Location: Guyton, Angiotensin, 2008 @ 17611508dcdf / guyton_angiotensin_2008.cellml

Author:
pmr2.import <nobody@models.cellml.org>
Date:
2008-11-17 23:37 +1300
Desc:
committing version02 of guyton_angiotensin_2008
Permanent Source URI:
http://models.cellml.org/workspace/guyton_angiotensin_2008/rawfile/17611508dcdf5439048ead8baef3100638686268/guyton_angiotensin_2008.cellml

<?xml version='1.0' encoding='utf-8'?>
<model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:xlink="http://www.w3.org/1999/xlink" name="angiotensin_CellML1_0_model" cmeta:id="angiotensin_CellML1_0_model">

	
<!-- ===============================================	DOCUMENTATION	=================================================== -->
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
  <articleinfo>
  <title>Guyton Model: Angiotensin</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 CellML model has been validated. Due to the differences between procedural code (in this case C-code) and declarative languages (CellML), some aspects of the original model were 
		not able to be encapsulated by the CellML model (such as the damping of variables). This may effect the transient behaviour of the model, however the steady-state behaviour would remain
		the same. The equations in this file and the steady-state output from the model conform to the results from the MODSIM program.
    </para>
  </section>
  <sect1 id="sec_structure">
  <title>Model Structure</title>

<para>
Arthur Guyton (1919-2003) was an American physiologist who became famous for his 1950s experiments in which he studied the physiology of cardiac output and its relationship with the peripheral circulation.  The results of these experiments challenged the conventional wisdom that it was the heart itself that controlled cardiac output.  Instead Guyton demonstrated that it was the need of the body tissues for oxygen which was the real regulator of cardiac output.  The "Guyton Curves" describe the relationship between right atrial pressures and cardiac output, and they form a foundation for understanding the physiology of circulation. 
</para>

<para>
The Guyton model of fluid, electrolyte, and circulatory regulation is an extensive mathematical model of human circulatory physiology, capable of simulating a variety of experimental conditions, and contains a number of linked subsystems relating to circulation and its neuroendocrine control.
</para>

<para>
This is a CellML translation of the Guyton model of the regulation of the circulatory system.  The complete model consists of separate modules each of which characterise a separate physiological subsystems.  The Circulation Dynamics is the primary system, to which other modules/blocks are connected.  The other modules characterise the dynamics of the kidney, electrolytes and cell water, thirst and drinking, hormone regulation, autonomic regulation, cardiovascular system etc, and these feedback on the central circulation model.  The CellML code in these modules is based on the C code from the programme C-MODSIM created by Dr Jean-Pierre Montani.
</para>

<para>
This particular CellML model describes the control functions of angiotensin, beginning with the control of angiotensin formation by the kidneys in response to changes in the rate of flow of fluid in the renal tubules at the macula densa (MDFLW), and extending through a series of curve-fitting and sensitivity controlled equations to determine the multiple feedback effects of angiotensin to control the various aspects of circulatory function.
</para>

<informalfigure float="0" id="full_diagram">
<mediaobject>
  <imageobject>
    <objectinfo>
      <title>model diagram</title>
    </objectinfo>
    <imagedata fileref="full_model.png"/>
  </imageobject>
</mediaobject>
<caption>A systems analysis diagram for the full Guyton model describing circulation regulation.</caption>
</informalfigure>


<informalfigure float="0" id="angiotensin_diagram">
<mediaobject>
  <imageobject>
    <objectinfo>
      <title>model diagram</title>
    </objectinfo>
    <imagedata fileref="angiotensin.png"/>
  </imageobject>
</mediaobject>
<caption>A schematic diagram of the components and processes described in the current CellML model.</caption>
</informalfigure> 

<para>
There are several publications referring to the Guyton model. One of these papers is cited below:
</para>

<para>
<ulink url="http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.ph.34.030172.000305">Circulation: Overall Regulation</ulink>,  A.C. Guyton, T.G. Coleman, and H.J. Granger, 1972, <ulink url="http://www.biophysj.org/">
            <emphasis>Annual Review of Physiology</emphasis>
          </ulink>, 34, 13-44.  (A <ulink url="http://arjournals.annualreviews.org/doi/pdf/10.1146/annurev.ph.34.030172.000305?cookieSet=1">PDF</ulink> version of the article are available to journal subscribers on the <emphasis>Annual Review of Physiology</emphasis> website.)  <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&amp;cmd=Retrieve&amp;dopt=AbstractPlus&amp;list_uids=4334846&amp;query_hl=1&amp;itool=pubmed_docsum">PubMed ID: 4334846</ulink>
</para>

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


<!-- ============================================================================================================================ -->



	<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
		<rdf:Description rdf:about="#angiotensin_CellML1_0_model">
			<rdf:value>
			This section calculates the control functions of angiotensin, beginning with the 
			control of angiotensin formation by the kidneys in response to changes in the rate 
			of flow of fluid in the renal tubules at the macula densa (MDFLW), and extending 
			through a series of curve-fitting and sensitivity controlled equations to determine 
			the multiple feedback effects of angiotensin to control the various aspects of 
			circulatory function.
			</rdf:value>
		</rdf:Description>
	</rdf:RDF>

<!-- ========================================	ENVIRONMENT COMPONENT	============================================= -->
   <component name="environment">
      <variable cmeta:id="environment_time" name="time" units="second" private_interface="none" public_interface="out"/>
   </component>

