without IS (1.0 μM) to evaluate the calcium transient and the calcium leak. In rabbit RVOT tissues, IS (0.1 and 1.0 μM) attenuated the contractility and shortened the AP durations in a dose-dependent manner. In addition, IS (0.1 and 1.0 μM) enhanced the pro-arrhythmia effects of isoproterenol (ISO, 1.0 μM) and rapid ventricular pacing in RVOT (before versus after ISO, 25% versus 83%, N = 12). In RVOT cardiomyocytes, IS (1.0 μM) significantly decreased the L-type calcium currents but increased the sodium-calcium exchanger and sodium window currents. Cardiomyocytes treated with IS (1.0 μM) had lower calcium transients but higher diastolic calcium and calcium leak than those without IS treatment. Pretreatment with secretoneurin (SN, 30 nM, a potent neuropeptide, suppressing CaMKII) or KN-93 (0.1 μM, a CaMKII inhibitor) prevented IS-induced ionic current changes and arrhythmogenesis. In conclusion, IS modulates RVOT electrophysiology and arrhythmogenesis via enhanced CaMKII activity, which is attenuated by SN, leading to a novel therapeutic target for CKD arrhythmias.