Original Articles
The effect of arterial P<x on relative
retinal blood flow in monkeys
Gerard Eperon, Melvin Johnson, and Noble J. David
The relationship of blood oxygenation to retinal blood flow has been studied in rhesus
monkeys. Constriction of major retinal arteries and veins during hyperoxia and dilation during
hypoxia are demonstrated. Together with mean circulation times based on the technique of
fluorescein densitometry curves, these data allow an estimation of retinal blood flow, which
increases considerably in hypoxia and shows a moderate decrease in hyperoxia. These findings
indicate that the retinal circulation parallels that of the brain in adjusting to changes in
arterial Po, with compensatory changes in blood flow.
Key words: autoregulation, blood gases, densitometry, fluorescein angiography, hyperoxia,
hypoxia, microcirculation, monkeys, retinal blood flow, vasoconstriction, vasodilation.
R
vessels in man as vasodilation and vasoconstriction, respectively. Duguet, Dumont,
and Bailliart- measured an increase of some
20 per cent in retinal vessel diameters at an
altitude of 6,000 m. Sieker and Hickam'
reporting changes in retinal vascular reactivity in different disease states, measured
constriction following hyperoxia and dilation with hypoxia in the retinal arteries and
veins.
In 1959, Hickam and Frayser1 devised a
technique in man for estimation of retinal
venous oxygen saturation based on densitometry measurements taken from simultaneous red-green photography. Arteriovenous
oxygen difference was found to decrease
both in hyperoxia and hypoxia (5 minutes
of 10 per cent O2 in inspired air).5"7 Seeking a more direct estimate of blood flow,
Hickam and Frayser" in 1965 first utilized
serial fluorescein angiograms to develop a
method based on dye dilution curves constructed from optical densities measured on
fluorescein negatives. This method was also
'etinal circulation, like that of the
brain, is thought to be regulated almost
entirely by local metabolic conditions
rather than by neural control demonstrable
by other organs. The vascular bed of the
retina has been shown to be highly sensitive to the gas content of the blood, and its
accessability to photographic techniques
has allowed the study of vascular changes
down to the capillary level. In 1940, Cusick,
Benson, and Boothby' first recorded the
effects of anoxia and hyperoxia on retinal
From the Departments of Ophthalmology and
Neurology, University of Miami School of Medicine, and the Neurology Service, Veterans Administration Hospital, Miami, Fla.
Supported in part by Grant No. 5R01EY 0093 and
the Research Program, Veterans Administration
Hospital, Miami, Fla.
Submitted for publication May 23, 1974.
Reprint requests: Dr. Noble J. David, Veterans
Administration Hospital, 1201 N.W. 16 St.,
Miami, Fla. 33125.
342
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Effect of arterial Po2 on retinal blood flow 343
Volume 14
Number 5
chosen with minor modifications by Bulpitt
and Dollery," and Tsacopoulos and David,10
and may be considered the method of
choice insofar as estimation of retinal circulation time is concerned.
Tsacopoulos and David10 have shown
that retinal blood flow in monkeys increased consistently with an increase of
carbon dioxide partial pressure in the arterial blood. In this paper we demonstrate
with the same method, and in the same
animal, that the retinal blood flow is similarly sensitive to arterial blood oxygen
tension. To the best of our knowledge, the
only report of the effect of arterial blood
oxygenation on the retinal blood flow in
man is that of Hickam and Frayser." In this
paper we demonstrate the isolated effect
of varying Pao., over a wide range in the
monkey with particular emphasis on
hypoxia, which has received less attention
than hyperoxia from investigators of retinal
circulation.
Method
The basic principles of the method have been
described by Hickam and Fraysers and the details
of our technique by Tsacopoulos and David.10
The essentials will be recalled briefly here with the
few minor modifications used in this study.
Blood flow (V) of any vascular system can be
determined by the vascular volume (V) and the
mean circulation time ( t r ) :
V =
V
-
As an aliquot of the vascular volume the
diameter of the major retinal vessels (retinal
veins in this study) are measured on photographic
negatives taken with a Zeiss fundus camera
(providing a constant image when in focus).