<!-- ========================================	ANGIOTENSIN TOP-LEVEL COMPONENT	============================================= -->
	<component name="angiotensin" cmeta:id="angiotensin">
		<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
			<rdf:Description rdf:about="#angiotensin">
				<rdf:value>
				Encapsulation grouping component containing all the components in the Angiotensin Model. The inputs and 
				outputs of the Angiotensin Model must be passed by this component.
				</rdf:value>
			</rdf:Description>
		</rdf:RDF>

		<variable name="time" units="second" private_interface="out" public_interface="in"/>

<!-- Inputs from components in other models -->
		<variable name="MDFLW" initial_value="1.00051" units="dimensionless" private_interface="out" public_interface="none"/>
	</component>

<!-- INPUT CONNECTIONS -->
	<connection>
		<map_components component_1="angiotensin" component_2="environment"/>
		<map_variables variable_1="time" variable_2="time"/>
	</connection>

<!-- ========================================	INSTANTANEOUS ANGIONTENSIN FORMATION	============================================= -->
	<component name="instantaneous_angiotensin_formation" cmeta:id="instantaneous_angiotensin_formation">
		<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
			<rdf:Description rdf:about="#instantaneous_angiotensin_formation">
				<rdf:value>
				AN1:  
				This block damps the variations in rate of fluid flow in the renal tubules at 
				the macula densa (MDFLW).  The damped outflow is the variable MDFLW3.
				NB - REMOVED DAMPING FORM AN1!!!!

				AN2:  
				This block calculates the formation rate of angiotensin (ANGSCR) at different 
				levels of MDFLW3.
				</rdf:value>
			</rdf:Description>
		</rdf:RDF>
		
<!-- Inputs from other components -->
		<variable name="MDFLW" units="dimensionless" private_interface="none" public_interface="in"/>

<!-- Outputs to other components -->
		<variable name="ANGSCR" units="dimensionless" private_interface="none" public_interface="out"/>

<!-- Internal variables -->
		<variable name="MDFLW3" units="dimensionless" private_interface="none" public_interface="none"/>

		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply id="AN1">
				<eq/>
				<ci>MDFLW3</ci>
				<ci>MDFLW</ci>
			</apply>
			<apply id="AN2">
				<eq/>
				<ci>ANGSCR</ci>
				<piecewise>
					<piece>
						<apply>
							<divide/>
							<cn cellml:units="dimensionless">1</cn>
							<apply>
								<plus/>
								<cn cellml:units="dimensionless">1</cn>
								<apply>
									<times/>
									<apply>
										<minus/>
										<ci>MDFLW3</ci>
										<cn cellml:units="dimensionless">1</cn>
									</apply>
									<cn cellml:units="dimensionless">72</cn>
								</apply>
							</apply>
						</apply>
						<apply>
							<gt/>
							<ci>MDFLW3</ci>
							<cn cellml:units="dimensionless">1</cn>
						</apply>
					</piece>
					<otherwise>
						<apply>
							<minus/>
							<cn cellml:units="dimensionless">10</cn>
							<apply>
								<divide/>
								<cn cellml:units="dimensionless">9</cn>
								<apply>
									<plus/>
									<cn cellml:units="dimensionless">1</cn>
									<apply>
										<times/>
										<apply>
											<minus/>
											<cn cellml:units="dimensionless">1</cn>
											<ci>MDFLW3</ci>
										</apply>
										<cn cellml:units="dimensionless">8</cn>
									</apply>
								</apply>
							</apply>
						</apply>
					</otherwise>
				</piecewise>
			</apply>
		</math>
	</component>

<!-- INPUT CONNECTIONS -->
	<connection>
		<map_components component_1="instantaneous_angiotensin_formation" component_2="angiotensin"/>
		<map_variables variable_1="MDFLW" variable_2="MDFLW"/>
	</connection>

<!-- ========================================	TIME-DELAYED ANGIOTENSIN FORMATION	============================================= -->
	<component name="time_delayed_angiotensin_formation" cmeta:id="time_delayed_angiotensin_formation">
		<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
			<rdf:Description rdf:about="#time_delayed_angiotensin_formation">
				<rdf:value>
				AN4, AN5, AN6, AN7, and AN8:  
				Calculation of additional formation of angiotensin caused after a long-term delay.  
				That is, when the JG cells are stimulated over long periods of time, in addition to
				their acute effects on secretion rate of renin and subsequent formation of angiotensin,
				there is a long-term increase in numbers of active JG cells to give a long-term delayed 
				response over a period of days.  The variable ANXM adjusts the magnitude of this 
				delayed response.  ANX is the total response without regard to the time delay.  ANV is 
				the time-constant of the time delay.  ANX1 is the total extra secretion after factoring
				in the time delay effects of blocks 6, 7, and 8.
				</rdf:value>
			</rdf:Description>
		</rdf:RDF>
		
<!-- Inputs from other components -->
		<variable name="ANGSCR" units="dimensionless" private_interface="none" public_interface="in"/>
		<variable name="time" units="second" private_interface="none" public_interface="in"/>

<!-- Outputs to other components -->
		<variable name="ANX1" initial_value="0.0" units="dimensionless" private_interface="none" public_interface="out"/>

