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 CalciumIndependent
Transient Outward Current I_{to1} in Shaping Action
Potential Morphology and Duration. Circ Res. 87:10261033,
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 WinslowRiceJafri canine ventricular cell
model (Circ. Res. 84:571586, 1999).
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 javabased 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 Xserver
installed and running on your system. There are two ways to use
the online 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.
Second method:
if your machine is behind a firewall, you can run
the model with the secure shell, SSH.
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.
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 online
XSIM User Manual for the complete description of XSIM
functionalities.
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 modelsimulated hKv4.3 currents at 35 ^{o}C.
(file: circres00_fig2a.par)
Figure 3a. Voltagedependence of peak
current for the I_{Kv1.4} model at room temperature. Peak
currentvoltage relationship normalized to the peak current at
+100 mV. (file: circres00_fig3a.par)
Figure 4a. Canine I_{to1} model
electrophysiological characteristics at 35 ^{o}C. Peak
currentvoltage 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 ^{o}C) and
were then scaled to 35 ^{o} C using a Q_{10}
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
Q_{10}^{(T294)/10} = 6 when the
temperature T=308 K (or 35 ^{o}C).
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
steadystate). 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 Ltype Ca^{2+} channel and Ltype Ca^{2+}
current magnitude. (file: circres00_fig6.par)
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:

Influences
of external and internal inoic concentrations on the action
potential. (file: CaoIncr.par)
The NSR would like to thank Joseph Greenstein and
Dr. Raimond Winslow for their help during the model implementation
and verification process.
