Dechun Yin1, Na Yang2, Zhipeng Tian3, Adonis Z Wu4, Dongzhu Xu5, Mu Chen6, Nicholas J Kamp7, Zhuo Wang8, Changyu Shen9, Zhenhui Chen7, Shien-Fong Lin4, Michael Rubart-von der Lohe10, Peng-Sheng Chen7, Thomas H Everett11. 1. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China. 2. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Gynecological and Obstetric Ultrasound, the First Affiliated Hospital of Harbin Medical University, Harbin, China. 3. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cardiology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, China. 4. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Institute of Biomedical Engineering, National Chiao Tung University, Hsin-Chu, Taiwan. 5. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 6. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 7. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. 8. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China. 9. Richard and Susan Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 10. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana. 11. Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: theveret@iu.edu.
Abstract
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 (IKAS). OBJECTIVE: The purpose of this study was to determine whether ondansetron causes action potential duration (APD) prolongation by IKAS 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 (APD80) 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 APD80 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 APD80 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 APD80 (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 IKAS 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.
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 (IKAS). OBJECTIVE: The purpose of this study was to determine whether ondansetron causes action potential duration (APD) prolongation by IKAS 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 (APD80) 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 APD80 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 APD80 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 APD80 (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 IKAS 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.
Authors: James E Tisdale; Brian R Overholser; Heather A Wroblewski; Kevin M Sowinski; Kwadwo Amankwa; Steven Borzak; Joanna R Kingery; Rita Coram; Douglas P Zipes; David A Flockhart; Richard J Kovacs Journal: J Clin Pharmacol Date: 2011-11-01 Impact factor: 3.126
Authors: Adonis Z Wu; Mu Chen; Dechun Yin; Thomas H Everett; Zhenhui Chen; Michael Rubart; James N Weiss; Zhilin Qu; Peng-Sheng Chen Journal: Heart Rhythm Date: 2020-07-21 Impact factor: 6.343