<!-- Parameters from parameter_file -->
		<variable name="ANXM" units="dimensionless" private_interface="none" public_interface="in"/>
		<variable name="ANV" units="dimensionless" private_interface="none" public_interface="in"/>

<!-- Internal variables -->
		<variable name="ANX" units="dimensionless" private_interface="none" public_interface="none"/>

		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply id="AN4_and_AN5">
				<eq/>
				<ci>ANX</ci>
				<apply>
					<times/>
					<apply>
						<minus/>
						<ci>ANGSCR</ci>
						<cn cellml:units="dimensionless">1</cn>
					</apply>
					<ci>ANXM</ci>
				</apply>
			</apply>
			<apply id="AN6_to_AN8">
				<eq/>
				<apply>
					<diff/>
					<bvar>
						<ci>time</ci>
					</bvar>
					<ci>ANX1</ci>
				</apply>
				<apply>
					<divide/>
					<apply>
						<minus/>
						<ci>ANX</ci>
						<ci>ANX1</ci>
					</apply>
					<ci>ANV</ci>
				</apply>
			</apply>
		</math>
	</component>

<!-- INPUT CONNECTIONS -->
	<connection>
		<map_components component_1="time_delayed_angiotensin_formation" component_2="instantaneous_angiotensin_formation"/>
		<map_variables variable_1="ANGSCR" variable_2="ANGSCR"/>
	</connection>
	<connection>
		<map_components component_1="time_delayed_angiotensin_formation" component_2="angiotensin"/>
		<map_variables variable_1="time" variable_2="time"/>
	</connection>

<!-- PARAMETER CONNECTIONS -->
	<connection>
		<map_components component_1="time_delayed_angiotensin_formation" component_2="parameter_values"/>
		<map_variables variable_1="ANXM" variable_2="ANXM"/>
		<map_variables variable_1="ANV" variable_2="ANV"/>
	</connection>

<!-- ========================================	TOTAL ANGIOTENSIN FORMATION	============================================= -->
	<component name="total_angiotensin_formation" cmeta:id="total_angiotensin_formation">
		<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
			<rdf:Description rdf:about="#total_angiotensin_formation">
				<rdf:value>
				AN9:  
				Summation of instantaneous formation of angiotensin (ANGSCR) plus the time delayed 
				formation of angiotensin (ANX1).

				AN10:  
				Calculation of the total rate of formation of angiotensin (ANPR) in case some of 
				the renal mass (and therefore some of the JG cells) has been removed or destroyed. 
				Factor REK is equal to the proportion of kidney mass that is still functional.

				AN11:  
				This sets the lower limit of ANPR to a very low level, almost zero, below which 
				this cannot fall.  The reason for this is to prevent a negative value from appearing.
				</rdf:value>
			</rdf:Description>
		</rdf:RDF>
		
<!-- Inputs from other components -->
		<variable name="ANGSCR" units="dimensionless" private_interface="none" public_interface="in"/>
		<variable name="ANX1" units="dimensionless" private_interface="none" public_interface="in"/>

<!-- Outputs to other components -->
		<variable name="ANPR" units="dimensionless" private_interface="none" public_interface="out"/>

<!-- Parameters from parameter_file -->
		<variable name="REK" units="dimensionless" private_interface="none" public_interface="in"/>

<!-- Internal variables -->
		<variable name="ANPRT" units="dimensionless" private_interface="none" public_interface="none"/>

		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply id="AN9_and_AN10">
				<eq/>
				<ci>ANPRT</ci>
				<apply>
					<times/>
					<apply>
						<plus/>
						<ci>ANGSCR</ci>
						<ci>ANX1</ci>
					</apply>
					<ci>REK</ci>
				</apply>
			</apply>
			<apply id="AN11">
				<eq/>
				<ci>ANPR</ci>
				<piecewise>
					<piece>
						<cn cellml:units="dimensionless">0.00001</cn>
						<apply>
							<lt/>
							<ci>ANPRT</ci>
							<cn cellml:units="dimensionless">0.00001</cn>
						</apply>
					</piece>
					<otherwise>
						<ci>ANPRT</ci>
					</otherwise>
				</piecewise>
			</apply>
		</math>
	</component>

<!-- INPUT CONNECTIONS -->
	<connection>
		<map_components component_1="total_angiotensin_formation" component_2="instantaneous_angiotensin_formation"/>
		<map_variables variable_1="ANGSCR" variable_2="ANGSCR"/>
	</connection>
	<connection>
		<map_components component_1="total_angiotensin_formation" component_2="time_delayed_angiotensin_formation"/>
		<map_variables variable_1="ANX1" variable_2="ANX1"/>
	</connection>

<!-- PARAMETER CONNECTIONS -->
	<connection>
		<map_components component_1="total_angiotensin_formation" component_2="parameter_values"/>
		<map_variables variable_1="REK" variable_2="REK"/>
	</connection>

<!-- ========================================	ARTIFICIAL ANGIOTENSIN FORMATION	============================================= -->
	<component name="artificial_angiotensin_formation" cmeta:id="artificial_angiotensin_formation">
		<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
			<rdf:Description rdf:about="#artificial_angiotensin_formation">
				<rdf:value>
				AN11A:  
				This block allows the addition of infused angiotensin (ANGINF) to the amount of 
				angiotensin that is formed in the body (ANPR).

