- Author:
- David Nickerson <nickerso@users.sourceforge.net>
- Date:
- 2017-11-30 15:35:25+13:00
- Desc:
- rename variables to valid CellML identifiers
- Permanent Source URI:
- https://models.cellml.org/workspace/4e3/rawfile/05b3384ebffa15c5270486a6b9249a3360e34ebf/Kapela_VSM.proj
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<control name="modelSource">// Kapela_VSM_Ephys_Model - Model of vascular smooth muscle electrophysiology
// ***********************************************************************************
// V A S C U L A R S M O O T H M U S C L E C E L L
// E L E C T R O P H Y S I O L O G Y M O D E L
// ***********************************************************************************
//
// This script presents the vascular smooth mucle cell electrophysiology model
// as developed by Kapela et al. (J Theor Biol 253:238-260, 2008). This code
// was reproduced from the paper and also from the model code written in Fortran
// graciously supplied by Kapela and Tsoukias.
//
// Comments on generation of model code from original paper:
//
// 1) All concentrations are converted to mM from the units given in the
// original paper by Kapela because all empirical expressions given assume
// the units of mM in order to be correct.
//
// 2) For the Na-K-Cl cotransporter, the units on the cotransport coefficient,
// L_NaKCl, is n(moles^2)/(J*s*cm^2) instead of (nmoles^2)/(J*s*cm^2)
//
// 3) For the IP3 receptor, the units on the rate constant of Ca2+ release
// by the IP3 receptor, Ibar_IP3, is 1/ms instead of mM/ms
//
// 4) For the non-selective cation channels, the DAG concentration for half-
// maximum activation, K_NSC, is 3000nM not 300nM as listed in paper
//
// 5) For the alpha-1 adrenoreceptor and IP3 formation, the ratio of activities
// of the ligand-bound to ligand-unbound receptor species, delta_G, is a
// fixed parameter throughout the simulation and is estimated based on the
// initial conditions specified below. However the rate of hydrolysis of
// PIP2, r_hG, is initially estimated and then recalculated during the
// simulation.
//
// 6) For the sGC activation, the time constant for the change in rate of
// cGMP formation, tau_sGC, is determined differently from that in paper.
// In the paper:
// _
// | tau_asGC if (Vbar_cGMP-V_cGMP) >= 0
// tau_sGC = <
// |_tau_dsGC otherwise
//
// where tau_asGC and tau_dsGC are the sGC activation and inactivation time
// constants which are fixed. In code from Kapela and Tsoukias a slightly
// different formulation is employed:
// _
// | 1/((k_3sGC*NO) + k_DrsGC) if (Vbar_cGMP-V_cGMP) >= 0
// tau_sGC = <
// |_1/(k_m2sGC + k_DrsGC); otherwise
//
// where k_DrsGC is the baseline inverse time constant such that when NO is
// not present the activation time constant is equal to 1/k_DrsGC. This
// change in formulation reduces the overshooting of the cGMP concentration
// into negative values when Vbar_cGMP is zero.
//
// 7) For the store-operated cation channel, the activation gating probability,
// P_SOC, formulation is changed from a simple algebraic expression:
//
// 1
// P_SOC = ------------------
// (1 + Ca_u/K_SOC)
//
// to a first order kinetic expression:
//
// 1
// Pbar_SOC = ------------------
// (1 + Ca_u/K_SOC)
//
// dP_SOC Pbar_SOC - P_SOC
// -------- = ------------------
// dt tau_SOC
//
// where tau_SOC is set to 100 ms. The justification for the slow kinetics
// on this activation gate is not specified in the code.
//
// 8) For the Na-Ca exchanger, the scaling current, g_NCX, is set to a value of
// 0.000487 pA instead of the range of values listed in the paper of
// 0.0487 to 0.487 nS. Again the justification is not elaborated on either
// in the code or paper.
//
// 9) For figure 6 the NE desensitization is eliminated by setting the rate of
// phosphorylation of surface alpha-adrenoreptors to zero and for the sGC
// block setting v_cGMPmax to 1/1000 of the normal level. V_cGMPmax is not
// set to zero because cGMP levels overshoot and become negative leading to
// errors as solved by the ode solver.
import nsrunit;
unit conversion on;
math main {
// *******************************************************************************************
// Fixed Parameters for K A P E L A V S M E P H Y S M O D E L
// *******************************************************************************************
real
// Universal constants
F = 96485.3399 coulomb/mol, // Faraday constant
R = 8314.472 coulomb*mV/(K*mol), // Gas constant
T = 293 K, // Temperature
N_Avo = 6.022e23 1/mol, // Avogadro's number
// Membrane properties
C_m = 25 picofarad, // Total membrane capacitance
// Ionic valences
z_K = 1 dimensionless, // Potassium valence
z_Na = 1 dimensionless, // Sodium valence
z_Ca = 2 dimensionless, // Calcium valence
z_Cl = -1 dimensionless, // Chloride valence
// External ionic concentrations
Ca_e = 2.0 mM, // External Ca concentration
Na_e = 140 mM, // External Na concentration
K_e = 5 mM, // External K concentration
Cl_e = 129 mM, // External Cl concentration
// Compartmental volumes
Vol_i = 1 picoliter, // Cytsolic volume
Vol_Ca = 0.7 picoliter, // Cyto volume avail to Ca
Vol_SRu = 0.07 picoliter, // SR uptake volume
Vol_SRr = 0.007 picoliter, // SR release volume
// L-type voltage operated Ca channel
P_VOCC = 1.88e-5 cm/s, // L-type Ca permeability
// Large conductance Ca-activated K channel
N_BKCa = 6.6e6 1/cm^2, // Ca-act K channel density
tau_pf = 0.84 ms, // Ca-act K fast time const
tau_ps = 35.9 ms, // Ca-act K slow time const
dV_50KCaNO = 46.3 mV, // Max NO-ind V50KCa shift
dV_50KCacGMP = 76 mV, // Max cGMP-ind V50KCa shift
P_BKCa = 3.9e-13 cm^3/s, // Ca-act K perm-surf prod
// Voltage dependent K channel
g_Kv = 1.35 nanosiemens, // Max whole cell Kv conduct
tau_q1 = 371 ms, // V-depend K fast inact tau
tau_q2 = 2884 ms, // V-depend K slow inact tau
// Unspecified K leak channels
g_Kleak = 0.067 nanosiemens, // Max whole cell Kleak cond
// Non-selective cation channels
K_NSC = 3e-3 mM, // Half-max act DAG concen
d_NSCmin = 0.0244 dimensionless, // Min constiuent activation
PNa_NSC = 5.11e-7 cm/s, // Whole cell Na NSC perm
// Store-operated non-selective cation channel
gCa_SOC = 0.0083 nanosiemens, // Max whole cell Ca conduct
gNa_SOC = 0.0575 nanosiemens, // Max whole cell Na conduct
K_SOC = 1e-4 mM, // Half-max act Ca concen
tau_SOC = 100 ms, // SOC act gate tau
// Calcium-activated chloride channel
g_ClCa = 0.23 nanosiemens/picofarad, // Max conduct Ca-act Cl
R_ClcGMPmin = 0.0132 dimensionless, // cGMP-indep component
n_ClCa = 2 dimensionless, // Ca-act Cl Ca Hill coeff
K_ClCa = 3.65e-4 mM, // EC50 Ca-act Cl Ca concen
n_ClcGMP = 3.3 dimensionless, // Ca-act Cl cGMP Hill coeff
K_ClcGMP = 6.4e-3 mM, // EC50 Ca-act Cl cGMP concen
// Plasma membrane Ca pump
Ibar_PMCA = 5.37 picoampere, // Max PM Ca-ATPase current
K_mPMCA = 1.70e-4 mM, // PM Ca-ATPase Michaelis K
// Plasma membrane Na-Ca exchanger (Lindblad et al. 1996)
g_NCX = 0.000487 picoampere, // NC exch scale fact adjust
d_NCX = 0.0003 dimensionless, // See Lindblad 1996
gamma_NCX = 0.45 dimensionless, // See Lindblac 1996
// Na-K pump
Ibar_NaK = 2.3083 picoampere/picofarad, // Max NaK pump current
n_HKe = 1.1 dimensionless, // Ext K Hill coerricient
K_dKe = 1.6 mM, // Ext K binding constant
n_HNai = 1.7 dimensionless, // Cyto Na Hill coefficient
Na_dNai = 22 mM, // Cyto Na binding constant
Q_10 = 1.87 dimensionless, // Temp correction to NCX for 10 K
// Na-K_Cl cotransporter (Strieter et al. 1990)
L_NaKCl = 1.79e-17 mol^2/(J*s*cm^2), // Na-K-Cl cotrans coeff
// Sarcoplasmic reticulum IP3 receptor
Ibar_IP3 = 2880e-6 1/ms, // Max rate Ca release IP3
K_IP3 = 1.20e-4 mM, // Disoc cnst IP3-IP3 recpt
K_actIP3 = 1.70e-4 mM, // Disoc cnst Ca activation
k_onIP3 = 1.4 1/(ms*mM), // Rate Ca bnd to inhib site
K_inhIP3 = 1.00e-4 mM, // Disoc cnst Ca inhibition
// Sarcoplasmic reticulum SERCA, uptake, release and internal diffusion
Ibar_SERCA = 6.68 picoampere, // Max SERCA current control
K_mup = 1e-3 mM, // SERCA Michaelis constant
tau_tr = 1000 ms, // SR int diff time constant
R_leak = 1.07e-5 dimensionless, // SR leak parameter control
tau_rel = 0.0333 ms, // SR Ca release time const
CSQNbar = 15 mM, // Ave calsequestrin conc SR
K_CSQN = 0.8 mM, // Bind aff calsequestrin
// Sarcoplasmic reticulum ryanodine receptor four state model
K_r1 = 2500 1/(ms*mM^2), // Rate Ca bnd to act site
K_r2 = 1.05 1/(ms*mM), // Rate Ca bnd to inact site
K_mr1 = 0.0076 1/ms, // Rate Ca unbnd from act
K_mr2 = 0.084 1/ms, // Rate Ca unbnd from inact
// Alpha1-adrenoceptor activation and IP3 formation (Bennett et al. 2005)
k_rG = 1.75e-7 1/ms, // Receptor recycling rate
xi_G = 0.85 dimensionless, // Frac of mobile receptors
R_TG = 2e4 dimensionless, // Total number of recptors (# recpetprs)
k_pG = 0.1e-3 1/ms, // Recept phos rate Bennett
K_1G = 0.01 mM, // Unphos recept dissoc const
k_eG = 6e-6 1/ms, // Receptor endocytosis rate
K_2G = 0.2 mM, // Phos recept dissoc const
k_aG = 0.17e-3 1/ms, // G-protein activation rate
G_TG = 1e5 dimensionless, // Tot # G-protein molecules (# molecules)
k_dG = 1.5e-3 1/ms, // G-protein deactiv rate
alpha_G = 2.781e-8 1/ms, // Eff signal gain param
K_cG = 0.4e-3 mM, // Ca-PLC dissoc constant
gamma_G = N_Avo*Vol_i, // Conv of # PIP2 to concen (pL/mole)
k_degG = 1.25e-3 1/ms, // IP3 degradation rate
r_rG = 0.015e-3 1/ms, // PIP2 replenishment rate
PIP2_T = 5e7 dimensionless, // Total # PIP2 molecules (# molecules)
// sGC activation and cGMP formation (Condorelli 2001, Tsoukias 2004, Yang 2005)
V_cGMPmax = 1.26e-7 mM/ms, // Max cGMP formation rate
k_2sGC = 0.64e-5 1/ms, // See Condorelli et al.
k_3sGC = 4.2 1/(ms*mM), // See Condorelli et al.
k_m1sGC = 15e-3 1/ms, // See Condorelli et al.
k_DsGC = 0.4e-3 1/ms, // See Condorelli et al.
k_m2sGC = 0.1e-6 1/ms, // See Condorelli et al.
k_1sGC = 2e3 1/(ms*mM), // See Condorelli et al.
k_DrsGC = 0.1e-3 1/ms, // See Kapela code
k_pdecGMP = 0.0695e-3 1/ms, // See Yang et al.
