Location: Chen, Popel, 2006 @ c73d92175961 / chen_popel_2006.cellml

Author:
Mathieu Deneux <mathieu.deneux@gmail.com>
Date:
2016-08-01 10:00:45+12:00
Desc:
Added a SEDML file
Permanent Source URI:
https://models.cellml.org/workspace/36b/rawfile/c73d921759611a208248c1b7db2af89056693424/chen_popel_2006.cellml

<?xml version="1.0"?>
<!--  FILE :  chen_2006.xml

CREATED :  30th August 2007

LAST MODIFIED : 30th August 2007

AUTHOR :  Catherine Lloyd
          Bioengineering Institute
          The University of Auckland
          
MODEL STATUS :  This model conforms to the CellML 1.1 Specification.

DESCRIPTION :  This file contains a CellML description of Chen and Popel's 2006 mathematical model of biochemical pathways of nitric oxide release from vascular endothelial cells.

CHANGES:  
  
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" cmeta:id="chen_2006" name="chen_2006">

<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
  <articleinfo>
  <title>Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells</title>
  <author>
    <firstname>Catherine</firstname>
          <surname>Lloyd</surname>
    <affiliation>
      <shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
    </affiliation>
  </author>
</articleinfo>
  <section id="sec_status">
    <title>Model Status</title>
    <para>
This CellML model runs in OpenCell and COR and is known to be mathematically consistent with the publication it was based on. The units are consistent. An additional variable and equation has been added to allow the CellML model to reproduce Figure 2 of the publication. The three different graphs of this figure can be produced by altering the variable 'Fe3' in the 'Fe3' component (this variable represents the concentration of eNOS in its Fe3+ bound state) to 0.045, 0.030 or 0.015 micromolar. In this particular version of the model it has been set to 0.045.
</para>
  </section>
  <sect1 id="sec_structure">
  <title>Model Structure</title>

<para>
ABSTRACT: Vascular endothelium expressing endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO), which has a number of important physiological functions in the microvasculature. The rate of NO production by the endothelium is a critical determinant of NO distribution in the vascular wall. We have analyzed the biochemical pathways of NO synthesis and formulated a model to estimate NO production by the microvascular endothelium under physiological conditions. The model quantifies the NO produced by eNOS based on the kinetics of NO synthesis and the availability of eNOS and its intracellular substrates. The predicted NO production from microvessels was in the range of 0.005-0.1 microM/s. This range of predicted values is in agreement with some experimental values but is much lower than other rates previously measured or estimated from experimental data with the help of mathematical modeling. Paradoxical discrepancies between the model predictions and previously reported results based on experimental measurements of NO concentration in the vicinity of the arteriolar wall suggest that NO can also be released through eNOS-independent mechanisms, such as catalysis by neuronal NOS (nNOS). We also used our model to test the sensitivity of NO production to substrate availability, eNOS concentration, and potential rate-limiting factors. The results indicated that the predicted low level of NO production can be attributed primarily to a low expression of eNOS in the microvascular endothelial cells.
</para>

<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
  <imageobject>
    <objectinfo>
      <title>model diagram</title>
    </objectinfo>
    <imagedata fileref="chen_2006.png"/>
  </imageobject>
</mediaobject>
<caption>Schematic diagram of the mathematical model.  Pathway of nitric oxide (NO) synthesis catalysed by endothelial nitric oxide synthase (eNOS, or eNOS3).  The heme iron (Fe) is the main catalysis site and is used to represent the enzyme in this figure and also in the model.  The heme ion of eNOS binds L-arginine (Arg), hydroxyl-L-arginine (NOHA), and oxygen (O2), and undergoes a series of oxygenation and reduction reactions.</caption>
</informalfigure>

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

<para>
Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells, Kejing Chen and Aleksander S. Popel, 2006, <emphasis>Free Radical Biology and Medicine</emphasis>
          , 41, 668-680. <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/16864000">PubMed ID: 16864000</ulink>
</para>

</sect1>
</article>
</documentation> 





  <units name="micromolar">
    <unit prefix="micro" units="mole"/>
    <unit exponent="-1" units="litre"/>
  </units>
  
