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 Ca(2+) and Na(+) regulation and oxidative stress, providing proarrhythmogenic substrates in atriums. Methods: Electromechanical analyses of rabbit atrial tissues were conducted. Intracellular Ca(2+) 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 Ca(2+) 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 Ca(2+) transient amplitudes and sarcoplasmic reticulum (SR) Ca(2+) stores, and increased SR Ca(2+) 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 Ca(2+) and Na(+) dysregulation, which may result from enhanced oxidative stress and activation of the TNF-α/NLRP3 inflammasome pathway in ziprasidone-treated myocytes.