K_mpde = 1e-3 mM, // Michaelis-Menten constant
// Ionic balances
Sbar_CM = 0.1 mM, // Calmodulin concen
K_dCM = 2.60e-4 mM, // Calmodulin-Ca dissoc const
Bbar_F = 0.1 mM, // Other Ca buffers concen
K_dB = 5.298e-4 mM; // Other buff-Ca dissoc const
// *******************************************************************************************
// Calc Params for K A P E L A V S M E P H Y S M O D E L
// *******************************************************************************************
real
// Universal constants
RT = R*T, // RT term ((C*mV)/mole)
FRT = F/RT, // F/RT term (1/mV)
// Membrane properties
A_m = C_m/(1e6 picofarad/cm^2), // Area scaled by capacitance (cm^2)
// Non-selective cation channels
PK_NSC = 1.06*PNa_NSC, // Whole cell K NSC perm (cm/s)
PCa_NSC = 4.54*PNa_NSC, // Whole cell Ca NSC perm (cm/s)
// Na-K pump
Q = Q_10^((T - (309.15 K))/(10 K)), // Temp correction to NCX (unitless)
// sGC activation and cGMP formation
B5_sGC mM, // cGMP production rate NO snstvty numer term
A0_sGC mM^2, // cGMP production rate denom term
A1_sGC mM; // cGMP production rate NO snstvty denom term
// *******************************************************************************************
// Variables for K A P E L A V S M E P H Y S M O D E L
// *******************************************************************************************
realDomain // DOMAIN VARIABLE
time msec; time.min=0;
time.max=200000; time.delta=0.5;
real // STATE VARIABLES
V_m(time) mV, // Membrane potential, V_m
d_L(time) dimensionless, // L-type Ca act gate prob, d_L
f_L(time) dimensionless, // L-type Ca inact gate prob, f_L
Ca_i(time) mM, // Cytosolic Ca concen, Ca_i
p_f(time) dimensionless, // Ca-act K fast gate prob, p_f
p_s(time) dimensionless, // Ca-act K slow gate prob, p_s
p_K(time) dimensionless, // K_V p activ gate prob, p_K
q_1(time) dimensionless, // K_V q fast activ prob, q_1
q_2(time) dimensionless, // K_V q slow activ prob, q_2
P_SOC(time) dimensionless, // SOC act gate prob, P_SOC
h_IP3(time) dimensionless, // IP3 act gate prob, h_IP3
Ca_u(time) mM, // SR uptake Ca concen, Ca_u
Ca_r(time) mM, // SR release Ca concen, Ca_r
R_10(time) dimensionless, // RyR w/act Ca bnd, R_10
R_11(time) dimensionless, // RyR w/act-inact Ca bnd, R_11
R_01(time) dimensionless, // RyR w/ inact Ca bnd, R_01
R_supSG(time) dimensionless, // # unphos recept, R_supSG
R_supSPG(time) dimensionless, // # phos recept, R_supSPG
IP3(time) mM, // Cytosolic IP3 concen, IP3
PIP2(time) dimensionless, // # cyto PIP2 molecles, PIP2
G(time) dimensionless, // # sctive G protein, G
V_cGMP(time) mM/ms, // Rate of cGMP form, V_cGMP
cGMP_i(time) mM, // Cytosolic cGMP concen, cGMP_i
Na_i(time) mM, // Cytosolic Na concen, Na_i
K_i(time) mM, // Cytosolic K concen, K_i
Cl_i(time) mM; // Cytosolic Cl concen, Cl_i
real // INTERMEDIATE VARIABLES
// Reversal potentials
E_K(time) mV, // Nernst potential K
E_Na(time) mV, // Nernst potential Na
E_Ca(time) mV, // Nernst potential Ca
E_Cl(time) mV, // Nernst potential Cl
// L-type voltage operated Ca2+ channels
dbar_L(time) dimensionless, // Steady state d_L gate prob
fbar_L(time) dimensionless, // Steady state f_L gate prob
tau_dL(time) ms, // d_L gate time constant
tau_fL(time) ms, // f_L gate time constant
I_VOCC(time) picoampere, // Total L-type Ca channel current
// Large conductance Ca2+ activated K+ channels
P_KCa(time) dimensionless, // Total open prob BKCa channel
i_KCa(time) picoampere, // BKCa single channel current
R_NO(time) dimensionless, // BKCa voltage dependency NO sensitivity
R_cGMP(time) dimensionless, // BKCa voltage dependency cGMP sensitivity
V_50KCa(time) mV, // BKCa votage dependency
pbar_o(time) dimensionless, // BKCa steady state p gate probabiility
I_BKCa(time) picoampere, // Total BKCa channel current
// Voltage-dependent K+ channels
pbar_K(time) dimensionless, // Steady state p_K gate probability
qbar(time) dimensionless, // Steady state q_1 and q_2 gate prob
tau_pK(time) ms, // p_K gate time constant
I_Kv(time) picoampere, // Total Kv channel current
// Unspecified K+ leak channels
I_Kleak(time) picoampere, // Total K leak channel current
// Non-selective cation channels
Po_NSC(time) dimensionless, // Steady state Po gate probability
DAG(time) mM, // Diacylglycerol concentration
INa_NSC(time) picoampere, // NSC channel total Na current
IK_NSC(time) picoampere, // NSC channel total K current
ICa_NSC(time) picoampere, // NSC channel total Ca current
I_NSC(time) picoampere, // Total NSC channel current
// Store-operated non-selective cation channels
Pbar_SOC(time) dimensionless, // Steady state P_SOC gate probability
INa_SOC(time) picoampere, // SOC channel total Na current
ICa_SOC(time) picoampere, // SOC channel total Ca current
I_SOC(time) picoampere, // Total SOC channel current
// Ca2+ activated chloride channels
alpha_Cl(time) dimensionless, // Ca-act Cl channel cGMP sensitivity term
K_ClCacGMP(time) mM, // Ca-act Cl channel cGMP sensitivity
P_Cl(time) dimensionless, // Ca-act Cl channel P_Cl gate prob
I_ClCa(time) picoampere, // Total Ca-act Cl channel current
// Plasma membrane Ca2+ pump
I_PMCA(time) picoampere, // Total plasma membrane Ca pump current
// Plasma membrane Na+ - Ca2+ exchanger
R_NCXcGMP(time) dimensionless, // NCX cGMP sensitivity
phi_F(time) dimensionless, // Forward rate term
phi_R(time) dimensionless, // Reverse rate term
I_NCX(time) picoampere, // Total Na/Ca exchanger current
// Na+/K+ ATPase
I_NaK(time) picoampere, // Total Na/K ATPase current
// Na+ - K+ - Cl- cotransporter
R_NaKClcGMP(time) dimensionless, // Na/K/Cl cotrnsprtr cGMP sensitivity
ICl_NaKCl(time) picoampere, // Na/K/Cl cotrnsprtr total Cl current
INa_NaKCl(time) picoampere, // Na/K/Cl cotrnsprtr total Na current
IK_NaKCl(time) picoampere, // Na/K/Cl cotrnsprtr total K current
// IP3 receptor
I_IP3(time) picoampere, // Total IP3 Ca2+ current from SR
// Sarcoplasmic reticulum
I_SERCA(time) picoampere, // Total SERCA pump current
I_tr(time) picoampere, // Total SR uptk to rlse comptmt Ca2+ current
I_rel(time) picoampere, // Total SR Ca2+ release current
// Ryanodine receptor
R_00(time) dimensionless, // RyR no act or inact Ca bnd
// Alpha1-adrenoreceptor activation and IP3 formation
rho_rG(time) dimensionless, // Alpha1-adrnocptr NE sensitivity term
r_hG(time) 1/ms, // Basln IP3 production rate w/Ca senstivty
// sGC activation and cGMP formation
Vbar_cGMP(time) mM/ms, // Steady state rate of cGMP production
tau_sGC(time) ms, // sGC/cGMP time constant
// Ionic balances
ICa_totm(time) picoampere, // Total plasma membrane Ca2+ current
INa_totm(time) picoampere, // Total plasma membrane Na+ current
IK_totm(time) picoampere, // Total plasma membrane K+ current
ICl_totm(time) picoampere; // Total plasma membrane Cl- current
extern real // INPUT VARIABLES
NO(time) mM, // Input nitric oxide concentration
NE(time) mM, // Input norepinephrine concentration
I_stim(time) picoampere; // Input stimulation current
// *******************************************************************************************
// Init Conds for K A P E L A V S M E P H Y S M O D E L
// *******************************************************************************************
// Specification and calculation of ICs from minimal set of specified ICs
real
V_m0 = -59.4 mV, // Intial Vm
d_L0 = 1/(1+exp(-V_m0/(8.3 mV))), // Calc L-type Ca d gate (unitless)
f_L0 = 1/(1+exp((V_m0+(42 mV))/(9.1 mV))), // Calc L-type Ca f gate (unitless)
Ca_i0 = 68.0e-6 mM, // Initial cyto Ca concen
NO_0 = 1e-12 mM, // Initial NO concen
cGMP_i0 = 0 mM, // Initial cGMP concen
R_NO0 = NO_0 / (NO_0 + (0.2e-3 mM)), // Calc BKCa NO reg factor (unitless)
R_cGMP0 = (cGMP_i0^2) // Calc BKCa cGMP reg factor (unitless)
/ ((cGMP_i0^2) + ((0.55e-3 uM)^2)),
V_50KCa0 = ((-41.7 mV) // Calc BKCa half activation
* log(Ca_i0/(1 mM))) - (128.2 mV) // membrane voltage (mV)
- (dV_50KCaNO * R_NO0)
- (dV_50KCacGMP * R_cGMP0),
p_f0 = 1 / (1 + exp(-(V_m0-V_50KCa0) // Calc BKCa fast p gate (unitless)
/(18.25 mV))),
p_s0 = 1 / (1 + exp(-(V_m0-V_50KCa0) // Calc BKCa slow p gate (unitless)
/(18.25 mV))),
p_K0 = 1/(1+exp(-(V_m0+(11 mV))/(15 mV))), // Calc V-dep K var p gate (unitless)
q_10 = 1/(1+exp((V_m0+(40 mV))/(14 mV))), // Calc V-dep K fix q1 gate (unitless)
q_20 = 1/(1+exp((V_m0+(40 mV))/(14 mV))), // Calc V-dep K fix q2 gate (unitless)
P_SOC0 = 0 dimensionless, // Initial SOC act gate prob
h_IP30 = K_inhIP3 / (Ca_i0+K_inhIP3), // Calc IP3 recept h gate (unitless)
Ca_u0 = 0.66 mM, // Initial SR uptake Ca concen
Ca_r0 = 0.57 mM, // Initial SR release Ca concen
R_100 = 0.0033 dimensionless, // Initial RyR w/ act Ca bnd
R_110 = 4e-6 dimensionless, // Initial RyR w/ act-inact Ca bnd
R_010 = 0.9955 dimensionless, // Initial RyR w/ inact Ca bnd
R_supSG0 = R_TG * xi_G, // Calc unphos NE recept # (unitless)
R_supSPG0 = 0 dimensionless, // Initial # phos surf receptrs (unitless)
IP3_0 = 0 mM, // Initial cyto IP2 concen
PIP2_0 = PIP2_T - ((1 + (k_degG/r_rG)) // Calc cyto PIP2 # molec (unitless)
* gamma_G * IP3_0),
r_hG0 = (k_degG * gamma_G * IP3_0) // Calc Hydrol rate PIP2 (1/ms)
/ PIP2_0,
G_0 = (r_hG0*(K_cG+Ca_i0)) // Calc act G protein in PM (unitless)
/ (alpha_G*Ca_i0),
V_cGMP0 = 0 mM/ms, // Initial rate of cGMP formation
Na_i0 = 8.4 mM, // Initial cyto Na concen
K_i0 = 140 mM, // Initial cyto K concen
Cl_i0 = 59.4 mM, // Initial cyto Cl concen
deltaG_0 = (k_dG*G_0) // Calc ratio act lig unbnd (unitless)
