• Background

The I_to1 model shown below was recently developed by Joseph L. Greenstein (Greenstein JL, Wu R, Po S, Tomaselli GF, Winslow RL. Role of the Calcium-Independent Transient Outward Current I_to1 in Shaping Action Potential Morphology and Duration. Circ Res. 87:1026-1033, 2000). For a detailed description of this model, please see the online data supplement for this article, which can be found at http://www.circresaha.org.

The model of canine I_to1 is formulated as the combination of these Kv4.3 and Kv1.4 currents, and is incorporated in the Winslow-Rice-Jafri canine ventricular cell model (Circ. Res. 84:571-586, 1999). 

• Implementation

Two models are implemented: one is for I_to1 alone, and the other one integrates the I_to1 channel model into a cell model (WRJ3). The implementation of the two models are based on the above two papers and the integrative cell model corresponds to the Version 3 of the Canine Ventricular Cell Model originally developed at Dr. Raimond Winslow's laboratory. We wrote model description files (ito1.mod and wrj3.mod) containing the published equations, model parameter values and initial conditions. The WRJ3 model program was then generated automatically with our new java-based model simulation environment, JSIM (Currently, the runtime model control interface is  XSIM, which allows users at runtime to control parameter values, result display, data analysis, sensitivity analysis, etc).

The modeling software and the two models are free for download.  

• Using the Model via Internet

In order to run the model, you need to have a X-server installed and running on your system. There are two ways to use the on-line model simulation. Choose one of the following methods that is suited to your internet connection:

First method: if your computer is not behind a firewall, you can run the model directly through the web by clicking on the parameter file names in the next section, for example, circres00_fig2a.par.

• UNIX users: please set your computer to accept the X-applications sent by the NSR server. You need to type the following at the prompt: "xhost +nsr.bioeng.washington.edu"

• Windows/Mac users: if you are new to X-server, please read the step-by-step instructions on how to download, install and start a X-server.

Second method: if your machine is behind a firewall, you can run the model with the secure shell, SSH. 

• UNIX users: please type the following at the UNIX prompt: 

ssh nsr.bioeng.washington.edu -p 1234 <filename>

Replace <filename> with one of the parameter files in the next section, for example, circres00_fig2a.par. Read the FAQ if you have problems.

• MS-Windows users: please read the FAQ and follow the instructions there.

After you start the model, you will get two windows shown up on your screen. The small window is the XSIM control window. The big window shows the model diagram. Move the windows around, so you can see both clearly.

You can then click on the run button in the XSIM control window to start a simulation run. Click on the "results" and choose "Plot Area 1" and "Plot Area 2" to view the results. See our on-line XSIM User Manual for the complete description of XSIM functionalities.

• Illustrations

Five simulations have been set up to reproduce the figures that appeared in the Circ. Res. paper by Greenstein et al., 2000.

Figure 2a. Electrophysiological characteristics of the model-simulated hKv4.3 currents at 35 ^oC. (file: circres00_fig2a.par)

Figure 3a. Voltage-dependence of peak current for the I_Kv1.4 model at room temperature. Peak current-voltage relationship normalized to the peak current at +100 mV. (file: circres00_fig3a.par)

Figure 4a. Canine I_to1 model electrophysiological characteristics at 35 ^oC. Peak current-voltage relationship simulated from a holding potential of -80 mV and normalized to the peak current at +60 mV. (file: circres00_fig4a.par)

Note: The parameters of the Kv1.4 model were fit based on data obtained at room temperature (21 ^oC) and were then scaled  to 35 ^o C using a Q₁₀ value of 3.6 based on measurements of inactivation kinetics made on native I_to1 (see the online data supplement to Greenstein et al. for details). The calculation of the scaling factor is

Q₁₀^(T-294)/10 = 6 when the temperature T=308 K (or 35 ^oC).

Note that the scaling factor needs to be applied to only four parameters, alpha_a0, beta_a0, alpha_i0 and beta_i0, in order to scale all transition rates in the Kv1.4 model. 

Figure 5a. Effect of I_Kv4.3 current density on canine action potential shape and duration (1 Hz steady-state). Action potentials simulated with the WRJ canine ventricular cell model with increasing values of G_Kv4.3. (file: circres00_fig5a.par)

Figure 6. Effects of I_Kv4.3 current density on canine action potential, open probability of the L-type Ca²⁺ channel and L-type Ca²⁺ current magnitude.  (file: circres00_fig6.par)

• More use of the model 

Simulation of heart failure

The model is implemented so that two different conditions, normal and congestive heart failure (CHF), can be simulated by toggling a switch. An example is given here of the action potential at normal and CHF conditions. (file: ap_chf.par)

Exploring underlying mechanisms

With J2XSIM, users can easily modify the model equations (ito1.mod and wrj3.mod) and generate new models without programming.

User contributions

If you have interesting parameter sets that you want to share with others, please contact us. Here is an example from Dr. James Bassingthwaighte:

1. Influences of external and internal inoic concentrations on the action potential. (file: CaoIncr.par)

• FAQ on running the model

• Acknowledgements

The NSR would like to thank Joseph Greenstein and Dr. Raimond Winslow for their help during the model implementation and verification process.