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From the Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth.
Abstract
PURPOSE. To describe the nature of oxygen level changes in specific layers in the rat retina under graded levels of systemic hyperoxia, with and without hypercapnia.
METHODS. Oxygen-sensitive microelectrodes were used to measure oxygen tension as a function of depth through the retina of anesthetized, mechanically ventilated rats. Breathing mixtures were manipulated to produce stepwise increments in systemic oxygen levels, with or without 5% CO2. Retinal arteriovenous oxygen differences were also measured as an indicator of oxygen delivery through the retinal circulation. Systemic blood gas levels were measured under each condition.
RESULTS. Hyperoxia increases PO2 throughout the retina to a varying extent in different retinal layers, with the increase more pronounced in the outer retina than in the inner retina. Simultaneous hypercapnia results in further increases in retinal oxygen levels. The lowest intraretinal oxygen level was consistently found in the inner plexiform layer (IPL), between the two capillary layers that support this region. There was a greater than fourfold increase in oxygen supply from the choroid with hyperoxia but, remarkably, the retinal circulation continued to provide a net delivery of oxygen to the retina.
CONCLUSIONS. Hyperoxia results in a significant but nonuniform increase in oxygen level in all layers of the rat retina, which is augmented by hypercapnia. The persistence of a minimum oxygen level in the IPL, despite the dramatic increase in oxygen flux from the choroid, suggests that oxygen consumption increases significantly in the IPL under hyperoxic conditions.
Oxygen is the primary biologic oxidant for energy production in mammalian cells.1 Alterations in oxygen supply to the retina are thought to play a role in many retinal diseases, and there have been numerous attempts at manipulation of the intraretinal oxygen environment as part of a therapeutic strategy. Retinal vascular occlusion has been treated with systemic hyperoxia alone2 (to increase retinal oxygen levels) or in combination with hypercapnia (to prevent the oxygen-induced contraction of the vessels), but the effect that this therapy has on intraretinal oxygen levels has yet to be quantified, even in a normal retina. Supplemental oxygen therapy in animal models of degenerative retinal diseases has recently been reported to slow down the progression of the disease if delivered at the appropriate stage.3 Oxygen therapy has also been reported to be beneficial in human patients with RP.4 In the developing retina in man and animals, the oversupply of oxygen can also lead to sight-threatening complications, and strategies for ameliorating the retinal consequences of systemic oxygen level changes have been put forward.5 6
Given the potential importance of strategies intended to manipulate the retinal oxygen environment by adjusting systemic parameters such as arterial oxygen and CO2 levels, it would be valuable if we were able to predict reliably the effect that such manipulations create within the retina. However, there are several confounding factors that make this task more difficult than might be anticipated.
The retina in man and most mammals receives its oxygen from both the retinal and the choroidal vascular systems, which have markedly different regulatory properties. There is also evidence that the two distinct capillary layers of the retinal circulation may react differently to systemic perturbations.7 The relationship between oxygen content of the blood and the PO2 level is greatly influenced by the properties of the hemoglobin saturation curve. The heterogeneous nature of the oxygen uptake in different retinal layers has been confirmed for the outer retina8 and may well be a feature of the inner retinal layers. The possibility that oxygen uptake may be influenced by oxygen level per se9 10 is a further confounding factor that limits our ability to predict intraretinal oxygen distribution in the face of systemic manipulations.