/ (k_aG*(G_TG-G_0)); // to lig bnd receptors
// Initial conditions based on iniital values given above
when(time=time.min) {
V_m = V_m0; // Init membrane potential, V_m (mV)
d_L = d_L0; // Init L-type Ca act prob, d_L (unitless)
f_L = f_L0; // Init L-type Ca inact prob, f_L (unitless)
Ca_i = Ca_i0; // Init cyto Ca concen, Ca_i (mM)
p_f = p_f0; // Init Ca-act K fst gte prob, p_f (unitless)
p_s = p_s0; // Init Ca-act K slw gte prob, p_s (unitless)
p_K = p_K0; // Init K_V p activ gate prob, p_K (unitless)
q_1 = q_10; // Init K_V q fast activ prob, q_1 (unitless)
q_2 = q_20; // Init K_V q slow activ prob, q_2 (unitless)
P_SOC = 0; // Init SOC act gate prob, P_SOC (unitless)
h_IP3 = h_IP30; // Init IP3 act gate prob, h_IP3 (unitless)
Ca_u = Ca_u0; // Init SR uptake Ca concen, Ca_u (mM)
Ca_r = Ca_r0; // Init SR release Ca concen, Ca_r (mM)
R_10 = R_100; // Init RyR w/act Ca bnd, R_10 (unitless)
R_11 = R_110; // Init RyR w/at-inct Ca bnd, R_11 (unitless)
R_01 = R_010; // Init RyR w/ inact Ca bnd, R_01 (unitless)
R_supSG = R_supSG0; // Init # unphos recept, R_supSG (unitless)
R_supSPG = R_supSPG0; // Init # phos recept, R_supSPG (unitless)
IP3 = IP3_0; // Init cyto IP3 concen, IP3 (mM)
PIP2 = PIP2_0; // Init # cyto PIP2 molecles, PIP2 (unitless)
G = G_0; // Init # sctive G protein, G (unitless)
V_cGMP = V_cGMP0; // Init rate of cGMP form, V_cGMP (mM/ms)
cGMP_i = cGMP_i0; // Init cyto cGMP concen, cGMP_i (mM)
Na_i = Na_i0; // Init cyto Na concen, Na_i (mM)
K_i = K_i0; // Init cyto K concen, K_i (mM)
Cl_i = Cl_i0; // Init cyto Cl concen, Cl_i (mM)
}
// Reversal potentials
E_K = 1/(z_K*FRT) * ln(K_e/K_i);
E_Na = 1/(z_Na*FRT) * ln(Na_e/Na_i);
E_Ca = 1/(z_Ca*FRT) * ln(Ca_e/Ca_i);
E_Cl = 1/(z_Cl*FRT) * ln(Cl_e/Cl_i);
// L-type voltage operated Ca2+ channels
dbar_L = 1 / (1 + exp(-V_m/(8.3 mV)));
fbar_L = 1 / (1 + exp((V_m+(42 mV))/(9.1 mV)));
tau_dL = ((2.5 ms) * exp(-((V_m+(40 mV))/(30 mV))^2)) + (1.15 ms);
tau_fL = ((65 ms) * exp(-((V_m+(35 mV))/(25 mV))^2)) + (45 ms);
I_VOCC = A_m * P_VOCC * d_L * f_L * V_m * ((z_Ca^2)*F*FRT)
* (Ca_e - Ca_i*exp(V_m*z_Ca*FRT)) / (1 - exp(V_m*z_Ca*FRT));
d_L:time = (dbar_L - d_L) / tau_dL;
f_L:time = (fbar_L - f_L) / tau_fL;
// Large conductance Ca2+ activated K+ channels
P_KCa = 0.17*p_f + 0.83*p_s;
i_KCa = P_BKCa * V_m * F*FRT
* (K_e - K_i*exp(V_m*FRT)) / (1 - exp(V_m*FRT));
R_NO = NO / (NO+(0.2e-3 mM));
R_cGMP = cGMP_i^2 / (cGMP_i^2 + (1.5e-3 mM)^2);
V_50KCa =-((41.7 mV)*log(Ca_i/(1 mM))) - (128.2 mV)
- (dV_50KCaNO*R_NO) - (dV_50KCacGMP*R_cGMP);
pbar_o = 1 / (1 + exp(-(V_m-V_50KCa)/(18.25 mV)));
I_BKCa = A_m * N_BKCa * P_KCa * i_KCa;
p_f:time = (pbar_o - p_f) / tau_pf;
p_s:time = (pbar_o - p_s) / tau_ps;
// Voltage-dependent K+ channels
pbar_K = 1 / (1 + exp(-(V_m+(11 mV))/(15 mV)));
qbar = 1 / (1 + exp((V_m+(40 mV))/(14 mV)));
tau_pK = (61.49 ms) * exp((-0.0268 1/mV)*V_m);
I_Kv = g_Kv * p_K * (0.45*q_1 + 0.55*q_2) * (V_m - E_K);
p_K:time = (pbar_K - p_K) / tau_pK;
q_1:time = (qbar - q_1) / tau_q1;
q_2:time = (qbar - q_2) / tau_q2;
// Unspecified K+ leak channels
I_Kleak = g_Kleak * (V_m - E_K);
// Non-selective cation channels
Po_NSC = 0.4344 + (0.5656 / (1 + exp(-(V_m - (47.12 mV))/(24.24 mV))));
DAG = IP3;
INa_NSC = A_m * ((DAG/(DAG+K_NSC)) + d_NSCmin) * Po_NSC * PNa_NSC
* V_m * F*FRT * (Na_e - Na_i*exp(V_m*FRT)) / (1 - exp(V_m*FRT));
IK_NSC = A_m * ((DAG/(DAG+K_NSC)) + d_NSCmin) * Po_NSC * PK_NSC
* V_m * F*FRT * (K_e - K_i*exp(V_m*FRT)) / (1 - exp(V_m*FRT));
ICa_NSC = A_m * d_NSCmin * Po_NSC * PCa_NSC * V_m * (z_Ca^2)*F*FRT
* (Ca_e - Ca_i*exp(z_Ca*V_m*FRT)) / (1 - exp(z_Ca*V_m*FRT));
I_NSC = INa_NSC + IK_NSC + ICa_NSC;
// Store-operated non-selective cation channels
Pbar_SOC = 1 / (1 + Ca_u/K_SOC);
INa_SOC = gNa_SOC * P_SOC * (V_m - E_Na);
ICa_SOC = gCa_SOC * P_SOC * (V_m - E_Ca);
I_SOC = INa_SOC + ICa_SOC;
P_SOC:time = (Pbar_SOC - P_SOC) / tau_SOC;
// Ca2+ activated chloride channels
alpha_Cl = ((cGMP_i/(1 mM))^n_ClcGMP) / (((cGMP_i/(1 mM))^n_ClcGMP)
+ ((K_ClcGMP/(1 mM))^n_ClcGMP));
K_ClCacGMP = (1 - (0.9*alpha_Cl)) * (4.00e-4 mM);
P_Cl = R_ClcGMPmin * (((Ca_i/(1 mM))^n_ClCa) / (((Ca_i/(1 mM))^n_ClCa)
+ ((K_ClCa/(1 mM))^n_ClCa))) + alpha_Cl * (((Ca_i/(1 mM))^n_ClCa)
/ (((Ca_i/(1 mM))^n_ClCa) + ((K_ClCacGMP/(1 mM))^n_ClCa)));
I_ClCa = C_m * g_ClCa * P_Cl *(V_m - E_Cl);
// Plasma membrane Ca2+ pump
I_PMCA = Ibar_PMCA * (Ca_i /(Ca_i + K_mPMCA));
// Plasma membrane Na+ - Ca2+ exchanger
R_NCXcGMP = 1 + 0.55 * (cGMP_i/(cGMP_i+(4.5e-2 mM)));
phi_F = exp(gamma_NCX*V_m*FRT);
phi_R = exp((gamma_NCX-1)*V_m*FRT);
I_NCX = g_NCX * R_NCXcGMP * ((Na_i^3)*Ca_e*phi_F - (Na_e^3)*Ca_i*phi_R)
/ (1 + d_NCX*((Na_e^3)*Ca_i + (Na_i^3)*Ca_e));
// Na+ - K+ pump
I_NaK = C_m * Ibar_NaK * Q * ((K_e/(1 mM))^n_HKe)
/ (((K_e/(1 mM))^n_HKe) + ((K_dKe/(1 mM))^n_HKe))
* ((Na_i/(1 mM))^n_HNai) / (((Na_i/(1 mM))^n_HNai)
+ ((Na_dNai/(1 mM))^n_HNai)) * (V_m+(150 mV)) / (V_m+(200 mV));
// Na+ - K+ - Cl- cotransporter
R_NaKClcGMP = 1 + (3.5 * (cGMP_i/(cGMP_i+(6.4e-3 mM))));
ICl_NaKCl = -R_NaKClcGMP * z_Cl * A_m * L_NaKCl * F*RT
* log((Na_e/Na_i)*(K_e/K_i)*(Cl_e/Cl_i)^2);
INa_NaKCl = -0.5 * ICl_NaKCl;
IK_NaKCl = -0.5 * ICl_NaKCl;
// IP3 receptor
I_IP3 = Ibar_IP3 * z_Ca * Vol_Ca * F * ((IP3/(IP3+K_IP3))
* (Ca_i/(Ca_i+K_actIP3)) * h_IP3)^3 * (Ca_u - Ca_i);
h_IP3:time = k_onIP3 * (K_inhIP3 - ((Ca_i+K_inhIP3) * h_IP3));
// Sarcoplasmic reticulum
I_SERCA = Ibar_SERCA * (Ca_i/(Ca_i+K_mup));
I_tr = (Ca_u - Ca_r) * z_Ca * F * Vol_SRu / tau_tr;
I_rel = ((R_10^2) + R_leak) * (Ca_r - Ca_i) * z_Ca * F * Vol_SRr / tau_rel;
Ca_u:time = (I_SERCA - I_tr - I_IP3) / (z_Ca * F * Vol_SRu);
Ca_r:time = ((I_tr-I_rel) / (z_Ca*F*Vol_SRr))
/ (1 + (CSQNbar*K_CSQN)/((K_CSQN+Ca_r)^2));
// Ryanodine receptor
R_00 = 1 - R_10 - R_11 - R_01;
R_10:time = (K_r1*(Ca_i^2)*R_00) - ((K_mr1+(K_r2*Ca_i))*R_10) + (K_mr2*R_11);
R_11:time = (K_r2*Ca_i*R_10) - ((K_mr1+K_mr2)*R_11) + (K_r1*(Ca_i^2)*R_01);
R_01:time = (K_r2*Ca_i*R_00) + (K_mr1*R_11) - ((K_mr2+(K_r1*(Ca_i^2)))*R_01);
// Alpha1-adrenoreceptor activation and IP3 formation
rho_rG = (NE*R_supSG) / (xi_G*R_TG*(K_1G+NE));
r_hG = alpha_G * (Ca_i/(Ca_i+K_cG)) * G;
R_supSG:time = (k_rG*xi_G*R_TG) - (k_rG + ((k_pG*NE)/(K_1G+NE)))*R_supSG
- (k_rG*R_supSPG);
R_supSPG:time = NE * ((k_pG*R_supSG)/(K_1G+NE) - (k_eG*R_supSPG)/(K_2G+NE));
G:time = (k_aG * (deltaG_0+rho_rG) * (G_TG-G)) - k_dG*G;
IP3:time = ((r_hG*PIP2)/gamma_G) - (k_degG*IP3);
PIP2:time = -((r_hG + r_rG)*PIP2)
- (r_rG*gamma_G*IP3) + (r_rG*PIP2_T);
// sGC activation and cGMP formation
B5_sGC = k_2sGC / k_3sGC;
A0_sGC = ((k_m1sGC+k_2sGC)*k_DsGC + (k_m1sGC*k_m2sGC)) / (k_1sGC*k_3sGC);
A1_sGC = ((k_1sGC+k_3sGC)*k_DsGC + (k_2sGC+k_m2sGC)*k_1sGC) / (k_1sGC*k_3sGC);
Vbar_cGMP = V_cGMPmax * ((B5_sGC*NO) + NO^2) / (A0_sGC + (A1_sGC*NO) + NO^2);
tau_sGC = if ((Vbar_cGMP-V_cGMP) >= (0 mM/ms))
(1/((k_3sGC*NO) + k_DrsGC))
else
(1/(k_m2sGC + k_DrsGC));
V_cGMP:time = (Vbar_cGMP - V_cGMP) / tau_sGC;
cGMP_i:time = V_cGMP - (k_pdecGMP * ((cGMP_i^2)/(cGMP_i+K_mpde)));
// Ionic balances
ICa_totm = ICa_SOC + I_VOCC - 2*I_NCX + I_PMCA + ICa_NSC;
INa_totm = INa_NaKCl + INa_SOC + 3*I_NaK + 3*I_NCX + INa_NSC;
IK_totm = IK_NaKCl + I_BKCa + I_Kv + IK_NSC + I_Kleak - 2*I_NaK;
ICl_totm = ICl_NaKCl + I_ClCa;
Ca_i:time = -((ICa_totm + I_SERCA - I_rel - I_IP3)/(z_Ca*F*Vol_Ca))
/ (1 + ((Sbar_CM*K_dCM)/((K_dCM+Ca_i)^2)) + ((Bbar_F*K_dB)/((K_dB+Ca_i)^2)));
Na_i:time = -(INa_totm / (F*Vol_i));
K_i:time = -(IK_totm / (F*Vol_i));
Cl_i:time = -(ICl_totm / (z_Cl*F*Vol_i));
// Membrane potential
V_m:time = 1/C_m * (-(I_VOCC + I_BKCa + I_Kv + I_Kleak + I_NSC + I_SOC
+ I_ClCa + I_PMCA + I_NCX + I_NaK) + I_stim);
}
// ***********************************************************************************
// References for V S M E P H Y S M O D E L
// ***********************************************************************************
//
// Bennett MR, Farnell L and Gibson WG
// A quantitative description of the contraction of blood vessels following the
// release of noradrenaline from sympathetic varicosities.
// Journal of Theoretical Biology 234:107-122, 2005.
//
// Condorelli P and Geroge SC
// In vivo control of soluble guanylate cyclase activation by nitric oxide: a
// kinetic analysis.
// Biophysical Journal 80:2110-2119, 2001
//
// Lindblad DS, Murphey CR, Clark JW and Giles WR
// A model of the action potential and underlying membrane currents in a rabbit
// atrial cell.
// American Journal of Physiology 271:H1666-H1696 ,1996.
//
// Strieter J, Stephenson JL, Palmer LG and Weinstein AM
// Volume-activated chloride permeability can mediate cell volume regulation in
// a mathematical model of a tight epithelium.
// Journal of General Physiology 96:319-344, 1990.
//
// Tsoukias NM, Kavdia M and Popel AS
// A theoretical model of nitric oxide transport in arterioles: frequency vs.
// amplitude-dependent control of cGMP formation.
// American Journal of Physiology 286:H1043-H1056, 2004
//
// Yang J, Clark JW, Bryan RM and Robertson CS
// Mathematical modeling of the nitric oxide/cGMP pathway in the vascular smooth
// muscle cell.
// American Journal of Physiology 289:H886-H897, 2005.
//
// ***********************************************************************************</control>
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<control name="customRTML"></control>
<control name="customBuilt" value="false"/>
<options name="buildOptions">
<control name="maxBuildTime" value="120"/>
