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

Dechun Yin, Na Yang, Zhipeng Tian, Adonis Z. Wu, Dongzhu Xu, Mu Chen, Nicholas J. Kamp, Zhuo Wang, Changyu Shen, Zhenhui Chen, Shien Fong Lin, Michael Rubart-von der Lohe, Peng Sheng Chen, Thomas H. Everett

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalHeart Rhythm
DOIs
StateAccepted/In press - Jan 1 2019

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Apamin
Ondansetron
Potassium
Rabbits
Calcium
pamidronate
Confidence Intervals
Heart Failure
Action Potentials
Ventricular Fibrillation
Cardiac Arrhythmias
Small-Conductance Calcium-Activated Potassium Channels
Long QT Syndrome
Antiemetics
Hypokalemia
Heart Ventricles

Keywords

  • Electrophysiology
  • Heart failure
  • Ondansetron
  • Optical mapping
  • Ventricular fibrillation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

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

In: Heart Rhythm, 01.01.2019.

Research output: Contribution to journalArticle

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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.",
keywords = "Electrophysiology, Heart failure, Ondansetron, Optical mapping, Ventricular fibrillation",
author = "Dechun Yin and Na Yang and Zhipeng Tian and Wu, {Adonis Z.} and Dongzhu Xu and Mu Chen and Kamp, {Nicholas J.} and Zhuo Wang and Changyu Shen and Zhenhui Chen and Lin, {Shien Fong} and {Rubart-von der Lohe}, Michael and Chen, {Peng Sheng} and Everett, {Thomas H.}",
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T1 - Effects of ondansetron on apamin-sensitive small conductance calcium-activated potassium currents in pacing-induced failing rabbit hearts

AU - Yin, Dechun

AU - Yang, Na

AU - Tian, Zhipeng

AU - Wu, Adonis Z.

AU - Xu, Dongzhu

AU - Chen, Mu

AU - Kamp, Nicholas J.

AU - Wang, Zhuo

AU - Shen, Changyu

AU - Chen, Zhenhui

AU - Lin, Shien Fong

AU - Rubart-von der Lohe, Michael

AU - Chen, Peng Sheng

AU - Everett, Thomas H.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Electrophysiology

KW - Heart failure

KW - Ondansetron

KW - Optical mapping

KW - Ventricular fibrillation

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