The growing use of rat models of retinal disease11 12 makes understanding the systemic parameters that influence the intraretinal oxygen environment in this species particularly important if subtle differences between healthy and diseased animals are to be exposed.11 12 13 The rat, in common with humans and primates, has a central retinal artery that branches out to form the retinal vascular network. This is not the case in most other animals, such as the cat and pig, in which the majority of intraretinal measurements of this type have been made.14 15 16
Because microelectrode-based technologies can be used to measure intraretinal oxygen tension as a function of retinal depth, direct measurements can be made under each of the systemic conditions of interest. We have demonstrated that such measurements can be closely correlated with key intraretinal landmarks such as the inner limiting membrane (ILM), the superficial and deep retinal capillary layers, the localized oxygen uptake of the inner segments of the photoreceptors, and the penetration of Bruch’s membrane in the rat.7 Comparison with histologic sections can then be used to determine the oxygen environment within the vascular structures and in each of the cell layers.7 To date, there has been no reported measurement of intraretinal oxygen distribution during stepwise increases in systemic arterial oxygen levels, nor has there been an intraretinal investigation into the effects of systemic hypercapnia. This report is intended to fill this gap in our knowledge and to serve as baseline data for comparison with future studies in rat models of retinal disease. This information is also likely to improve our understanding of the basic physiology of the mammalian retina in terms of the oxygen environment and the oxygen requirements of different retinal cell classes.
Methods
Animal Preparation
The rats (male, Sprague–Dawley) were housed two per cage on
sawdust with a 12 hour–12 hour light–dark cycle. Ambient light levels
were approximately 50 lux. They were fed standard laboratory rat chow
with water ad libitum. On the day of the experiment the rat was
anesthetized with an intraperitoneal injection of 100 mg/kg
5-ethyl-5-(1'-methyl-propyl)-2-thiobarbiturate (Inactin, Byk Gulden,
Konstantz, Germany). Atropine sulfate (20 mg) was administered
intramuscularly to minimize salivation. The trachea was cannulated for
mechanical ventilation, the left internal jugular vein for venous
infusion, and the femoral artery for continuous blood pressure
monitoring and occasional aspiration of arterial blood (60 µl) for
blood gas analysis (model 238; Ciba–Corning, Medfield, MA).
The rat was then mounted prone in a modified Stellar stereotaxic system
(model 51400; Stoelting, Chicago, IL) and the head fixed in position.
The rat was paralyzed with a loading dose of 8 to 16 mg gallamine
triethiodide, (40 mg/ml, Flaxedil; May and Baker, Dagenham, UK) into
the jugular vein and artificially respired (rodent respirator, model
683; Harvard Apparatus, Holliston, MA) with a ventilation rate of 90
breaths/min and a tidal volume appropriate to ensure normal arterial
PCO2 levels with air ventilation. Rectal
temperature was monitored and maintained at 37.5°C by a homeothermic
blanket (Harvard Apparatus). All procedures conformed to the ARVO
Statement for the Use of Animals in Ophthalmic and Vision Research.
Ocular Surgery
The left eye was used for all experiments. The pupil was dilated
with 1% tropicamide (Mydriacyl; Alcon, Sydney, Australia). The
upper eyelid was partially removed, and an eye ring was sutured to the
conjunctiva at the limbus and fixed to the stereotaxic framework. A
small incision was made in the superior nasal quadrant with a diamond
knife, just posterior to the limbus to allow entry of the
microelectode. Damage to the larger choroidal vessels or posterior lens
capsule was avoided. A planoconcave contact lens was placed on the
cornea to allow the vitreous and the fundus to be visualized using an
operating microscope during all intraocular manipulations.
