Divergent Electrophysiologic Effects of Sacubitril in Digitalis- and Pinacidil-Related Shortened Repolarization: Experimental Evidence for Harmful Effects of Digitalis Glycosides.

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Christian Ellermann, Carlo Mengel, Julian Wolfes, Felix K Wegner, Benjamin Rath, Florian Reinke, Lars Eckardt, Gerrit Frommeyer
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引用次数: 0

Abstract

Background: Recent studies reported an abbreviation of cardiac repolarization induced by sacubitril. Thus, the purpose of this study was to evaluate the electrophysiologic effects of sacubitril in the presence of drugs that shorten the QT interval. Methods and Results: 25 rabbit hearts were retrogradely perfused. After generating baseline data, hearts were allocated to two groups. In the first group (n = 12), the IK,ATP opener pinacidil (1 µM) significantly reduced action potential duration at 90% of repolarization (APD90), QT intervals and effective refractory periods (ERP). Additional administration of sacubitril (5 µM) slightly reduced APD90. The digitalis glycoside ouabain (0.2 µM) significantly shortened repolarization duration and refractory periods. Additional infusion of sacubitril abbreviated repolarization duration and ERP. Ventricular vulnerability was assessed by delivering premature extra stimuli and burst stimulation. Significantly more ventricular arrhythmias occurred with pinacidil (26 episodes vs. 5 episodes under baseline conditions, p < 0.05). Additional sacubitril treatment had no significant proarrhythmic effect (24 episodes). Ouabain alone did not provoke ventricular arrhythmias (6 episodes vs. 3 under baseline conditions, p = ns) whereas additional sacubitril treatment significantly increased the occurrence of VT episodes (29 episodes, p < 0.01). Conclusions: Sacubitril abbreviates cardiac repolarization in ouabain-pretreated hearts. While sacubitril had no proarrhythmic effect in the presence of pinacidil, the combination of sacubitril and ouabain amplified the arrhythmic risk. The underlying mechanism is a further abbreviation of refractory periods and cardiac repolarization that facilitate ventricular arrhythmias. These findings add further evidence to the proarrhythmic capacity of digitalis glycosides in the presence of other drugs that influence cardiac repolarization.

苏必利对洋地黄和松酸苷缩短复极的不同电生理效应:洋地黄苷有害作用的实验证据。
背景:最近的研究报道了苏比利致心脏复极的缩短。因此,本研究的目的是评估在缩短QT间期的药物存在下,苏比利的电生理效应。方法与结果:对25只家兔心脏进行逆行灌注。生成基线数据后,将心脏分为两组。在第一组(n = 12)中,IK、ATP开启剂pinacidil(1µM)显著降低了90%复极时的动作电位持续时间(APD90)、QT间期和有效不应期(ERP)。另外给药5µM的sacubitril可略微降低APD90。0.2µM的洋地黄糖苷哇巴因显著缩短复极化持续时间和不应期。额外输注苏比利可缩短复极持续时间和ERP。通过提供过早的额外刺激和burst刺激来评估心室易损性。pinacidil组室性心律失常发生率明显增加(26次vs基线条件下5次,p < 0.05)。额外的sacubitril治疗无明显的促心律失常作用(24次)。单独使用瓦巴因不会引起室性心律失常(6次,而基线条件下为3次,p = ns),而额外的苏比利治疗显著增加了室性心律失常的发生(29次,p < 0.01)。结论:苏比利可缩短瓦阿因预处理心脏的心脏复极。虽然在pinacidil存在时,sacubitril没有促心律失常的作用,但sacubitril和瓦巴因联合使用会增加心律失常的风险。其潜在机制是不应期和心脏复极的进一步缩短,从而促进室性心律失常。这些发现进一步证明了洋地黄苷在影响心脏复极的其他药物存在时的促心律失常能力。
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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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