				AN11B:  
				This block allows one to disregard all the previous blocks and to set the total 
				rate of angiotensin entering the circulatory system (ANPR1) to a constant level, ANGKNS. 
				When ANGKNS is equal to zero or less, then Block 11B is ineffective.
				</rdf:value>
			</rdf:Description>
		</rdf:RDF>
		
<!-- Inputs from other components -->
		<variable name="ANPR" units="dimensionless" private_interface="none" public_interface="in"/>

<!-- Outputs to other components -->
		<variable name="ANPR1" units="dimensionless" private_interface="none" public_interface="out"/>

<!-- Parameters from parameter_file -->
		<variable name="ANGKNS" units="dimensionless" private_interface="none" public_interface="in"/>
		<variable name="ANGINF" units="dimensionless" private_interface="none" public_interface="in"/>

		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply id="AN11A_and_AN11B">
				<eq/>
				<ci>ANPR1</ci>
				<piecewise>
					<piece>
						<ci>ANGKNS</ci>
						<apply>
							<gt/>
							<ci>ANGKNS</ci>
							<cn cellml:units="dimensionless">0</cn>
						</apply>
					</piece>
					<otherwise>
						<apply>
							<plus/>
							<ci>ANPR</ci>
							<ci>ANGINF</ci>
						</apply>
					</otherwise>
				</piecewise>
			</apply>
		</math>
	</component>

<!-- INPUT CONNECTIONS -->
	<connection>
		<map_components component_1="artificial_angiotensin_formation" component_2="total_angiotensin_formation"/>
		<map_variables variable_1="ANPR" variable_2="ANPR"/>
	</connection>

<!-- PARAMETER CONNECTIONS -->
	<connection>
		<map_components component_1="artificial_angiotensin_formation" component_2="parameter_values"/>
		<map_variables variable_1="ANGKNS" variable_2="ANGKNS"/>
		<map_variables variable_1="ANGINF" variable_2="ANGINF"/>
	</connection>

<!-- ========================================	ANGIOTENSIN CONCENTRATION	============================================= -->
	<component name="angiotensin_concentration" cmeta:id="angiotensin_concentration">
		<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
			<rdf:Description rdf:about="#angiotensin_concentration">
				<rdf:value>
				AN12, AN13, and AN14:  
				These blocks convert the rate of entry of angiotensin into the body fluids (ANPR1), 
				into the concentration of angiotensin (ANC) considering the normal value to be the 
				numeral 1.  The value ANT is the time constant for rate of change of angiotensin 
				concentration in the body fluids.  The value Z12 is a damping coefficient to allow 
				damping of this conversion so that the model can be run faster for long-term simulations.
				</rdf:value>
			</rdf:Description>
		</rdf:RDF>
		
<!-- Inputs from other components -->
		<variable name="ANPR1" units="dimensionless" private_interface="none" public_interface="in"/>
		<variable name="time" units="second" private_interface="none" public_interface="in"/>

<!-- Outputs to other components -->
		<variable name="ANC" initial_value="0.859476" units="dimensionless" private_interface="none" public_interface="out"/>

<!-- Parameters from parameter_file -->
		<variable name="ANT" units="dimensionless" private_interface="none" public_interface="in"/>

		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply id="AN812_to_AN14">
				<eq/>
				<apply>
					<diff/>
					<bvar>
						<ci>time</ci>
					</bvar>
					<ci>ANC</ci>
				</apply>
				<apply>
					<divide/>
					<apply>
						<minus/>
						<ci>ANPR1</ci>
						<ci>ANC</ci>
					</apply>
					<ci>ANT</ci>
				</apply>
			</apply>
		</math>
	</component>

<!-- INPUT CONNECTIONS -->
	<connection>
		<map_components component_1="angiotensin_concentration" component_2="artificial_angiotensin_formation"/>
		<map_variables variable_1="ANPR1" variable_2="ANPR1"/>
	</connection>
	<connection>
		<map_components component_1="angiotensin_concentration" component_2="angiotensin"/>
		<map_variables variable_1="time" variable_2="time"/>
	</connection>

<!-- PARAMETER CONNECTIONS -->
	<connection>
		<map_components component_1="angiotensin_concentration" component_2="parameter_values"/>
		<map_variables variable_1="ANT" variable_2="ANT"/>
	</connection>

<!-- ========================================	GENERAL ANGIOTENSIN MULTIPLIER	============================================= -->
	<component name="general_angiotensin_multiplier" cmeta:id="general_angiotensin_multiplier">
		<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
			<rdf:Description rdf:about="#general_angiotensin_multiplier">
				<rdf:value>
				AN15:  
				This is an equation that allows one to convert the concentration of angiotensin (ANC) 
				into an angiotensin multiplier (ANM) which describes the multiplicative effect of 
				angiotensin on various physiological functions, assuming the normal value of ANM 
				to be 1.0.  The value ANMUL is the upper limit to the level of ANM.  ANMLL is the 
				lower limit of ANM.  And the value ANCSNS is a sensitivity value for adjusting the 
				quantitative effect of ANC on ANM.
				</rdf:value>
			</rdf:Description>
		</rdf:RDF>
		
<!-- Inputs from other components -->
		<variable name="ANC" units="dimensionless" private_interface="none" public_interface="in"/>

<!-- Outputs to other components -->
		<variable cmeta:id="general_angiotensin_multiplier_ANM" name="ANM" units="dimensionless" private_interface="none" public_interface="out"/>

