Retinal Vascular Autoregulation Research Articles

Effects of semaglutide and empagliflozin on oxygenation, vascular autoregulation, and central thickness of the retina in people with type 2 diabetes: A prespecified secondary analysis of a randomised clinical trial

AimsSemaglutide and empagliflozin have shown cardiovascular protection. In SUSTAIN-6, semaglutide was associated with an increased risk of diabetic retinopathy. We investigated whether changes in retinal oxygenation, retinal vascular autoregulation, and central retinal thickness are altered by semaglutide, empagliflozin or the combination. MethodsThis study was a prespecified, secondary outcome from a randomised, 32 weeks partly placebo-controlled, partly open-label, clinical trial on the effects of semaglutide and empagliflozin on arterial stiffness and kidney oxygenation. A total of 120 participants with type 2 diabetes, established or high risk of cardiovascular disease and age ≥50 years were randomised into four parallel groups (semaglutide, empagliflozin, the combination or tablet placebo, n = 30 for each group). We primarily hypothesized that semaglutide would increase venular oxygenation. ResultsWe found no changes in retinal arteriolar, venular or venular-arteriolar oxygenation nor in retinal vessel diameter regardless of treatment group.Semaglutide increased central retinal thickness compared to placebo with ~1 % (3.8 μm 95 % CI [0.9;6.7], p = 0.009) with no changes in the empagliflozin or combination group. ConclusionNeither semaglutide, empagliflozin nor the combination alters markers of retinal function. The effect of semaglutide on central retinal thickness was small, but the clinical significance is uncertain.

Chronic social defeat stress causes retinal vascular dysfunction

PurposeThe roles of vascular dysfunction and chronic stress have been extensively discussed in the pathophysiology of glaucoma. Our aim was to test whether chronic stress causes retinal vascular dysfunction and therewith induces retinal ganglion cells (RGCs) loss. MethodsTwelve mice underwent chronic social defeat (CSD) stress, while 12 mice received control treatment only. Intraocular pressure (IOP) was measured with a rebound tonometer. Blood plasma corticosterone concentration and adrenal gland weight were used to assess stress levels. Brn-3a staining in retinas and PPD staining in optic nerve cross sections were conducted to assess the survival of RGCs and axons respectively. The ET-1 and α-SMA levels were determined in retina. Retinal vascular autoregulation, functional response to various vasoactive agents and vascular mechanics were measured using video microscopy. ResultsNo significant difference in IOP levels was observed during and after CSD between CSD mice and controls. CSD stress caused hypercortisolemia 2 days post-CSD. However, increased corticosterone levels went back to normal 8 months after CSD. CSD-exposed mice developed adrenal hyperplasia 3 days post-CSD, which was normalized by 8 months. RGC and axon survival were similar between CSD mice and controls. However, CSD stress caused irreversible, impaired autoregulation and vascular dysfunction of retinal arterioles in CSD mice. In addition, impaired maximal dilator capacity of retinal arterioles was observed 8 months post-CSD rather than 3 days post-CSD. Remarkably, ET-1 levels were increased 3 days post-CSD while α-SMA levels were decreased 8 months post-CSD. ConclusionsWe found that CSD stress does not cause IOP elevation, nor loss of RGCs and their axons. However, it strikingly causes irreversible impaired autoregulation and endothelial function in murine retinal arterioles. In addition, CSD changed vascular mechanics on a long-term basis. Increased ET-1 levels and loss of pericytes in retina vessels may involve in this process.

Downregulation of Retinal Connexin 43 in GFAP-Expressing Cells Modifies Vasoreactivity Induced by Perfusion Ocular Pressure Changes.

