Elnakish Mohammad T, Canan Benjamin D, Kilic Ahmet, Mohler Peter J, Janssen Paul M L
Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, USA; Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, USA; Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Pharmacol Res. 2017 Jan;115:309-318. doi: 10.1016/j.phrs.2016.11.033. Epub 2016 Nov 30.
Ventricular tachycardia is the leading cause of sudden arrhythmic death in the U.S. Recently, the moderate I channel activator, zacopride, was shown to suppress triggered ventricular tachycardia in rats. Nonetheless, concerns were raised about the possibility of pro-arrhythmic activity after I channel stimulation based on the promising anti-arrhythmic strategy of I blockade in other animal models. Therefore, the goal of the current study was to investigate the ex-vivo effects of zacopride on triggered arrhythmia and contractility in ventricular human myocardium in order to validate data that was solely obtained from animal models. Application of 100nmol/L isoproterenol and 0.5mmol/L caffeine led to triggered arrhythmia in isolated cardiac muscles from non-failing and end-stage failing hearts. However, the occurrence of arrhythmia in muscles of non-failing hearts was markedly higher than those of end-stage failing hearts. Interestingly, zacopride eliminated the ex-vivo triggered arrhythmia in these muscles of non-failing and failing hearts in a concentration-dependent manner, with an effective IC in the range of 28-40μmol/L. Conversely, in the absence of isoproterenol/caffeine, zacopride led to a negative inotropic effect in a concentration-dependent manner. Reduced cardiac contraction was clearly observed at high zacopride concentration of 200μmol/L, along with the occurrence of contractile alternans in muscles of non-failing and failing hearts. Zacopride shows promising antiarrhythmic effects against triggered arrhythmia in human ventricular myocardium. However, in the absence of Ca overload/arrhythmia, zacopride, albeit at high concentrations, decreases the force of contraction and increases the likelihood of occurrence of contractile alternans, which may predispose the heart to contractile dysfunction and/or arrhythmia. Overall, our results represent a key step in translating this drug from the benchtop to the bedside in the research area.
室性心动过速是美国心律失常性猝死的主要原因。最近，中等强度的I通道激活剂扎考必利被证明可抑制大鼠的触发型室性心动过速。尽管如此，基于在其他动物模型中I通道阻滞这一有前景的抗心律失常策略，人们对I通道刺激后促心律失常活性的可能性提出了担忧。因此，本研究的目的是研究扎考必利对人心室心肌触发型心律失常和收缩性的离体效应，以验证仅从动物模型获得的数据。应用100nmol/L异丙肾上腺素和0.5mmol/L咖啡因可导致非衰竭和终末期衰竭心脏的离体心肌出现触发型心律失常。然而，非衰竭心脏肌肉中心律失常的发生率明显高于终末期衰竭心脏。有趣的是，扎考必利以浓度依赖性方式消除了非衰竭和衰竭心脏这些肌肉中的离体触发型心律失常，有效IC在28 - 40μmol/L范围内。相反，在没有异丙肾上腺素/咖啡因的情况下，扎考必利以浓度依赖性方式导致负性肌力作用。在200μmol/L的高扎考必利浓度下，明显观察到心脏收缩力降低，同时非衰竭和衰竭心脏的肌肉中出现收缩性交替。扎考必利对人心室心肌的触发型心律失常显示出有前景的抗心律失常作用。然而，在没有钙超载/心律失常的情况下，扎考必利尽管浓度很高，但会降低收缩力并增加收缩性交替出现的可能性，这可能使心脏易患收缩功能障碍和/或心律失常。总体而言，我们的结果是该药物在研究领域从实验台转化到临床应用的关键一步。