<!-- Parameters from parameter_file -->
		<variable name="ANMUL" units="dimensionless" private_interface="none" public_interface="in"/>
		<variable name="ANMLL" units="dimensionless" private_interface="none" public_interface="in"/>
		<variable name="ANCSNS" units="dimensionless" private_interface="none" public_interface="in"/>

		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply id="AN15">
				<eq/>
				<ci>ANM</ci>
				<apply>
					<minus/>
					<ci>ANMUL</ci>
					<apply>
						<divide/>
						<apply>
							<minus/>
							<ci>ANMUL</ci>
							<cn cellml:units="dimensionless">1</cn>
						</apply>
						<apply>
							<plus/>
							<apply>
								<times/>
								<apply>
									<divide/>
									<apply>
										<minus/>
										<ci>ANMLL</ci>
										<cn cellml:units="dimensionless">1</cn>
									</apply>
									<apply>
										<minus/>
										<ci>ANMLL</ci>
										<ci>ANMUL</ci>
									</apply>
								</apply>
								<apply>
									<minus/>
									<ci>ANC</ci>
									<cn cellml:units="dimensionless">1</cn>
								</apply>
								<ci>ANCSNS</ci>
							</apply>
							<cn cellml:units="dimensionless">1</cn>
						</apply>
					</apply>
				</apply>
			</apply>
		</math>
	</component>

<!-- INPUT CONNECTIONS -->
	<connection>
		<map_components component_1="general_angiotensin_multiplier" component_2="angiotensin_concentration"/>
		<map_variables variable_1="ANC" variable_2="ANC"/>
	</connection>

<!-- PARAMETER CONNECTIONS -->
	<connection>
		<map_components component_1="general_angiotensin_multiplier" component_2="parameter_values"/>
		<map_variables variable_1="ANMUL" variable_2="ANMUL"/>
		<map_variables variable_1="ANMLL" variable_2="ANMLL"/>
		<map_variables variable_1="ANCSNS" variable_2="ANCSNS"/>
	</connection>

<!-- ========================================	ANGIOTENSIN EFFECT ON CIRCULATION	============================================= -->
	<component name="angiotensin_effect_on_circulation" cmeta:id="angiotensin_effect_on_circulation">
		<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
			<rdf:Description rdf:about="#angiotensin_effect_on_circulation">
				<rdf:value>
				AN16, AN17, and AN18:  
				These blocks are a sensitivity controller for converting the basic effect of the 
				angiotensin multiplier (ANM) on other functional systems of the circulation (ANU).  
				The sensitivity adjustment is the factor ANUM in Block 17.

				AN19:  
				This block sets the lower limit to which ANU can fall (ANULL).
				</rdf:value>
			</rdf:Description>
		</rdf:RDF>
		
<!-- Inputs from other components -->
		<variable name="ANM" units="dimensionless" private_interface="none" public_interface="in"/>

<!-- Outputs to other components -->
		<variable cmeta:id="angiotensin_effect_on_circulation_ANU" name="ANU" units="dimensionless" private_interface="none" public_interface="out"/>

<!-- Parameters from parameter_file -->
		<variable name="ANUM" units="dimensionless" private_interface="none" public_interface="in"/>
		<variable name="ANULL" units="dimensionless" private_interface="none" public_interface="in"/>

<!-- Internal variables -->
		<variable name="ANU1" units="dimensionless" private_interface="none" public_interface="none"/>

		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply id="AN16_to_AN18">
				<eq/>
				<ci>ANU1</ci>
				<apply>
					<plus/>
					<apply>
						<times/>
						<apply>
							<minus/>
							<ci>ANM</ci>
							<cn cellml:units="dimensionless">1</cn>
						</apply>
						<ci>ANUM</ci>
					</apply>
					<cn cellml:units="dimensionless">1</cn>
				</apply>
			</apply>
			<apply id="AN19">
				<eq/>
				<ci>ANU</ci>
				<piecewise>
					<piece>
						<ci>ANULL</ci>
						<apply>
							<lt/>
							<ci>ANU1</ci>
							<ci>ANULL</ci>
						</apply>
					</piece>
					<otherwise>
						<ci>ANU1</ci>
					</otherwise>
				</piecewise>
			</apply>
		</math>
	</component>

<!-- INPUT CONNECTIONS -->
	<connection>
		<map_components component_1="angiotensin_effect_on_circulation" component_2="general_angiotensin_multiplier"/>
		<map_variables variable_1="ANM" variable_2="ANM"/>
	</connection>

<!-- PARAMETER CONNECTIONS -->
	<connection>
		<map_components component_1="angiotensin_effect_on_circulation" component_2="parameter_values"/>
		<map_variables variable_1="ANUM" variable_2="ANUM"/>
		<map_variables variable_1="ANULL" variable_2="ANULL"/>
	</connection>

<!-- ========================================	ANGIOTENSIN EFFECT ON VENOUS CONSTRICTION	============================================= -->
	<component name="angiotensin_effect_on_venous_constriction" cmeta:id="angiotensin_effect_on_venous_constriction">
		<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
			<rdf:Description rdf:about="#angiotensin_effect_on_venous_constriction">
				<rdf:value>
				AN20, AN21, and AN22:  
				Calculation of the effect of angiotensin on venous constriction (ANUVN), with 
				sensitivity controlled by ANUVM in Block 21.
				</rdf:value>
			</rdf:Description>
		</rdf:RDF>
		
