Www.physiome.org 1 SIAM Life Sciences, San Diego 2012.

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

www.physiome.org 3

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.

www.physiome.org 4

Pathways of Oxygen and Carbon Dioxide Transport and Exchange – A Big Picture

Exchange Systems


J.Bassingthwaighte www.physiome.org 5

Capillary-tissue exchange across a thin membrane:bolus injection at t=0


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


Adenosine Affect on Coronary Flow: Conflicting Observations?

www.physiome.org 7

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 = 1.7Hill coeff = 5

Stepp et al Circ Res 79: 601, 1996 Fig 6Kroll et al Circ Res 73: 846, 1993 Fig 2

www.physiome.org 8

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


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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

www.physiome.org 10

Sequestered Enzymes: switch-like behavior

A feature of branch-point competition


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


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

www.physiome.org 14

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


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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.


www.physiome.org 18

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


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

Www.physiome.org 1 SIAM Life Sciences, San Diego 2012.

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