  <units name="first_order_rate_constant">
    <unit exponent="-1" units="second"/>
  </units>

  <units name="second_order_rate_constant">
    <unit exponent="-1" units="second"/>
    <unit exponent="-1" units="micromolar"/>
  </units>

  <units name="flux">
    <unit units="micromolar"/>
    <unit exponent="-1" units="second"/>
  </units>

  
  <component name="environment">
    <variable cmeta:id="environment_time" name="time" public_interface="out" units="second"/>
  </component>

  <component cmeta:id="Arg" name="Arg">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Arg">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Arg</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">L-arginine</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable cmeta:id="Arg_Arg" initial_value="100.0" name="Arg" public_interface="out" units="micromolar"/>

    <variable name="S" units="flux"/>
    
    <variable name="Fe3" public_interface="in" units="micromolar"/>
    <variable name="Fe3_Arg" public_interface="in" units="micromolar"/>
    <variable name="Fe2_Arg" public_interface="in" units="micromolar"/>
    <variable name="Fe2" public_interface="in" units="micromolar"/>
    <variable name="k1" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k_1" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k4" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k_4" public_interface="in" units="first_order_rate_constant"/>
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    <math xmlns="http://www.w3.org/1998/Math/MathML" id="0"> 
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          <minus/> 
          <apply>
            <plus/>
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              <times/>
              <ci> k_1 </ci>
              <ci> Fe3_Arg </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_4 </ci>
              <ci> Fe2_Arg </ci>
            </apply>
            <ci> S </ci>
          </apply>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k1 </ci>
              <ci> Arg </ci>
              <ci> Fe3 </ci>
            </apply>
            <apply>
              <times/>
              <ci> k4 </ci>
              <ci> Arg </ci>
              <ci> Fe2 </ci>
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        </apply>
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      <apply>
        <eq/> 
        <ci> S </ci> 
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          <minus/>
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            <plus/>
            <apply>
              <times/>
              <ci> k1 </ci>
              <ci> Arg </ci>
              <ci> Fe3 </ci>
            </apply>
            <apply>
              <times/>
              <ci> k4 </ci>
              <ci> Arg </ci>
              <ci> Fe2 </ci>
            </apply>
          </apply> 
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k_1 </ci>
              <ci> Fe3_Arg </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_4 </ci>
              <ci> Fe2_Arg </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>
  
  <component cmeta:id="Fe3" name="Fe3">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Fe3">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Fe3</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">neuronal nitric oxide synthase (heme iron 3+)</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable initial_value="0.045" name="Fe3" public_interface="out" units="micromolar"/>
    
    <variable name="Arg" public_interface="in" units="micromolar"/>
    <variable name="Fe3_Arg" public_interface="in" units="micromolar"/>
    <variable name="Fe3_NO" public_interface="in" units="micromolar"/>
    <variable name="Fe2_NO" public_interface="in" units="micromolar"/>
    <variable name="O2" public_interface="in" units="micromolar"/>
    <variable name="Fe3_NOHA" public_interface="in" units="micromolar"/>
    <variable name="NOHA" public_interface="in" units="micromolar"/>
    <variable name="k1" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k_1" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k2" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k13" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k14" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k8" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k_8" public_interface="in" units="second_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="1"> 
      <apply>
        <eq/> 
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          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> Fe3 </ci> 
        </apply>
        <apply>
          <minus/> 
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k_1 </ci>
              <ci> Fe3_Arg </ci>
            </apply>
            <apply>
              <times/>
              <ci> k14 </ci>
              <ci> Fe3_NO </ci>
            </apply>
            <apply>
              <times/>
              <ci> k13 </ci>
              <ci> Fe2_NO </ci>
              <ci> O2 </ci>
            </apply>
            <apply>
              <times/>
              <ci> k8 </ci>
              <ci> Fe3_NOHA </ci>
            </apply>
          </apply>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k1 </ci>
              <ci> Arg </ci>
              <ci> Fe3 </ci>
            </apply>
            <apply>
              <times/>
              <ci> k2 </ci>
              <ci> Fe3 </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_8 </ci>
              <ci> NOHA </ci>
              <ci> Fe3 </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="Fe3_Arg" name="Fe3_Arg">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Fe3_Arg">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Fe3_Arg</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">neuronal nitric oxide synthase (heme iron 3+) bound to L-arginine</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable cmeta:id="Fe3_Arg_Fe3_Arg" initial_value="0.0" name="Fe3_Arg" public_interface="out" units="micromolar"/>
    