Intraretinal Oxygen Profiles
The microelectrode techniques were similar to those reported in
our earlier publications,7
11
17
except that our electrode
orientation and manipulation system was upgraded to a fully motorized
system18
under either handheld joystick control or under
automatic computer control during a measuring sequence. Whalen-type
recessed oxygen-sensitive microelectrodes19
were
manufactured and calibrated in our own laboratory. The microelectrode
entered the left eye through the entry hole, which was also the locus
of rotation of our microsurgical system, so that rotation of the
positioning system pivots about the entry point into the eye. The small
size of the electrode tip (1 µm) coupled with electrode beveling
techniques and the high-acceleration piezoelectric translation of the
electrode produced highly reproducible measurements of intraretinal and
preretinal oxygen distribution. Intraretinal oxygen profiles were
measured in the inferior retina, approximately 2 to 3 disc diameters
from the disc margin. Experience has shown that highly reproducible
oxygen measurements and identification of key intraretinal landmarks
can be made in this region.7
The electrode tip was placed
at the surface of the chosen area of retina under microscope
observation. The electrode was then stepped through the retina, under
computer control, until a peak oxygen level was reached within the
choroid. The measurement was repeated during stepwise withdrawal of the
electrode. Although very close agreement between the insertion and
withdrawal profiles was routinely achieved, the withdrawal profiles
were used for data analysis, because they tended to be less influenced
by artifacts associated with mechanical stress on the electrode tip
during penetration. Preretinal vitreous measurements were performed by
orienting the electrode to touch the surface of a retinal artery or
vein. The oxygen tension measured by the microelectrode and systemic
conditions such as arterial blood pressure and rectal temperature were
recorded continuously on an eight-channel chart recorder (LR8100,
Yokogawa, Tokyo, Japan). The readings of each channel were also
accessed every two seconds through a computer interface (GPIB;
IEEE) and the data logged directly to a spreadsheet along with
the relative position of the microelectrode. All experiments were
performed in photopic conditions.
Systemic Conditions
Ventilation mixtures were selected in increasing percentages of
oxygen from 20% to 100% in increments of 20%, in either the presence
or absence of 5% CO2. No correction to the
oxygen percentage was applied when 5% CO2 was
used; thus, the corresponding oxygen percentages in the hypercapnia
trial ranged from 19% to 95% oxygen. Intraretinal and vitreal oxygen
measurements and blood gas analysis were repeated under each
ventilatory condition. Experiments usually lasted 8 hours, after which
the rat was killed with an anesthetic overdose.
Statistics
All average values are stated as means ± SE. Significant
differences were determined using Student’s t-test, with
P < 0.05 accepted as significant. Linear regression
curve fits were performed using commercial software (SigmaPlot; Jandel
Scientific, Corte Madera, CA).
Results
Blood Gas Data
The systemic arterial blood gas data for increasing levels of
ventilatory oxygen percentage without any additional
CO2 are shown as filled circles in Figure 1
(n = 8). The air-breathing values of
PaO2 80.5 ± 3.6 mm Hg,
PaCO2 34.0 ± 2.3 mm Hg, pH
7.44 ± 0.02, were in agreement with our earlier work on
Sprague–Dawley rats.12
As anticipated, increasing levels
of inspired oxygen led to an approximately linear increase in systemic
arterial oxygen levels, up to 473 ± 17.9 mm Hg, with
PaCO2 and pH not significantly affected. The
systemic arterial blood gas data for increasing levels of ventilatory
oxygen percentage in the presence of 5% CO2 are also shown
in Figure 1
(empty circles; n = 11). The 19%
O2-5% CO2 values were
PaO2 84.9 ± 4.9 mm Hg,
PaCO2 55.3 ± 2.8 mm Hg, pH 7.29 ±
0.02. Increasing levels of inspired oxygen led to an approximately
linear increase in systemic arterial oxygen levels, up to 472 ±
12.9 mm Hg, with PaCO2 and pH not significantly
affected. Systemic arterial PaO2 was not
significantly influenced by hypercapnia, but the
PCO2 was elevated and the pH reduced (both
P < 0.001).
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Retinal Artery and Vein PO2 Levels
Under air-breathing conditions, the average oxygen tension in the
preretinal vitreous adjacent to a retinal artery was 31.8 ± 2.1
mm Hg, whereas next to a vein it was 18.7 ± 1.7 mm Hg. At
increasing inspired oxygen levels, the oxygen level at the surface of
the artery and vein increased. With 100% oxygen ventilation, the mean
arterial value was 207 ± 9.4 mm Hg, and the vein was 53.3 ±
5.0 mm Hg.