<control name="maxImplicitBlock" value="10"/>
<control name="initNaN" value="false"/>
<control name="abortNaN" value="false"/>
<control name="traceNaN" value="false"/>
<control name="traceVars" value=""/>
<control name="ignoreAllOverspec" value="false"/>
<control name="ignoreAllUnderspec" value="false"/>
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</options>
<vars name="vars">
<function name="fgen_1"/>
<function name="fgen_3"/>
<function name="fgen_2"/>
</vars>
<parset name="last">
<pargroups>
<pargroup name="inputs">
<control name="F" value="96485.3399"/>
<control name="R" value="8314.472"/>
<control name="T" value="293"/>
<control name="N_Avo" value="6.022E23"/>
<control name="C_m" value="25"/>
<control name="z_K" value="1"/>
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<control name="d_NCX" value="3E-4"/>
<control name="gamma_NCX" value=".45"/>
<control name="Ibar_NaK" value="2.3083"/>
<control name="n_HKe" value="1.1"/>
<control name="K_dKe" value="1.6"/>
<control name="n_HNai" value="1.7"/>
<control name="Na_dNai" value="22"/>
<control name="Q_10" value="1.87"/>
<control name="L_NaKCl" value="1.79E-17"/>
<control name="Ibar_IP3" value=".00288"/>
<control name="K_IP3" value="1.2E-4"/>
<control name="K_actIP3" value="1.7E-4"/>
<control name="k_onIP3" value="1.4"/>
<control name="K_inhIP3" value="1E-4"/>
<control name="Ibar_SERCA" value="6.68"/>
<control name="K_mup" value=".001"/>
<control name="tau_tr" value="1E3"/>
<control name="R_leak" value="1.07E-5"/>
<control name="tau_rel" value=".0333"/>
<control name="CSQNbar" value="15"/>
<control name="K_CSQN" value=".8"/>
<control name="K_r1" value="2500"/>
<control name="K_r2" value="1.05"/>
<control name="K_mr1" value=".0076"/>
<control name="K_mr2" value=".084"/>
<control name="k_rG" value="1.75E-7"/>
<control name="xi_G" value=".85"/>
<control name="R_TG" value="2E4"/>
<control name="k_pG" value="1E-4"/>
<control name="K_1G" value=".01"/>
<control name="k_eG" value="6E-6"/>
<control name="K_2G" value=".2"/>
<control name="k_aG" value="1.7E-4"/>
<control name="G_TG" value="1E5"/>
<control name="k_dG" value=".0015"/>
<control name="alpha_G" value="2.781E-8"/>
<control name="K_cG" value="4E-4"/>
<control name="k_degG" value=".00125"/>
<control name="r_rG" value="1.5E-5"/>
<control name="PIP2_T" value="5E7"/>
<control name="V_cGMPmax" value="1.26E-7"/>
<control name="k_2sGC" value="6.4E-6"/>
<control name="k_3sGC" value="4.2"/>
<control name="k_m1sGC" value=".015"/>
<control name="k_DsGC" value="4E-4"/>
<control name="k_m2sGC" value="1E-7"/>
<control name="k_1sGC" value="2E3"/>
<control name="k_DrsGC" value="1E-4"/>
<control name="k_pdecGMP" value="6.95E-5"/>
<control name="K_mpde" value=".001"/>
<control name="Sbar_CM" value=".1"/>
<control name="K_dCM" value="2.6E-4"/>
<control name="Bbar_F" value=".1"/>
<control name="K_dB" value="5.298E-4"/>
<control name="time.min" value="0"/>
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<control name="time.delta" value="0.5"/>
<control name="V_m0" value="-59.4"/>
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<control name="NO_0" value="1E-12"/>
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<control name="P_SOC0" value="0"/>
<control name="Ca_u0" value=".66"/>
<control name="Ca_r0" value=".57"/>
<control name="R_100" value=".0033"/>
<control name="R_110" value="4E-6"/>
<control name="R_010" value=".9955"/>
<control name="R_supSPG0" value="0"/>
<control name="IP3_0" value="0"/>
<control name="V_cGMP0" value="0"/>
<control name="Na_i0" value="8.4"/>
<control name="K_i0" value="140"/>
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<pargroup name="solver">
<control name="ode_which" value="Auto"/>
<control name="ode_Dopri5_reltol" value="1E-7"/>
<control name="ode_Dopri5_abstol" value="1E-7"/>
<control name="ode_Dopri5_nstep" value="100000"/>
<control name="ode_Dopri5_stiff" value="1000"/>
<control name="ode_Dopri5_round" value="2.3E-16"/>
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<control name="Gaussian.timeToRepeat" value="0"/>
<control name="LagNormal.area" value="1"/>
<control name="LagNormal.tMean" value="5"/>
<control name="LagNormal.RD" value=".3"/>
<control name="LagNormal.skewn" value="1.3"/>
<control name="LagNormal.frPeak" value="1E-6"/>
<control name="LagNormal.upslope" value="Regular"/>
<control name="LagNormal.timeToRepeat" value="0"/>
<control name="Longtail.PDF" value="LagNormal"/>
<control name="Longtail.area" value="1"/>
<control name="Longtail.tMean" value="5"/>
<control name="Longtail.RD" value=".3"/>
<control name="Longtail.skewn" value="1.3"/>
<control name="Longtail.frPeak" value="1E-6"/>
<control name="Longtail.upslope" value="Regular"/>
<control name="Longtail.tORfr" value="frJoin"/>
<control name="Longtail.tJoin" value="10"/>
<control name="Longtail.frJoin" value=".25"/>
<control name="Longtail.expORpow" value="Exponential"/>
<control name="Longtail.nExp" value="1"/>
<control name="Longtail.w1" value="1"/>
<control name="Longtail.w2" value=".25"/>
<control name="Longtail.w3" value=".0625"/>
<control name="Longtail.w4" value=".015625"/>
<control name="Longtail.k1" value="1"/>
<control name="Longtail.k2" value=".25"/>
<control name="Longtail.k3" value=".0625"/>
<control name="Longtail.k4" value=".015625"/>
<control name="Longtail.nPow" value="1"/>
<control name="Longtail.wpow1" value="1"/>
<control name="Longtail.wpow2" value=".5"/>
<control name="Longtail.wpow3" value=".25"/>
<control name="Longtail.wpow4" value=".125"/>
<control name="Longtail.beta1" value="2"/>
<control name="Longtail.beta2" value="1.5"/>
<control name="Longtail.beta3" value="1"/>
<control name="Longtail.beta4" value=".5"/>
<control name="Longtail.timeToRepeat" value="0"/>
<control name="GammaVar.area" value="1"/>
<control name="GammaVar.tMean" value="5"/>
<control name="GammaVar.RD" value=".3"/>
<control name="GammaVar.skewn" value="1.3"/>
<control name="GammaVar.frPeak" value="1E-6"/>
<control name="GammaVar.timeToRepeat" value="0"/>
<control name="Poisson.area" value="1"/>
<control name="Poisson.tMean" value="5"/>
<control name="Poisson.RD" value=".3"/>
<control name="Poisson.frPeak" value="1E-6"/>
<control name="Poisson.timeToRepeat" value="0"/>
<control name="RandomWalk.area" value="1"/>
<control name="RandomWalk.tMean" value="5"/>
<control name="RandomWalk.RD" value=".3"/>
<control name="RandomWalk.skewn" value="1"/>
<control name="RandomWalk.frPeak" value="1E-6"/>
<control name="RandomWalk.timeToRepeat" value="0"/>
<control name="DataCurve.ndim" value="1"/>
<control name="DataCurve.dataSet" value=""/>
<control name="DataCurve.name" value=""/>
<control name="domain0" value="time"/>
<control name="domain1" value=""/>
<control name="domain2" value=""/>
</pargroup>
<pargroup name="function:fgen_3">
<control name="desc" value=""/>
<control name="which" value="Pulse1"/>
<control name="Pulse1.startTime" value="0"/>
<control name="Pulse1.duration" value="2E5"/>
<control name="Pulse1.amplitude" value="0"/>
<control name="Pulse1.offset" value="0"/>
<control name="Pulse1.timeToRepeat" value="2E5"/>
<control name="Pulse2.p1Start" value="0"/>
<control name="Pulse2.p1Duration" value="1"/>
<control name="Pulse2.p1Amplitude" value="1"/>
<control name="Pulse2.offset" value="0"/>
<control name="Pulse2.p1TimeToRepeat" value="10"/>
<control name="Pulse2.p2Start" value="1"/>
<control name="Pulse2.p2Duration" value="2"/>
<control name="Pulse2.p2Amplitude" value="2"/>
<control name="Pulse2.p2TimeToRepeat" value="0"/>
<control name="Pulse3.p1Start" value="0"/>
<control name="Pulse3.p1Duration" value="1"/>
<control name="Pulse3.p1Amplitude" value="1"/>
<control name="Pulse3.offset" value="0"/>
<control name="Pulse3.p1TimeToRepeat" value="10"/>
<control name="Pulse3.p2Start" value="1"/>
<control name="Pulse3.p2Duration" value="2"/>
<control name="Pulse3.p2Amplitude" value="2"/>
<control name="Pulse3.p2TimeToRepeat" value="0"/>
<control name="Pulse3.p3Start" value="3"/>
<control name="Pulse3.p3Duration" value="3"/>
<control name="Pulse3.p3Amplitude" value="3"/>
<control name="Pulse3.p3TimeToRepeat" value="0"/>
<control name="ExtendedPulse3.offset" value="0"/>
<control name="ExtendedPulse3.timeToRepeat" value="3"/>
<control name="ExtendedPulse3.p1Start" value="0"/>
<control name="ExtendedPulse3.p1Duration" value=".5"/>
<control name="ExtendedPulse3.p1Amplitude" value="1"/>
<control name="ExtendedPulse3.p1LoopCnt" value="1"/>
<control name="ExtendedPulse3.p1AmpIncr" value="0"/>
<control name="ExtendedPulse3.p2Start" value="1"/>
<control name="ExtendedPulse3.p2Duration" value=".5"/>
<control name="ExtendedPulse3.p2Amplitude" value="2"/>
<control name="ExtendedPulse3.p2LoopCnt" value="3"/>
<control name="ExtendedPulse3.p2AmpIncr" value=".5"/>
<control name="ExtendedPulse3.p3Start" value="2"/>
<control name="ExtendedPulse3.p3Duration" value=".5"/>
<control name="ExtendedPulse3.p3Amplitude" value="3"/>
<control name="ExtendedPulse3.p3LoopCnt" value="0"/>
<control name="ExtendedPulse3.p3AmpIncr" value="0"/>
<control name="Ramp.startTime" value="1"/>
<control name="Ramp.duration" value="5"/>
<control name="Ramp.amplitude" value="-1"/>
<control name="Ramp.offset" value="1"/>
<control name="Ramp.exponent" value="3"/>
<control name="Ramp.timeToRepeat" value="10"/>
<control name="SquareWaveTrain.startTime" value="0"/>
<control name="SquareWaveTrain.duration" value="10"/>