    <variable name="Arg" public_interface="in" units="micromolar"/>
    <variable name="Fe3" public_interface="in" units="micromolar"/>
    <variable name="k1" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k_1" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k3" public_interface="in" units="first_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="2"> 
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            <ci>time</ci>
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          <ci> Fe3_Arg </ci> 
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              <times/>
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              <ci> k3 </ci>
              <ci> Fe3_Arg </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="Fe2" name="Fe2">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Fe2">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Fe2</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">neuronal nitric oxide synthase (heme iron 2+)</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable initial_value="0.0" name="Fe2" public_interface="out" units="micromolar"/>
    
    <variable name="Arg" public_interface="in" units="micromolar"/>
    <variable name="Fe3" public_interface="in" units="micromolar"/>
    <variable name="Fe2_Arg" public_interface="in" units="micromolar"/>
    <variable name="NOHA" public_interface="in" units="micromolar"/>
    <variable name="Fe2_NOHA" public_interface="in" units="micromolar"/>
    <variable name="k2" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k_4" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k4" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k9" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k_9" public_interface="in" units="second_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="3"> 
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          <ci> Fe2 </ci> 
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              <ci> k2 </ci>
              <ci> Fe3 </ci>
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              <ci> k_4 </ci>
              <ci> Fe2_Arg </ci>
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              <times/>
              <ci> k9 </ci>
              <ci> Fe2_NOHA </ci>
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          <apply>
            <plus/>
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              <times/>
              <ci> k4 </ci>
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	    </apply>
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              <ci> NOHA </ci>
	    </apply>
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        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="Fe2_Arg" name="Fe2_Arg">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Fe2_Arg">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Fe2_Arg</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">neuronal nitric oxide synthase (heme iron 2+) bound to L-arginine</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable cmeta:id="Fe2_Arg_Fe2_Arg" initial_value="0.0" name="Fe2_Arg" public_interface="out" units="micromolar"/>
    
    <variable name="Arg" public_interface="in" units="micromolar"/>
    <variable name="Fe3_Arg" public_interface="in" units="micromolar"/>
    <variable name="Fe2" public_interface="in" units="micromolar"/>
    <variable name="Fe3_O2_Arg" public_interface="in" units="micromolar"/>
    <variable name="O2" public_interface="in" units="micromolar"/>
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    <variable name="k3" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k5" public_interface="in" units="second_order_rate_constant"/>
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              <ci> k_5 </ci>
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              <ci> k4 </ci>
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              <ci> k5 </ci>
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              <times/>
              <ci> k_4 </ci>
              <ci> Fe2_Arg </ci>
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          </apply>
        </apply>
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    </math>
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  <component cmeta:id="Fe3_O2_Arg" name="Fe3_O2_Arg">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Fe3_O2_Arg">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Fe3_O2_Arg</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">oxidised neuronal nitric oxide synthase (heme iron 3+) bound to L-arginine</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
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              <ci> k6 </ci>
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    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Fe3_NOHA">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Fe3_NOHA</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">neuronal nitric oxide synthase (heme iron 3+) bound to hydroxyl-L-arginine</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable cmeta:id="Fe3_NOHA_Fe3_NOHA" initial_value="0.0" name="Fe3_NOHA" public_interface="out" units="micromolar"/>
    
    <variable name="Fe3_O2_Arg" public_interface="in" units="micromolar"/>
    <variable name="Fe3" public_interface="in" units="micromolar"/>
    <variable name="NOHA" public_interface="in" units="micromolar"/>
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    <variable name="time" public_interface="in" units="second"/>
    
