SIAM Life Sciences, San Diego 2012
www.physiome.org 1
Purine Degradation in Cardiac Endothelial Cells
Alb(intravascular)
Ado
Studies in
isolated KRBperfused guinea
pig heart.
Guinea pig has
xanthine
oxidase, which
binds and
oxidizes both Hx
and Xa.
AraH(extracellular)
Ino
Ado
Hx
Ino
XO
Xa
XO
Hx
SIAM Life Sciences, San Diego 2012
Uric Ac.
UA
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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.
SIAM Life Sciences, San Diego 2012
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Pathways of Oxygen and Carbon Dioxide
Transport and Exchange – A Big Picture
Exchange Systems
SIAM Life Sciences, San Diego 2012
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Capillary-tissue exchange across a thin membrane:
bolus injection at t=0
SIAM Life Sciences, San Diego 2012
J.Bassingthwaighte
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Competition for Tracer Transporters by High Adenosine
14C-Ado
extraction
at multiple levels
of background Ado:
Best estimate of
parameters of the
Ado Transporter:
Km = 112mM,
Vmax = 0.25
mmol.min-1cm-2
Km
with
S =500 cm2/g
from Schwartz et al., Am. J. Physiol. 279: H1502-H1511, 2000
SIAM Life Sciences, San Diego 2012
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Adenosine Affect on Coronary Flow:
Conflicting Observations?
Endogenous Source of Adenosine:
Blocking Ado Kinase --> Release from Cells.
Guinea pig heart
Exogenous Source of Adenosine:
Infusion into Coronary Artery.
Anesthetized Dog
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
SIAM Life Sciences, San Diego 2012
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Cell-cell interaction in vasoregulation
O2
H2O
Alkal.Pase
ATP escapes from the
cell during ischemia or
hypoxia. Adenosine too.
ATP
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
SIAM Life Sciences, San Diego 2012
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Cell-cell interaction in vasoregulation of local flow
H2O
O2
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.
SIAM Life Sciences, San Diego 2012
(after Kroll, Am.J.Physiol.272:2563,1997)
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Sequestered Enzymes: switch-like behavior
A feature of branch-point competition
E2
2
SIAM Life Sciences, San Diego 2012
P2
enzymes giving branch-point ultrasensitivity.
(Walsh and Koshland JBC 1985)
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“Strange” Competition among Binding Sites
kD
Transporter
Receptor
10-1 mM
10-3 mM
Concn
0.01, 10, 100 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.
SIAM Life Sciences, San Diego 2012
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Model: Spatial Diffusion with Competition
Disf
Ino
Ino
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Model fits to PCr and ATP during
repeated underperfusion of rabbit heart
Gustafson 510.3
nsr.bioeng.washington.edu
Ado Kinase is
blocked by
iodotuberocidin
causing Ado
release
Boston, 29Jan08
J.Bassingthwaighte
www.physiome.org 14
Neurohumoral
regulation
Functional
Modules
of the
Cardiome
System
Circulatory
system
dynamics
Whole ventricular
anatomic model
Coronary
system
Myocardial
mechanics
Cross-bridge
cycling
Organ
Action potential
propagation
Myofilament
activation
Excitationcontraction
coupling
Tissue
Ionic
currents
Cell
adenosine
substrates
Purine
metabolism:
[ATP], [PCr] …
Mitochondrial
metabolism
Cell
signaling
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
SIAM Life Sciences, San Diego 2012
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Conclusions with respect to
adenosine 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.
SIAM Life Sciences, San Diego 2012
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This is a treasure-house of
information, philosophy and logic.
It’s 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
SIAM Life Sciences, San Diego 2012
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A whole heart is like two sarcomeres in series
Antalya.19sep07
19
Strain Patterns with Asynchronous Activation
of a Two Segment “Ventricle”
Late:
Stretched
Before
activated
Tension
developed
by the two
elements
in series:
“Ventricular
Pressure”
Early:
Shortens
rapidly
Modification of Landesberg and Sideman
4-state crossbridge model by Brian Carlson
Antalya.19sep07
20
Energy consumption is higher in the
late-activated region
Late
Early
Early
Late
Antalya.19sep07
21