Oxygen Transport to Tissue. Satellite Symposium of the 28th International Congress of Physiological Sciences, Budapest, Hungary, 1980

317 Pages·1981·15.842 MB·English

by  A. G. B. Kovách, E. Dóra and M. Kessler (Eds.)

ADVANCES IN PHYSIOLOGICAL SCIENCES
Proceedings of the 28th International Congress of Physiological Sciences
Budapest 1980
Volumes
1 Regulatory Functions of the CNS. Principles of Motion and Organization
2 Regulatory Functions of the CNS. Subsystems
3 Physiology of Non-excitable Cells
4 Physiology of Excitable Membranes
5 Molecular and Cellular Aspects of Muscle Function
6 Genetics, Structure and Function of Blood Cells
7 Cardiovascular Physiology. Microcirculation and Capillary Exchange
8 Cardiovascular Physiology. Heart, Peripheral Circulation and Methodology
9 Cardiovascular Physiology. Neural Control Mechanisms
10 Respiration
11 Kidney and Body Fluids
12 Nutrition, Digestion, Metabolism
13 Endocrinology, Neuroendocrinology, Neuropeptides — I
14
Endocrinology, Neuroendocrinology, Neuropeptides - II
15
Reproduction and Development
16
Sensory Functions
17
Brain and Behaviour
18
Environmental Physiology
19
Gravitational Physiology
20
Advances in Animal and Comparative Physiology
21
History of Physiology
Satellite symposia of the 28th International Congress of Physiological Sciences
22 Neurotransmitters in Invertebrates
23 Neurobiology of Invertebrates
24 Mechanism of Muscle Adaptation to Functional Requirements
25 Oxygen Transport to Tissue
26 Homeostasis in Injury and Shock
27 Factors Influencing Adrenergic Mechanisms in the Heart
28 Saliva and Salivation
29 Gastrointestinal Defence Mechanisms
30 Neural Communications and Control
31 Sensory Physiology of Aquatic Lower Vertebrates
32 Contributions to Thermal Physiology
33 Recent Advances of Avian Endocrinology
34 Mathematical and Computational Methods in Physiology
35 Hormones, Lipoproteins and Atherosclerosis
36 Cellular Analogues of Conditioning and Neural Plasticity
(Each volume is available separately.)
ADVANCES IN
PHYSIOLOGICAL SCIENCES
Satellite Symposium of the 28th International Congress of Physiological Science*
Budapest, Hungary 1980
Volume 25
Oxygen Transport to Tissue
Editors
A. G. B. Kovach
Budapest, Hungary
E. Dora
Budapest, Hungary
M. Kessler
Erlangen, FRG
I. A. Silver
Bristol, England
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British Library Cataloguing in Publication Data
International Congress of Physiological Sciences.
Satellite Symposium (28th : 1980 : Budapest)
Advances in physiological sciences.
Vol. 25: Oxygen transport to tissue
1. Physiology - Congresses
I. Title II. Kovach, A. G. B.
591.1 QP1 80-42249
Pergamon Press ISBN 0 08 026407 7 (Series)
ISBN 0 08 027346 7 (Volume)
Akademiai Kiado ISBN 963 05 2691 3 (Series)
ISBN 963 05 2751 0' (Volume)
In order to make this volume available as economically and as
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Printed in Hungary
PREFACE
The Fourth Symposium on Oxygen Transport to Tissue, as a Satellite
of the 28th International Congress of Physiological Sciences organized
by IUPS, was held in Budapest between July 9 and 11, 1980. This volume
contains those papers which were presented at the Symposium, together
with the essential discussions that followed.
The Organizing Committee of the Symposium put particular emphasis
on the following topics: heterogeneities and 0 transport; autoregulation of
2
blood flow and 0 delivery; oxygen transport and organ function; rheology
2
and 0 transport. We have been most fortunate to have outstanding con-
2
tributors for the individual presentations and to have most stimulating
discussions.