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          <ci> Fe3_NOHA </ci> 
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            <plus/>
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              <times/>
              <ci> k6 </ci>
              <ci> Fe3_O2_Arg </ci>
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              <times/>
              <ci> k_8 </ci>
              <ci> Fe3 </ci>
              <ci> NOHA </ci>
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              <times/>
              <ci> k7 </ci>
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              <ci> k8 </ci>
              <ci> Fe3_NOHA </ci>
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  <component cmeta:id="Fe2_NOHA" name="Fe2_NOHA">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Fe2_NOHA">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Fe2_NOHA</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">neuronal nitric oxide synthase (heme iron 2+) bound to hydroxyl-L-arginine</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable cmeta:id="Fe2_NOHA_Fe2_NOHA" initial_value="0.0" name="Fe2_NOHA" public_interface="out" units="micromolar"/>
    
    <variable name="Fe2" public_interface="in" units="micromolar"/>
    <variable name="Fe3_NOHA" public_interface="in" units="micromolar"/>
    <variable name="NOHA" public_interface="in" units="micromolar"/>
    <variable name="Fe3_O2_NOHA" public_interface="in" units="micromolar"/>
    <variable name="O2" public_interface="in" units="micromolar"/>
    <variable name="k9" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k7" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k_9" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k_10" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k10" public_interface="in" units="second_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="7"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> Fe2_NOHA </ci> 
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            <plus/>
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              <times/>
              <ci> k7 </ci>
              <ci> Fe3_NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_10 </ci>
              <ci> Fe3_O2_NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_9 </ci>
              <ci> Fe2 </ci>
              <ci> NOHA </ci>
            </apply>
          </apply>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k9 </ci>
              <ci> Fe2_NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k10 </ci>
              <ci> Fe2_NOHA </ci>
              <ci> O2 </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="Fe3_O2_NOHA" name="Fe3_O2_NOHA">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Fe3_O2_NOHA">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Fe3_O2_NOHA</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">oxidised neuronal nitric oxide synthase (heme iron 3+) bound to hydroxyl-L-arginine</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable cmeta:id="Fe3_O2_NOHA_Fe3_O2_NOHA" initial_value="0.0" name="Fe3_O2_NOHA" public_interface="out" units="micromolar"/>
    
    <variable name="Fe2_NOHA" public_interface="in" units="micromolar"/>
    <variable name="O2" public_interface="in" units="micromolar"/>
    <variable name="k11" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k10" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k_10" public_interface="in" units="first_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="8"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> Fe3_O2_NOHA </ci> 
        </apply>
        <apply>
          <minus/> 
          <apply>
            <times/>
            <ci> k10 </ci>
            <ci> Fe2_NOHA </ci>
            <ci> O2 </ci>
          </apply>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k11 </ci>
              <ci> Fe3_O2_NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_10 </ci>
              <ci> Fe3_O2_NOHA </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="Fe3_NO" name="Fe3_NO">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Fe3_NO">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Fe3_NO</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">neuronal nitric oxide synthase (heme iron 3+) bound to nitric oxide</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable cmeta:id="Fe3_NO_Fe3_NO" initial_value="0.0" name="Fe3_NO" public_interface="out" units="micromolar"/>
    
    <variable name="Fe3_O2_NOHA" public_interface="in" units="micromolar"/>
    <variable name="k12" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k14" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k11" public_interface="in" units="first_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="9"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> Fe3_NO </ci> 
        </apply>
        <apply>
          <minus/> 
          <apply>
            <times/>
            <ci> k11 </ci>
            <ci> Fe3_O2_NOHA </ci>
          </apply>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k14 </ci>
              <ci> Fe3_NO </ci>
            </apply>
            <apply>
              <times/>
              <ci> k12 </ci>
              <ci> Fe3_NO </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="Fe2_NO" name="Fe2_NO">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Fe2_NO">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Fe2_NO</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">neuronal nitric oxide synthase (heme iron 2+) bound to nitric oxide</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable cmeta:id="Fe2_NO_Fe2_NO" initial_value="0.0" name="Fe2_NO" public_interface="out" units="micromolar"/>
    