<control name="SquareWaveTrain.amplitude" value="1"/>
<control name="SquareWaveTrain.offset" value="0"/>
<control name="SquareWaveTrain.shapeFactor" value=".5"/>
<control name="SquareWaveTrain.phase" value="0"/>
<control name="SquareWaveTrain.period" value="5"/>
<control name="SquareWaveTrain.timeToRepeat" value="0"/>
<control name="SawtoothTrain.startTime" value="0"/>
<control name="SawtoothTrain.duration" value="10"/>
<control name="SawtoothTrain.amplitude" value="1"/>
<control name="SawtoothTrain.offset" value="0"/>
<control name="SawtoothTrain.shapeFactor" value=".5"/>
<control name="SawtoothTrain.phase" value="0"/>
<control name="SawtoothTrain.period" value="5"/>
<control name="SawtoothTrain.timeToRepeat" value="0"/>
<control name="SineTrain.startTime" value="0"/>
<control name="SineTrain.duration" value="5"/>
<control name="SineTrain.amplitude" value="1"/>
<control name="SineTrain.offset" value="0"/>
<control name="SineTrain.phase" value="0"/>
<control name="SineTrain.period" value="5"/>
<control name="SineTrain.timeToRepeat" value="10"/>
<control name="Exponential.area" value="1"/>
<control name="Exponential.tMean" value="5"/>
<control name="Exponential.RD" value=".3"/>
<control name="Exponential.frPeak" value="1E-6"/>
<control name="Exponential.timeToRepeat" value="0"/>
<control name="Gaussian.area" value="1"/>
<control name="Gaussian.tMean" value="5"/>
<control name="Gaussian.RD" value=".3"/>
<control name="Gaussian.frPeak" value="1E-6"/>
<control name="Gaussian.timeToRepeat" value="0"/>
<control name="LagNormal.area" value="1"/>
<control name="LagNormal.tMean" value="5"/>
<control name="LagNormal.RD" value=".3"/>
<control name="LagNormal.skewn" value="1.3"/>
<control name="LagNormal.frPeak" value="1E-6"/>
<control name="LagNormal.upslope" value="Regular"/>
<control name="LagNormal.timeToRepeat" value="0"/>
<control name="Longtail.PDF" value="LagNormal"/>
<control name="Longtail.area" value="1"/>
<control name="Longtail.tMean" value="5"/>
<control name="Longtail.RD" value=".3"/>
<control name="Longtail.skewn" value="1.3"/>
<control name="Longtail.frPeak" value="1E-6"/>
<control name="Longtail.upslope" value="Regular"/>
<control name="Longtail.tORfr" value="frJoin"/>
<control name="Longtail.tJoin" value="10"/>
<control name="Longtail.frJoin" value=".25"/>
<control name="Longtail.expORpow" value="Exponential"/>
<control name="Longtail.nExp" value="1"/>
<control name="Longtail.w1" value="1"/>
<control name="Longtail.w2" value=".25"/>
<control name="Longtail.w3" value=".0625"/>
<control name="Longtail.w4" value=".015625"/>
<control name="Longtail.k1" value="1"/>
<control name="Longtail.k2" value=".25"/>
<control name="Longtail.k3" value=".0625"/>
<control name="Longtail.k4" value=".015625"/>
<control name="Longtail.nPow" value="1"/>
<control name="Longtail.wpow1" value="1"/>
<control name="Longtail.wpow2" value=".5"/>
<control name="Longtail.wpow3" value=".25"/>
<control name="Longtail.wpow4" value=".125"/>
<control name="Longtail.beta1" value="2"/>
<control name="Longtail.beta2" value="1.5"/>
<control name="Longtail.beta3" value="1"/>
<control name="Longtail.beta4" value=".5"/>
<control name="Longtail.timeToRepeat" value="0"/>
<control name="GammaVar.area" value="1"/>
<control name="GammaVar.tMean" value="5"/>
<control name="GammaVar.RD" value=".3"/>
<control name="GammaVar.skewn" value="1.3"/>
<control name="GammaVar.frPeak" value="1E-6"/>
<control name="GammaVar.timeToRepeat" value="0"/>
<control name="Poisson.area" value="1"/>
<control name="Poisson.tMean" value="5"/>
<control name="Poisson.RD" value=".3"/>
<control name="Poisson.frPeak" value="1E-6"/>
<control name="Poisson.timeToRepeat" value="0"/>
<control name="RandomWalk.area" value="1"/>
<control name="RandomWalk.tMean" value="5"/>
<control name="RandomWalk.RD" value=".3"/>
<control name="RandomWalk.skewn" value="1"/>
<control name="RandomWalk.frPeak" value="1E-6"/>
<control name="RandomWalk.timeToRepeat" value="0"/>
<control name="DataCurve.ndim" value="1"/>
<control name="DataCurve.dataSet" value=""/>
<control name="DataCurve.name" value=""/>
<control name="domain0" value="time"/>
<control name="domain1" value=""/>
<control name="domain2" value=""/>
</pargroup>
<pargroup name="function:fgen_2">
<control name="desc" value=""/>
<control name="which" value="Pulse1"/>
<control name="Pulse1.startTime" value="1.1E5"/>
<control name="Pulse1.duration" value="65000"/>
<control name="Pulse1.amplitude" value=".001"/>
<control name="Pulse1.offset" value="0"/>
<control name="Pulse1.timeToRepeat" value="2E5"/>
<control name="Pulse2.p1Start" value="0"/>
<control name="Pulse2.p1Duration" value="1"/>
<control name="Pulse2.p1Amplitude" value="1"/>
<control name="Pulse2.offset" value="0"/>
<control name="Pulse2.p1TimeToRepeat" value="10"/>
<control name="Pulse2.p2Start" value="1"/>
<control name="Pulse2.p2Duration" value="2"/>
<control name="Pulse2.p2Amplitude" value="2"/>
<control name="Pulse2.p2TimeToRepeat" value="0"/>
<control name="Pulse3.p1Start" value="0"/>
<control name="Pulse3.p1Duration" value="1"/>
<control name="Pulse3.p1Amplitude" value="1"/>
<control name="Pulse3.offset" value="0"/>
<control name="Pulse3.p1TimeToRepeat" value="10"/>
<control name="Pulse3.p2Start" value="1"/>
<control name="Pulse3.p2Duration" value="2"/>
<control name="Pulse3.p2Amplitude" value="2"/>
<control name="Pulse3.p2TimeToRepeat" value="0"/>
<control name="Pulse3.p3Start" value="3"/>
<control name="Pulse3.p3Duration" value="3"/>
<control name="Pulse3.p3Amplitude" value="3"/>
<control name="Pulse3.p3TimeToRepeat" value="0"/>
<control name="ExtendedPulse3.offset" value="0"/>
<control name="ExtendedPulse3.timeToRepeat" value="3"/>
<control name="ExtendedPulse3.p1Start" value="0"/>
<control name="ExtendedPulse3.p1Duration" value=".5"/>
<control name="ExtendedPulse3.p1Amplitude" value="1"/>
<control name="ExtendedPulse3.p1LoopCnt" value="1"/>
<control name="ExtendedPulse3.p1AmpIncr" value="0"/>
<control name="ExtendedPulse3.p2Start" value="1"/>
<control name="ExtendedPulse3.p2Duration" value=".5"/>
<control name="ExtendedPulse3.p2Amplitude" value="2"/>
<control name="ExtendedPulse3.p2LoopCnt" value="3"/>
<control name="ExtendedPulse3.p2AmpIncr" value=".5"/>
<control name="ExtendedPulse3.p3Start" value="2"/>
<control name="ExtendedPulse3.p3Duration" value=".5"/>
<control name="ExtendedPulse3.p3Amplitude" value="3"/>
<control name="ExtendedPulse3.p3LoopCnt" value="0"/>
<control name="ExtendedPulse3.p3AmpIncr" value="0"/>
<control name="Ramp.startTime" value="1"/>
<control name="Ramp.duration" value="5"/>
<control name="Ramp.amplitude" value="-1"/>
<control name="Ramp.offset" value="1"/>
<control name="Ramp.exponent" value="3"/>
<control name="Ramp.timeToRepeat" value="10"/>
<control name="SquareWaveTrain.startTime" value="0"/>
<control name="SquareWaveTrain.duration" value="10"/>
<control name="SquareWaveTrain.amplitude" value="1"/>
<control name="SquareWaveTrain.offset" value="0"/>
<control name="SquareWaveTrain.shapeFactor" value=".5"/>
<control name="SquareWaveTrain.phase" value="0"/>
<control name="SquareWaveTrain.period" value="5"/>
<control name="SquareWaveTrain.timeToRepeat" value="0"/>
<control name="SawtoothTrain.startTime" value="0"/>
<control name="SawtoothTrain.duration" value="10"/>
<control name="SawtoothTrain.amplitude" value="1"/>
<control name="SawtoothTrain.offset" value="0"/>
<control name="SawtoothTrain.shapeFactor" value=".5"/>
<control name="SawtoothTrain.phase" value="0"/>
<control name="SawtoothTrain.period" value="5"/>
<control name="SawtoothTrain.timeToRepeat" value="0"/>
<control name="SineTrain.startTime" value="0"/>
<control name="SineTrain.duration" value="5"/>
<control name="SineTrain.amplitude" value="1"/>
<control name="SineTrain.offset" value="0"/>
<control name="SineTrain.phase" value="0"/>
<control name="SineTrain.period" value="5"/>
<control name="SineTrain.timeToRepeat" value="10"/>
<control name="Exponential.area" value="1"/>
<control name="Exponential.tMean" value="5"/>
<control name="Exponential.RD" value=".3"/>
<control name="Exponential.frPeak" value="1E-6"/>
<control name="Exponential.timeToRepeat" value="0"/>
<control name="Gaussian.area" value="1"/>
<control name="Gaussian.tMean" value="5"/>
<control name="Gaussian.RD" value=".3"/>
<control name="Gaussian.frPeak" value="1E-6"/>
<control name="Gaussian.timeToRepeat" value="0"/>
<control name="LagNormal.area" value="1"/>
<control name="LagNormal.tMean" value="5"/>
<control name="LagNormal.RD" value=".3"/>
<control name="LagNormal.skewn" value="1.3"/>
<control name="LagNormal.frPeak" value="1E-6"/>
<control name="LagNormal.upslope" value="Regular"/>
<control name="LagNormal.timeToRepeat" value="0"/>
<control name="Longtail.PDF" value="LagNormal"/>
<control name="Longtail.area" value="1"/>
<control name="Longtail.tMean" value="5"/>
<control name="Longtail.RD" value=".3"/>
<control name="Longtail.skewn" value="1.3"/>
<control name="Longtail.frPeak" value="1E-6"/>
<control name="Longtail.upslope" value="Regular"/>
<control name="Longtail.tORfr" value="frJoin"/>
<control name="Longtail.tJoin" value="10"/>
<control name="Longtail.frJoin" value=".25"/>
<control name="Longtail.expORpow" value="Exponential"/>
<control name="Longtail.nExp" value="1"/>
<control name="Longtail.w1" value="1"/>
<control name="Longtail.w2" value=".25"/>
<control name="Longtail.w3" value=".0625"/>
