Location: Snyder, Palmer, Moore, 2000 @ 2dbd5645ad97 / snyder_palmer_moore_2000.cellml

Author:
Hanne <Hanne@hanne-nielsens-macbook.local>
Date:
2009-12-14 16:26:27+13:00
Desc:
Added images in ai and svg format, removed non pub med references
Permanent Source URI:
https://models.cellml.org/workspace/snyder_palmer_moore_2000/rawfile/2dbd5645ad978a2616f7a7265fd00c3ec92e7b48/snyder_palmer_moore_2000.cellml

<?xml version='1.0' encoding='utf-8'?>
<!--  FILE :  snyder_model_2000.xml

CREATED :  18th March 2002

LAST MODIFIED : 22nd April 2005

AUTHOR :  Catherine Lloyd
          The Bioengineering Institute
          The University of Auckland
          
MODEL STATUS :  This model conforms to the CellML 1.0 Specification released on
10th August 2000, and the 16/01/2002 CellML Metadata 1.0 Specification.

DESCRIPTION :  This file contains a CellML description of snyder et al's 2000
mathematical model of cardiocyte Ca2+ dynamics.

CHANGES:  
  22/07/2002 - CML - Added more metadata.
  22/04/2005 - PJV - Removed unnecessary type. Changed MathML id's to
                     make them unique.
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" cmeta:id="snyder_palmer_moore_2000_version01" name="snyder_palmer_moore_2000_version01">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
  <articleinfo>
  <title>A Mathematical Model Of Cardiocyte Ca2+ Dynamics</title>
  <author>
    <firstname>Catherine</firstname>
          <surname>Lloyd</surname>
    <affiliation>
      <shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
    </affiliation>
  </author>
</articleinfo>
  <section id="sec_status">
    <title>Model Status</title>
    <para>
            This is the original unchecked version of the model imported from the previous
            CellML model repository, 24-Jan-2006.
          </para>
  </section>
  <sect1 id="sec_structure">
<title>Model Structure</title>

<para>
The regulation of cytosolic Ca<superscript>2+</superscript> concentration, [Ca<superscript>2+</superscript>]<subscript>c</subscript>, in cardiac myocytes has been recognised to be the predominant determinant of cardiac contraction and relaxation dynamics.  Several models have been developed to describe [Ca<superscript>2+</superscript>]<subscript>c</subscript> regulation in cardiac myocytes and these have evolved to the point where they are able to predict intracellular Ca<superscript>2+</superscript> dynamics under experimental conditions.
</para>

<para>
In their 2000 study, Steven M. Snyder, Bradley M. Palmer and Russell L. Moore published a detailed mathematical model describing cardiocyte Ca<superscript>2+</superscript> dynamics with a novel representation of sarcoplasmic reticular Ca<superscript>2+</superscript> control (see the figure below).  The mathematical representation of the Ca<superscript>2+</superscript> regulatory mechanisms of a rat cardiac myocyte included a set of six differential equations.  
</para>

<para>
The complete original paper reference is cited below:
</para>

<para>
A Mathematical Model of Cardiocyte Ca<superscript>2+</superscript> Dynamics with a Novel Representation of Sarcoplasmic Reticular Ca<superscript>2+</superscript> Control, Steven M. Snyder, Bradley M. Palmer and Russell L. Moore, 2000, <emphasis>Biophysical Journal</emphasis>, 79, 94-115. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=10866940&amp;dopt=Abstract">PubMed ID: 10866940</ulink>  
</para>


<informalfigure float="0" id="fig_cell_diagram">
<mediaobject>
  <imageobject>
    <objectinfo>
      <title>cell schematic for the model</title>
    </objectinfo>
    <imagedata fileref="snyder_2000.png"/>
  </imageobject>
</mediaobject>
<caption>Cell schematic for the model representing three intracellular compartments with buffering, the extracellular space, and the related Ca<superscript>2+</superscript> movement processes.</caption>
</informalfigure>

</sect1>
</article>
</documentation>
  
  
  <!--
    Below, we define some additional units for association with variables and
    constants within the model. The identifiers are fairly self-explanatory.
  -->
  
  <units name="molar">
    <unit units="mole"/>
    <unit units="litre" exponent="-1"/>
  </units>
  
