<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : chen_model_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_model_2006" name="chen_popel_model_2006_version01">
<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>Bioengineering Institute, University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This model is mathematically correct and can be solved but it's output has not been checked against the publication.
</para>
<para>
ValidateCellML verifies this model as valid CellML with full unit consistency.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
Nitric oxide (NO) plays an essential role in a diverse range of physiological and pathological processes, including acting as a potent vasodilator. NO can be synthesised in a reaction catalysed by the enzyme nitric oxide synthase (NOS), of which there are three isoforms: neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). The substrates required for NO synthesis include: L-arginine (Arg), oxygen (O2), and nicotinamide adenine dinucleotide phosphate (NADPH). Once NO is synthesised in the vasculature, it diffuses into the smooth muscle of the blood vessel walls, resulting in muscle relaxation and vasodilation. As such, NO derived from NOS3 has been considered as the main regulator of vascular tone. However, despite its physiological importance, there is a general lack of data on NO production and how its distribution changes around arterioles under different oxygen conditions, mainly due to experimental limitations.
</para>
<para>
In the study described here in CellML, Kejing Chen and Aleksander Popel have focused on NO production catalysed by eNOS in particular, and they have developed a mathematical model to capture the characteristics of this biochemical pathway. A schematic diagram of the reactions included in this model is outlined in the figure below.
</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 complete 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/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16864000&query_hl=1&itool=pubmed_docsum">PubMed ID: 16864000</ulink>
</para>
</sect1>
</article>
</documentation>
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<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">
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<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>
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<variable 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"/>
<variable name="time" public_interface="in" units="second"/>
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<ci> Fe3_Arg </ci>
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<ci> Fe2_Arg </ci>
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<ci> S </ci>
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<apply>
<plus/>
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<times/>
<ci> k1 </ci>
<ci> Arg </ci>
<ci> Fe3 </ci>
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<apply>
<times/>
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<ci> Arg </ci>
<ci> Fe2 </ci>
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</apply>
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<ci> S </ci>
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<apply>
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<ci> k1 </ci>
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<ci> Fe3 </ci>
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<times/>
<ci> k4 </ci>
<ci> Arg </ci>
<ci> Fe2 </ci>
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<apply>
<plus/>
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<times/>
<ci> k_1 </ci>
<ci> Fe3_Arg </ci>
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<times/>
<ci> k_4 </ci>
<ci> Fe2_Arg </ci>
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</apply>
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</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"/>
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<ci> Fe3 </ci>
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<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> k_1 </ci>
<ci> Fe3_Arg </ci>
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<ci> Fe3_NO </ci>
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<apply>
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<ci> k13 </ci>
<ci> Fe2_NO </ci>
<ci> O2 </ci>
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<apply>
<times/>
<ci> k8 </ci>
<ci> Fe3_NOHA </ci>
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<times/>
<ci> k1 </ci>
<ci> Arg </ci>
<ci> Fe3 </ci>
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<apply>
<times/>
<ci> k2 </ci>
<ci> Fe3 </ci>
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<apply>
<times/>
<ci> k_8 </ci>
<ci> NOHA </ci>
<ci> Fe3 </ci>
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<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 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"/>
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<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>
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<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"/>
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<ci> Fe2_Arg </ci>
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<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>
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<variable name="Fe3_Arg" public_interface="in" units="micromolar"/>
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<variable name="k_4" public_interface="in" units="first_order_rate_constant"/>
<variable name="k3" public_interface="in" units="first_order_rate_constant"/>
<variable name="k5" public_interface="in" units="second_order_rate_constant"/>
<variable name="k_5" public_interface="in" units="first_order_rate_constant"/>
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<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>
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<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>
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<variable name="NOHA" public_interface="in" units="micromolar"/>
<variable name="k6" public_interface="in" units="first_order_rate_constant"/>
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<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>
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<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"/>
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<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>
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<ci> Fe3_O2_NOHA </ci>
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<ci> Fe3_O2_NOHA </ci>
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<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 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 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 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 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"/>
