Identification of i Kr Kinetics and Drug Binding in Native Myocytes

Abstract

Determining the effect of a compound on I Kr is a standard screen for drug safety. Often the effect is described using a single IC 50 value, which is unable to capture complex effects of a drug. Using verapamil as an example, we present a method for using recordings from native myocytes at several drug doses along with qualitative features of I Kr from published studies of HERG current to estimate parameters in a mathematical model of the drug effect on I Kr. I Kr was recorded from canine left ventricular myocytes using ruptured patch techniques. A voltage command protocol was used to record tail currents at voltages from -70 to -20 mV, following activating pulses over a wide range of voltages and pulse durations. Model equations were taken from a published I Kr Markov model and the drug was modeled as binding to the open state. Parameters were estimated using a combined global and local optimization algorithm based on collected data with two additional constraints on I Kr I-V relation and I Kr inactivation. The method produced models that quantitatively reproduce both the control I Kr kinetics and dose dependent changes in the current. In addition, the model exhibited use and rate dependence. The results suggest that: (1) the technique proposed here has the practical potential to develop data-driven models that quantitatively reproduce channel behavior in native myocytes; (2) the method can capture important drug effects that cannot be reproduced by the IC50 method. Although the method was developed for I Kr, the same strategy can be applied to other ion channels, once appropriate channel-specific voltage protocols and qualitative features are identified. © 2009 Biomedical Engineering Society.