Our special thanks are due to Mrs Ilona Erdei, Miss Klara Szuchanek,
Mrs Elza Papp and Mrs Leona Vasas of the Experimental Research Depart-
ment and 2nd Institute of Physiology, Semmelweis Medical University,
Budapest, Hungary, whose help was invaluable in the organization of the
meeting.
A. G. B. Kovach
E. Dora
M. Kessler
I.A. Silver
xiii
Adv. Physiol. Sci. Vol. 25. Oxygen Transport to Tissue
A. G. B. Kova'ch, E. Ddra, M. Kessler, /. A. Silver (eds)
TISSUE OXYGEN SUPPLY AND CRITICAL
OXYGEN PRESSURE
D. W. Lubbers
Max-Planck-1nstitut fur Systemphysiologie, Rheinlanddamm 201, 4600 Dortmund 1, FRG
Recently it has been questioned whether it is still sensible to use the
term "critical oxygen pressure" as an essential parameter to describe
tissue hypoxia or anoxia. In the following I like to show the usefulness
but also the limitation of this expression. Since the expression was coined
from physiological experiments I will begin to discuss these physiological
results.
It is well known that for the whole animal as well as for the isolated
organ in a certain range the consumption, vo, is independent of the
2
offered by the respired gas mixture or by the arterial blood (see for ex-
ample 19, 15, 4). When oxygen is reduced below this range a reaction
threshold is reached and compensatory mechanisms are put into action to
maintain the 0 consumption - and thus the energy consumption - at the
same level. But there is a point at which the compensatory mechanisms
are exhausted: This state can be called "critical threshold or critical
state of oxygen supply" or simply "critical oxygen supply". It means,
in this state the oxygen supply limits the oxygen consumption. The situa-
tion of a critical supply has been studied so extensively that it is
impossible to review or even mention the main experimental work; instead
of that, I shall discuss some examples to elucidate our problem. In the
earlier experiments the different criteria for a sufficient oxygen supply
that were applied, were: 1) oxygen consumption, 2) lactate balance, and
3) functional state. As later on measurements of tissue concentrations
became possible, the tissue concentration of lactate, pyruvate and adenine
nucleotides or a relationship such as the lactate/pyruvate ratio, the
phosphate potential or the energy charge (see Siesjo, 1978) were used.
1) The consumption criterion was used by Stainsby (1966). He measured
the dependence of the consumption of dog skeletal muscles (mm. gastro-
cnemius - plantaris) on the arterial Po , P o . The critical situation of
oxygen supply was produced by reducing p02* occurred during rest at
a
a P o of 8 kPa (60 mm Hg) and a P o of 3.33 kPa (25 mm Hg) and daring
2
worS at a p_09 of kPa (50 ^ ^gj and a of 1,33 kPa (l0 ^ H<?) •
Although the 6 consumption during work was 8 times higher than during
rest (40 ,ul 0/g . min as compared to 5 ,ul . min), the blood Po
2 2
values during work were smaller. This difference can be explained by the
increased number of perfused capillaries in the working muscle which re-
duce the supply area of a single capillary, and by the increased flow. The
experiments demonstrated the strong influence of flow and capillary geo-
metry.
3
2) The lactate balance criterion was used by Bretschneider (1958). He meas-
ured the arteirio-venous lactate difference of the dog heart muscle. As long
as the supply of the heart muscle was sufficient, lactate was consumed.
Insufficient oxygen supply was accompanied by lactate production. Bret-
schneider showed that the transition point from lactate consumption to
lactate production could be related to the magnitude of the venous Po^,
independent of the way by which the critical oxygen supply was produced.
He found in normal dogs (vo = 150 ,ul 0 /g . min) the transition point
2
was at about P =0.8 kPa (6 mm Hg). At an consumption reduced to a
third (vo = 5$ - 80,ul 0 /g . min) it was reduced to a V^o^ =0.26 kPa
2
(2 mm Hg) and at doubled 6^ consumption (vo = 300 ,ul ' min) ifc w as
increased to 1.87 kPa (14 mm Hg). These different transition points are
in accordance with the changes of flow and tissue respiration.