  <units name="flux">
    <unit units="mole"/>
    <unit units="second" exponent="-1"/>
  </units>
  
  <units name="first_order_rate_constant">
    <unit units="second" exponent="-1"/>
  </units>

  <units name="second_order_rate_constant">
    <unit units="molar" exponent="-1"/>
    <unit units="second" exponent="-1"/>
  </units>
  
  <!--
    The "environment" component is used to declare variables that are used by
    all or most of the other components, in this case just "time".
  -->
  <component name="environment">
    <variable units="second" public_interface="out" name="time"/>
  </component>
  
  
  <component name="Ca_influx_across_the_SR">
    <variable units="molar" public_interface="in" name="Ca_e"/>
    <variable units="molar" public_interface="in" name="Ca_f"/>
    <variable units="flux" public_interface="out" name="delta_Ca_e_rxn_1"/>
    <variable units="first_order_rate_constant" name="k1" initial_value="0.2"/>
    <variable units="flux" public_interface="out" name="r_rxn_1"/>
    <reaction reversible="no">
      <variable_ref variable="Ca_e">
        <role stoichiometry="1" direction="forward" delta_variable="delta_Ca_e_rxn_1" role="reactant"/>
      </variable_ref>
      <variable_ref variable="Ca_f">
        <role stoichiometry="1" direction="forward" role="product"/>
      </variable_ref>
      <variable_ref variable="r_rxn_1">
        <role role="rate">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <eq/>
              <ci> r_rxn_1 </ci>
              <apply>
                <times/>
                <ci> k1 </ci>
                <apply>
                  <minus/>
                  <ci> Ca_e </ci>
                  <ci> Ca_f </ci>
                </apply>
              </apply>
            </apply>
          </math>
        </role>
      </variable_ref>
    </reaction>
  </component>
  
  <component name="Ca_movement_through_the_SRRC">
    <variable units="molar" public_interface="in" name="Ca_2_S1"/>
    <variable units="molar" public_interface="in" name="Ca_S2"/>
    <variable units="molar" public_interface="in" name="S1"/>
    <variable units="molar" public_interface="in" name="S2"/>
    <variable units="molar" public_interface="in" name="Ca_f"/>
    <variable units="molar" public_interface="in" name="Ca_s"/>
    <variable units="flux" public_interface="out" name="delta_Ca_f_rxn_2"/>
    <variable units="flux" public_interface="out" name="delta_S1_rxn_2"/>
    <variable units="flux" public_interface="out" name="delta_Ca_2_S1_rxn_2"/>
    <variable units="flux" public_interface="out" name="delta_Ca_f_rxn_3"/>
    <variable units="flux" public_interface="out" name="delta_S2_rxn_3"/>
    <variable units="flux" public_interface="out" name="delta_Ca_S2_rxn_3"/>
    <variable units="second_order_rate_constant" name="k_on1" initial_value="2000000000.0"/>
    <variable units="first_order_rate_constant" name="k_off1" initial_value="1400.0"/>
    <variable units="second_order_rate_constant" name="k_on2" initial_value="13000000.0"/>
    <variable units="first_order_rate_constant" name="k_off2" initial_value="3.9"/>
    <variable units="first_order_rate_constant" name="k_s" initial_value="9.0"/>
    <variable units="dimensionless" name="cas1"/>
    <variable units="dimensionless" public_interface="out" name="dcas1_dt"/>
    <variable units="dimensionless" name="cas2"/>
    <variable units="dimensionless" public_interface="out" name="dcas2_dt"/>
    <variable units="dimensionless" name="r_o"/>
    <variable units="flux" name="r_rxn_2"/>
    <variable units="flux" name="r_rxn_3"/>
    <variable units="flux" public_interface="out" name="r_rxn_4"/>
    <variable units="second" public_interface="in" name="time"/>
    
