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Purine Degradation in Cardiac Endothelial Cells
Studies in isolated KRB-perfused guinea pig
heart.
Guinea pig has xanthine oxidase, which binds and
oxidizes both Hx and Xa.
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The Multiple-tracer Indicator Dilution Experiment
The multiple indicator dilutions study in an
isolated perfused heart experiment. A set of
three tracers, albumin demarcating the
intravascular transport, L-glucose, limited to
vascular interstitial space, and the target
D-glucose, that enters cells. The model analysis
is to determine the rates and mechanisms of
D-glucose permeation into endothelial and cardiac
cells.
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Pathways of Oxygen and Carbon Dioxide Transport
and Exchange A Big Picture
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Capillary-tissue exchange across a thin
membranebolus injection at t0
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Competition for Tracer Transporters by High
Adenosine
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Adenosine Affect on Coronary Flow Conflicting
Observations?
Exogenous Source of Adenosine Infusion into
Coronary Artery. Anesthetized Dog
Endogenous Source of Adenosine Blocking Ado
Kinase --gt Release from Cells. Guinea pig heart
Hill coefficient 1.7
Hill coeff 5
Kroll et al Circ Res 73 846, 1993 Fig 2
Stepp et al Circ Res 79 601, 1996 Fig 6
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Cell-cell interaction in vasoregulation
ATP escapes from the cell during ischemia or
hypoxia. Adenosine too. Alkaline phosphatase in
the ISF at the arteriolar terminae hydrolyzes ATP
to adenosine, activating A2 receptors on vascular
smooth muscle, causing relaxation. See work by
Schraders group Circ Res 15oct04
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Cell-cell interaction in vasoregulation of local
flow
Iodotuberocidin block
Adenosine is a vasodilator, by activating A2
receptors on smooth muscle cells. Using
vascularly infused adenosine has direct access to
endothelial cells, but not to myocytes or smooth
muscle cells. Likewise, venous effluent of
adenosine released from muscle cells is reduced
by endothelial uptake.
(after Kroll, Am.J.Physiol.2722563,1997)
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Sequestered Enzymes switch-like behaviorA
feature of branch-point competition
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Strange Competition among Binding Sites
kD Concn
Transporter 10-1 mM 0.01, 10,
100 mM Receptor 10-3 mM
10-4 mM
Switch-like receptor kinetics at Sin 10-5
mM Sout 100 mM
Increasing the concentration of low affinity
transporters, receptor appear cooperative.
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Model Spatial Diffusion with Competition
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Model fits to PCr and ATP during repeated
underperfusion of rabbit heart
Gustafson 510.3
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Ado Kinase is blocked by iodotuberocidin causing
Ado release
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FunctionalModulesof the Cardiome
Neurohumoral
regulation
System
Circulatory
system
dynamics
Whole ventricular
Organ
anatomic model
Myocardial
Action potential
Coronary
Tissue
mechanics
system
propagation
Excitation
-
Ionic
Cross
-
bridge
Myofilament
contraction
currents
cycling
activation
coupling
Cell
adenosine
Cell signaling
Purine
metabolism
ATP,
PCr

substrates
Mitochondrial
metabolism
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With EHNA blocking Ado deaminase, release of
endogenous Ado increases coronary blood flow
Iodotuberocidin blocks adenosine kinase (inside
cells), resulting in Ado release into ISF,
smooth muscle relaxation, and increased flow
(Hill coeff. 1).
Model calculation based on indicator dilution
data on capillary wall permeabilities
Kroll et al Circ Res 73 846, 1993 Fig 2
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Conclusions with respect toadenosine modulation
of vasomotion

• Apparent discrepancy in parameter estimates is
  almost reconciled by a multiscale model
  incorporating both the anatomy and the
  physiological kinetics.
• Restricted access and competition can appear to
  give high cooperativity when it is really due
  only to competition.
• In general, multicellular models are needed to
  understand the physiology.

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This is a treasure-house of information,
philosophy and logic. Its high class
entertainment too. Agreeing neither with Dawkins,
author of The Selfish Gene nor with those who
believe the gene carries the recipe for life,
Denis provides a perspective embracing environment
, gene, and circumstance, and leads us to the
understand that physiology is necessarily
integrating all these. ..jbb
135pp. Oxford University Press 2006
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A whole heart is like two sarcomeres in series
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Strain Patterns with Asynchronous Activation of a
Two Segment Ventricle
Tension developed by the two elements in
series Ventricular Pressure
Modification of Landesberg and Sideman 4-state
crossbridge model by Brian Carlson
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Energy consumption is higher in the
late-activated region
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A circulatory model with pressure flow
dynamics,baroreceptor and chemoreceptor feedback
The Classical Wiggers diagram of the cardiac
cycle

• For examples of incremental development from
  primitive models see Tutorials at
  www.physiome.org/Models/tutorial.html