Measurements are taken at seven to eleven specific
locations on the major veins in each experimental
state of the animal. They are expressed as per cent
of the control measurements and averaged. The
typical standard deviation of these measurements
for both arteries and veins is 4 to 5 per cent in
normoxia. These measurements actually indicate
change in the diameter of the red blood cell column but they can be taken as indirect measurements of change in vessel internal diameters since
both vary proportionately under different conditions of oxygenation.11 The change in diameter is
stable in man within five minutes after changing
the inhaled gas mixture.'' (i In our monkey experience, 15 minutes were necessary to reach an approximate steady-state of vessel diameter. The
length of the vessels, which may be used as a
conspicuous qualitative index of vessel reactivity
(tortuosity) can be neglected for blood-volume
estimation, since changes of this parameter for
different levels of Paco. are about 3 per cent
maximum,1" less than the uncertainty of the
measurements of the diameter (squared!) and unlikely to be of a different order of magnitude with
change in Pao,..
Mean circulation time (t r ) is obtained by subtracting the mean arterial transit time (t n ) from
the mean venous transit time (tv), measured from
the onset of injection:
Ctr = 1 , - 1 . ) .
The dilution curves were obtained in precisely
the same manner as previously described by
Tsacopoulos and David10 from this laboratory,
including attention to the following crucial details:
stability of the eye during photographic sequence,
dye dosage, and careful control of illumination
flash intensity, film development, and densitometry
readings. The fundus camera was identical to that
used, including filters and fiberoptic system for
monitoring the illuminating flash. Thirty minutes
after dye injection no trace of fluorescein could
be detected in the retinal vessels, and baseline
fluorescence could be taken as zero before another
trial was begun.
To compute the index of relative blood flow
the following formula was applied:
V,e.
trte)
Dv...
tr«)
Dv(c>
tr is the mean circulation time calculated as the
difference between the means of arterial and
venous transit times
t r = tv - Tn
"c" and "e" refer to control and experimental
states, respectively.
Dv(o)
—— is the mean ratio of the venous diameters
Dv<i-)
in experimental and control conditions.
Values for Pa0o, Paco., and pH were obtained
in each experimental state by a Blood MicroSystem (Radiometer, Copenhagen). Since the
measurements were not precisely reproducible, at
each blood-gas and pH determination three samples were taken, analyzed (maximum variation
was 10 per cent among the samples), and the
values averaged. In the controls, the ventilation
and the percentage of oxygen in the inspired mixture were adjusted to obtain normal values of
blood-gas partial pressures: in general, the percentage of oxygen was slightly above 21 per cent
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344 Eperon, Johnson, and David
and the ventilation approximately 180 c.c. per
kilogram per minute (rate: about 35 per minute).
When metabolic acidosis developed, pH was
adjusted to normal by the infusion of bicarbonate.1" Rectal temperature of the animals was
kept near 37.0° C , the temperature of the bloodgas analyzer.
Five general levels of Pao.. were studied: three
hypoxic, one control, and one hyperoxic, for each
animal. Sometimes four controls were performed,
one before each experimental trial, but most often
only two, one at the beginning and one before the
most severe hypoxia, which was always reserved
for the end of an experiment. The schedule of
the experimental conditions was varied in order to
avoid the possible ellect of the order of the different experiment states on results. The exception was prolonged hypoxia which might induce
change in vessel reactivity.1- The inspired mixture
was composed of different percentages of oxygen
and nitrous oxide, which provided light and continuous anesthesia, except during the relatively
short period of pure oxygen breathing. At that
time Pan. rose to about 400 mm. Hg, a lower
value than would be expected if linearity between
Ppo. in the inspired mixture and Pao. were
preserved,l:i a well-known effect of general anesthesia11- IS attributed to atelectasis. No attempt
was made to correlate Pa<>. with Ppo. (inspired
mixture) since this correlation may be loose.
Determination of blood-gases and pH values and
photographs for diameter measurements were
initiated 15 minutes after changing the gas mixture, at times sooner in severe hypoxia. This procedure occupied 10 minutes and was concluded
by serial photographs following fluorescein injection. Thirty minutes were then allowed for recovery at which time blood-gases and pH were
checked and corrections introduced as necessary.