    <reaction reversible="yes">
      <variable_ref variable="Ca_f">
        <role stoichiometry="1" direction="forward" delta_variable="delta_Ca_f_rxn_2" role="reactant"/>
      </variable_ref>
      <variable_ref variable="S1">
        <role stoichiometry="1" direction="forward" delta_variable="delta_S1_rxn_2" role="reactant"/>
      </variable_ref>
      <variable_ref variable="Ca_2_S1">
        <role stoichiometry="1" direction="forward" delta_variable="delta_Ca_2_S1_rxn_2" role="product"/>
      </variable_ref>
      <variable_ref variable="r_rxn_2">
        <role role="rate">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <eq/>
              <ci> r_rxn_2 </ci>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> k_on1 </ci>
                  <ci> Ca_f </ci>
                  <ci> S1 </ci>
                </apply>
                <apply>
                  <times/>
                  <apply>
                    <divide/>
                    <apply>
                      <power/>
                      <ci> k_off1 </ci>
                      <cn cellml:units="dimensionless"> 2.0 </cn>
                    </apply>
                    <apply>
                      <times/>
                      <ci> k_on1 </ci>
                      <ci> Ca_f </ci>
                    </apply>
                  </apply>
                  <ci> Ca_2_S1 </ci>
                </apply>
              </apply>
            </apply>
          </math>
        </role>
      </variable_ref>
    </reaction>
    
    <reaction reversible="yes">
      <variable_ref variable="Ca_f">
        <role stoichiometry="1" direction="forward" delta_variable="delta_Ca_f_rxn_3" role="reactant"/>
      </variable_ref>
      <variable_ref variable="S2">
        <role stoichiometry="1" direction="forward" delta_variable="delta_S2_rxn_3" role="reactant"/>
      </variable_ref>
      <variable_ref variable="Ca_S2">
        <role stoichiometry="1" direction="forward" delta_variable="delta_Ca_S2_rxn_3" role="product"/>
      </variable_ref>
      <variable_ref variable="r_rxn_3">
        <role role="rate">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <eq/>
              <ci> r_rxn_3 </ci>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> k_on2 </ci>
                  <ci> Ca_f </ci>
                  <ci> S2 </ci>
                </apply>
                <apply>
                  <times/>
                  <ci> k_off2 </ci>
                  <ci> Ca_S2 </ci>
                </apply>
              </apply>
            </apply>
          </math>
        </role>
      </variable_ref>
    </reaction>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply id="r_o_calculation">
        <eq/>
        <ci> r_o </ci>
        <apply>
          <times/>
          <ci> cas1 </ci>
          <apply>
            <minus/>
            <cn cellml:units="dimensionless"> 1.0 </cn>
            <ci> cas2 </ci>
          </apply>
        </apply>
      </apply>
      
      <apply id="dcas1_dt">
        <eq/>
        <apply>
          <diff/>
          <bvar>
            <ci> time </ci>
          </bvar>
          <ci> cas1 </ci>
        </apply>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k_on1 </ci>
            <ci> Ca_f </ci>
            <apply>
              <minus/>
              <cn cellml:units="dimensionless"> 1.0 </cn>
              <ci> cas1 </ci>
            </apply>
          </apply>
          <apply>
            <times/>
            <apply>
              <divide/>
              <apply>
                <power/>
                <ci> k_off1 </ci>
                <cn cellml:units="dimensionless"> 2.0 </cn>
              </apply>
              <apply>
                <times/>
                <ci> k_on1 </ci>
                <ci> Ca_f </ci>
              </apply>
            </apply>
            <ci> cas1 </ci>
          </apply>
        </apply>
      </apply>
      
      <apply id="dcas2_dt">
        <eq/>
        <apply>
          <diff/>
          <bvar>
            <ci> time </ci>
          </bvar>
          <ci> cas2 </ci>
        </apply>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k_on2 </ci>
            <ci> Ca_f </ci>
            <apply>
              <minus/>
              <cn cellml:units="dimensionless"> 1.0 </cn>
              <ci> cas2 </ci>
            </apply>
          </apply>
          <apply>
            <times/>
            <ci> k_off2 </ci>
            <ci> cas2 </ci>
          </apply>
        </apply>
      </apply>
    </math>
    