    <variable name="Fe3_NO" public_interface="in" units="micromolar"/>
    <variable name="O2" public_interface="in" units="micromolar"/>
    <variable name="k13" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k12" public_interface="in" units="first_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="10"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> Fe2_NO </ci> 
        </apply>
        <apply>
          <minus/> 
          <apply>
            <times/>
            <ci> k12 </ci>
            <ci> Fe3_NO </ci>
          </apply>
          <apply>
            <times/>
            <ci> k13 </ci>
            <ci> Fe2_NO </ci>
            <ci> O2 </ci>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="NO" name="NO">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#NO">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">NO</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">nitric oxide</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable cmeta:id="NO_NO" initial_value="0.0" name="NO" units="micromolar"/>
    
    <variable name="Fe3_NO" public_interface="in" units="micromolar"/>
    <variable name="k14" public_interface="in" units="first_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="11"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> NO </ci> 
        </apply>
        <apply>
          <times/>
          <ci> k14 </ci>
          <ci> Fe3_NO </ci>
        </apply>
      </apply>
    <apply><eq/><ci>dNOdt</ci><apply><times/><ci>k14</ci><ci>Fe3_NO</ci></apply></apply></math>
  <variable cmeta:id="NO_dNOdt" name="dNOdt" units="flux"/></component>

  <component name="citrulline">  
    <variable cmeta:id="citrulline_citrulline" initial_value="0.0" name="citrulline" units="micromolar"/>
    
    <variable name="Fe3_O2_NOHA" public_interface="in" units="micromolar"/>
    <variable name="k11" public_interface="in" units="first_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="12"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> citrulline </ci> 
        </apply>
        <apply>
          <times/>
          <ci> k11 </ci>
          <ci> Fe3_O2_NOHA </ci>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="NO3" name="NO3">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#NO3">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">NO3</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">nitrate</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable initial_value="0.0" name="NO3" units="micromolar"/>
    
    <variable name="Fe2_NO" public_interface="in" units="micromolar"/>
    <variable name="O2" public_interface="in" units="micromolar"/>
    <variable name="k13" public_interface="in" units="second_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="13"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> NO3 </ci> 
        </apply>
        <apply>
          <times/>
          <ci> k13 </ci>
          <ci> Fe2_NO </ci>
          <ci> O2 </ci>
        </apply>
      </apply>
    </math>
  </component>

  <component cmeta:id="NOHA" name="NOHA">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#NOHA">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">NOHA</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">hydroxyl-L-arginine</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF>  
    <variable initial_value="0.0" name="NOHA" public_interface="out" units="micromolar"/>
    
    <variable name="Fe2_NOHA" public_interface="in" units="micromolar"/>
    <variable name="Fe2" public_interface="in" units="micromolar"/>
    <variable name="Fe3_NOHA" public_interface="in" units="micromolar"/>
    <variable name="Fe3" public_interface="in" units="micromolar"/>
    <variable name="k_8" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k8" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k9" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k_9" public_interface="in" units="second_order_rate_constant"/>
    <variable name="time" public_interface="in" units="second"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML" id="14"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci> NOHA </ci> 
        </apply>
        <apply>
          <minus/>
          <apply>
            <plus/>  
            <apply>
              <times/>
              <ci> k8 </ci>
              <ci> Fe3_NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k9 </ci>
              <ci> Fe2_NOHA </ci>
            </apply>
          </apply>
          <apply>
            <plus/>
            <apply>
              <times/>
              <ci> k_8 </ci>
              <ci> Fe3 </ci>
              <ci> NOHA </ci>
            </apply>
            <apply>
              <times/>
              <ci> k_9 </ci>
              <ci> Fe2 </ci>
              <ci> NOHA </ci>
            </apply>
          </apply>
        </apply>
      </apply>
    </math>
  </component>

  <component name="model_constants"> 
    <variable cmeta:id="model_constants_O2" initial_value="172.0" name="O2" public_interface="out" units="micromolar"/>
    <variable initial_value="0.1" name="k1" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.1" name="k_1" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.91" name="k2" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.91" name="k3" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="1.89" name="k4" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="11.4" name="k_4" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="2.58" name="k5" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="98.0" name="k_5" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="12.6" name="k6" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.91" name="k7" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k8" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k_8" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="11.4" name="k9" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="1.89" name="k_9" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="3.33" name="k10" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="89.9" name="k_10" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="29.4" name="k11" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.91" name="k12" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.033" name="k13" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="53.9" name="k14" public_interface="out" units="first_order_rate_constant"/>
  </component>

