標題: | Effects of ondansetron on apamin-sensitive small conductance calcium-activated potassium currents in pacing-induced failing rabbit hearts |
作者: | Yin, Dechun Yang, Na Tian, Zhipeng Wu, Adonis Z. Xu, Dongzhu Chen, Mu Kamp, Nicholas J. Wang, Zhuo Shen, Changyu Chen, Zhenhui Lin, Shien-Fong Rubart-von der Lohe, Michael Chen, Peng-Sheng Everett, Thomas H. 分子醫學與生物工程研究所 Institute of Molecular Medicine and Bioengineering |
關鍵字: | Electrophysiology;Heart failure;Optical mapping;Ondansetron;Ventricular fibrillation |
公開日期: | 1-二月-2020 |
摘要: | BACKGROUND Ondansetron, a widely prescribed antiemetic, has been implicated in drug-induced long QT syndrome. Recent patch clamp experiments have shown that ondansetron inhibits the apamin-sensitive small conductance calcium-activated potassium current (I-KAS). OBJECTIVE The purpose of this study was to determine whether ondansetron causes action potential duration (APD) prolongation by I-KAS inhibition. METHODS Optical mapping was performed in rabbit hearts with pacing-induced heart failure (HF) and in normal hearts before and after ondansetron (100 nM) infusion. APD at 80% repolarization (APD(80)) and arrhythmia inducibility were determined. Additional studies with ondansetron were performed in normal hearts perfused with hypokalemic Tyrode's (2.4 mM) solution before or after apamin administration. RESULTS The corrected QT interval in HF was 326 ms (95% confidence interval [CI] 306-347 ms) at baseline and 364 ms (95% CI 351-378 ms) after ondansetron infusion (P < .001). Ondansetron significantly prolonged APD(80) in the HF group and promoted early afterdepolarizations, steepened the APD restitution curve, and increased ventricular vulnerability. Ventricular fibrillation was not inducible in HF ventricles at baseline, but after ondansetron infusion, ventricular fibrillation was induced in 5 of the 7 ventricles (P = .021). In hypokalemia, apamin prolonged APD(80) from 163 ms (95% CI 146-180 ms) to 180 ms (95% CI 156-204 ms) (P = .018). Subsequent administration of ondansetron failed to further prolong APD(80) (180 ms [95% CI 156-204 ms] vs 179 ms [95% CI 165-194 ms]; P = .789). The results were similar when ondansetron was administered first, followed by apamin. CONCLUSION Ondansetron is a specific I-KAS blocker at therapeutic concentrations. Ondansetron may prolong the QT interval in HF by inhibiting small conductance calcium-activated potassium channels, which increases the vulnerability to ventricular arrhythmias. |
URI: | http://dx.doi.org/10.1016/j.hrthm.2019.09.008 http://hdl.handle.net/11536/153704 |
ISSN: | 1547-5271 |
DOI: | 10.1016/j.hrthm.2019.09.008 |
期刊: | HEART RHYTHM |
Volume: | 17 |
Issue: | 2 |
起始頁: | 332 |
結束頁: | 340 |
顯示於類別: | 期刊論文 |