<!-- Inputs from other components -->
		<variable name="ANU" units="dimensionless" private_interface="none" public_interface="in"/>

<!-- Outputs to other components -->
		<variable cmeta:id="angiotensin_effect_on_venous_constriction_ANUVN" name="ANUVN" units="dimensionless" private_interface="none" public_interface="out"/>

<!-- Parameters from parameter_file -->
		<variable name="ANUVM" units="dimensionless" private_interface="none" public_interface="in"/>

		<math xmlns="http://www.w3.org/1998/Math/MathML">
			<apply id="AN20_to_AN22">
				<eq/>
				<ci>ANUVN</ci>
				<apply>
					<plus/>
					<apply>
						<times/>
						<apply>
							<minus/>
							<ci>ANU</ci>
							<cn cellml:units="dimensionless">1</cn>
						</apply>
						<ci>ANUVM</ci>
					</apply>
					<cn cellml:units="dimensionless">1</cn>
				</apply>
			</apply>
		</math>
	</component>

<!-- INPUT CONNECTIONS -->
	<connection>
		<map_components component_1="angiotensin_effect_on_venous_constriction" component_2="angiotensin_effect_on_circulation"/>
		<map_variables variable_1="ANU" variable_2="ANU"/>
	</connection>

<!-- PARAMETER CONNECTIONS -->
	<connection>
		<map_components component_1="angiotensin_effect_on_venous_constriction" component_2="parameter_values"/>
		<map_variables variable_1="ANUVM" variable_2="ANUVM"/>
	</connection>

	
<!-- ==========================================================	PARAMETER VALUES	================================================================ -->
	<component name="parameter_values" cmeta:id="parameter_values">
		<variable name="ANXM" units="dimensionless" initial_value="0" private_interface="none" public_interface="out"/>	<!-- sensitivity controller of ANX [P] -->
		<variable name="ANV" units="dimensionless" initial_value="5000" private_interface="none" public_interface="out"/>	<!-- time constant, angiotensin secretion [P] -->
		<variable name="REK" units="dimensionless" initial_value="1" private_interface="none" public_interface="out"/>	<!-- total functional renal mass, ratio to normal [P] -->
		<variable name="ANGINF" units="dimensionless" initial_value="0" private_interface="none" public_interface="out"/>	<!-- rate of exogenous angiotensin infusion [P] -->
		<variable name="ANGKNS" units="dimensionless" initial_value="0" private_interface="none" public_interface="out"/>	<!-- overriding value for angiotensin secretion [P] -->
		<variable name="ANT" units="dimensionless" initial_value="12" private_interface="none" public_interface="out"/>	<!-- time constant, angiotensin accumulation and destruction [P] -->
		<variable name="Z12" units="dimensionless" initial_value="5" private_interface="none" public_interface="out"/>	<!-- damping factor, angiotensin system [P] -->
		<variable name="ANMUL" units="dimensionless" initial_value="1.8" private_interface="none" public_interface="out"/>	<!-- ANM upper limit [P] -->
		<variable name="ANMLL" units="dimensionless" initial_value="0.7" private_interface="none" public_interface="out"/>	<!-- ANM lower limit [P] -->
		<variable name="ANCSNS" units="dimensionless" initial_value="0.4" private_interface="none" public_interface="out"/>	<!-- sensitivity controller of ANM [P] -->
		<variable name="ANULL" units="dimensionless" initial_value="0.8" private_interface="none" public_interface="out"/>	<!-- ANU lower limit [P] -->
		<variable name="ANUM" units="dimensionless" initial_value="6" private_interface="none" public_interface="out"/>	<!-- sensitivity controller of ANU [P] -->
		<variable name="ANUVM" units="dimensionless" initial_value="0" private_interface="none" public_interface="out"/>	<!-- sensitivity controller of ANUVN [P] -->
	</component>

<!-- ============================================================		GROUPING		=============================================================== -->
   <group>
      <relationship_ref relationship="containment"/>
      <component_ref component="angiotensin">
			<component_ref component="instantaneous_angiotensin_formation"/>
			<component_ref component="time_delayed_angiotensin_formation"/>
			<component_ref component="total_angiotensin_formation"/>
			<component_ref component="artificial_angiotensin_formation"/>
			<component_ref component="angiotensin_concentration"/>
			<component_ref component="general_angiotensin_multiplier"/>
			<component_ref component="angiotensin_effect_on_circulation"/>
			<component_ref component="angiotensin_effect_on_venous_constriction"/>
      </component_ref>
   </group>
      
   <group>
      <relationship_ref relationship="encapsulation"/>
      <component_ref component="angiotensin">
			<component_ref component="parameter_values"/>
			<component_ref component="instantaneous_angiotensin_formation"/>
			<component_ref component="time_delayed_angiotensin_formation"/>
			<component_ref component="total_angiotensin_formation"/>
			<component_ref component="artificial_angiotensin_formation"/>
			<component_ref component="angiotensin_concentration"/>
			<component_ref component="general_angiotensin_multiplier"/>
			<component_ref component="angiotensin_effect_on_circulation"/>
			<component_ref component="angiotensin_effect_on_venous_constriction"/>
      </component_ref>
   </group>
   