<control name="Longtail.w4" value=".015625"/>
<control name="Longtail.k1" value="1"/>
<control name="Longtail.k2" value=".25"/>
<control name="Longtail.k3" value=".0625"/>
<control name="Longtail.k4" value=".015625"/>
<control name="Longtail.nPow" value="1"/>
<control name="Longtail.wpow1" value="1"/>
<control name="Longtail.wpow2" value=".5"/>
<control name="Longtail.wpow3" value=".25"/>
<control name="Longtail.wpow4" value=".125"/>
<control name="Longtail.beta1" value="2"/>
<control name="Longtail.beta2" value="1.5"/>
<control name="Longtail.beta3" value="1"/>
<control name="Longtail.beta4" value=".5"/>
<control name="Longtail.timeToRepeat" value="0"/>
<control name="GammaVar.area" value="1"/>
<control name="GammaVar.tMean" value="5"/>
<control name="GammaVar.RD" value=".3"/>
<control name="GammaVar.skewn" value="1.3"/>
<control name="GammaVar.frPeak" value="1E-6"/>
<control name="GammaVar.timeToRepeat" value="0"/>
<control name="Poisson.area" value="1"/>
<control name="Poisson.tMean" value="5"/>
<control name="Poisson.RD" value=".3"/>
<control name="Poisson.frPeak" value="1E-6"/>
<control name="Poisson.timeToRepeat" value="0"/>
<control name="RandomWalk.area" value="1"/>
<control name="RandomWalk.tMean" value="5"/>
<control name="RandomWalk.RD" value=".3"/>
<control name="RandomWalk.skewn" value="1"/>
<control name="RandomWalk.frPeak" value="1E-6"/>
<control name="RandomWalk.timeToRepeat" value="0"/>
<control name="DataCurve.ndim" value="1"/>
<control name="DataCurve.dataSet" value=""/>
<control name="DataCurve.name" value=""/>
<control name="domain0" value="time"/>
<control name="domain1" value=""/>
<control name="domain2" value=""/>
</pargroup>
</pargroups>
<vars name="vars">
<assign name="vars">
<control name="F" value="96485.3399"/>
<control name="R" value="8314.472"/>
<control name="T" value="293"/>
<control name="N_Avo" value="6.022E23"/>
<control name="C_m" value="25"/>
<control name="z_K" value="1"/>
<control name="z_Na" value="1"/>
<control name="z_Ca" value="2"/>
<control name="z_Cl" value="-1"/>
<control name="Ca_e" value="2"/>
<control name="Na_e" value="140"/>
<control name="K_e" value="5"/>
<control name="Cl_e" value="129"/>
<control name="Vol_i" value="1"/>
<control name="Vol_Ca" value=".7"/>
<control name="Vol_SRu" value=".07"/>
<control name="Vol_SRr" value=".007"/>
<control name="P_VOCC" value="1.88E-5"/>
<control name="N_BKCa" value="6.6E6"/>
<control name="tau_pf" value=".84"/>
<control name="tau_ps" value="35.9"/>
<control name="dV_50KCaNO" value="46.3"/>
<control name="dV_50KCacGMP" value="76"/>
<control name="P_BKCa" value="3.9E-13"/>
<control name="g_Kv" value="1.35"/>
<control name="tau_q1" value="371"/>
<control name="tau_q2" value="2884"/>
<control name="g_Kleak" value=".067"/>
<control name="K_NSC" value=".003"/>
<control name="d_NSCmin" value=".0244"/>
<control name="PNa_NSC" value="5.11E-7"/>
<control name="gCa_SOC" value=".0083"/>
<control name="gNa_SOC" value=".0575"/>
<control name="K_SOC" value="1E-4"/>
<control name="tau_SOC" value="100"/>
<control name="g_ClCa" value=".23"/>
<control name="R_ClcGMPmin" value=".0132"/>
<control name="n_ClCa" value="2"/>
<control name="K_ClCa" value="3.65E-4"/>
<control name="n_ClcGMP" value="3.3"/>
<control name="K_ClcGMP" value="6.4"/>
<control name="Ibar_PMCA" value="5.37"/>
<control name="K_mPMCA" value="1.7E-4"/>
<control name="g_NCX" value="4.87E-4"/>
<control name="d_NCX" value="3E-4"/>
<control name="gamma_NCX" value=".45"/>
<control name="Ibar_NaK" value="2.3083"/>
<control name="n_HKe" value="1.1"/>
<control name="K_dKe" value="1.6"/>
<control name="n_HNai" value="1.7"/>
<control name="Na_dNai" value="22"/>
<control name="Q_10" value="1.87"/>
<control name="L_NaKCl" value="1.79E-17"/>
<control name="Ibar_IP3" value=".00288"/>
<control name="K_IP3" value="1.2E-4"/>
<control name="K_actIP3" value="1.7E-4"/>
<control name="k_onIP3" value="1.4"/>
<control name="K_inhIP3" value="1E-4"/>
<control name="Ibar_SERCA" value="6.68"/>
<control name="K_mup" value=".001"/>
<control name="tau_tr" value="1E3"/>
<control name="R_leak" value="1.07E-5"/>
<control name="tau_rel" value=".0333"/>
<control name="CSQNbar" value="15"/>
<control name="K_CSQN" value=".8"/>
<control name="K_r1" value="2500"/>
<control name="K_r2" value="1.05"/>
<control name="K_mr1" value=".0076"/>
<control name="K_mr2" value=".084"/>
<control name="k_rG" value="1.75E-7"/>
<control name="xi_G" value=".85"/>
<control name="R_TG" value="2E4"/>
<control name="k_pG" value="1E-4"/>
<control name="K_1G" value=".01"/>
<control name="k_eG" value="6E-6"/>
<control name="K_2G" value=".2"/>
<control name="k_aG" value="1.7E-4"/>
<control name="G_TG" value="1E5"/>
<control name="k_dG" value=".0015"/>
<control name="alpha_G" value="2.781E-8"/>
<control name="K_cG" value="4E-4"/>
<control name="k_degG" value=".00125"/>
<control name="r_rG" value="1.5E-5"/>
<control name="PIP2_T" value="5E7"/>
<control name="V_cGMPmax" value="1.26E-7"/>
<control name="k_2sGC" value="6.4E-6"/>
<control name="k_3sGC" value="4.2"/>
<control name="k_m1sGC" value=".015"/>
<control name="k_DsGC" value="4E-4"/>
<control name="k_m2sGC" value="1E-7"/>
<control name="k_1sGC" value="2E3"/>
<control name="k_DrsGC" value="1E-4"/>
<control name="k_pdecGMP" value="6.95E-5"/>
<control name="K_mpde" value=".001"/>
<control name="Sbar_CM" value=".1"/>
<control name="K_dCM" value="2.6E-4"/>
<control name="Bbar_F" value=".1"/>
<control name="K_dB" value="5.298E-4"/>
<control name="time.min" value="0"/>
<control name="time.max" value="2E5"/>
<control name="time.delta" value="0.5"/>
<control name="V_m0" value="-59.4"/>
<control name="Ca_i0" value="6.8E-5"/>
<control name="NO_0" value="1E-12"/>
<control name="cGMP_i0" value="0"/>
<control name="P_SOC0" value="0"/>
<control name="Ca_u0" value=".66"/>
<control name="Ca_r0" value=".57"/>
<control name="R_100" value=".0033"/>
<control name="R_110" value="4E-6"/>
<control name="R_010" value=".9955"/>
<control name="R_supSPG0" value="0"/>
<control name="IP3_0" value="0"/>
<control name="V_cGMP0" value="0"/>
<control name="Na_i0" value="8.4"/>
<control name="K_i0" value="140"/>
<control name="Cl_i0" value="59.4"/>
<control name="P_SOC__init" value="0"/>
<control name="NO" value="fgen_1"/>
<control name="NE" value="fgen_2"/>
<control name="I_stim" value="fgen_3"/>
</assign>
<solver name="solver">
<control name="ode_which" value="Auto"/>
<control name="ode_Dopri5_reltol" value="1E-7"/>
<control name="ode_Dopri5_abstol" value="1E-7"/>
<control name="ode_Dopri5_nstep" value="100000"/>
<control name="ode_Dopri5_stiff" value="1000"/>
<control name="ode_Dopri5_round" value="2.3E-16"/>
<control name="ode_Dopri5_safety" value=".9"/>
<control name="ode_Dopri5_loselect" value=".2"/>
<control name="ode_Dopri5_hiselect" value="10"/>
<control name="ode_Dopri5_beta" value=".04"/>
<control name="ode_Euler_nstep" value="2"/>
<control name="ode_RK2_nstep" value="2"/>
<control name="ode_Fehlberg_minstep" value="1E-4"/>
<control name="ode_Fehlberg_maxstep" value=".1"/>
<control name="ode_Fehlberg_tol" value="1E-6"/>
<control name="ode_KM_minstep" value="1E-4"/>
<control name="ode_KM_maxstep" value=".1"/>
<control name="ode_KM_tol" value="1E-6"/>
<control name="ode_Radau_reltol" value="1E-4"/>
<control name="ode_Radau_abstol" value="1E-7"/>
<control name="ode_Radau_nstep" value="100000"/>
<control name="ode_Radau_round" value="1E-16"/>
<control name="ode_Radau_safety" value=".9"/>
<control name="ode_Radau_minord" value="3"/>
<control name="ode_Radau_maxord" value="7"/>
<control name="ode_Radau_initord" value="3"/>
<control name="ode_Radau_newton" value="7"/>
<control name="ode_Radau_jacob" value=".001"/>
<control name="ode_Radau_losize" value="1"/>
<control name="ode_Radau_hisize" value="1.2"/>
<control name="ode_Radau_loselect" value=".2"/>
<control name="ode_Radau_hiselect" value="8"/>
<control name="ode_Radau_locontract" value=".002"/>
<control name="ode_Radau_hicontract" value=".8"/>
<control name="ode_Radau_hiorder" value="1.2"/>
<control name="ode_Radau_loorder" value=".8"/>
<control name="ode_RK4_nstep" value="2"/>
<control name="ode_CVode_reltol" value="1E-7"/>
<control name="ode_CVode_abstol" value="1E-8"/>
<control name="ode_CVode_maxsteps" value="100000"/>
<control name="ode_CVode_stiff" value="false"/>
<control name="pde_which" value="LSFEA"/>
<control name="pde_MacCormack_FCT" value="false"/>
<control name="fzero_unbound" value="ggopt"/>
<control name="fzero_bound" value="simplex"/>
<control name="fzero_errtol" value="1E-6"/>
<control name="fzero_maxcalls" value="500"/>
<control name="fzero_maxiters" value="100"/>
<control name="fzero_eps" value="1E-6"/>
<control name="fzero_istep" value=".01"/>
<control name="fzero_npoints" value="5"/>
<control name="fzero_randseed" value="0"/>
<control name="fzero_inittemp" value="100"/>
<control name="fzero_populationsize" value="50"/>
<control name="fzero_mutationrate" value=".1"/>
<control name="fzero_crossoverrate" value=".5"/>
<control name="fzero_mutationstep" value=".05"/>
<control name="fzero_elitecutoff" value=".5"/>
<control name="fzero_selectmethod" value="1"/>
<control name="random_seed" value="0"/>
</solver>
<function name="fgen_1">
<control name="desc" value=""/>
<control name="which" value="Pulse1"/>
<function name="Pulse1">
<control name="startTime" value="0"/>
<control name="duration" value="2E5"/>
<control name="amplitude" value="1E-12"/>