    <reaction reversible="no">
      <variable_ref variable="Ca_s">
        <role stoichiometry="1" direction="forward" role="reactant"/>
      </variable_ref>
      <variable_ref variable="Ca_f">
        <role stoichiometry="1" direction="forward" role="product"/>
      </variable_ref>
      <variable_ref variable="r_rxn_4">
        <role role="rate">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <eq/>
              <ci> r_rxn_4 </ci>
              <apply>
                <times/>
                <ci> k_s </ci>
                <ci> r_o </ci>
                <apply>
                  <minus/>
                  <ci> Ca_s </ci>
                  <ci> Ca_f </ci>
                </apply>
              </apply>
            </apply>
          </math>
        </role>
      </variable_ref>
    </reaction>
  </component>
  
  <component name="Ca_efflux_across_the_SR_by_NaCa_exchange">
    <variable units="molar" public_interface="in" name="Ca_e"/>
    <variable units="molar" public_interface="in" name="Ca_f"/>
    <variable units="flux" public_interface="out" name="delta_Ca_e_rxn_5"/>
    <variable units="molar" name="Km_NaCaX" initial_value="0.000036"/>
    <variable units="flux" name="Vmax_NaCaX" initial_value="0.0012"/>
    <variable units="flux" public_interface="out" name="r_rxn_5"/>
    <reaction reversible="no">
      <variable_ref variable="Ca_f">
        <role stoichiometry="1" direction="forward" role="reactant"/>
      </variable_ref>
      <variable_ref variable="Ca_e">
        <role stoichiometry="1" direction="forward" delta_variable="delta_Ca_e_rxn_5" role="product"/>
      </variable_ref>
      <variable_ref variable="r_rxn_5">
        <role role="rate">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <eq/>
              <ci> r_rxn_5 </ci>
              <apply>
                <divide/>
                <apply>
                  <times/>
                  <ci> Vmax_NaCaX </ci>
                  <ci> Ca_f </ci>
                </apply>
                <apply>
                  <plus/>
                  <ci> Km_NaCaX </ci>
                  <ci> Ca_f </ci>
                </apply>
              </apply>
            </apply>
          </math>
        </role>
      </variable_ref>
    </reaction>
  </component>
  
  <component name="Ca_movement_between_the_fuzzy_space_and_cytosol">
    <variable units="molar" public_interface="in" name="Ca_c"/>
    <variable units="molar" public_interface="in" name="Ca_f"/>
    <variable units="first_order_rate_constant" name="kf" initial_value="2500.0"/>
    <variable units="flux" public_interface="out" name="r_rxn_6"/>
    <reaction reversible="no">
      <variable_ref variable="Ca_f">
        <role stoichiometry="1" direction="forward" role="reactant"/>
      </variable_ref>
      <variable_ref variable="Ca_c">
        <role stoichiometry="1" direction="forward" role="product"/>
      </variable_ref>
      <variable_ref variable="r_rxn_6">
        <role role="rate">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <eq/>
              <ci> r_rxn_6 </ci>
              <apply>
                <times/>
                <ci> kf </ci>
                <apply>
                  <minus/>
                  <ci> Ca_f </ci>
                  <ci> Ca_c </ci>
                </apply>
              </apply>
            </apply>
          </math>
        </role>
      </variable_ref>
    </reaction>
  </component>
  
