Identification of I sub(Kr) Kinetics and Drug Binding in Native Myocytes

• Published in: Annals of biomedical engineering 2009-07, Vol.37 (7), p.1294-1309
• Main Authors: Zhou, Qinlian, Zygmunt, Andrew C, Cordeiro, Jonathan M, Siso-Nadal, Fernando, Miller, Robert E, Buzzard, Gregery T, Fox, Jeffrey J
• Format: Article
• Language: English
• ISSN: 0090-6964; 1573-9686
• DOI: 10.1007/s10439-009-9690-5

Determining the effect of a compound on I sub(Kr) is a standard screen for drug safety. Often the effect is described using a single IC sub(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 sub(Kr) from published studies of HERG current to estimate parameters in a mathematical model of the drug effect on I sub(Kr). I sub(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 -20mV, following activating pulses over a wide range of voltages and pulse durations. Model equations were taken from a published I sub(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 sub(Kr) I-V relation and I sub(Kr) inactivation. The method produced models that quantitatively reproduce both the control I sub(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 IC sub(50) method. Although the method was developed for I sub(Kr), the same strategy can be applied to other ion channels, once appropriate channel-specific voltage protocols and qualitative features are identified.