<control name="offset" value="0"/>
<control name="timeToRepeat" value="2E5"/>
</function>
<function name="Pulse2">
<control name="p1Start" value="0"/>
<control name="p1Duration" value="1"/>
<control name="p1Amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="p1TimeToRepeat" value="10"/>
<control name="p2Start" value="1"/>
<control name="p2Duration" value="2"/>
<control name="p2Amplitude" value="2"/>
<control name="p2TimeToRepeat" value="0"/>
</function>
<function name="Pulse3">
<control name="p1Start" value="0"/>
<control name="p1Duration" value="1"/>
<control name="p1Amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="p1TimeToRepeat" value="10"/>
<control name="p2Start" value="1"/>
<control name="p2Duration" value="2"/>
<control name="p2Amplitude" value="2"/>
<control name="p2TimeToRepeat" value="0"/>
<control name="p3Start" value="3"/>
<control name="p3Duration" value="3"/>
<control name="p3Amplitude" value="3"/>
<control name="p3TimeToRepeat" value="0"/>
</function>
<function name="ExtendedPulse3">
<control name="offset" value="0"/>
<control name="timeToRepeat" value="3"/>
<control name="p1Start" value="0"/>
<control name="p1Duration" value=".5"/>
<control name="p1Amplitude" value="1"/>
<control name="p1LoopCnt" value="1"/>
<control name="p1AmpIncr" value="0"/>
<control name="p2Start" value="1"/>
<control name="p2Duration" value=".5"/>
<control name="p2Amplitude" value="2"/>
<control name="p2LoopCnt" value="3"/>
<control name="p2AmpIncr" value=".5"/>
<control name="p3Start" value="2"/>
<control name="p3Duration" value=".5"/>
<control name="p3Amplitude" value="3"/>
<control name="p3LoopCnt" value="0"/>
<control name="p3AmpIncr" value="0"/>
</function>
<function name="Ramp">
<control name="startTime" value="1"/>
<control name="duration" value="5"/>
<control name="amplitude" value="-1"/>
<control name="offset" value="1"/>
<control name="exponent" value="3"/>
<control name="timeToRepeat" value="10"/>
</function>
<function name="SquareWaveTrain">
<control name="startTime" value="0"/>
<control name="duration" value="10"/>
<control name="amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="shapeFactor" value=".5"/>
<control name="phase" value="0"/>
<control name="period" value="5"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="SawtoothTrain">
<control name="startTime" value="0"/>
<control name="duration" value="10"/>
<control name="amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="shapeFactor" value=".5"/>
<control name="phase" value="0"/>
<control name="period" value="5"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="SineTrain">
<control name="startTime" value="0"/>
<control name="duration" value="5"/>
<control name="amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="phase" value="0"/>
<control name="period" value="5"/>
<control name="timeToRepeat" value="10"/>
</function>
<function name="Exponential">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="Gaussian">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="LagNormal">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1.3"/>
<control name="frPeak" value="1E-6"/>
<control name="upslope" value="Regular"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="Longtail">
<control name="PDF" value="LagNormal"/>
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1.3"/>
<control name="frPeak" value="1E-6"/>
<control name="upslope" value="Regular"/>
<control name="tORfr" value="frJoin"/>
<control name="tJoin" value="10"/>
<control name="frJoin" value=".25"/>
<control name="expORpow" value="Exponential"/>
<control name="nExp" value="1"/>
<control name="w1" value="1"/>
<control name="w2" value=".25"/>
<control name="w3" value=".0625"/>
<control name="w4" value=".015625"/>
<control name="k1" value="1"/>
<control name="k2" value=".25"/>
<control name="k3" value=".0625"/>
<control name="k4" value=".015625"/>
<control name="nPow" value="1"/>
<control name="wpow1" value="1"/>
<control name="wpow2" value=".5"/>
<control name="wpow3" value=".25"/>
<control name="wpow4" value=".125"/>
<control name="beta1" value="2"/>
<control name="beta2" value="1.5"/>
<control name="beta3" value="1"/>
<control name="beta4" value=".5"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="GammaVar">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1.3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="Poisson">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="RandomWalk">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="DataCurve">
<control name="ndim" value="1"/>
<control name="dataSet" value=""/>
<control name="name" value=""/>
</function>
<control name="domain0" value="time"/>
<control name="domain1" value=""/>
<control name="domain2" value=""/>
</function>
<function name="fgen_3">
<control name="desc" value=""/>
<control name="which" value="Pulse1"/>
<function name="Pulse1">
<control name="startTime" value="0"/>
<control name="duration" value="2E5"/>
<control name="amplitude" value="0"/>
<control name="offset" value="0"/>
<control name="timeToRepeat" value="2E5"/>
</function>
<function name="Pulse2">
<control name="p1Start" value="0"/>
<control name="p1Duration" value="1"/>
<control name="p1Amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="p1TimeToRepeat" value="10"/>
<control name="p2Start" value="1"/>
<control name="p2Duration" value="2"/>
<control name="p2Amplitude" value="2"/>
<control name="p2TimeToRepeat" value="0"/>
</function>
<function name="Pulse3">
<control name="p1Start" value="0"/>
<control name="p1Duration" value="1"/>
<control name="p1Amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="p1TimeToRepeat" value="10"/>
<control name="p2Start" value="1"/>
<control name="p2Duration" value="2"/>
<control name="p2Amplitude" value="2"/>
<control name="p2TimeToRepeat" value="0"/>
<control name="p3Start" value="3"/>
<control name="p3Duration" value="3"/>
<control name="p3Amplitude" value="3"/>
<control name="p3TimeToRepeat" value="0"/>
</function>
<function name="ExtendedPulse3">
<control name="offset" value="0"/>
<control name="timeToRepeat" value="3"/>
<control name="p1Start" value="0"/>
<control name="p1Duration" value=".5"/>
<control name="p1Amplitude" value="1"/>
<control name="p1LoopCnt" value="1"/>
<control name="p1AmpIncr" value="0"/>
<control name="p2Start" value="1"/>
<control name="p2Duration" value=".5"/>
<control name="p2Amplitude" value="2"/>
<control name="p2LoopCnt" value="3"/>
<control name="p2AmpIncr" value=".5"/>
<control name="p3Start" value="2"/>
<control name="p3Duration" value=".5"/>
<control name="p3Amplitude" value="3"/>
<control name="p3LoopCnt" value="0"/>
<control name="p3AmpIncr" value="0"/>
</function>
<function name="Ramp">
<control name="startTime" value="1"/>
<control name="duration" value="5"/>
<control name="amplitude" value="-1"/>
<control name="offset" value="1"/>
<control name="exponent" value="3"/>
<control name="timeToRepeat" value="10"/>
</function>
<function name="SquareWaveTrain">
<control name="startTime" value="0"/>
<control name="duration" value="10"/>
<control name="amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="shapeFactor" value=".5"/>
<control name="phase" value="0"/>
<control name="period" value="5"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="SawtoothTrain">
<control name="startTime" value="0"/>
<control name="duration" value="10"/>
<control name="amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="shapeFactor" value=".5"/>
<control name="phase" value="0"/>
<control name="period" value="5"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="SineTrain">
<control name="startTime" value="0"/>
<control name="duration" value="5"/>
<control name="amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="phase" value="0"/>
<control name="period" value="5"/>
<control name="timeToRepeat" value="10"/>
</function>
<function name="Exponential">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="Gaussian">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="LagNormal">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1.3"/>
<control name="frPeak" value="1E-6"/>
<control name="upslope" value="Regular"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="Longtail">
<control name="PDF" value="LagNormal"/>
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1.3"/>
<control name="frPeak" value="1E-6"/>
<control name="upslope" value="Regular"/>
<control name="tORfr" value="frJoin"/>
<control name="tJoin" value="10"/>
<control name="frJoin" value=".25"/>
<control name="expORpow" value="Exponential"/>
<control name="nExp" value="1"/>
<control name="w1" value="1"/>
<control name="w2" value=".25"/>
<control name="w3" value=".0625"/>
<control name="w4" value=".015625"/>
<control name="k1" value="1"/>
<control name="k2" value=".25"/>
<control name="k3" value=".0625"/>
<control name="k4" value=".015625"/>
<control name="nPow" value="1"/>
<control name="wpow1" value="1"/>
<control name="wpow2" value=".5"/>
<control name="wpow3" value=".25"/>
<control name="wpow4" value=".125"/>
<control name="beta1" value="2"/>
<control name="beta2" value="1.5"/>
<control name="beta3" value="1"/>
<control name="beta4" value=".5"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="GammaVar">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1.3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="Poisson">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="RandomWalk">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="DataCurve">
