Action Potential Peak Shape Analysis As A New Tool For Antiarrhythmic Drug Development

Abstract

Cardiac arrhythmia is a critical heart condition characterized by abnormal electrical activity of the heart. There are a wide variety of drugs which are approved for the treatment of arrhythmia; many of them are acting on voltage dependent sodium, potassium or calcium channels. One of the problems concerning determination of the major mechanism of action of antiarrhythmics is that measurement of their effects on the different ion channels is time-consuming and usually done utilizing different experimental conditions. In order to counter this problem, in this study we applied a novel method, action potential shape analysis, to determine the effect of selected antiarrhythmics on voltage dependent sodium, potassium and calcium channels without performing time-consuming voltage-clamp experiments on each ion channel. Our method is based on fitting ion channel parameters to intracellularly or extracellularly recorded action potentials in a realistic model of NG108-15 cells and quantifying drug effects through their action on the shape of the action potentials and consequently on the fitted ion channel parameters. For this study we selected four drugs, quinidine, lidocaine, encanide, and amidarone, representing Class Ia, Ib, Ic and Class III antiarrhythmics, respectively. Quinidine, encanide and amidarone blocked both sodium and potassium channels, while lidocaine, at the measured membrane potential, shifted the activation of sodium channels in a depolarizing direction. Amidarone showed profound calcium channel blocking properties. Our work is a first step towards establishing a new assay system, based on the analysis of the shape of intracellularly and eventually extracellularly recorded action potentials, which can be used for fast quantitative analysis of drug effects on ion channel currents and classification of antiarrhythmics, and also for measurement of possible cardiac side effects of drug candidates