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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.
Afiliación
  • Yin D; 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.
  • Yang N; 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.
  • Tian Z; 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.
  • Wu AZ; 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.
  • Xu D; 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.
  • Chen M; 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.
  • Kamp NJ; Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
  • Wang Z; 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.
  • Shen C; Richard and Susan Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
  • Chen Z; Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
  • Lin SF; 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.
  • Rubart-von der Lohe M; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.
  • Chen PS; Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
  • Everett TH; Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: theveret@iu.edu.
Heart Rhythm ; 17(2): 332-340, 2020 02.
Article en En | MEDLINE | ID: mdl-31513946
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Fibrilación Ventricular / Estimulación Cardíaca Artificial / Ondansetrón / Insuficiencia Cardíaca / Ventrículos Cardíacos Tipo de estudio: Diagnostic_studies / Etiology_studies Límite: Animals Idioma: En Revista: Heart Rhythm Año: 2020 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Fibrilación Ventricular / Estimulación Cardíaca Artificial / Ondansetrón / Insuficiencia Cardíaca / Ventrículos Cardíacos Tipo de estudio: Diagnostic_studies / Etiology_studies Límite: Animals Idioma: En Revista: Heart Rhythm Año: 2020 Tipo del documento: Article País de afiliación: China