<control name="ndim" value="1"/>
<control name="dataSet" value=""/>
<control name="name" value=""/>
</function>
<control name="domain0" value="time"/>
<control name="domain1" value=""/>
<control name="domain2" value=""/>
</function>
<function name="fgen_2">
<control name="desc" value=""/>
<control name="which" value="Pulse1"/>
<function name="Pulse1">
<control name="startTime" value="1.1E5"/>
<control name="duration" value="65000"/>
<control name="amplitude" value=".001"/>
<control name="offset" value="0"/>
<control name="timeToRepeat" value="2E5"/>
</function>
<function name="Pulse2">
<control name="p1Start" value="0"/>
<control name="p1Duration" value="1"/>
<control name="p1Amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="p1TimeToRepeat" value="10"/>
<control name="p2Start" value="1"/>
<control name="p2Duration" value="2"/>
<control name="p2Amplitude" value="2"/>
<control name="p2TimeToRepeat" value="0"/>
</function>
<function name="Pulse3">
<control name="p1Start" value="0"/>
<control name="p1Duration" value="1"/>
<control name="p1Amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="p1TimeToRepeat" value="10"/>
<control name="p2Start" value="1"/>
<control name="p2Duration" value="2"/>
<control name="p2Amplitude" value="2"/>
<control name="p2TimeToRepeat" value="0"/>
<control name="p3Start" value="3"/>
<control name="p3Duration" value="3"/>
<control name="p3Amplitude" value="3"/>
<control name="p3TimeToRepeat" value="0"/>
</function>
<function name="ExtendedPulse3">
<control name="offset" value="0"/>
<control name="timeToRepeat" value="3"/>
<control name="p1Start" value="0"/>
<control name="p1Duration" value=".5"/>
<control name="p1Amplitude" value="1"/>
<control name="p1LoopCnt" value="1"/>
<control name="p1AmpIncr" value="0"/>
<control name="p2Start" value="1"/>
<control name="p2Duration" value=".5"/>
<control name="p2Amplitude" value="2"/>
<control name="p2LoopCnt" value="3"/>
<control name="p2AmpIncr" value=".5"/>
<control name="p3Start" value="2"/>
<control name="p3Duration" value=".5"/>
<control name="p3Amplitude" value="3"/>
<control name="p3LoopCnt" value="0"/>
<control name="p3AmpIncr" value="0"/>
</function>
<function name="Ramp">
<control name="startTime" value="1"/>
<control name="duration" value="5"/>
<control name="amplitude" value="-1"/>
<control name="offset" value="1"/>
<control name="exponent" value="3"/>
<control name="timeToRepeat" value="10"/>
</function>
<function name="SquareWaveTrain">
<control name="startTime" value="0"/>
<control name="duration" value="10"/>
<control name="amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="shapeFactor" value=".5"/>
<control name="phase" value="0"/>
<control name="period" value="5"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="SawtoothTrain">
<control name="startTime" value="0"/>
<control name="duration" value="10"/>
<control name="amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="shapeFactor" value=".5"/>
<control name="phase" value="0"/>
<control name="period" value="5"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="SineTrain">
<control name="startTime" value="0"/>
<control name="duration" value="5"/>
<control name="amplitude" value="1"/>
<control name="offset" value="0"/>
<control name="phase" value="0"/>
<control name="period" value="5"/>
<control name="timeToRepeat" value="10"/>
</function>
<function name="Exponential">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="Gaussian">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="LagNormal">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1.3"/>
<control name="frPeak" value="1E-6"/>
<control name="upslope" value="Regular"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="Longtail">
<control name="PDF" value="LagNormal"/>
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1.3"/>
<control name="frPeak" value="1E-6"/>
<control name="upslope" value="Regular"/>
<control name="tORfr" value="frJoin"/>
<control name="tJoin" value="10"/>
<control name="frJoin" value=".25"/>
<control name="expORpow" value="Exponential"/>
<control name="nExp" value="1"/>
<control name="w1" value="1"/>
<control name="w2" value=".25"/>
<control name="w3" value=".0625"/>
<control name="w4" value=".015625"/>
<control name="k1" value="1"/>
<control name="k2" value=".25"/>
<control name="k3" value=".0625"/>
<control name="k4" value=".015625"/>
<control name="nPow" value="1"/>
<control name="wpow1" value="1"/>
<control name="wpow2" value=".5"/>
<control name="wpow3" value=".25"/>
<control name="wpow4" value=".125"/>
<control name="beta1" value="2"/>
<control name="beta2" value="1.5"/>
<control name="beta3" value="1"/>
<control name="beta4" value=".5"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="GammaVar">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1.3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="Poisson">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="RandomWalk">
<control name="area" value="1"/>
<control name="tMean" value="5"/>
<control name="RD" value=".3"/>
<control name="skewn" value="1"/>
<control name="frPeak" value="1E-6"/>
<control name="timeToRepeat" value="0"/>
</function>
<function name="DataCurve">
<control name="ndim" value="1"/>
<control name="dataSet" value=""/>
<control name="name" value=""/>
</function>
<control name="domain0" value="time"/>
<control name="domain1" value=""/>
<control name="domain2" value=""/>
</function>
</vars>
<control name="desc" value=""/>
<control name="locked" value="false"/>
<control name="notes"></control>
</parset>
<imageset name="images"/>
<loops name="loops">
<loop name="outer">
<control name="mode" value="auto"/>
<control name="ntimes" value="3"/>
<control name="npars" value="1"/>
<looppar name="looppar0">
<control name="par" value=""/>
<control name="values" value=""/>
<control name="enabled" value="true"/>
</looppar>
</loop>
<loop name="inner">
<control name="mode" value="auto"/>
<control name="ntimes" value="3"/>
<control name="npars" value="1"/>
<looppar name="looppar0">
<control name="par" value=""/>
<control name="values" value=""/>
<control name="enabled" value="true"/>
</looppar>
</loop>
</loops>
<sens name="sens">
<control name="npars" value="1"/>
<senspar name="senspar0">
<control name="par" value=""/>
<control name="delta" value=".01"/>
<control name="enabled" value="true"/>
</senspar>
</sens>
<optim name="optim">
<control name="npars" value="1"/>
<control name="nmatches" value="1"/>
<control name="alg" value="simplex"/>
<control name="maxCalls" value="50"/>
<control name="maxIters" value="10"/>
<control name="maxStaticIters" value="0"/>
<control name="errTol" value=".001"/>
<control name="stepTol" value="1E-6"/>
<control name="gradTol" value="1E-6"/>
<control name="npoints" value="5"/>
<control name="eps" value="1E-6"/>
<control name="randomSeed" value="0"/>
<control name="initTemp" value="100"/>
<control name="populationSize" value="25"/>
<control name="mutationRate" value=".1"/>
<control name="crossoverRate" value=".5"/>
<control name="mutationStep" value=".05"/>
<control name="selectMethod" value="roulette"/>
<control name="eliteCutoff" value=".5"/>
<control name="calcCovMat" value="true"/>
<control name="reportPrec" value="4"/>
<optgraph name="pars">
<control name="log" value="linear"/>
</optgraph>
<optgraph name="normPars">
<control name="log" value="linear"/>
</optgraph>
<optgraph name="rmsError">
<control name="log" value="linear"/>
</optgraph>
<optgraph name="dataToMatch">
<control name="log" value="linear"/>
</optgraph>
<optgraph name="unwgtResid">
<control name="log" value="linear"/>
</optgraph>
<optgraph name="wgtResid">
<control name="log" value="linear"/>
</optgraph>
<optgraph name="pointWgts">
<control name="log" value="linear"/>
</optgraph>
<optpar name="optpar0">
<control name="par" value=""/>
<control name="min" value="NaN"/>
<control name="max" value="NaN"/>
<control name="step" value=".01"/>
<control name="enabled" value="true"/>
</optpar>
<optmatch name="optmatch0">
<control name="src" value=""/>
<control name="data" value=""/>
<control name="expr" value=""/>
<control name="pointWgts" value="1"/>
<control name="step" value="1"/>
<control name="enabled" value="true"/>
</optmatch>
</optim>
<montecarlo name="montecarlo">
<control name="noptims" value="50"/>
<control name="randomSeed" value="0"/>
<control name="dist" value="gaussian"/>
<control name="magnitude" value=".1"/>
<control name="addMethod" value="proportional"/>
<control name="graphView" value="histogram"/>
<control name="graphPar1" value=""/>
<control name="graphPar2" value=""/>
<control name="graphOptNo" value="1"/>
<control name="graphLog" value="false"/>
<control name="graphBins" value="10"/>
</montecarlo>
<browser name="browser">
<control name="which" value="variables"/>
<control name="varCollapse" value="true"/>
<control name="varNodeTextColor" value="disabled"/>
<control name="varNodeFillColor" value="unitType"/>
<control name="varNodeBorderColor" value="toolType"/>
<control name="varNodeShape" value="isInput"/>
<control name="seqNodeTextColor" value="disabled"/>
<control name="seqNodeFillColor" value="itemType"/>
<control name="seqNodeBorderColor" value="phase"/>
<control name="seqNodeShape" value="hasDeT"/>
<layout name="layout"/>
</browser>
<rtml name="rtml"/>
</model>
</project>
</JSim>