<!-- SIMULATION METADATA -->
<RDF:RDF xmlns:RDF="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
  <RDF:Description RDF:about="http://www.cellml.org/models/guyton_angiotensin_2008_version02/download#angiotensin_CellML1_0_model">
    <NS1:simulation xmlns:NS1="http://www.cellml.org/metadata/simulation/1.0#" RDF:resource="rdf:#$QQv43"/>
  </RDF:Description>
  <RDF:Description RDF:about="rdf:#$4SdBX3">
    <RDF:first RDF:resource="rdf:#$5SdBX3"/>
    <RDF:rest RDF:resource="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/>
  </RDF:Description>
  <RDF:Description RDF:about="rdf:#$3SdBX3">
    <NS1:boundIntervals xmlns:NS1="http://www.cellml.org/metadata/simulation/1.0#" RDF:resource="rdf:#$4SdBX3"/>
  </RDF:Description>
  <RDF:Description xmlns:NS1="http://www.cellml.org/metadata/simulation/1.0#" RDF:about="rdf:#$5SdBX3" NS1:endingValue="100"/>
  <RDF:Description xmlns:NS1="http://www.cellml.org/metadata/simulation/1.0#" RDF:about="rdf:#$SQv43" NS1:endingValue="100" NS1:nonstandard-pointDensity="10000"/>
  <RDF:Description xmlns:NS1="http://www.cellml.org/metadata/simulation/1.0#" RDF:about="rdf:#$d2Cb93" NS1:nonstandard-pointDensity="100000"/>
  <RDF:Description RDF:about="http://www.cellml.org/models/guyton_angiotensin_2008_version02/download#angiotensin_CellML1_0_model#LfY7zdZ%60EYs">
    <NS1:simulation xmlns:NS1="http://www.cellml.org/metadata/simulation/1.0#" RDF:resource="rdf:#$b2Cb93"/>
    <NS1:simulation xmlns:NS1="http://www.cellml.org/metadata/simulation/1.0#" RDF:resource="rdf:#$3SdBX3"/>
  </RDF:Description>
  <RDF:Description RDF:about="rdf:#$QQv43">
    <NS1:boundIntervals xmlns:NS1="http://www.cellml.org/metadata/simulation/1.0#" RDF:resource="rdf:#$RQv43"/>
  </RDF:Description>
  <RDF:Description RDF:about="rdf:#$RQv43">
    <RDF:first RDF:resource="rdf:#$SQv43"/>
    <RDF:rest RDF:resource="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/>
  </RDF:Description>
  <RDF:Description RDF:about="rdf:#$b2Cb93">
    <NS1:boundIntervals xmlns:NS1="http://www.cellml.org/metadata/simulation/1.0#" RDF:resource="rdf:#$c2Cb93"/>
  </RDF:Description>
  <RDF:Description RDF:about="rdf:#$c2Cb93">
    <RDF:first RDF:resource="rdf:#$d2Cb93"/>
    <RDF:rest RDF:resource="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/>
  </RDF:Description>
</RDF:RDF>


<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:ns7="http://www.cellml.org/metadata/simulation/1.0#">
  <rdf:Description rdf:about="rdf:#$QQv43">
    <ns7:boundIntervals rdf:resource="rdf:#$RQv43"/>
  </rdf:Description>
  <rdf:Description rdf:about="#angiotensin_CellML1_0_model">
    <ns7:simulation rdf:resource="rdf:#$QQv43"/>
  </rdf:Description>
  <rdf:Description rdf:about="rdf:#$c2Cb93">
    <rdf:rest rdf:resource="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/>
    <rdf:first rdf:resource="rdf:#$d2Cb93"/>
  </rdf:Description>
  <rdf:Description rdf:about="rdf:#$b2Cb93">
    <ns7:boundIntervals rdf:resource="rdf:#$c2Cb93"/>
  </rdf:Description>
  <rdf:Description rdf:about="#general_angiotensin_multiplier">
    <rdf:value>
				AN15:  
				This is an equation that allows one to convert the concentration of angiotensin (ANC) 
				into an angiotensin multiplier (ANM) which describes the multiplicative effect of 
				angiotensin on various physiological functions, assuming the normal value of ANM 
				to be 1.0.  The value ANMUL is the upper limit to the level of ANM.  ANMLL is the 
				lower limit of ANM.  And the value ANCSNS is a sensitivity value for adjusting the 
				quantitative effect of ANC on ANM.
				</rdf:value>
  </rdf:Description>
  <rdf:Description rdf:about="#angiotensin">
    <rdf:value>
				Encapsulation grouping component containing all the components in the Angiotensin Model. The inputs and 
				outputs of the Angiotensin Model must be passed by this component.
				</rdf:value>
  </rdf:Description>
  <rdf:Description rdf:about="rdf:#$5SdBX3">
    <ns7:endingValue>100</ns7:endingValue>
  </rdf:Description>
  <rdf:Description rdf:about="rdf:#$4SdBX3">
    <rdf:rest rdf:resource="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/>
    <rdf:first rdf:resource="rdf:#$5SdBX3"/>
  </rdf:Description>
  <rdf:Description rdf:about="#instantaneous_angiotensin_formation">
    <rdf:value>
				AN1:  
				This block damps the variations in rate of fluid flow in the renal tubules at 
				the macula densa (MDFLW).  The damped outflow is the variable MDFLW3.
				NB - REMOVED DAMPING FORM AN1!!!!