We agree with Hickam and Frayser8 that this
estimate of relative blood flow is necessarily crude,
due to uncertainty in the computation of vascular
volume. Moreover, as pointed out by Ben-Sira and
Riva,1<; the fluorescein dilution curve method has
inherent limitations: (1) the fluorescein is largely
associated with the plasma alone (whose speed
does not necessarily reflect that of whole blood),
(2) fluorescence is absorbed by red cells and by
the dye itself so that fluorescence intensity is
affected differently according to repartition of the
dye s (center or periphery of the vessel). In spite
of these drawbacks and the tedium of the multiple
density readings, this method, which does little
to disturb the vascular system, appears not only
valid, but likely is the best available for documentation of retinal circulatory dynamics under different physiologic conditions.
This method has been criticized by Ben-Sira and
RivaUi who regard their photoelectric technique
as more accurate than any photographic method.
We would argue that most of their reservations are
Incest igatioe Ophthalmology
May 1975
no longer valid. The granularity of Plus-X film
does not limit sensitivity appreciably; determination of the initial dye appearance can be made
directly and checked by extrapolation. Stability of
flash intensity and stability of the eye have been
discussed previously. The variable slit, incorporated into a Leitz microscope and connected to
a densitometer (Photovolt Corporation, New York
City) allows a precise definition of the area to be
measured (a rectangle 200 /t wide whose other
dimension is the diameter of the vessel).
The fixed size of photosensitive area in the
photoelectric technique"1 cannot yield intensity
measurements truly representative of the fluorescein concentration at a given location on a
vessel. Even in the ideal and unlikely instance in
which diameter of the vessel exactly corresponds
to the diameter of the sensitive spot, measurements would be biased by unequal repartition of
dye across the vessel wall, since the center of the
vessel would have more effect on the measurement than the sides due to the circular format of
the spot. Moreover, Ben-Sira and Riva11' used
about twenty times less fluorescein with respect
to the weight of the animal than did other authors,
quite outside the range of linearity.s
Results
Control values for arterial blood gases.
pH, and pressure were (N = 43):
Pa 0 . : 95 ± 6 mm. Hg
Pa co ,: 38 ± 2 mm. Hg
pH : 7.40 ± 0.02
MAP: 114 ± 13 mm. Hg
(Mean arterial blood pressure [MAP]
equals the arithmetic mean of diastolic and
systolic pressures.)
In order to estimate the possible effect
on retinal circulation by factors other than
Pa,), we distributed the data into five
categories (Table I) according to the level
of blood oxygenation reached. The Pa()._.
values of these categories are:
Severe hypoxia:
35 ± 6 mm. Hg (N = 15)
Mild hypoxia:
59 ± 8 mm. Hg (N = 9)
Control (excluding initial control
values):
94 ± 6 mm. Hg (N = 26)
Mild hyperoxia:
204 ± 17 mm. Hg (N = 6)
Severe hyperoxia:
387 ± 44 mm. Hg (N = 9)
The initial control data of an experiment
was considered a reference value with
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Volume 14
Number 5
Effect of arterial Po2 on retinal blood flow 345
Table I
Severe
hypoxia
(27 mm. Hg
<Pa02
<47 mm. Hg)
PaO2
Mean
S.D.
n
P.*
Pat
PaCo2 Mean diff
S.D.
n
Part A
Pt
pH
Mean diff
S.D.
n
Pt
MAP Mean diff
S.D.
n
Pt
DlA a
Mean
S.D.
n
Pi
P2
PartB
DIAv
Mean
S.D.
n
P.
P2
CT
Mean
S.D.
n
Pi
P2
PartC
RBF
Mean
S.D.
n
Pi
P2
Mild
hypoxia
(50 mm. Hg
<Pa02
<77 mm. Hg)
3 7 . 0 - $p<0.001-64.1
8.4
6.8
9
15
<0.001
<0.001
<0.001
<0.001
Normal
(83 mm. Hg
<Pa02
<I08 mm. Hg)
97.2
7.5
15
n.s.
