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Effects of ondansetron on apamin-sensitive small conductance calcium-activated potassium currents in pacing-induced failing rabbit hearts

  • Dechun Yin
    Affiliations
    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
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  • Na Yang
    Affiliations
    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
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  • Zhipeng Tian
    Affiliations
    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
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  • Adonis Z. Wu
    Affiliations
    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
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  • Dongzhu Xu
    Affiliations
    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
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  • Mu Chen
    Affiliations
    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
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  • Nicholas J. Kamp
    Affiliations
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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  • Zhuo Wang
    Affiliations
    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
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  • Changyu Shen
    Affiliations
    Richard and Susan Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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  • Zhenhui Chen
    Affiliations
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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  • Shien-Fong Lin
    Affiliations
    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
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  • Michael Rubart-von der Lohe
    Affiliations
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
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  • Peng-Sheng Chen
    Affiliations
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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  • Thomas H. Everett IV
    Correspondence
    Address reprint requests and correspondence: Dr Thomas H. Everett IV, Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, 1800 N Capitol Avenue, Ste E400E, Indianapolis, IN 46202.
    Affiliations
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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Published:September 09, 2019DOI:https://doi.org/10.1016/j.hrthm.2019.09.008

      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.

      Keywords

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