  <component name="Ca_uptake_by_SR_Ca_ATPase">
    <variable units="molar" public_interface="in" name="Ca_c"/>
    <variable units="molar" public_interface="in" name="Ca_s"/>
    <variable units="molar" name="Km_s" initial_value="0.00000025"/>
    <variable units="flux" name="Vmax_s" initial_value="0.000525"/>
    <variable units="flux" public_interface="out" name="r_rxn_7"/>
    <reaction reversible="no">
      <variable_ref variable="Ca_c">
        <role stoichiometry="1" direction="forward" role="reactant"/>
      </variable_ref>
      <variable_ref variable="Ca_s">
        <role stoichiometry="1" direction="forward" role="product"/>
      </variable_ref>
      <variable_ref variable="r_rxn_7">
        <role role="rate">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <eq/>
              <ci> r_rxn_7 </ci>
              <apply>
                <divide/>
                <apply>
                  <times/>
                  <ci> Vmax_s </ci>
                  <apply>
                    <minus/>
                    <apply>
                      <power/>
                      <ci> Ca_c </ci>
                      <cn cellml:units="dimensionless"> 2.0 </cn>
                    </apply>
                    <apply>
                      <divide/>
                      <apply>
                        <power/>
                        <ci> Ca_s </ci>
                        <cn cellml:units="dimensionless"> 2.0 </cn>
                      </apply>
                      <apply>
                        <power/>
                        <cn cellml:units="dimensionless"> 7000.0 </cn>
                        <cn cellml:units="dimensionless"> 2.0 </cn>
                      </apply>
                    </apply>  
                  </apply>
                </apply>
                <apply>
                  <plus/>
                  <apply>
                    <power/>
                    <ci> Km_s </ci>
                    <cn cellml:units="dimensionless"> 2.0 </cn>
                  </apply>
                  <apply>
                    <power/>
                    <ci> Ca_c </ci>
                    <cn cellml:units="dimensionless"> 2.0 </cn>
                  </apply>
                  <apply>
                    <divide/>
                    <apply>
                      <power/>
                      <ci> Ca_s </ci>
                      <cn cellml:units="dimensionless"> 2.0 </cn>
                    </apply>
                    <apply>
                      <power/>
                      <cn cellml:units="dimensionless"> 7000.0 </cn>
                      <cn cellml:units="dimensionless"> 2.0 </cn>
                    </apply>
                  </apply>  
                </apply>
              </apply>
            </apply>
          </math>
        </role>
      </variable_ref>
    </reaction>
  </component>
  
  <component name="Ca_buffering_in_the_SR">
    <variable units="molar" public_interface="in" name="Ca_CSQ"/>
    <variable units="molar" public_interface="in" name="Ca_s"/>
    <variable units="flux" public_interface="out" name="delta_Ca_CSQ_rxn_8"/>
    <variable units="second_order_rate_constant" name="K_ons" initial_value="8772.0"/>
    <variable units="first_order_rate_constant" name="K_offs" initial_value="5.596536"/>
    <variable units="molar" name="Bmax_s" initial_value="0.008"/>
    <variable units="flux" public_interface="out" name="r_rxn_8"/>
    <reaction reversible="yes">
      <variable_ref variable="Ca_s">
        <role stoichiometry="1" direction="forward" role="reactant"/>
      </variable_ref>
      <variable_ref variable="Ca_CSQ">
        <role stoichiometry="1" direction="forward" delta_variable="delta_Ca_CSQ_rxn_8" role="product"/>
      </variable_ref>
      <variable_ref variable="r_rxn_8">
        <role role="rate">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <eq/>
              <ci> r_rxn_8 </ci>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> K_ons </ci>
                  <ci> Ca_s </ci>
                  <apply>
                    <minus/>
                    <ci> Bmax_s </ci>
                    <ci> Ca_CSQ </ci>
                  </apply>
                </apply>
                <apply>
                  <times/>
                  <ci> K_offs </ci>
                  <ci> Ca_CSQ </ci>
                </apply>
              </apply>
            </apply>
          </math>
        </role>
      </variable_ref>
    </reaction>
  </component>
  
  <component name="fuzzy_space_calcium">
    <variable units="molar" public_interface="out" name="Ca_f"/>
    
    <variable units="molar" name="Rt" initial_value="0.00000015"/>
    <variable units="molar" name="Bmax_f1" initial_value="0.0002"/>
    <variable units="molar" name="Bmax_f2" initial_value="0.0011"/>
    <variable units="molar" name="Kb_f1" initial_value="0.000017"/>
    <variable units="molar" name="Kb_f2" initial_value="0.000013"/>
    <variable units="molar" name="Ca_f1"/>
    <variable units="molar" name="Ca_f2"/>
    <variable units="dimensionless" name="V_f" initial_value="0.0013"/>
    