PurposeGlia and their communication via connexin 43 (Cx43) gap junctions are known to mediate neurovascular coupling, a process driven by metabolic demand. However, it is unclear whether Cx43 mediated glial communication intermediates classical autoregulation. Here we used viral transfection and a glial fibrillary acidic protein (GFAP) promoter to downregulate glial Cx43 to evaluate its role in retinal vascular autoregulation to ocular perfusion pressure (OPP) reduction.MethodsAdult rats were intravitreally injected with the viral active construct or a control. Three weeks after the injection, eyes were imaged using confocal scanning laser ophthalmoscopy before and during a period of OPP decrease induced by blood draw to lower blood pressure or by manometric IOP elevation. Vessel diameter responses to the OPP decrease were compared between Cx43-downregulated and control-injected eyes. The extent of Cx43 downregulation was evaluated by Western blot and immunohistochemistry.ResultsIn control eyes, the OPP decrease induced dilatation of arterioles, but not venules. In Cx43-downregulated eyes, Cx43 expression in whole retina was decreased by approximately 40%. In these eyes, the resting diameter of the venules increased significantly, but there was no effect on arterioles. In Cx43-downregulated eyes, vasoreactivity evoked by blood pressure lowering was significantly compromised in both arterioles (P = 0.005) and venules (P = 0.001). Cx43 downregulation did not affect the arteriole responses to IOP elevation, whereas the responses of the venules showed a significantly greater decrease in diameter (P < 0.001).ConclusionsThe downregulation of retinal Cx43 in GFAP–expressing cells compromises vasoreactivity of both arterioles and venules in response to an OPP decrease achieved via blood pressure lowering or IOP elevation. The results also suggest that Cx43-mediated glial communication actively regulates resting venular diameter.

Optical coherence tomography angiography study of the retinal vascular plexuses in type 1 diabetes without retinopathy.

Previous data suggest the existence of retinal vascular changes and impaired autoregulation in the very early stages of diabetic retinopathy (DR). We compared the retinal plexuses between patients with type 1 diabetes (T1D) without DR and a demographically similar healthy cohort, using optical coherence tomography angiography (OCT-A). Patients with T1D and no signs of DR were prospectively recruited from an outpatient clinic. Using OCT-A (AngioVue®), the parafoveal superficial (SCP) and deep (DPC) capillary plexus as well as the foveal avascular zone (FAZ) and perimeter were gathered. Mean comparison tests and linear regression analysis were used as statistical tests (STATA v14). Studied population included 48 subjects (24 T1D). The analysis of SCP revealed an attenuation of the capillary network compared with the control group in both parafoveal (51.8 ± 4.5 vs. 55.8 ± 3.2, p < 0.001) and perifoveal (51.9 ± 3.3 vs. 53.9 ± 1.9, p = 0.01) regions. A similar finding was observed in the DCP for both parafoveal (56.4 ± 4.3 vs. 60.4 ± 2.2, p < 0.001) and perifoveal (54.7 ± 3.9 vs. 60.8 ± 3.4, p = 0.001) sectors. Also, a longer time since T1D diagnosis was associated with a larger FAZ area (p = 0.055) and perimeter (p = 0.03). Significant differences in the retinal microvasculature were observed between healthy subjects and T1D patients using OCT-A, even before clinically detectable disease on fundus biomicroscopy.

Changes in Retinal Vascular Caliber after Intravitreal Aflibercept Treatment for Diabetic Macular Oedema

Diabetic retinopathy is characterised by impaired retinal vascular autoregulation with signs of early retinal hyperperfusion and subsequent capillary drop out and peripheral ischemia. Initial retinal vascular dilation indicates disease progression and subsequent constriction signals a proliferative state. In this pilot study, we examined the effect of intravitreal aflibercept on retinal vessel diameter in patients with diabetic macular oedema. Twelve eyes of nine treatment-naive patients with diabetic macular oedema were examined during the first three months of treatment with aflibercept. The calibers of retinal arteries and veins and the central retinal arterial and vein equivalent were registered over the course of treatment. The evolution of the diabetic macular oedema was also registered and correlated to the retinal vascular caliber. During treatment, there was a significant reduction in the diameter of retinal arteries as well as in the central retinal arterial equivalent. The calibers of the retinal veins were also reduced, but not significantly. Macular oedema was significantly reduced, which however did not correlate with the vascular caliber changes. This pilot study demonstrates for the first time a possible significant reduction in retinal arterial caliber under aflibercept treatment for diabetic macular oedema. Further studies are needed to verify whether this response to intravitreal anti-VEGF treatment also signifies an improvement in retinal vascular homeostasis.

