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

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標題:	Ziprasidone Induces Rabbit Atrium Arrhythmogenesis via Modification of Oxidative Stress and Sodium/Calcium Homeostasis
作者:	Tai, Buh-Yuan Lu, Ming-Kun Yang, Hsiang-Yu Tsai, Chien-Sung Lin, Chih-Yuan
貢獻者:	Department of Pharmacy, Chia Nan University of Pharmacy & Science National Defense Medical Center Tri-Service General Hospital
關鍵字:	sarcoplasmic-reticulum ca2+ late sodium current protein-kinase-ii ventricular myocytes leak camkii risk fibrillation inhibition sudden
日期:	2022
上傳時間:	2023-12-11 13:57:14 (UTC+8)
出版者:	MDPI
摘要:	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-alpha 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-alpha/NLRP3 inflammasome pathway in ziprasidone-treated myocytes.
關聯:	BIOMEDICINES, v.10, n.5, pp.976
Appears in Collections:	[藥學系(所)] 期刊論文

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