    <variable units="flux" public_interface="in" name="r_rxn_1"/>
    <variable units="flux" public_interface="in" name="r_rxn_4"/>
    <variable units="flux" public_interface="in" name="r_rxn_5"/>
    <variable units="flux" public_interface="in" name="r_rxn_6"/>
    <variable units="dimensionless" public_interface="in" name="dcas1_dt"/>
    <variable units="dimensionless" public_interface="in" name="dcas2_dt"/>
    <variable units="second" public_interface="in" name="time"/> 
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply id="Ca_f_diff_eq">
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci> time </ci>
          </bvar> 
          <ci> Ca_f </ci> 
        </apply>
        <apply>
          <divide/>
          <apply>
            <plus/>
            <apply>
              <minus/>
              <ci> r_rxn_4 </ci> 
              <apply>
                <plus/>
                <apply>
                  <times/>
                  <ci> Rt </ci>
                  <apply>
                    <plus/>
                    <ci> dcas1_dt </ci>
                    <ci> dcas2_dt </ci>
                  </apply>
                </apply>
                <ci> r_rxn_6 </ci>
                <ci> r_rxn_5 </ci>
              </apply>
            </apply>
            <ci> r_rxn_1 </ci>
          </apply>
          <apply>
            <plus/>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> Bmax_f1 </ci>
                <ci> Kb_f1 </ci>
              </apply>
              <apply>
                <power/>
                <apply>
                  <plus/>
                  <ci> Ca_f1 </ci>
                  <ci> Kb_f1 </ci>
                </apply>
                <cn cellml:units="dimensionless"> 2.0 </cn>
              </apply>
            </apply>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> Bmax_f2 </ci>
                <ci> Kb_f2 </ci>
              </apply>
              <apply>
                <power/>
                <apply>
                  <plus/>
                  <ci> Ca_f2 </ci>
                  <ci> Kb_f2 </ci>
                </apply>
                <cn cellml:units="dimensionless"> 2.0 </cn>
              </apply>
            </apply>
            <ci> V_f </ci>
          </apply>
        </apply>
      </apply>
    </math>
  </component>
  
  <component name="cytosolic_calcium">
    <variable units="molar" public_interface="out" name="Ca_c" initial_value="1.0e-7"/>
    
    <variable units="molar" name="Bmax_c" initial_value="0.00012"/>
    <variable units="molar" name="dye_c"/>
    <variable units="molar" name="Kb_c" initial_value="0.00000096"/>
    <variable units="molar" name="Kb_dye"/>
    <variable units="molar" name="Ca_f1"/>
    <variable units="molar" name="Ca_f2"/>
    <variable units="dimensionless" name="V_c" initial_value="0.9287"/>
    
    <variable units="flux" public_interface="in" name="r_rxn_6"/>
    <variable units="flux" public_interface="in" name="r_rxn_7"/>
    <variable units="second" public_interface="in" name="time"/> 
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
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          </bvar> 
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            <ci> r_rxn_7 </ci>
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                <times/>
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              </apply>
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                <power/>
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                  <ci> Kb_c </ci>
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            </apply>
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                  <ci> Kb_dye </ci>
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                <cn cellml:units="dimensionless"> 2.0 </cn>
              </apply>
            </apply>
            <ci> V_c </ci>
          </apply>
        </apply>
      </apply>
    </math>
  </component> 
  
  <component name="SR_calcium">
    <variable units="molar" public_interface="out" name="Ca_s"/>
    
    <variable units="dimensionless" name="V_s" initial_value="0.07"/>
    
    <variable units="flux" public_interface="in" name="r_rxn_4"/>
    <variable units="flux" public_interface="in" name="r_rxn_7"/>
    <variable units="flux" public_interface="in" name="r_rxn_8"/>
    <variable units="second" public_interface="in" name="time"/> 
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply id="Ca_s_diff_eq">
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci> time </ci>
          </bvar> 
          <ci> Ca_s </ci> 
        </apply>
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          <divide/>
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            <minus/>
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            <ci> r_rxn_4 </ci>
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          <apply>
            <minus/>
            <ci> V_s </ci>
            <ci> r_rxn_8 </ci>
          </apply>
        </apply>
      </apply>
    </math>
  </component>
  
  <component name="extracellular_calcium">
    <variable units="molar" public_interface="out" name="Ca_e"/>
    
    <variable units="flux" public_interface="in" name="delta_Ca_e_rxn_1"/>
    <variable units="flux" public_interface="in" name="delta_Ca_e_rxn_5"/>
    <variable units="second" public_interface="in" name="time"/> 
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply id="extracellular_calcium_Ca_e_diff_eq">
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci> time </ci>
          </bvar> 
          <ci> Ca_e </ci> 
        </apply>
        <apply>
          <plus/>
          <ci> delta_Ca_e_rxn_1 </ci>
          <ci> delta_Ca_e_rxn_5 </ci>
        </apply>
      </apply>
    </math>
  </component> 
  