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<connection>
<map_components component_1="Fe3_Arg" component_2="Arg"/>
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<map_variables variable_1="Arg" variable_2="Arg"/>
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<connection>
<map_components component_1="Fe2_Arg" component_2="Arg"/>
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<map_variables variable_1="Arg" variable_2="Arg"/>
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<connection>
<map_components component_1="Arg" component_2="model_constants"/>
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<connection>
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<connection>
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<connection>
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<connection>
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<connection>
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<map_variables variable_1="k1" variable_2="k1"/>
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<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"/>
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<map_variables variable_1="k_1" variable_2="k_1"/>
<map_variables variable_1="k3" variable_2="k3"/>
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<connection>
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<map_variables variable_1="Fe2_Arg" variable_2="Fe2_Arg"/>
</connection>
<connection>
<map_components component_1="Fe2" component_2="Fe3"/>
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<connection>
<map_components component_1="Fe2" component_2="Fe2_NOHA"/>
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<map_variables variable_1="Fe2_NOHA" variable_2="Fe2_NOHA"/>
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<connection>
<map_components component_1="Fe2" component_2="NOHA"/>
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<map_variables variable_1="NOHA" variable_2="NOHA"/>
</connection>
<connection>
<map_components component_1="Fe2" component_2="model_constants"/>
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<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"/>
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<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"/>
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<connection>
<map_components component_1="Fe2_Arg" component_2="model_constants"/>
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<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"/>
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<connection>
<map_components component_1="Fe3_O2_Arg" component_2="model_constants"/>
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<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"/>
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<connection>
<map_components component_1="Fe3_NOHA" component_2="NOHA"/>
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<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>
<map_components component_1="Fe2_NOHA" component_2="Fe3_O2_NOHA"/>
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<map_variables variable_1="Fe3_O2_NOHA" variable_2="Fe3_O2_NOHA"/>
</connection>
<connection>
<map_components component_1="Fe2_NOHA" component_2="model_constants"/>
<map_variables variable_1="O2" variable_2="O2"/>
<map_variables variable_1="k7" variable_2="k7"/>
<map_variables variable_1="k_10" variable_2="k_10"/>
<map_variables variable_1="k10" variable_2="k10"/>
<map_variables variable_1="k9" variable_2="k9"/>
<map_variables variable_1="k_9" variable_2="k_9"/>
</connection>
<connection>
<map_components component_1="Fe3_O2_NOHA" component_2="model_constants"/>
<map_variables variable_1="O2" variable_2="O2"/>
<map_variables variable_1="k11" variable_2="k11"/>
<map_variables variable_1="k_10" variable_2="k_10"/>
<map_variables variable_1="k10" variable_2="k10"/>
</connection>
<connection>
<map_components component_1="Fe3_NO" component_2="Fe3_O2_NOHA"/>
<map_variables variable_1="Fe3_O2_NOHA" variable_2="Fe3_O2_NOHA"/>
</connection>
<connection>
<map_components component_1="Fe3_NO" component_2="model_constants"/>
<map_variables variable_1="k11" variable_2="k11"/>
<map_variables variable_1="k14" variable_2="k14"/>
<map_variables variable_1="k12" variable_2="k12"/>
</connection>
<connection>
<map_components component_1="Fe2_NO" component_2="Fe3_NO"/>
<map_variables variable_1="Fe3_NO" variable_2="Fe3_NO"/>
</connection>
<connection>
<map_components component_1="Fe2_NO" component_2="model_constants"/>
<map_variables variable_1="O2" variable_2="O2"/>
<map_variables variable_1="k13" variable_2="k13"/>
<map_variables variable_1="k12" variable_2="k12"/>
</connection>
<connection>
<map_components component_1="NO" component_2="Fe3_NO"/>
<map_variables variable_1="Fe3_NO" variable_2="Fe3_NO"/>
</connection>
<connection>
<map_components component_1="NO" component_2="model_constants"/>
<map_variables variable_1="k14" variable_2="k14"/>
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<connection>
<map_components component_1="citrulline" component_2="Fe3_O2_NOHA"/>
<map_variables variable_1="Fe3_O2_NOHA" variable_2="Fe3_O2_NOHA"/>
</connection>
<connection>
<map_components component_1="citrulline" component_2="model_constants"/>
<map_variables variable_1="k11" variable_2="k11"/>
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<connection>
<map_components component_1="Fe2_NO" component_2="NO3"/>
<map_variables variable_1="Fe2_NO" variable_2="Fe2_NO"/>
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<connection>
<map_components component_1="NO3" component_2="model_constants"/>
<map_variables variable_1="O2" variable_2="O2"/>
<map_variables variable_1="k13" variable_2="k13"/>
</connection>
<connection>
<map_components component_1="NOHA" component_2="model_constants"/>
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<map_variables variable_1="k_8" variable_2="k_8"/>
<map_variables variable_1="k9" variable_2="k9"/>
<map_variables variable_1="k_9" variable_2="k_9"/>
</connection>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Bag rdf:about="rdf:#36ef5196-6987-4836-a2d9-8e8e4cb3500b">
<rdf:li>nitric oxide</rdf:li>
<rdf:li>nitric oxide synthase</rdf:li>
<rdf:li>signal transduction</rdf:li>
<rdf:li>cerebral aneurysm</rdf:li>
</rdf:Bag>
<rdf:Seq rdf:about="rdf:#7c0f991c-9cdb-4e86-96cd-8f6bd4bcc293">
<rdf:li rdf:resource="rdf:#a50a4d59-e944-41eb-a67d-7fd570407960"/>
<rdf:li rdf:resource="rdf:#01e66475-8298-427e-a3bf-b9d44466c2b0"/>
</rdf:Seq>
<rdf:Description rdf:about="rdf:#be93619a-5308-42fd-a646-cef142f42d46">
<vCard:FN xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">Catherine Lloyd</vCard:FN>
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