Limprasutr Vudhiporn, Saengklub Nakkawee, Meedech Pradtana, Kijtawornrat Anusak, Hamlin Robert L
Department of Veterinary Physiology, Faculty of Veterinary Science, Chulalongkorn University, Thailand.
Department of Physiology, Faculty of Pharmacy, Mahidol University, Thailand.
J Toxicol Sci. 2017;42(5):579-587. doi: 10.2131/jts.42.579.
The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for drug-induced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. After rabbits were anesthetized with isoflurane, body surface electrocardiograms and left ventricular pressure were recorded. The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5). The EMW in anesthetized rabbits ranged from 1.3 to 53.3 msec. All three drugs known to lengthen QT intervals prolonged QT and QTcF interval while the EMW was markedly decreased to negative values. Pinacidil significantly produced QT and QTcF shortening and significantly abbreviated the EMW (p < 0.05). This study demonstrated that the EMW is associated with QT intervals (p < 0.001). It is negative in the presence of QT-prolonging drugs while it is more positive in the presence of QT-shortening drugs. The results suggest that the EMW in anesthetized rabbits can be used in drug safety evaluation in addition to the QT interval.
当前的监管指南建议使用QT间期来评估新化学实体致心律失常潜力的风险。最近，机电窗（EMW），即电收缩期和机械收缩期持续时间的差值，已被提议作为药物诱导的尖端扭转型室性心动过速（TdP）的标志物；然而，短QT模型中EMW的数据尚不可得。本研究旨在将EMW表征为长QT综合征2型（LQT2）和短QT综合征（SQTS）麻醉兔模型中药物诱导的室性心律失常的标志物，该模型中输注了已知可延长或缩短QT间期的参考化合物。用异氟烷麻醉兔子后，记录体表心电图和左心室压力。通过静脉输注多非利特（n = 6）、奎尼丁（n = 6）和索他洛尔（n = 6）产生LQT2，而通过静脉递增浓度的尼可地尔（n = 7）、匹那地尔（n = 5）和克罗卡林（n = 5）诱导SQTS。麻醉兔的EMW范围为1.3至53.3毫秒。已知的所有三种延长QT间期的药物均延长了QT和QTcF间期，而EMW显著降低至负值。匹那地尔显著缩短了QT和QTcF，并显著缩短了EMW（p < 0.05）。本研究表明EMW与QT间期相关（p < 0.001）。在存在延长QT的药物时它为负值，而在存在缩短QT的药物时它更偏向正值。结果表明，除QT间期外，麻醉兔的EMW可用于药物安全性评估。