Diabetic macular edema: Evidence-based management.

Diabetic macular edema (DME) is the most common cause of vision loss in patients with diabetic retinopathy with an increasing prevalence tied to the global epidemic in type 2 diabetes mellitus. Its pathophysiology starts with decreased retinal oxygen tension that manifests as retinal capillary hyperpermeability and increased intravascular pressure mediated by vascular endothelial growth factor (VEGF) upregulation and retinal vascular autoregulation, respectively. Spectral domain optical coherence tomography (SD-OCT) is the cornerstone of clinical assessment of DME. The foundation of treatment is metabolic control of hyperglycemia and blood pressure. Specific ophthalmic treatments include intravitreal anti-VEGF drug injections, intravitreal corticosteroid injections, focal laser photocoagulation, and vitrectomy, but a substantial fraction of eyes respond incompletely to all of these modalities resulting in visual loss and disordered retinal structure and vasculature visible on SD-OCT and OCT angiography. Efforts to close the gap between the results of interventions within randomized clinical trials and in real-world contexts, and to reduce the cost of care increasingly occupy innovation in the social organization of ophthalmic care of DME. Pharmacologic research is exploring other biochemical pathways involved in retinal vascular homeostasis that may provide new points of intervention effective in those cases unresponsive to current treatments.

Retinal Vascular Autoregulation during Phase IV of the Valsalva Maneuver: An Optical Coherence Tomography Angiography Study in Healthy Chinese Adults.

The impairment of retinal vascular autoregulation can be an early manifestation of many systemic and ocular diseases. Therefore, quantifying retinal vascular autoregulation in a non-invasive manner is very important. This study evaluated the effects of a Valsalva maneuver (VM)-induced blood pressure increases on retinal vascular autoregulation. Parafoveal and peripapillary retinal vessel density were measured with optical coherence tomography angiography before (baseline) and 5 s after each subject completed a VM (Phase IV [VM-IV]). Hemodynamic parameters and intraocular pressure (IOP) were examined. Blood pressure (systolic, diastolic, and mean arterial) and ocular perfusion pressure significantly increased during VM-IV, but IOP and heart rate (HR) did not change. The VM-induced blood pressure overshoot significantly decreased parafoveal (8.43%) and peripapillary (1.57%) perfused retinal vessel density (both P < 0.001). The response in the parafoveal region was greater than that in the peripapillary region (P < 0.001), and was age-dependent (r = 0.201, P < 0.05). Foveal avascular zone area detectable with OCTA significantly increased from baseline by 6.63% during VM-IV (P < 0.05). Autoregulatory responses to a VM did not show gender-related differences in either retinal region. The autoregulation of retinal vessels may vary in different regions of the fundus. Optical coherence tomography angiography could be a useful method for evaluating the autoregulation of the retinal vascular system.

Effect of Brimonidine on Retinal Vascular Autoregulation and Short-term Visual Function in Normal Tension Glaucoma

To assess whether brimonidine 0.15% alters retinal vascular autoregulation and short-term visual function in normal tension glaucoma patients who demonstrate retinal vascular dysregulation. Nonrandomized clinical trial. In this prospective study, 46 normal tension glaucoma patients not previously treated with brimonidine underwent retinal vascular autoregulation testing and visual function assessment using frequency doubling technology perimetry and equivalent noise motion sensitivity testing. We measured blood flow in a major temporal retinal artery with subjects seated and then while reclined for 30 minutes. Patients having a change in retinal blood flow with posture change outside the range previously found in healthy subjects were classified as having retinal vascular dysregulation. They were treated with brimonidine 0.15% for 8 weeks and designated for retesting. Twenty-three patients demonstrated retinal vascular dysregulation at the initial visit. Younger age (P = .050) and diabetes (P = .055) were marginally significant risk factors for retinal vascular dysregulation. After the 8-week course with brimonidine, 14 of the 17 patients who completed the study showed a return of posture-induced retinal blood flow changes to levels consistent with normal retinal vascular autoregulation (P < .0001). We found no significant changes in frequency doubling technology perimetry or in motion detection parameters following treatment with brimondine (P > .09 for all tests performed). Brimonidine significantly improved impaired retinal vascular autoregulation in normal tension glaucoma patients, but short-term alteration in visual function could not be demonstrated.