  <connection>
    <map_components component_1="Arg" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>
  
  <connection>
    <map_components component_1="Fe3" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="Fe3_Arg" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>
  
  <connection>
    <map_components component_1="Fe2" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="Fe2_Arg" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>
  
  <connection>
    <map_components component_1="Fe3_O2_Arg" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="Fe3_NOHA" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="Fe2_NOHA" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>
  
  <connection>
    <map_components component_1="Fe3_O2_NOHA" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="Fe3_NO" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>
  
  <connection>
    <map_components component_1="Fe2_NO" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="NO" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="citrulline" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="NO3" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="NOHA" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="Fe3" component_2="Arg"/>
    <map_variables variable_1="Fe3" variable_2="Fe3"/>
    <map_variables variable_1="Arg" variable_2="Arg"/>
  </connection>

  <connection>
    <map_components component_1="Fe2" component_2="Arg"/>
    <map_variables variable_1="Fe2" variable_2="Fe2"/>
    <map_variables variable_1="Arg" variable_2="Arg"/>
  </connection>

  <connection>
    <map_components component_1="Fe3_Arg" component_2="Arg"/>
    <map_variables variable_1="Fe3_Arg" variable_2="Fe3_Arg"/>
    <map_variables variable_1="Arg" variable_2="Arg"/>
  </connection>

  <connection>
    <map_components component_1="Fe2_Arg" component_2="Arg"/>
    <map_variables variable_1="Fe2_Arg" variable_2="Fe2_Arg"/>
    <map_variables variable_1="Arg" variable_2="Arg"/>
  </connection>

  <connection>
    <map_components component_1="Arg" component_2="model_constants"/>
    <map_variables variable_1="k1" variable_2="k1"/>
    <map_variables variable_1="k_1" variable_2="k_1"/>
    <map_variables variable_1="k4" variable_2="k4"/>
    <map_variables variable_1="k_4" variable_2="k_4"/>
  </connection>  
  
  <connection>
    <map_components component_1="Fe3" component_2="Fe3_Arg"/>
    <map_variables variable_1="Fe3" variable_2="Fe3"/>
    <map_variables variable_1="Fe3_Arg" variable_2="Fe3_Arg"/>
  </connection>

  <connection>
    <map_components component_1="Fe3" component_2="Fe3_NOHA"/>
    <map_variables variable_1="Fe3" variable_2="Fe3"/>
    <map_variables variable_1="Fe3_NOHA" variable_2="Fe3_NOHA"/>
  </connection>

  <connection>
    <map_components component_1="Fe3" component_2="NOHA"/>
    <map_variables variable_1="Fe3" variable_2="Fe3"/>
    <map_variables variable_1="NOHA" variable_2="NOHA"/>
  </connection>  

  <connection>
    <map_components component_1="Fe3" component_2="Fe3_NO"/>
    <map_variables variable_1="Fe3_NO" variable_2="Fe3_NO"/>
  </connection>

  <connection>
    <map_components component_1="Fe3" component_2="Fe2_NO"/>
    <map_variables variable_1="Fe2_NO" variable_2="Fe2_NO"/>
  </connection>

  <connection>
    <map_components component_1="Fe3" component_2="model_constants"/>
    <map_variables variable_1="O2" variable_2="O2"/>
    <map_variables variable_1="k1" variable_2="k1"/>
    <map_variables variable_1="k_1" variable_2="k_1"/>
    <map_variables variable_1="k2" variable_2="k2"/>
    <map_variables variable_1="k8" variable_2="k8"/>
    <map_variables variable_1="k_8" variable_2="k_8"/>
    <map_variables variable_1="k13" variable_2="k13"/>
    <map_variables variable_1="k14" variable_2="k14"/>
  </connection>

  <connection>
    <map_components component_1="Fe3_Arg" component_2="model_constants"/>
    <map_variables variable_1="k1" variable_2="k1"/>
    <map_variables variable_1="k_1" variable_2="k_1"/>
    <map_variables variable_1="k3" variable_2="k3"/>
  </connection>

