昂丹司琼对起搏诱导心力衰竭兔心中小电导钙激活钾电流的影响。
Effects of ondansetron on apamin-sensitive small conductance calcium-activated potassium currents in pacing-induced failing rabbit hearts.
机构信息
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.
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.
出版信息
Heart Rhythm. 2020 Feb;17(2):332-340. doi: 10.1016/j.hrthm.2019.09.008. Epub 2019 Sep 9.
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).
OBJECTIVE
The purpose of this study was to determine whether ondansetron causes action potential duration (APD) prolongation by I 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) 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 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 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 (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 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.
背景
昂丹司琼是一种广泛应用的止吐药物，已被证实与药物诱导的长 QT 综合征有关。最近的膜片钳实验表明，昂丹司琼抑制了蜂毒肽敏感的小电导钙激活钾电流（I）。
目的
本研究旨在确定昂丹司琼是否通过抑制 I 来延长动作电位时程（APD）。
方法
采用光学标测技术，在兔心力衰竭（HF）模型和正常心脏中进行起搏诱导，分别在给予昂丹司琼（100 nM）前后进行研究。测量 80%复极化时程（APD）和心律失常的易感性。在正常心脏中，采用低钾 Tyrode 液（2.4 mM）灌流，分别在给予蜂毒肽前后进行昂丹司琼处理。
结果
HF 患者的校正 QT 间期在基础状态下为 326 ms（95%置信区间 [CI] 306-347 ms），给予昂丹司琼后为 364 ms（95% CI 351-378 ms）（P<.001）。在 HF 组，昂丹司琼显著延长了 APD，促进了早期后除极，使 APD 复极曲线变陡，并增加了心室易损性。在基础状态下，HF 心室中不能诱发心室颤动，但在给予昂丹司琼后，7 个心室中有 5 个心室（P=.021）可以诱发心室颤动。在低钾血症中，蜂毒肽将 APD 从 163 ms（95% CI 146-180 ms）延长至 180 ms（95% CI 156-204 ms）（P=.018）。随后给予昂丹司琼并不能进一步延长 APD（180 ms [95% CI 156-204 ms] 比 179 ms [95% CI 165-194 ms]；P=.789）。当首先给予昂丹司琼，然后给予蜂毒肽时，结果相似。
结论
在治疗浓度下，昂丹司琼是一种特异性的 I 抑制剂。昂丹司琼通过抑制小电导钙激活钾通道延长 HF 患者的 QT 间期，增加了心室心律失常的易感性。
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