Effects of Dorzolamide-Timolol and Brimonidine-Timolol on Retinal Vascular Autoregulation and Ocular Perfusion Pressure in Primary Open Angle Glaucoma

To assess whether dorzolamide 2%-timolol 0.5% (D/T) and/or brimonidine 0.2%-timolol 0.5% (B/T) alters retinal vascular autoregulation (RVA) and seated ocular perfusion pressure (sOPP) in primary open angle glaucoma (POAG) patients who demonstrate retinal vascular dysregulation (RVD) on timolol 0.5% alone. In this prospective, observer-masked, crossover study, 21 POAG patients with untreated intraocular pressure (IOP) >21 mmHg were treated for 6 weeks with timolol 0.5%. Subsequently, we measured inferior temporal retinal artery blood flow in the left eye with subjects seated and then while reclined for 30 min using the Canon Laser Blood Flowmeter. Subjects with a change in retinal blood flow in response to posture change outside of the range previously found in healthy subjects were designated as having RVD and randomized to either D/T or B/T for 6 weeks and re-tested. This was followed by treatment with the opposite medication. Seven of the 21 subjects demonstrated RVD in response to posture change following timolol 0.5%. Multiple linear regression analysis indicated that lower sOPP was the main determinant of RVD (P=0.033). After treatment with D/T, all 7 converted from RVD to normal RVA status (P=0.001). Four of 6 subjects showed a similar return to normal RVA following B/T (P=0.066). Mid-morning sOPP was 41.1±5.5 mmHg post-timolol, 46.3±6.5 mmHg post-D/T, and 38.6±6.0 mmHg post-B/T (D/T vs. B/T, P=0.026). D/T significantly improved RVA in POAG patients exhibiting RVD while on timolol 0.5% alone. D/T also increased sOPP compared to B/T. There was no significant difference (P=0.37) between D/T and B/T in improving RVA.

Effect of acute postural variation on diabetic macular oedema

This study aimed to study the pathophysiology of diabetic macular oedema (DMO) by analysis of concomitant changes in macular volume (MV), mean arterial blood pressure (MABP), intraocular pressure (IOP), and retinal artery and vein diameters in response to acute postural changes in patients with DMO and healthy subjects. Thirteen patients with DMO (13 eyes) and five healthy subjects (five eyes) were examined after resting in a chair for 15 mins using optical coherence tomography to measure MV and fundus photography to assess retinal vessel diameters. The patients then lay down for 60 mins, during which they were examined repeatedly before they were reseated and examined again. Intraocular pressure was measured using pulse-air tonometry, arterial blood pressure by sphygomanometry and fluid columns using rulers and a spirit level. In healthy subjects, retinal artery (p = 0.02) and vein (p = 0.001) diameters decreased when subjects lay down, whereas MV remained stable. In patients with DMO, no orthostatic variation in retinal vessel diameters could be demonstrated, whereas MV had increased by 2.4 +/- 0.6% (mean +/- standard error of the mean; p = 0.006) 50 mins after assuming a recumbent position. In both healthy subjects and DMO patients, MABP decreased and IOP increased in a recumbent position, with no significant difference between the groups. The increase in MV that occurs in DMO when changing from a seated to a recumbent position is associated with a failure of retinal artery contraction, a response seen in healthy subjects that appears to counter-regulate the increase in ocular perfusion pressure caused by assuming a recumbent position.