—
-4.0§
2.9
9
<0.01
-1.21F
3.1
15
-0.017§
0.075
15
n.s. (<0.2)
+0.025§
0.015
9
<0.005
+0.018H
0.043
15
n.s.
-19.3§
14.7
15
<0.001
-7.5 §
8.0
9
<0.01
-8.7ir
-2.2§
4.0
15
<0.05
Severe
hyperoxia
(315 mm. Hg
<Pa02
<470 mm. Hg)
Mild
h vperoxia
(185 mm. Hg
<Pao.z
<230 mm. Hg)
n.s.
18.8
15
n.s.
211.2—Jp<0.001—409.3
58.8
30.3
9
5
<0.001
<0.00l
<0.001
<0.001
-1.4§
2.1
5
n.s.(<0.1)
-3.6§
3.7
9
<0.01
+0.018§
0.022
5
n.s.(<0.1)
+0.019§
0.041
9
<0.0l
+0.6§
9.2
5
n.s.
95.05.3
+ 7.65}
11.8
9
<0.05
n. s.
-92.9
3.7
9
<0.001
<0.001
n s.
-92.9
5.1
9
<0.005
<0.001
120.4~-:tp<0.01—106.2
7.7
7.9
15
9
<0.02
<0.001
<0.001
<0.01
100.1
2.9
15
n.s.
—
n.s.
<0.01
134.0^$p<0.001—109.0
8.0
4.8
9
15
<0.001
<0.001
<0.001
<0.001
100.3
3.2
15
n.s.
—
93.67.9
5
n.s.
<0.01
n.s .
102.6
19.0
14
n.s.
—
103.0
11.5
9
n.s.
n.s.
101.2
20.0
14
n.s.
—
87.6
11.0
9
<0.005
<<0.00l
96.223.5
13
n.s.
n.s.
^98.6
12.5
9
n.s.
n.s.
197.6—tP<0.001—124.4
41.6
14.0
14
9
<0.005
<<0.001
<<0.001
<<0.001
5
°pi compares the mean of the experimental sample with the single value 100 per cent which represents no change.
fpa compares the mean of the experimental sample with the mean of the observed control (normal) states.
("p" values were obtained by matched-pair t-tests.
{Calculated as the mean of the differences between each experimental state and the normal state immediately preceeding.
^Calculated as the mean of all the differences between the first normal and each succeeding normal of each experiment.
which the values of later control observations, as those taken during experimental
states, were compared in each animal.
From Table I, Part A, it can be ascertained that the later controls do not differ
significantly from the initial as to PaCoj5
pH, and MAP. On the other hand, there
are, in some cases, definite changes of these
parameters as individual experimental data
are compared with the control values immediately preceding. These changes are
generally small, and amount to a maximum
of 4.0 mm. Hg and +0.025 for PaCo_, and
pH, respectively (both in mild hypoxia);
but the decrease in MAP in the severely
hypoxic condition is not negligible. Pilot
measurements of intraocular pressure
(IOP) showed a maximum change of 3
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346 Eperon, Johnson, and David
Inoestigative Ophthalmology
May 1975
J.IIO
ARTERIES
I I 0
2 0
VEIN S
P„ 0
..
20
4 0
60
80
100
80
200
400
600
Fig. 1, A and B. Relationship (individual results) between change in Pao2 and vessel diameter
(both expressed in per cent of first control). The insert depicts scatter of control values
subsequent to initial control. The logarithmic scale on the abscissa was chosen for convenience.
mm. Hg between experimental state and
control, the change also observed between
serial controls. The important parameter
for blood flow is the perfusion pressure,
defined as the difference between MAP
and IOP. Changes in IOP appear minor
and can be neglected all the more safely
because changes in IOP and MAP tend to
move in the same direction and cancel
their effects on perfusion pressure. Table
I, Part B, indicates the changes in vessel
diameter with corresponding changes in
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Effect of arterial Po2 on retinal blood flow
Volume 14
Number 5
347
UJ
4.J 4 0
40
60
80
100
200
400
600
Fig. 2. Relationship (individual results) between change in Pao. and circulation time (both
expressed in per cent of first control). The insert depicts scatter of control values subsequent
to first control. The logarithmic scale on the abscissa was chosen for convenience.