3) The functional state criterion for supply was used by Opitz and
Schneider (1950) in their review and analysis of the oxygen supply of the
brain. They found that the functional state can be at best correlated with
the venous Po^ in the sinus sagittalis. The normal P o^ of 4.53 kPa (35
mm Hg) can decrease to ca 3.73 kPa (28 mm Hg) withou? any detectable
reaction but with a further decrease in P o blood flow increases to
maintain the P o close to this level. Further reduction of P o shows
first signs of changes in the ECG and in man higher mental functions are
impaired. The critical oxygen supply is reached when the P o becomes
smaller than 2.53 - 2.27 kPa (19 - 17 mm Hg). Under this condition man
looses consciousness. The changes, however, are still reversible. They
become irreversible when V^o^ is lowered to 1.6 kPa (12 mm Hg) over a
certain period of time.
The direct tissue measurements of lactate and adenine nucleotides corrobo-
rate these results (17). These examples show the complexity of our system
but they also demonstrate that there is a definite state at which a criti-
cal supply is reached. The occurrence of a critical 0 supply is in-
fluenced by many parameters but the venous Po^ - and not the venous O
content - seems to be an important indicator of tissue oxygen supply. How
can this be explained: It can be easily deduced from the physiological laws
of oxygen supply, which concern 1) the 0^ transport by blood 2) the 0^
transport by diffusion and 3) the behavior of tissue oxygen consumption.
1) 0^ transport by blood
The amount of oxygen which can be supplied to the tissue depends on a) the
oxygen content of blood, Co^, and b) blood flow, 6.
a) Oxygen content of blood. Under physiological conditions the main amount
of oxygen is chemically bound to hemoglobin
Co(c.hem) = 1. 34 . c . So
2 Rb 2
c , concentration of hemoglobin in g/dl; So^, fractional oxygen saturation;
1.J4, ml 0^ per g hemoglobin.
and only a small amount of oxygen is physically dissolved
Co(phys) = a . Po
2 p 2
a 0 solubility coefficient of plasma.
p/ 2
Thus the total amount of oxygen
Co(blood) = Co(chem) + Co(phys)
2 2 2
depends essentially on the hemoglobin concentration and the fractional
0 saturation. The fractional 0 saturation depends on the blood Pc^- This
2
dependence is described by the 0 dissociation curve.
o
4
b) Effect of flow. The 0 content of the arterial blood is offered and
delivered to the tissue. In steady state the difference between the 0
content of arterial and venous blood, the AVDo times blood flow corre-
2
sponds to the tissue respiration
(Ca°2 - Cv°2) • B = Y°2
AVDo
2
It is important to note that with constant tissue respiration the AVDo is
2
a hyperbolic function: that means that small flow changes are very effec-
tive in offering more 0^ or in reducing the 0 supply, whereas at high flow
the same absolute change has practically no effect.
2) (X, transport by diffusion
The oxygen transport within the tissue is mainly performed by diffusion.
The parameters, which govern the diffusion process can be easily seen from
the diffusion equation for a simple layer
D, diffusion coefficient; x, thickness of diffusion layer.
The C> flux, Io2' depends a) on the oxygen conductivity (D . ) and b) on
2 a
the Po gradient, A Vo^/& x.
a) In the product (D .a ) D determines the "spged" with which the molecules
travel - according to equation s = 6 D . t, s is the square of the mean
distance which the molecule travels during time t - and a gives the number
of molecules which actually travel. The oxygen conductivity (D .a ) char-
acterizes the individual property of the tissue; it increases with temper-
ature as well as with content of water and lipids, but under normal physi-
ological conditions its variation is only small.
b) The Po gradient is the important factor for the 0^ transport. We should
mention that fo£ diffusion of gases the oxygen pressure is the driving
force and not the oxygen content. This is especially important for systems
with varying values of a . The importance of the oxygen pressure for the 0^
transport in the tissue explains why the critical oxygen supply could be
correlated to the venous oxygen pressure and not to the venous oxygen
content of the blood.
