www.physiome.org 1 siam life sciences, san diego 2012
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www.physiome.org 1SIAM Life Sciences, San Diego 2012
www.physiome.org 2
Purine Degradation in Cardiac Endothelial Cells
Alb(intravascular)
AraH(extracellular)
Ado
Ino
Hx
Uric Ac.
Guinea pig has xanthine oxidase, which binds and oxidizes both Hx and Xa.
Ado
Ino
Hx
Xa
UA
XO
XO
Studies in isolated KRB-perfused guinea pig heart.
SIAM Life Sciences, San Diego 2012
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The Multiple-tracer Indicator Dilution Experiment
SIAM Life Sciences, San Diego 2012
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.
www.physiome.org 4
Pathways of Oxygen and Carbon Dioxide Transport and Exchange – A Big Picture
Exchange Systems
SIAM Life Sciences, San Diego 2012
J.Bassingthwaighte www.physiome.org 5
Capillary-tissue exchange across a thin membrane:bolus injection at t=0
SIAM Life Sciences, San Diego 2012
www.physiome.org 6
Competition for Tracer Transporters by High Adenosine
from Schwartz et al., Am. J. Physiol. 279: H1502-H1511, 2000
14C-Ado extractionat multiple levels of background Ado: Best estimate of parameters of theAdo Transporter:
Km = 112M,Vmax = 0.25 mol.min-1cm-2
with S =500 cm2/g
Km
SIAM Life Sciences, San Diego 2012
Adenosine Affect on Coronary Flow: Conflicting Observations?
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Endogenous Source of Adenosine: Blocking Ado Kinase --> Release from Cells.
Guinea pig heart
Exogenous Source of Adenosine: Infusion into Coronary Artery.
Anesthetized Dog
SIAM Life Sciences, San Diego 2012
Hill coefficient = 1.7Hill coeff = 5
Stepp et al Circ Res 79: 601, 1996 Fig 6Kroll et al Circ Res 73: 846, 1993 Fig 2
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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
H2O O2
ATPAlkal.Pase
SIAM Life Sciences, San Diego 2012
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Cell-cell interaction in vasoregulation of local flow
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.
H2O O2
(after Kroll, Am.J.Physiol.272:2563,1997)SIAM Life Sciences, San Diego 2012
Iodotuberocidin block
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Sequestered Enzymes: switch-like behavior
A feature of branch-point competition
SIAM Life Sciences, San Diego 2012
enzymes giving branch-point ultrasensitivity.(Walsh and Koshland JBC 1985)
2
E2 P2
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“Strange” Competition among Binding Sites
Transporter 10-1 mM 0.01, 10, 100 mMReceptor 10-3 mM 10-4 mM
kD Concn
Switch-likereceptor kinetics atSin = 10-5 mMSout = 100 mM
SIAM Life Sciences, San Diego 2012
Increasing the concentration of low affinity transporters, receptor appear cooperative.
www.physiome.org 12SIAM Life Sciences, San Diego 2012
Model: Spatial Diffusion with Competition
Disf
Ino
Ino
nsr.bioeng.washington.edu
Model fits to PCr and ATP during repeated underperfusion of rabbit heart
Gustafson 510.3
Boston, 29Jan08J.Bassingthwaighte
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Ado Kinase is blocked by iodotuberocidin causing Ado release
FunctionalModules
of the Cardiome
Ionic currents
Excitation-contraction
coupling
Cross-bridgecycling
Coronary system
Purine metabolism:
[ATP], [PCr] …
Mitochondrialmetabolism
adenosine
substrates
Myofilamentactivation
Myocardial mechanics
Action potential propagation
Whole ventricular anatomic model
Circulatory system
dynamics
Neurohumoral regulation
System
Organ
Tissue
CellCellsignaling
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With EHNA blocking Ado deaminase, release of endogenous Ado increases coronary blood flow
Kroll et al Circ Res 73: 846, 1993 Fig 2
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
SIAM Life Sciences, San Diego 2012
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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.
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 embracingenvironment, 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
Antalya.19sep07 19
A whole heart is like two sarcomeres in series
Antalya.19sep07 20
Strain Patterns with Asynchronous Activation of a Two Segment “Ventricle”
Early:Shortensrapidly
Late:StretchedBeforeactivated
Early:Shortensrapidly
Tensiondevelopedby the two elements in series:“VentricularPressure”
Modification of Landesberg and Sideman4-state crossbridge model by Brian Carlson
Antalya.19sep07 21
Energy consumption is higher in the late-activated region
Late
Early
Late
Early
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