Pa,):,. In the same way the first control is
taken as reference so that subsequent controls are treated as experimental values
(repeat control observations). That sample did not differ significantly (for PaOL,,
PaO()^, pH, and MAP) with the fixed value
of 100 per cent as compared with the initial
control. The diameter of the arteries and
veins also did not vary significantly. The
comparison between experimental states
and controls is made in two ways: (1) the
experimental group is compared to the
initial control (taken as reference value
and made equal to 100 per cent); (2) the
experimental group is compared to repeat
control observations, or two experimental
groups are compared to each other. During
hyperoxia, both arteries and veins constrict
slightly and similarly. Changes in diameter
for the two levels of hyperoxia are not
significantly different. If one considers all
the data for hyperoxia together, the results
obtained for the diameter of the arteries
and veins is 93.6 ± 4.4 and 93.1 ± 5.9, respectively, in per cent of the reference. The
difference for both arteries and veins is
highly significant (p < 0.001). During
hypoxia, marked vasodilation occurs, more
obvious in the veins than in the arteries.
During mild hypoxia the increase in diameter is moderate but significant, whereas
with further fall in Pa o . the increase is 34
per cent and 20 per cent, respectively. These
results are significantly different from those
of both normal and mildly hypoxic levels.
Individual results are plotted in Fig. 1
(A and B) against per cent change in Pao.,
along a logarithmic scale chosen for convenience. The insert depicts the scatter of
the observed control data. In seven of the
animals two intermediate levels of moderate hypoxemia were investigated; the individual increase of diameter between these
two levels was not significant. Although
vessel reactivity seems to increase with a
decrease in Pa()l, in moderate hypoxia (a
nonlinear relationship) further vasodilation
eventually stops at the lowest Pao., values.
Finally, a roughly S-shaped curve may well
represent this relationship, although some
caution is necessary because of scattering
of the data.
Circulation time was calculated for each
experimental condition and each subsequent control as a percentage of the first
control. A pressure factor, the ratio of the
MAP of the experimental state to the MAP
of the first control was then introduced into
the results. This factor in an ideal system
cancels the effect of a change in pressure
on circulation time, since a change in pressure across the length of a tubing directly
changes the average speed of liquid (or
the flow itself) within the tube. In Fig. 2
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348 Eperon, Johnson, and David
Investigative Ophthalmology
May 1975
4. 140
.- 11 0
40
60
80
2 00
400
600
Fig. 3. Relationship (individual results) between change in Pao. and relative blood flow (both
expressed in per cent of first control, with the RBF corrected for pressure). The insert depicts
scatter of control values subsequent of first control. The logarithmic scale on the abscissa was
chosen for convenience.
are shown the individual results corrected
for pressure. The insert shows the scatter
of the subsequent control states. It can be
observed that the values are somewhat
spread out, especially in severe hypoxia.
In this condition some of the animals experienced a prolonged circulation time
even after correction for arterial pressure.
This observation must be ascribed to badly
altered hemodynamics, possibly involving
the whole body in that very unphysiologic
condition. The results were distributed into
the same categories as were used for the
diameters. The mild hyperoxic category
was omitted because it consisted of only
three values. The highest value obtained
in severe hypoxia shown in Fig. 2 seemed
erratic and was not included in the computation. The results are shown in Table I,
Part C. This slope is so slight that is is
not significantly different from horizontal
(p < 0.1), but from the individual results
(Fig. 2) it seems very likely that the normal reaction to hypoxia is shortening of
the circulation time, obscured in the statistical analysis by only a few widely scattered values. The relative blood flow is
determined mainly by the change in vascular volume, which is represented by the
square of venous diameter, so that the
general relationship between percentage of
Pa()J and relative blood flow, corrected for
pressure (Fig. 3) is similar to that of the
diameter: there is a slight decrease in hyperoxia and a dramatic increase in hypoxia,
but in severe hypoxia there is no further
increase in blood flow compared to less
severe hypoxia; there is even a decrease
or plateau in five of the seven animals on
which two different low levels of PaOl, were
investigated. No precise estimate can be
given in severe hypoxia since the general
hemodynamic condition varies greatly from
animal to animal. It can be roughly stated
that under optimal conditions the retinal
blood flow can at least be doubled in hypoxia. The results for blood flow have been