Two other important factors which influence the diffusion are c) the
consumption and d) the distances over which the oxygen has to be trans-
ported. The influence of these factors can be shown in a simple model
consisting of a capillary which supplies oxygen to the surrounding cylin-
drical space (Krogh model (8))
with
z
c, capillary; t, tissue; z, cylinder.
This Krogh-Erlang equation shows that
c) the 0 consumption is linearly related to the oxygen pressure difference.
2
5
APo , which is necessary to transport the oxygen into the tissue and that
d) the geometry enters as approximately a squared function. This explains
rhat in the resting muscle with a few open capillaries and consequently a
large supply area a higher capillary Po is necessary to supply the tissue
2
with oxygen than in the working muscle.
Fig. 1
Calculated Po^ profile in resting and working skeletal muscle
Fig. 1 shows the calculated Po^ decrease in skeletal muscle assuming accord-
ing to Stainsby (1966) a radius of r = 80,um in resting and of r = 18 .urn
in the working state. One sees that the A £o„ of 1.8 kPa (13.5 mm Hg) in
the resting state is larger than the A Po of 0.35 kPa (2.6 mm Hg) in the
working state. In spite of an 8 times smaller 0^ consumption, the about
4 fold increase in radius (from IS to QO .urn) produces a Po decrease about
5 times larger in the resting than in the working muscle. Since in the
resting state the total amount of oxygen which has to leave a single capil-
lary is larger than that in the working state, the Po^ gradient in the
neighborhood of the capillary is much steeper in the resting state than
in the working state. This demonstrates directly how efficient the re-
duction of the radius of the tissue cylinder is in regard to the tissue
oxygen transport.
3) Behavior of tissue oxygen consumption
The main consumer of oxygen is oxidative phosphorylation. The reactions
involved are thoroughly discussed in other papers. For our point of view
it is important to note that the mitochondria with their respiratory chains
are perfect oxygen sinks. Under normal physiological conditions each mole-
cule of oxygen which meets the mitochondria reacts with the cytochrome
oxidase if ATP is needed so that the oxygen concentration becomes zero.
This means that the total capillary Po is available for the oxygen trans-
2
port.
With isolated mitochondria it has been shown (5, 2) that down to Po
2
values of 0.0027 kPa (0.02 mm Hg) the respiratory rate can remain un-
changed. This corresponds to an oxygen concentration of about 0.033,uM in
the medium; in lipids the actual concentration may be somewhat larger be-
cause of the higher a. Below this Po value the 0 consumption decreases.
6
With isolated mitochondria we could titrate the redox state of cytochrome
aa by adding stepwise very small amounts of oxygen (21,12). 100% oxida-
tion was reached at Po values in the medium of ca. 0.008 kPa (0.06 +0.07
mm Hg; n = 20), a Po value hardly detectable by a Platinum electrode.
These low critical Po values measured by the Pt electrode in steady state
2
could not be detected in kinetic measurements (20). Here the redox state
of cytochrome aa changed at Po^ values in the range between 0.2 kPa -
0.93 kPa (1.5 - 7 mm Hg). Whereas in steady state experiments a good re-
producibility could be achieved, the same was not possible in kinetic ex-
periments. This may have been caused by methodological artifacts:
1) Because of the finite response time of the Pt electrode the Po tracing
of the electrode runs behind the true Po of the medium and thereby falsi-
2
fies the true signal: the reading of the electrode is too high (and too
late).
2) The observed kinetics depends not only on the kinetics of the respira-
tory chain but also on the response time of the electrode.
3) Furthermore, it cannot be excluded that the mitochondria of the cells
have a fixed layer of medium which also would delay the electrode signal.