Retinal Blood Flow Response to Posture Change in Glaucoma Patients Compared with Healthy Subjects

To characterize the retinal vascular autoregulatory response to ocular perfusion pressure (OPP) changes in patients with glaucoma and in healthy control subjects. Observational cohort study. Eighteen patients with open-angle glaucoma (OAG) and 8 control subjects, all females ages 40 to 60 years, were studied. Only subjects with known maximum intraocular pressure less than 22 mmHg in both eyes were included. Arterial diameter and blood speed in the inferior temporal retinal artery of the left eye were measured simultaneously at baseline while sitting, while reclining for approximately 30 minutes, and once again sitting using a retinal laser Doppler instrument. Blood flow rate was computed automatically. Brachial artery blood pressure and heart rate also were measured. Change in blood flow rate while reclining for approximately 30 minutes compared with baseline blood flow rate measured while seated. In control subjects, arterial diameter decreased by 7.5+/-3.4% (P = 0.0003) and blood speed increased by 24.6+/-10.8% (P = 0.004) while reclining compared with baseline. The concomitant change in the blood flow rate (6.5+/-12.0%; P = 0.15) compared with baseline was not statistically significant. In contrast, OAG patients showed a much broader range of blood flow changes in response to posture change (14.9+/-37.7%; P = 0.086) compared with baseline. Although there were no significant differences in the flow changes compared with baseline in either group, there was a significant difference in the variance of the blood flow changes in the OAG patients compared with the controls (P = 0.0025). Division of the OAG patients into subgroups revealed a significant (P = 0.031) association between baseline OPP and the retinal blood flow response to posture change. The authors describe the hemodynamic details of retinal vascular autoregulation in response to posture-induced changes in OPP in healthy subjects and document the lack of such autoregulation in a selected group of patients with OAG.

Matrix Metalloproteinase‐2 Expression and Apoptogenic Activity in Retinal Pericytes

Diabetic retinopathy (DR) commences as a basement membrane disorder with a dramatic loss of the innate retinal vascular autoregulation. In this process, retinal pericytes, which regulate endothelial cell proliferation and survival, undergo morphometric changes consistent with apoptosis. The ability of retinal pericytes to survive is dependent on their interaction with extracellular matrix (ECM) proteins, which are susceptible to rapid degradation by matrix metalloproteinases (MMPs). Here, we examined the potential involvement of MMPs and a membrane-type MMP in retinal pericyte death in experimental diabetes and in cultured retinal pericytes. Our data showed that chemically induced diabetes of 6 months' duration significantly increased the expression and activity of both MMP-2 and its physiological activator MT1-MMP. TdT-mediated dUTP nick end labeling (TUNEL)-positive pericytes and endothelial cells were concomitantly detected within the retinal capillaries of diabetic animals. In situ zymography showed a weak MMP activity in control retinas but an intense perivascular MMP activity in retinas from diabetic animals. In vitro studies showed that hyperglycemia-induced retinal pericyte apoptosis in vitro was attenuated by a specific MMP inhibitor. Incubation of pericytes with purified MMP-2 significantly increased the number of apoptotic cells. Our data suggest that increased MMP-2 activity compromises retinal pericyte survival possibly through MMP-2 action on ECM proteins and/or direct association of MMP-2 with integrins, which promotes apoptosis/anoikis by loss of cell contact with an appropriate ECM.

Role of endothelin in diabetic retinopathy.

Endothelin-1 (ET-1) is a 21 amino acid peptide originally purified from conditioned medium of cultures of porcine aortic endothelial cells. It is now known that there are three endothelin genes in the human genome (ET-1, ET-2, and ET-3 genes). ET-1 and ET-2 are both strong vasoconstrictors, whereas ET-3 is a potentially weaker vasoconstrictor compared to the other two isoforms. Besides being a very potent vasoconstrictor, ET-1 also acts as a mitogen on the vascular smooth muscle and thus it may play a role in the development of vascular diseases. There is evidence that impaired auto-regulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. It is known that the ability of the diabetic's circulation to distribute blood is affected, especially during increased blood flow. In most tissues this causes no serious burden, but three tissues are usually susceptible to disturbance. They are the retina, renal cortex, and peripheral nerves. Retinal vascular auto-regulation is defined as the ability of the blood vessels to keep blood flow constant under varying perfusion pressure in order to match it to tissue oxygen and metabolic requirements. The failure of auto-regulation is an important and often early feature of diabetic retinopathy. Since human retina vessels lack extrinsic innervation, retinal vessel calibre and local blood flow are normally regulated by non-nervous mechanisms intrinsic to the retina. There is now a considerable body of evidence suggesting that retinal pericytes are the main regulators of vascular tone in the retinal capillaries because they contain components of contractile proteins similar to vascular smooth muscle cells and because they also possess ET-1 receptors. Furthermore. ET-1 has been shown to cause vasoconstriction of retinal vessels as well as to have mitogenic effects on retinal pericytes. Hence, alterations in the pericyte-ET interaction may have a role causing early hemodynamic and histopathological abnormalities found in diabetic retinopathy. On the contrary, Chakrabarti et al. demonstrate that retinas from the chronic diabetic BB/W rats (6 months) show an increase in ET-1, ET-3, ET(A) receptor and ET(B) receptor mRNA expressions when compared to those from control rats. Similar results are noted by them using immunohistochemical methods. Finally, an increased ocular, and retina tissue levels of ET-1 in diabetic rats have also been reported by Chakravarthy et al., as well as by Takagi et al. All of these findings suggest that endothelins may also be involved in the pathogenesis of more advanced diabetic retinopathy, such as capillary occlusion and subsequent neovascularization. This review summarizes the reported literature on the role of ET-1 in the development of diabetic retinopathy.

