Limits...
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.

Show MeSH

Related in: MedlinePlus

Action potential simulations. 5 accepted models from fitting to data under the complex protocol plus the two qualitative constraints in an action potential model14 at a cycle length of 500 ms. In order to produce action potential durations similar to the original model, all 5 Markov type models were scaled by a factor of 5. (a) IKr currents. (b) Action potentials
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2690829&req=5

Fig6: Action potential simulations. 5 accepted models from fitting to data under the complex protocol plus the two qualitative constraints in an action potential model14 at a cycle length of 500 ms. In order to produce action potential durations similar to the original model, all 5 Markov type models were scaled by a factor of 5. (a) IKr currents. (b) Action potentials

Mentions: To further test the results from the third cost function, we incorporated the resulting Markov type IKr models into a canine ventricular myocyte action potential model14 by replacing its original Hodgkin–Huxley type IKr model. We then simulated action potentials at various cycle lengths, and measured both the IKr currents and the action potentials (Fig. 6). The different parameter sets produce very similar results, as the maximal difference in peak current compared to the mean is 10%, and the maximal difference in action potential duration compared to the mean is 1.5%.Figure 6


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)

Action potential simulations. 5 accepted models from fitting to data under the complex protocol plus the two qualitative constraints in an action potential model14 at a cycle length of 500 ms. In order to produce action potential durations similar to the original model, all 5 Markov type models were scaled by a factor of 5. (a) IKr currents. (b) Action potentials
© Copyright Policy
Related In: Results  -  Collection

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

Fig6: Action potential simulations. 5 accepted models from fitting to data under the complex protocol plus the two qualitative constraints in an action potential model14 at a cycle length of 500 ms. In order to produce action potential durations similar to the original model, all 5 Markov type models were scaled by a factor of 5. (a) IKr currents. (b) Action potentials
Mentions: To further test the results from the third cost function, we incorporated the resulting Markov type IKr models into a canine ventricular myocyte action potential model14 by replacing its original Hodgkin–Huxley type IKr model. We then simulated action potentials at various cycle lengths, and measured both the IKr currents and the action potentials (Fig. 6). The different parameter sets produce very similar results, as the maximal difference in peak current compared to the mean is 10%, and the maximal difference in action potential duration compared to the mean is 1.5%.Figure 6

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