				AN2:  
				This block calculates the formation rate of angiotensin (ANGSCR) at different 
				levels of MDFLW3.
				</rdf:value>
  </rdf:Description>
  <rdf:Description rdf:about="#angiotensin_effect_on_circulation">
    <rdf:value>
				AN16, AN17, and AN18:  
				These blocks are a sensitivity controller for converting the basic effect of the 
				angiotensin multiplier (ANM) on other functional systems of the circulation (ANU).  
				The sensitivity adjustment is the factor ANUM in Block 17.

				AN19:  
				This block sets the lower limit to which ANU can fall (ANULL).
				</rdf:value>
  </rdf:Description>
  <rdf:Description rdf:about="#angiotensin_concentration">
    <rdf:value>
				AN12, AN13, and AN14:  
				These blocks convert the rate of entry of angiotensin into the body fluids (ANPR1), 
				into the concentration of angiotensin (ANC) considering the normal value to be the 
				numeral 1.  The value ANT is the time constant for rate of change of angiotensin 
				concentration in the body fluids.  The value Z12 is a damping coefficient to allow 
				damping of this conversion so that the model can be run faster for long-term simulations.
				</rdf:value>
  </rdf:Description>
  <rdf:Description rdf:about="#time_delayed_angiotensin_formation">
    <rdf:value>
				AN4, AN5, AN6, AN7, and AN8:  
				Calculation of additional formation of angiotensin caused after a long-term delay.  
				That is, when the JG cells are stimulated over long periods of time, in addition to
				their acute effects on secretion rate of renin and subsequent formation of angiotensin,
				there is a long-term increase in numbers of active JG cells to give a long-term delayed 
				response over a period of days.  The variable ANXM adjusts the magnitude of this 
				delayed response.  ANX is the total response without regard to the time delay.  ANV is 
				the time-constant of the time delay.  ANX1 is the total extra secretion after factoring
				in the time delay effects of blocks 6, 7, and 8.
				</rdf:value>
  </rdf:Description>
  <rdf:Description rdf:about="rdf:#$3SdBX3">
    <ns7:boundIntervals rdf:resource="rdf:#$4SdBX3"/>
  </rdf:Description>
  <rdf:Description rdf:about="#artificial_angiotensin_formation">
    <rdf:value>
				AN11A:  
				This block allows the addition of infused angiotensin (ANGINF) to the amount of 
				angiotensin that is formed in the body (ANPR).

				AN11B:  
				This block allows one to disregard all the previous blocks and to set the total 
				rate of angiotensin entering the circulatory system (ANPR1) to a constant level, ANGKNS. 
				When ANGKNS is equal to zero or less, then Block 11B is ineffective.
				</rdf:value>
  </rdf:Description>
  <rdf:Description rdf:about="rdf:#$SQv43">
    <ns7:nonstandard-pointDensity>10000</ns7:nonstandard-pointDensity>
    <ns7:endingValue>100</ns7:endingValue>
  </rdf:Description>
  <rdf:Description rdf:about="#angiotensin_effect_on_venous_constriction">
    <rdf:value>
				AN20, AN21, and AN22:  
				Calculation of the effect of angiotensin on venous constriction (ANUVN), with 
				sensitivity controlled by ANUVM in Block 21.
				</rdf:value>
  </rdf:Description>
  <rdf:Description rdf:about="#angiotensin_CellML1_0_model#LfY7zdZ%60EYs">
    <ns7:simulation rdf:resource="rdf:#$b2Cb93"/>
    <ns7:simulation rdf:resource="rdf:#$3SdBX3"/>
  </rdf:Description>
  <rdf:Description rdf:about="rdf:#$RQv43">
    <rdf:rest rdf:resource="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/>
    <rdf:first rdf:resource="rdf:#$SQv43"/>
  </rdf:Description>
  <rdf:Description rdf:about="rdf:#$d2Cb93">
    <ns7:nonstandard-pointDensity>100000</ns7:nonstandard-pointDensity>
  </rdf:Description>
  <rdf:Description rdf:about="#total_angiotensin_formation">
    <rdf:value>
				AN9:  
				Summation of instantaneous formation of angiotensin (ANGSCR) plus the time delayed 
				formation of angiotensin (ANX1).

				AN10:  
				Calculation of the total rate of formation of angiotensin (ANPR) in case some of 
				the renal mass (and therefore some of the JG cells) has been removed or destroyed. 
				Factor REK is equal to the proportion of kidney mass that is still functional.

				AN11:  
				This sets the lower limit of ANPR to a very low level, almost zero, below which 
				this cannot fall.  The reason for this is to prevent a negative value from appearing.
				</rdf:value>
  </rdf:Description>
  <rdf:Description rdf:about="#angiotensin_CellML1_0_model">
    <rdf:value>
			This section calculates the control functions of angiotensin, beginning with the 
			control of angiotensin formation by the kidneys in response to changes in the rate 
			of flow of fluid in the renal tubules at the macula densa (MDFLW), and extending 
			through a series of curve-fitting and sensitivity controlled equations to determine 
			the multiple feedback effects of angiotensin to control the various aspects of 
			circulatory function.
			</rdf:value>
  </rdf:Description>
</rdf:RDF>
</model>