Regional retinal blood flow and vascular autoregulation.

The temporal retina is larger than the nasal retina and contains the metabolically active fovea. The variation in the distribution of blood between the temporal and nasal retinal circulations was investigated in 15 healthy volunteers, and the autoregulatory capacity of the temporal and nasal circulations was quantitated using 60% oxygen in the inspired air. Retinal blood flow was determined from red cell velocity using laser Doppler velocimetry and retinal vessel diameter from retinal photographs using a digital image analysis system. Volume flow was lower in the nasal than the temporal circulation by 52.49% (p < 0.001). This is a consequence of both significantly smaller vessels (20.4%, p < 0.001) and slower blood velocity in the nasal circulation (24.64%, p = 0.003) compared with the temporal vessels. After breathing 60% oxygen for 10 minutes, there was significant vasoconstriction (temporal, 10.42 +/- 1.24%, p < 0.001; nasal, 7.66 +/- 1.48%, p < 0.001), slower red cell velocity (temporal, 27.10 +/- 3.92%, p < 0.001; nasal, 27.36 +/- 5.51%, p < 0.001) and a significant reduction in the volumetric flow rate (temporal, 41.16 +/- 3.64%, p < 0.001; nasal, 37.99 +/- 5.07%, p < 0.001). The reduction in the haemodynamic parameters was comparable in the temporal and nasal circulations, indicating similar autoregulatory capacity. Retinal vascular conductance was calculated from volume flow and retinal perfusion pressure. It was 53% larger in the temporal than the nasal circulations. This provides an index of the metabolic needs of the different regions of the retina.

The effect of acute ethanol consumption on the human retinal circulation: a study in diabetic and non-diabetic subjects.

The effects of acute ethanol consumption on retinal haemodynamics and retinal vascular autoregulation to oxygen in the human retinal circulation were studied in 10 diabetic (mean age +/- SD: 38.2 +/- 11.1) and 16 non-diabetic (mean age +/- SD: 32.4 +/- 8.8) subjects. Subjects drank 0.5 g of ethanol, as vodka, per kg of body weight, diluted in sugar-free orange juice. Retinal blood flow was determined using laser Doppler velocimetry and computerised image analysis. The effect of ethanol on oxygen reactivity, as a measure of autoregulation, was also determined after 60% oxygen inhalation. All subjects demonstrated a significant fall in mean arterial blood pressure (control group 3.3%, p = 0.04, diabetic subjects 5.7%, p = 0.05), after ethanol intake. Ethanol caused no significant change in retinal blood flow. Oxygen reactivity was found to be 38.3% (22.4-47.7, median and interquartile range) in the non-diabetic subjects at baseline, and 30.7% (10.8-42.1) after ethanol ingestion. In diabetic subjects, the oxygen reactivity was 33.2% (19.8-46.8) at baseline and 24.5% (21.1-32.1) after ethanol. In this study ethanol did not significantly affect retinal blood flow or impair autoregulation. These results suggest that the retinal circulation may be able to autoregulate despite the presence of ethanol, in contrast to other vascular beds where ethanol changes flow.