distributed in the usual categories (Table
I. P a r t C ) .
Discussion
An inverse relationship between Pao2 and
estimated retinal blood flow is anticipated
in this study since a regulatory mechanism
compensating for variations in blood-oxygen content would seem appropriate to
supply a tissue with such a high metabolic
rate as the retina. It should be remembered
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Volume 14
Number 5
Effect of arterial Po2 on retinal blood flow 349
that blood-oxygen content is not linearly
related to PaoL>, e.g., elevation of Pa0o from
95 mm. Hg to 400 mm. Hg results in only
a 10 per cent increase in oxygen content
(oxygen fixed on hemoglobin plus dissolved
oxygen). Considering the latter increment
in oxygen delivery, our findings of the decrease of retinal blood flow in hyperoxia
appear to compensate approximately for
change in blood oxygenation. This finding
contrasts with the results of Hickam and
Frayser'1 who measured a retinal blood flow
equal to 57 per cent of control in subjects
breathing pure oxygen. This marked reduction together with a decrease of arteriovenous blood-oxygen difference yielded
oxygen uptake estimations as low as 44
per cent of control,'"" a reduction which
has been ascribed to oxygen delivery to
the retina by the choriocapillaris.ir' The
respiratory conditions of Hickam and Frayser'ss human subjects were not controlled.
Other differences in experimental conditions make comparison with our results
difficult: a different species observed in
our study under anesthesia and after a
longer interval between change in inhaled
gas mixture and measurements. Hickam
and FrayserV estimates of retinal circulation time are based on only five subjects.
Nonetheless, we are inclined to believe
a real species difference is indicated by our
results, especially since we measured less
vasoconstriction in hyperoxia than did they.
Our results neither support nor exclude
the theory of a large oxygen supply from
the choroid to the outer layers of the retina,
although in hyperoxia significant reduction
in blood flow has not been observed in the
brain.14- 17 One study indicates a possible
parallel reduction of choroidal blood flow
in hyperoxia in rabbits.1S Hypoxia produced
an important increase in blood flow due to
vasodilation. Reduction of Pa,), below a critical level failed to produce any further increase in flow even when correction was
introduced for changes in systemic arterial
pressure, probably because maximal vascular dilation had already occurred. Hickam
and Frayser" found a 16 per cent increase
in blood flow and a 15 per cent reduction
in oxygen delivery for man breathing a
10 per cent oxygen gas mixture. This appears to be a small change in flow compared with our results. Hickam, Frayser,
and Ross4 and Hickam and Frayser''' found
that breathing 10 per cent oxygen produced
an arterial saturation of 70 per cent, which
corresponds to an arterial oxygen tension
of 37 mm. Hg19; at this level of blood oxygenation, the change in flow (even before
any pressure correction) was greater in
our experiments. Again, comparison is difficult clue in part to the small number of
individuals in their study-0 and the scatter
of our results with such low levels of blood
oxygenation. If mean arteriovenous oxygen
can be estimated at 75 per cent of normal
and if such a decrease is to be compensated
by comparable change in blood flow, a 33
per cent increase is expected. In our experiments hypoxia appears to have been
amply compensated in most animals.
An interesting difference between retina
and brain in different experimental conditions is the "threshold" at which cerebral
blood flow is increased in hypoxia14- 17> -';
there is no augmentation above a Pa<>., of
50 mm. Hg and a sharp rise around 30 mm.
Hg. No such threshold is apparent in the
retina. A few remarks must be added concerning the two parameters used in its
computation. The vessels, depending upon
their size, neither constrict nor dilate to
the same extent. Dollery and co-workers2have shown that the largest vessels, especially the veins, dilated proportionately
less than those three times smaller in diameter which are still measurable on fundus
photographs. The smallest vessels, most important in determining the resistance of
the vascular bed, are not accessible for
measurements.