  <component name="calsequestrin_bound_calcium">
    <variable units="molar" public_interface="out" name="Ca_CSQ"/>
    
    <variable units="flux" public_interface="in" name="delta_Ca_CSQ_rxn_8"/>
    <variable units="second" public_interface="in" name="time"/> 
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply id="calsequestrin_bound_calcium_Ca_e_diff_eq">
        <eq/> 
        <apply>
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          <bvar>
            <ci> time </ci>
          </bvar> 
          <ci> Ca_CSQ </ci> 
        </apply>
        <ci> delta_Ca_CSQ_rxn_8 </ci>
      </apply>
    </math>
  </component> 
  
  <component name="SRRC_fast_activating_binding_site">
    <variable units="molar" public_interface="out" name="S1"/>
    
    <variable units="flux" public_interface="in" name="delta_S1_rxn_2"/>
    <variable units="second" public_interface="in" name="time"/> 
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
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        <eq/> 
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          <diff/> 
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          </bvar> 
          <ci> S1 </ci> 
        </apply>
        <ci> delta_S1_rxn_2 </ci>
      </apply>
    </math>
  </component>
  
  <component name="SRRC_slow_inactivating_binding_site">
    <variable units="molar" public_interface="out" name="S2"/>
    
    <variable units="flux" public_interface="in" name="delta_S2_rxn_3"/>
    <variable units="second" public_interface="in" name="time"/> 
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply id="S2_diff_eq">
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci> time </ci>
          </bvar> 
          <ci> S2 </ci> 
        </apply>
        <ci> delta_S2_rxn_3 </ci>
      </apply>
    </math>
  </component>
  
  <component name="Ca_bound_to_the_SRRC_fast_activating_binding_site">
    <variable units="molar" public_interface="out" name="Ca_2_S1"/>
    
    <variable units="flux" public_interface="in" name="delta_Ca_2_S1_rxn_2"/>
    <variable units="second" public_interface="in" name="time"/> 
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply id="Ca_2_S1_diff_eq">
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        <ci> delta_Ca_2_S1_rxn_2 </ci>
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    </math>
  </component>
  
  <component name="Ca_bound_to_the_SRRC_slow_inactivating_binding_site">
    <variable units="molar" public_interface="out" name="Ca_S2"/>
    
    <variable units="flux" public_interface="in" name="delta_Ca_S2_rxn_3"/>
    <variable units="second" public_interface="in" name="time"/> 
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply id="Ca_S2_diff_eq">
        <eq/> 
        <apply>
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            <ci> time </ci>
          </bvar> 
          <ci> Ca_S2 </ci> 
        </apply>
        <ci> delta_Ca_S2_rxn_3 </ci>
      </apply>
    </math>
  </component>
  
  <connection>
    <map_components component_2="extracellular_calcium" component_1="Ca_influx_across_the_SR"/>
    <map_variables variable_2="Ca_e" variable_1="Ca_e"/>
    <map_variables variable_2="delta_Ca_e_rxn_1" variable_1="delta_Ca_e_rxn_1"/>
  </connection> 
  
  <connection>
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    <map_variables variable_2="Ca_f" variable_1="Ca_f"/>
    <map_variables variable_2="r_rxn_1" variable_1="r_rxn_1"/>
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  <connection>
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    <map_variables variable_2="Ca_2_S1" variable_1="Ca_2_S1"/>
    <map_variables variable_2="delta_Ca_2_S1_rxn_2" variable_1="delta_Ca_2_S1_rxn_2"/>
  </connection>
  
  <connection>
    <map_components component_2="Ca_bound_to_the_SRRC_slow_inactivating_binding_site" component_1="Ca_movement_through_the_SRRC"/>
    <map_variables variable_2="Ca_S2" variable_1="Ca_S2"/>
    <map_variables variable_2="delta_Ca_S2_rxn_3" variable_1="delta_Ca_S2_rxn_3"/>
  </connection>
  