  <connection>
    <map_components component_1="Fe2" component_2="Fe2_Arg"/>
    <map_variables variable_1="Fe2" variable_2="Fe2"/>
    <map_variables variable_1="Fe2_Arg" variable_2="Fe2_Arg"/>
  </connection> 

  <connection>
    <map_components component_1="Fe2" component_2="Fe3"/>
    <map_variables variable_1="Fe3" variable_2="Fe3"/>
  </connection>

  <connection>
    <map_components component_1="Fe2" component_2="Fe2_NOHA"/>
    <map_variables variable_1="Fe2" variable_2="Fe2"/>
    <map_variables variable_1="Fe2_NOHA" variable_2="Fe2_NOHA"/>
  </connection>

  <connection>
    <map_components component_1="Fe2" component_2="NOHA"/>
    <map_variables variable_1="Fe2" variable_2="Fe2"/>
    <map_variables variable_1="NOHA" variable_2="NOHA"/>
  </connection>  

  <connection>
    <map_components component_1="Fe2" component_2="model_constants"/>
    <map_variables variable_1="k4" variable_2="k4"/>
    <map_variables variable_1="k_4" variable_2="k_4"/>
    <map_variables variable_1="k9" variable_2="k9"/>
    <map_variables variable_1="k_9" variable_2="k_9"/>
    <map_variables variable_1="k2" variable_2="k2"/>
  </connection>

  <connection>
    <map_components component_1="Fe3_O2_Arg" component_2="Fe2_Arg"/>
    <map_variables variable_1="Fe3_O2_Arg" variable_2="Fe3_O2_Arg"/>
    <map_variables variable_1="Fe2_Arg" variable_2="Fe2_Arg"/>
  </connection> 

  <connection>
    <map_components component_1="Fe2_Arg" component_2="Fe3_Arg"/>
    <map_variables variable_1="Fe3_Arg" variable_2="Fe3_Arg"/>
  </connection>

  <connection>
    <map_components component_1="Fe2_Arg" component_2="model_constants"/>
    <map_variables variable_1="O2" variable_2="O2"/>
    <map_variables variable_1="k4" variable_2="k4"/>
    <map_variables variable_1="k_4" variable_2="k_4"/>
    <map_variables variable_1="k5" variable_2="k5"/>
    <map_variables variable_1="k_5" variable_2="k_5"/>
    <map_variables variable_1="k3" variable_2="k3"/>
  </connection>

  <connection>
    <map_components component_1="Fe3_O2_Arg" component_2="model_constants"/>
    <map_variables variable_1="O2" variable_2="O2"/>
    <map_variables variable_1="k5" variable_2="k5"/>
    <map_variables variable_1="k_5" variable_2="k_5"/>
    <map_variables variable_1="k6" variable_2="k6"/>
  </connection>

  <connection>
    <map_components component_1="Fe3_NOHA" component_2="Fe3_O2_Arg"/>
    <map_variables variable_1="Fe3_O2_Arg" variable_2="Fe3_O2_Arg"/>
  </connection>

  <connection>
    <map_components component_1="Fe3_NOHA" component_2="NOHA"/>
    <map_variables variable_1="NOHA" variable_2="NOHA"/>
    <map_variables variable_1="Fe3_NOHA" variable_2="Fe3_NOHA"/>
  </connection> 

  <connection>
    <map_components component_1="Fe3_NOHA" component_2="model_constants"/>
    <map_variables variable_1="k6" variable_2="k6"/>
    <map_variables variable_1="k7" variable_2="k7"/>
    <map_variables variable_1="k8" variable_2="k8"/>
    <map_variables variable_1="k_8" variable_2="k_8"/>
  </connection>

  <connection>
    <map_components component_1="Fe2_NOHA" component_2="NOHA"/>
    <map_variables variable_1="NOHA" variable_2="NOHA"/>
    <map_variables variable_1="Fe2_NOHA" variable_2="Fe2_NOHA"/>
  </connection> 

  <connection>
    <map_components component_1="Fe2_NOHA" component_2="Fe3_NOHA"/>
    <map_variables variable_1="Fe3_NOHA" variable_2="Fe3_NOHA"/>
  </connection>

  <connection>
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