The exact determination of the critical Pc^' i#e' the deviation from linea-
rity, which indicates the change in respiratory rate, is diffucult since
the respiratory rate is not always sufficiently constant. For example, in
a test (n = 180) only about 50% of all curves showed a normal statistical
scatter of the respiratory rate (16). In all other cases systematic devia-
tions of the respiratory rate occurred; often - but the opposite is also
possible - the respiratory rate descreased slightly down to lower Po
2
values, in this case the point of deviation is found to be different with
a large Po range from that found with a small one: With large ranges the
2
critical Po was found between 1.87 and 1.47 kPa (14-11 mm Hg) and with
2
small ranges only between 0.4 and 0.13 kPa (3 - 1 mm Hg). Similar data
( 2o, 21, 12,) were found with liver, kidney and ascites tumor cells and
their corresponding mitochondria. The variation of the respiratory rate
was somewhat substrate-dependent. This points to the fact that constant 0
2
consumption and the entrance of limitations at the same Po level can only
2
be expected if the energy need and substrate supply remain unchanged. That
is obviously not always the case.
In general, then, our analysis suggests that in hypoxic tissue the region
with normal oxygen supply is surrounded by a zone of hypoxia in which the
0 concentration limits the 0 consumption. Under this condition the cri-
2 2
tical 0 supply is determined by the critical capillary Po which is
2
reached when in the periphery of the tissue the critical mitochondrial Po
is reached.
As already mentioned from tissue experiments it has been determined that
with decreasing 0 supply at first a reaction threshold is reached at which
2
for example blood flow increases before a critical state of oxygen supply
occurs. This leads to the important question of whether or not these re-
actions are caused by local critical hypoxia (Hypoxia hypothesis 15, 22).
We tried to answer this question experimentally. The Krogh-Erlang equation
shows that local tissue Po mirrors the capillary Po, oxygen conductivity,
2 2
tissue respiration and geometry, i.e. the local balance between oxygen
supply and oxygen consumption (lO).
7
frequency
n = 2010, 6 exp.
20-
ion
0 6 11 16 21 26 31 36 41U6B1 56 61 66 71 76 81 86 91
I 5 M0I15I20I25I30I35U0IA5I50I55I60I65I70I75I8OI85I90I95
ven. PO2 PO2 I mm Hg
Fig. 2
Pc>2 histogram of guinea pig brain
Fig. 2 shows for example the normal Po^ histogram of a brain (guinea pig,
light barbiturate anesthesia) (9). As expected, the local Po^ varies con-
siderably. It is interesting that 5% of all Po^ values are in the lowest
class. In this class values very close to zero (and sometimes not distin-
guishable from zero) are often found, without any sign of hypoxia. With Po^
needle electrodes (3) it is sometimes difficult to ascertain the exact zero,
but using membrane covered multiwire electrodes (7) it has been verified
that these low Po^ values occur in normal tissue. The Po^ histogram also
shows that many tissue Po^ values are much lower than the venous Po^ of
4.53 kPa (34 mm Hg). This points to the fact that the capillary network of
the tissue is much more complicated than assumed in the Krogh model. It
is known that capillaries have different lengths and consequently with the
same pressure gradient they must have different flow velocities.
Fig. 3 shows histograms of Po^ and of mean flow velocity from the surface
of a beating cat heart (18). With air respiration the Po histogram of the
heart muscle is shifted more to the right than that of the guinea pig brain.
The histogram of mean velocities measured by - pH clearance (13) shows
large differences in mean flow velocities. This is understandable if one
takes into account that the lengths of the capillaries in heart muscle vary
between 100 and 800,10311 with the maximum fraction having a length of 400.um.
These different capillaries will have different Po^ profiles and thus tne
venous Po is a mixture of the different capillary venous Po^ values.
Consequently, the absolute value of the mixed venous Po is not related in
a simple way to anoxic or hypoxic zones as assumed in the Krogh model.
Therefore, one needs very local methods such as the Po^ histogram to detect
such changes. To answer our question we found that flow velocity changed
despite no detectable anoxic Po^ values in tissue. We can therefore
assume that at decreasing 0 supply in the tissue a signal is produced
which has nothing to do with the critical state of oxygen supply which
concerns the energy need. What kind of signal that may be - whether a single
8