Identification ofIKr Kinetics and Drug Binding in Native Myocytes

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Abstract

Determining the effect of a compound on IKr is a standard screen for drug safety. Often the effect is described using a single IC50 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 IKr from published studies of HERG current to estimate parameters in a mathematical model of the drug effect on IKr. IKr 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 IKr 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 IKrI-V relation and IKr inactivation. The method produced models that quantitatively reproduce both the control IKr 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 IKr, the same strategy can be applied to other ion channels, once appropriate channel-specific voltage protocols and qualitative features are identified.

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