  <connection>
    <map_components component_2="SRRC_fast_activating_binding_site" component_1="Ca_movement_through_the_SRRC"/>
    <map_variables variable_2="S1" variable_1="S1"/>
    <map_variables variable_2="delta_S1_rxn_2" variable_1="delta_S1_rxn_2"/>
  </connection>
  
  <connection>
    <map_components component_2="SRRC_slow_inactivating_binding_site" component_1="Ca_movement_through_the_SRRC"/>
    <map_variables variable_2="S2" variable_1="S2"/>
    <map_variables variable_2="delta_S2_rxn_3" variable_1="delta_S2_rxn_3"/>
  </connection> 
  
  <connection>
    <map_components component_2="fuzzy_space_calcium" component_1="Ca_movement_through_the_SRRC"/>
    <map_variables variable_2="Ca_f" variable_1="Ca_f"/>
    <map_variables variable_2="dcas1_dt" variable_1="dcas1_dt"/>
    <map_variables variable_2="dcas2_dt" variable_1="dcas2_dt"/>
    <map_variables variable_2="r_rxn_4" variable_1="r_rxn_4"/>
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  <connection>
    <map_components component_2="SR_calcium" component_1="Ca_movement_through_the_SRRC"/>
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    <map_variables variable_2="r_rxn_4" variable_1="r_rxn_4"/>
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  <connection>
    <map_components component_2="fuzzy_space_calcium" component_1="Ca_efflux_across_the_SR_by_NaCa_exchange"/>
    <map_variables variable_2="Ca_f" variable_1="Ca_f"/>
    <map_variables variable_2="r_rxn_5" variable_1="r_rxn_5"/>
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  <connection>
    <map_components component_2="extracellular_calcium" component_1="Ca_efflux_across_the_SR_by_NaCa_exchange"/>
    <map_variables variable_2="Ca_e" variable_1="Ca_e"/>
    <map_variables variable_2="delta_Ca_e_rxn_5" variable_1="delta_Ca_e_rxn_5"/>
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  <connection>
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    <map_variables variable_2="Ca_f" variable_1="Ca_f"/>
    <map_variables variable_2="r_rxn_6" variable_1="r_rxn_6"/>
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  <connection>
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  <connection>
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    <map_variables variable_2="Ca_c" variable_1="Ca_c"/>
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  <connection>
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    <map_variables variable_2="r_rxn_7" variable_1="r_rxn_7"/>
  </connection> 
  
  <connection>
    <map_components component_2="SR_calcium" component_1="Ca_buffering_in_the_SR"/>
    <map_variables variable_2="Ca_s" variable_1="Ca_s"/>
    <map_variables variable_2="r_rxn_8" variable_1="r_rxn_8"/>
  </connection>
  
  <connection>
    <map_components component_2="calsequestrin_bound_calcium" component_1="Ca_buffering_in_the_SR"/>
    <map_variables variable_2="Ca_CSQ" variable_1="Ca_CSQ"/>
    <map_variables variable_2="delta_Ca_CSQ_rxn_8" variable_1="delta_Ca_CSQ_rxn_8"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="Ca_movement_through_the_SRRC"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection> 
  
  <connection>
    <map_components component_2="environment" component_1="fuzzy_space_calcium"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection> 
  
  <connection>
    <map_components component_2="environment" component_1="cytosolic_calcium"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection> 
  
  <connection>
    <map_components component_2="environment" component_1="SR_calcium"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection> 
  
  <connection>
    <map_components component_2="environment" component_1="extracellular_calcium"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="calsequestrin_bound_calcium"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection> 
  
  <connection>
    <map_components component_2="environment" component_1="SRRC_fast_activating_binding_site"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection> 
  
  <connection>
    <map_components component_2="environment" component_1="SRRC_slow_inactivating_binding_site"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="Ca_bound_to_the_SRRC_fast_activating_binding_site"/>
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  </connection> 
              
  <connection>
    <map_components component_2="environment" component_1="Ca_bound_to_the_SRRC_slow_inactivating_binding_site"/>
    <map_variables variable_2="time" variable_1="time"/>
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            A Mathematical Model of Cardiocyte Ca2+ Dynamics with a Novel                    Representation of Sarcoplasmic Reticular Ca2+ Control
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