For 19% O2–5% CO2 breathing the mean retinal artery contact value was 49.5 ± 4.4 mm Hg, whereas that for the vein was 28.6 ± 4.6. At increasing inspired oxygen levels the oxygen level at the surface of the artery and vein increased. With 95% O2–5% CO2 ventilation the arterial value was 296 ± 9.7 mm Hg, and the vein was 76.9 ± 1.9 mm Hg. Under all conditions the oxygen level adjacent to the retinal artery was significantly less than that in the femoral artery (P < 0.001). Under hypercapnic conditions the retinal artery oxygen level was higher than with hyperoxia alone. The oxygen level adjacent to the retinal vein was also significantly increased by hypercapnia, except at the 19%O2–5%CO2 level, at which the increase was not statistically significant. Under both normocapnic and hypercapnic conditions the retinal arteriovenous oxygen difference increased with each increment in oxygen ventilation (P < 0.05). The arteriovenous oxygen differences were significantly increased under hypercapnic conditions.
Discussion
The feasibility of raising intraretinal oxygen levels by systemic manipulation of ventilatory parameters was well demonstrated in the present study. Although supplemental oxygen ventilation increased oxygen levels throughout the retina, the effect was further enhanced by hypercapnia. This was most likely because of the vasodilating influence of the pH changes associated with hypercapnia, particularly in the retinal circulation in which autoregulatory mechanisms are more highly developed.20 21 22 Hypercapnia produced a clearly visible dilatation of the retinal vasculature in each animal in our study.
Oxygen Uptake in the IPL
A feature of every intraretinal oxygen measurement in
air-breathing rats was the presence of a minimum oxygen tension lying
between the superficial and the deep capillary layers of the retinal
circulation. The oxygen contribution from both the superficial and the
deep capillary layers is evident from the nature of the oxygen
gradients flowing into this region. This region encompasses the IPL.
The IPL contains an abundance of synaptic processes between the bipolar
cells and the retinal ganglion cells, and synaptic connections from the
amacrine cells are also present. The main function of the inner retina,
similar to that of the central nervous system, is the generation,
processing, and transmission of nerve impulses. This activity can only
be accomplished if the required ionic gradients are maintained, which
requires considerable energy.23
Increased Oxygen Uptake in Hyperoxia
The striking feature of the hyperoxia measurements was the
maintenance of the intraretinal oxygen minimum in the IPL, even in the
face of dramatically increased oxygen flux from the choroid. This
increased oxygen flux did not reach the inner retinal boundary with the
vitreous, because the oxygen gradients indicated a sustained flow of
oxygen into the retina from the superficial capillary bed. The most
likely explanation for this phenomenon is that the oxygen uptake of the
retina increased under hyperoxic conditions. The possibility of the
extra oxygen being washed out by the retinal circulation is excluded by
the observation of a significant arteriovenous oxygen difference, with
the arteries having a higher oxygen level than the veins under all
conditions. This is consistent with other work in the rat in which
arterial and venous oxygen levels were measured
noninvasively.24
Although the presence of the retinal
circulation precludes a quantitative analysis of intraretinal oxygen
consumption,25
there are still several points that can be
made in an attempt to understand our experimental results. There is
general agreement that the oxygen uptake of the inner half of the rat
retina is of the same order as that of the outer
retina.26
27
A similar finding has been reported for the
pig retina.28
If the oxygen requirements of the inner and
outer halves of the retina are assumed to be equal, then a doubling of
the oxygen flux from the choroid would be expected to support the
entire retinal thickness in the event that the contribution from the
retinal circulation were removed. This assumes that the retinal
ischemia per se does not increase the oxygen demand because of the
restricted supply of other metabolites such as glucose. Although we
think that this assumption is unlikely to be correct, for the present
discussion it still serves a useful purpose. It is clear from our
observations that the oxygen flux from the choroid increased by a
factor of more than four in hyperoxia (based on outer retinal
gradients, Figs. 2
3
). Because the oxygen contribution from the
retinal circulation is still present, at least to some degree, the
total use of oxygen within the retina must have increased.
