The increase in SaO
2 level during pure O
2 breathing indicates that systemic hyperoxia was readily achieved in our experimental protocol. The group-averaged PR decreased during systemic hyperoxia, a finding that has been reported earlier in humans.
9 12 Systemic hyperoxia was accompanied by hypocapnia, a physiological response attributed to the decrease in the affinity of hemoglobin for CO
2 in the presence of high blood O
2 partial pressure.
13 BP values were not altered throughout the O
2 session, as also reported earlier.
10
The increase in SaO
2 and EtCO
2 levels during carbogen breathing indicated that systemic hyperoxia and hypercapnia were achieved. No adverse effects were experienced by any of the subjects during carbogen breathing. Systemic BP increased during carbogen breathing, which was likely an effect of the CO
2 rather than the O
2 content of the gas because BP was not altered during pure O
2 breathing in the present study and in earlier studies.
14 15 16
The decrease in the SaO
2 level during the hypoxic test session indicated that systemic hypoxia was readily achieved. The hypoxic gas mixture was apparently well tolerated by all subjects because none reported any discomfort. The 89% SaO
2 level achieved during systemic hypoxia would correspond to a Pa
o 2 of approximately 55 to 60 mm Hg, based on the oxygen–hemoglobin dissociation curve.
17 This Pa
o 2 value also took into account the decrease in EtCO
2 observed during the inhalation of the hypoxic gas. This decrease in EtCO
2, which is a good indicator of the alveolar P
co 2,
13 was not accompanied by a group-averaged increase in the RR. Considering the Henderson–Hasselbach equation
17 and assuming a constant bicarbonate level, it is predicted that the averaged baseline arterial pH level was increased by only approximately 0.05 U, a change too small to further modify the level of Pa
o 2. An increase in the group-averaged PR during systemic hypoxia was likely to increase blood flow and, therefore, oxygenation to tissue. Increases in PR and cardiac output are physiological responses known to occur as immediate adaptations to acute altitude-induced hypoxia.
18 The BP increased slightly during systemic hypoxia, a finding reported earlier during experimentally induced
11 or high-altitude
19 hypoxia. Collectively, these results indicate that not only was systemic hypoxia attained, it led to some compensatory mechanisms in attempts to maintain adequate tissue oxygenation.
P50 and N95 components of the pERG are thought to originate from preganglion and ganglion cells, respectively.
20 Studies have concluded that retinal ganglion cells (RGCs) are particularly sensitive to conditions decreasing normal perfusion or oxygen supply to the retina. Papst et al.
21 concluded that ocular hypertension alters RGC function because of a decrease in the oxygen supply to the retina. It has been shown that RGCs are more sensitive to transient complete ischemia than the more distal retinal cells.
22 23 pERG has been used to detect retinal ischemia sufficient to lead to preproliferative diabetic retinopathy.
24 Experimental reductions in the OPP in humans have shown that RGC function, indexed by the pERG, was attenuated in proportion to the decrease in OPP.
25 26
Although pERG was not altered during systemic hyperoxia or hypercapnia/hyperoxia in the present study, the N95 component of the pERG was attenuated and delayed in the presence of systemic hypoxia. This implies that the preganglion and ganglion cells were generally resistant to altered blood gas perturbations, except when the blood oxygen content was reduced. It is well known that the central retinal artery circulation has the capacity to adjust blood supply to the tissue in the presence of altered physiology. Hence, it has been shown that systemic hyperoxia reduces retinal vessel diameter
5 6 and blood flow,
5 27 whereas systemic hypercapnia, accompanied or not by systemic hyperoxia, increases retinal vessel diameter and blood flow.
12 28 29 Furthermore, studies in humans and monkeys have shown that retinal vessels dilate and retinal blood flow increases in the presence of systemic hypoxia accompanied or not by isocapnia.
8 30 31 In the present study, systemic hyperoxia accompanied by hypocapnia (pure oxygen breathing) or hypercapnia (carbogen breathing) did not alter the function of the RGCs. Systemic hypoxia was also accompanied by hypocapnia and resulted in a decrease and a delay in the N95 component of the pERG. It is, therefore, valid to conclude that it was the decrease in arterial blood oxygen content that led to altered neural function.
The N95 component was already delayed during systemic hypoxia, but its amplitude decreased a little afterward only when the hypoxic gas was stopped. Conversely, the data show that the delay already started to recover by that time, though the SaO2 level indicated that systemic hypoxia was still present. These results suggest that systemic hypoxia may differentially alter signaling time (depressed by longer duration of hypoxia) and amplitude (more sensitive to the early effects of systemic hypoxia) of the RGC response. Further studies using a shorter exposure to deeper levels of hypoxia or longer exposure to the same level of systemic hypoxia will be required to better elaborate the timing and amplitude responsivity of the RGCs to hypoxia.
Studies in the cat have shown that RGC function is resistant to mild systemic hypoxia but that it is altered drastically when the degree of hypoxia is more severe.
32 33 In these studies, a hypoxic level that kept the arterial P
o 2 value greater than 35 to 45 mm Hg did not alter RGC function. Furthermore, the PR and BP were not altered either when the P
o 2 values remained higher than 45 mm Hg,
33 whereas these two physiological variables were seen to increase in the present study at a Pa
o 2 approximating 55 to 60 mm Hg. From such animal studies, it has been concluded that the inner retina is well protected against mild systemic hypoxia, a phenomenon attributed to the regulatory capacity of the central retinal artery circulation.
34 35 36 In light of these animal studies, and considering our present results, it may be that mild systemic hypoxia induces more effects in humans and that it leads to metabolic changes that are not fully compensated by vascular regulation or that some retinal neurons in the human retina are particularly sensitive to a decrease in blood oxygen content.
Previous studies have shown that the photopically and scotopically recorded a-wave was not altered during mild systemic hypoxia but that the b-wave was attenuated.
11 37 38 In addition, though the photopic oscillatory potentials were not depressed, the amplitude of OP3 tended to decrease with mild systemic hypoxia.
11 Taken together, these results suggest that the innermost retinal layers are more sensitive than the outermost layers to low-level systemic hypoxia. Furthermore, because the neurogenerators of the ERG a-wave and the P50 component of the pERG were not altered but those giving rise to the ERG b-wave and the N95 component of the pERG were attenuated, it is reasonable to propose that some neurons are more sensitive to mild systemic hypoxia through a mechanism that could possibly involve biochemical or metabolic processes or a limited capacity of the retinal vasculature to regulate its blood flow and maintain adequate oxygenation to tissues in the presence of hypoxia. Earlier studies in humans, however, show that systemic hypoxia increases the standing potential of the eye and diminishes the light rise of the electro-oculogram,
39 40 indicating that the outermost retina is also affected by the decreased blood oxygen content. The level of systemic hypoxia attained in those studies was slightly greater than that obtained in the present investigation. Further studies using graded levels of systemic hypoxia will be required to determine the relative susceptibility of the various retinal neurons to decreased blood oxygen content.
In conclusion, our results indicate that RGCs in humans are particularly sensitive to acute, transient, mild systemic hypoxic stress.
The authors thank all the volunteer subjects for their participation in this study.