Ziprasidone Induces Rabbit Atrium Arrhythmogenesis via Modification of Oxidative Stress and Sodium/Calcium Homeostasis

Background: Atypical antipsychotics increase the risk of atrial arrhythmias and sudden cardiac death. This study investigated whether ziprasidone, a second-generation antipsychotic, affected intracellular Ca²⁺ and Na⁺ regulation and oxidative stress, providing proarrhythmogenic substrates in atriums. Methods: Electromechanical analyses of rabbit atrial tissues were conducted. Intracellular Ca²⁺ monitoring using Fluo-3, the patch-clamp method for ionic current recordings, and a fluorescence study for the detection of reactive oxygen species and intracellular Na⁺ levels were conducted in enzymatically dissociated atrial myocytes. Results: Ziprasidone-treated atriums showed sustained triggered activities after rapid pacing, which were inhibited by KN-93 and ranolazine. A reduced peak L-type Ca²⁺ channel current and enhanced late Na⁺ current were observed in ziprasidone-treated atrial myocytes, together with an increased cytosolic Na⁺ level. KN-93 suppressed the enhanced late Na⁺ current in ziprasidone-treated atrial myocytes. Atrial myocytes treated with ziprasidone showed reduced Ca²⁺ transient amplitudes and sarcoplasmic reticulum (SR) Ca²⁺ stores, and increased SR Ca²⁺ leakage. Cytosolic and mitochondrial reactive oxygen species production was increased in atrial myocytes treated with ziprasidone. TNF-α and NLRP3 were upregulated in ziprasidone-treated myocytes, and the level of phosphorylated calcium/calmodulin-dependent protein kinase II protein was increased. Conclusions: Our results suggest that ziprasidone increases the occurrence of atrial triggered activity and causes intracellular Ca²⁺ and Na⁺ dysregulation, which may result from enhanced oxidative stress and activation of the TNF-α/NLRP3 inflammasome pathway in ziprasidone-treated myocytes.