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Identification of Ikr kinetics and drug binding in native myocytes.

Zhou Q, Zygmunt AC, Cordeiro JM, Siso-Nadal F, Miller RE, Buzzard GT, Fox JJ - Ann Biomed Eng (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Gene Network Sciences, 58 Charles Street, Cambridge, MA 02141, USA. qzhou@gnsbiotech.com

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 IC(50) 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.

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State diagram of the IKr Markov model structure. Arrows refer to transitions between states. The rate constants are shown above (below) the arrows
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Fig2: State diagram of the IKr Markov model structure. Arrows refer to transitions between states. The rate constants are shown above (below) the arrows

Mentions: The Markov model we studied is a set of coupled ordinary differential equations that follows the five state formulation given in Mazhari et al.29 with three closed states (C1, C2, and C3), one open state (O), and one inactive state (I) (Fig. 2). In this formulation, each state variable represents the fraction of channels in a particular conformation. The channel only conducts current in the open state. At rest, the channels are in a closed state. Following a depolarizing change in membrane potential, the channels will be activated (changing from closed to open) and will conduct current. After sustained activation the channel will be inactivated (changing from open to inactive) and become non-conducting.Figure 2


Identification of Ikr kinetics and drug binding in native myocytes.

Zhou Q, Zygmunt AC, Cordeiro JM, Siso-Nadal F, Miller RE, Buzzard GT, Fox JJ - Ann Biomed Eng (2009)

State diagram of the IKr Markov model structure. Arrows refer to transitions between states. The rate constants are shown above (below) the arrows
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690829&req=5

Fig2: State diagram of the IKr Markov model structure. Arrows refer to transitions between states. The rate constants are shown above (below) the arrows
Mentions: The Markov model we studied is a set of coupled ordinary differential equations that follows the five state formulation given in Mazhari et al.29 with three closed states (C1, C2, and C3), one open state (O), and one inactive state (I) (Fig. 2). In this formulation, each state variable represents the fraction of channels in a particular conformation. The channel only conducts current in the open state. At rest, the channels are in a closed state. Following a depolarizing change in membrane potential, the channels will be activated (changing from closed to open) and will conduct current. After sustained activation the channel will be inactivated (changing from open to inactive) and become non-conducting.Figure 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Gene Network Sciences, 58 Charles Street, Cambridge, MA 02141, USA. qzhou@gnsbiotech.com

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 IC(50) 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.

Show MeSH
Related in: MedlinePlus