The transit time, even after correction
for pressure, did not undergo any significant change at different Pai)2 levels. This
was unexpected, since flow is supposed to
change with variations in vascular resistance caused by variations in vessel diameter. Vasodilation of the smallest vessels
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350 Eperon, Johnson, and David
' Ophthalmology
May 1975
Fig. 4. Comparison Huorescein angiograms of same eye, A, in control condition, and B, in hypoxia (breathing 10 per cent O-). Note vessel dilation and increase in fluorescence intensity in B.
in hypoxia is conspicuous in fundus photographs (Figs. 4 and 5). Hickam and Fraysers also failed to record any significant
change in circulation time in hypoxia.
The use of the correction factor for
pressure was made in an attempt to cancel
the effect of this variable on retinal circulation time and blood flow. The correction
factor does not alter the general relationship; uncorrected results also show a definite increase in blood flow in hypoxia and
a moderate reduction in hyperoxia. So do
the results based on the average of controls
in one experiment rather than the first only
(corrected or not). The prominent effect
of the correction was a reduction ol the
scatter.
Blood flow is only the first in a series of
variables occurring between a change in
blood-oxygen content and its use by retinal
cells. A fuller understanding of the physiology of retinal oxygen supply requires some
knowledge of tissue oxygen tension and
consumption. In the cat, periretinal vitreous
oxygen tension does not vary much with
a decrease in PaUL..n It is worth noting that
a decrease in tissue oxygen tension does
not necessarily imply a decrease in consumption. In the brain, no significant
change of oxygen consumption has been
found in severe hypoxia.17' -:<
Concerning the metabolism of the retina,
important questions are yet to be solved:
what is the minimum oxygenation level
required to support normal oxygen consumption? When does functional hypoxia
begin? These two levels are not necessarily
the same, as pointed out for the brain by
Kety and Schmidt.21 McDowell11 observed
a change in the electrocorticogram virtually
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Volume 14
Number 5
Effect of arterial Po^ on retinal hlood flow
351
Fig. 5. Fluorescein angiogram taken between arterial and venous peak intensities with the
monkey breathing 10 per cent OJ. Note capillary detail around macular area.
as soon as blood flow increased in hypoxia.
Another important question, which this experiment does not intend to answer, is the
way by which hypoxia acts on the vessel
wall and the blood flow. In the brain it
has been convincingly demonstrated by
Kogure and co-workers-1 that a local parenchymal acidosis through anaerobic glycolysis (due probably to increased lactate)
is the active factor. Wahl and co-workers-1
confirmed this conclusion by a different approach: local injection of acidic or basic
solutions brought about respective vasodilation or vasocon.striction. This observation favors the hypothesis that the vascular
adjustment to a change in both Pao.. and
Pa<;o., would be mediated, probably in the
retina, as well as in the brain, by a change
in pH in the tissue. The fact that in the
present experiments, arterial pH virtually
does not change in hypoxia, is not evidence
against the role of tissue pH as a vasoregulator. In the experiments of Shimojyo and
co-workers17 hypoxia produced a significant
shift of arterial pH toward basic values.
Increase in blood flow mediated by pH
may be more important to flush out lactatcs
produced by anerobic glycolysis than to
provide oxygen.
This study, in conjunction with that of
Tsacopoulos and David,10 has demonstrated
that there is a sensitive mechanism in the
retina, providing appropriate vascular adjustments to changes in the gas content of
blood. Since all these experiments were
made in conditions of controlled ventilation with a careful adjustment of arterial
P,,,, P(•,,-„-, and pH, it has been shown how
these two gases, independently of each
other, influence the retinal circulation in
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352 Eperon, Johnson, and David
Investigative Ophthalmology
May 1975
monkeys. It has been demonstrated in this
paper that a change in blood oxygenation
may be as effective as a change in blood
carbon dioxide content in altering blood
flow. We would speculate that hypoxia as
well as hypercapnia both increase the retinal blood flow by a common mechanism,
namely an increase in [H+] concentration.
The authors wish to acknowledge the contributions of Marcos Tsacopoulos, M.D., who established this laboratory method, Mr. Lyman Hazelton, who served as mathematician and computer
programmer, and Miss Rita Stein, who prepared
the manuscript.
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