Oxygen Uptake in Different Retinal Layers
Enzymes associated with oxidative metabolism, most notably
cytochrome oxidase, have been shown to be concentrated in specific
retinal layers, the inner segments of the photoreceptors, the outer
plexiform layer, the IPL, and the ganglion cells. The highest
concentration is found in the inner segments of the photoreceptors, but
a considerably thicker region of moderate staining encompassing the IPL
is also evident.6
The existence of an oxygen-consuming
layer in the relatively avascular region between the two retinal
capillary beds would account for the consistent appearance of the
minimum oxygen tension in this area. Although cytochrome oxidase
staining in the outer plexiform layer is significant, this layer is
very thin in the rat, and any consumption is masked by the presence of
the deep retinal capillary bed in this region in our chosen retinal
location (2–3 disc diameters). This also applies to the relatively
sparse ganglion cell layer with the adjacent superficial retinal
capillaries.
Oxygen-Dependent Uptake
A further requirement to explain our observations under hyperoxic
conditions would be a relationship between oxygen level and oxygen
uptake.10
27
This topic has been the focus of much
interest, because such a mechanism also fulfills the role of an oxygen
sensor, which is known to be an important element in blood flow control
in many organs.29
30
It has been suggested that the 50%
metabolic rate for mitochondria inside an intact cell lies between an
oxygen level of 10 to 15 mm Hg.10
This suggests that the
oxygen uptake of the IPL may not be saturated at the oxygen levels that
were encountered in the IPL of the rat in our studies. Thus, the muted
increase in oxygen level in the IPL when compared with that in the
choroid and the retinal artery, may have been caused by an oxygen-level
regulation of oxygen uptake in this region. Increased oxygen uptake by
the photoreceptor inner segments may also be present during hyperoxic
conditions, although Linsenmeier and Yancey31
found no
increase in outer retinal oxygen uptake in hyperoxia in the cat.
However, others speculated that outer retinal oxygen consumption is
increased in hyperoxia, having noted a similar increase in oxygen flux
from the choroid in hyperoxic pigs.16
21
Re-examining
their oxygen profiles in the light of our own findings indicates an
involvement of the inner retina in the increased oxygen consumption in
their study.
Under hypercapnic conditions it may be anticipated that the relationship between oxygen level and oxygen consumption may be influenced by the consequent pH changes.30 In our study, the increase in retinal arteriovenous oxygen difference in hypercapnia, despite the visible dilatation of the retinal vasculature, suggests that the oxygen delivery from the retinal circulation is increased when compared with hyperoxia alone. Without quantitative blood flow information, this point cannot be proved, but there is a strong possibility that inner retinal oxygen uptake is increased under hypercapnic conditions.
Disease Models
It is interesting to note that the oxygen uptake of the IPL is no
longer evident in the urethane model of photoreceptor
degeneration.11
This is unlikely to be because of a loss
of signal input from the degenerated photoreceptors, as the Royal
College of Surgeons (RCS) rat model of photoreceptor degeneration shows
a significant oxygen uptake of the remaining inner retina in
vitro.27
We have also confirmed this result in
measurements in vivo of oxygen uptake in the inner retina of the RCS
rat (unpublished observations). The maintenance of oxygen metabolism in
the inner retina in the absence of a functional outer retina is an area
requiring further study.
The present study quantified the influence of systemic manipulation of oxygen levels in the rat on intraretinal oxygen levels. The enhancement of these effects by hypercapnia was also demonstrated. The apparently large oxygen uptake by the IPL and the increase in this oxygen uptake as more oxygen is made available are novel observations that require more detailed studies to elucidate the importance of such mechanisms in normal and ischemic retinas.
Acknowledgements
The authors thank Dean Darcey and Vanessa Moscarda for their technical assistance and Marcos Tsacopoulos for valuable discussions in relation to the manuscript.
Footnotes
Reprint requests: Dao-Yi Yu, Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, Perth, Western Australia 6009.
Supported by a grant from the National Health and Medical Research Council of Australia and by the Ophthalmic Research Institute of Australia.
Submitted for publication January 5, 1999; revised March 29, 1999; accepted April 13, 1999.
Proprietary interest category: N.
References
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