Electroretinogram in Unilateral Vascular Stress in Nondiabetic and Diabetic Subjects

The oscillatory potentials (OP's) of the flash-elicited electroretinogram (ERG) are vulnerable to changes in retinal circulation such as occur in insulin-dependent diabetes mellitus (IDDM). In an earlier study it was shown that rod-isolated ERG's were more sensitive than cone-isolated ERG's to transient changes in the ocular perfusion pressure (OPP). In the present study, a comparison was made of the susceptibility of scotopic white, red, and blue flash OP's to transiently decreased perfusion in normals. Scotopic white flash OP's were then compared to those obtained in subjects with IDDM. The OPP was decreased by 20 and 40% through scleral suction in 10 normotensive healthy volunteers, as well as in 11 young subjects with IDDM. The data indicate that white flash OP's include early cone and later rod contributions. Both red and blue OP's were more variable than white OP's. For white flash OP's, component-specific changes to decreased OPP were found. The overall OP response profiles for the diabetic subjects during a stepwise short-term decrease in the OPP did not differ from those for nondiabetic subjects. The results are discussed in relation to retinal vascular autoregulation (AR) and choroidal blood flow.

The effect of photocoagulation on the oxygenation and ultrastructure of avascular retina

Panretinal photocoagulation has been shown to raise preretinal oxygen tension in cats and monkeys breathing 100% oxygen. However, in normoxia, there is no significant difference between normal and photocoagulated areas. This is thought to be due to autoregulatory vasoconstriction of the retinal circulation. In avascular rabbit retina, photocoagulation effects on retinal oxygenation can be studied without the influence of retinal vascular autoregulation. We measured normoxic preretinal oxygen tension of normal and photocoagulated rabbit retina at 1, 7, 14 and 28 days after photocoagulation using polarographic oxygen electrodes. For all time points, preretinal oxygen tension of photocoagulated retina (42 ± 14 torr; mean ± s.d.) was higher than untreated retina (14 ± 10 torr; mean ± s.d., P < 0·001). Light and electron microscopy of lasered retina showed that the improved oxygenation corresponded to loss of mitochondria-rich inner segments of the photoreceptors.

Retinal blood velocity in patients with leukocyte disorders.

The blue light entoptic phenomenon was used to measure retinal blood velocity in eight patients with chronic granulocytic leukemia, six patients with leukopenia, and matched control subjects. The retinal leukocyte velocity of the leukemic patients was 0.53 +/- 0.26 (mean +/- SD) mm/s, whereas that of the matched control subjects was 0.46 +/- 0.14 mm/s. There was no significant difference between these two groups (power: 96% for a difference of 0.2 mm/s and 66% for 0.1 mm/s). There was also no significant difference between the leukocyte velocities of the leukopenic patients and control subjects (0.47 +/- 0.19 mm/s and 0.55 +/- 0.14 mm/s, respectively; 89% power for a difference of 0.2 mm/s, 59% for 0.1). There was a correlation between the leukocyte count and the number of leukocytes seen in the entoptoscope. The results suggest that retinal vascular autoregulation can compensate for changes in leukocyte numbers that might have been expected to alter retinal blood flow.

Retinal Vascular Autoregulation in Conditions of Hyperoxia and Hypoxia Using the Blue Field Entoptic Phenomenon

Autoregulation of retinal blood flow was studied in seven normal volunteers. The stimuli to autoregulation used were hyperoxia and hypoxia under controlled conditions of isocapnia. Macular blood flow was measured using the blue field entoptic phenomenon, and retinal artery and vein diameters were measured using a computerized digitising system. Results under conditions of isocapnic hypoxia showed a 38% average increase in blood flow and an increase in diameter of 8.2% and 7.4% in retinal arteries and veins, respectively. In hyperoxia, blood flow fell by an average of 36% and retinal artery and vein diameter decreased by 5.6% and 10.%, respectively.

Retinal vascular autoregulation in normal subjects.

The retinal arterial diameter and its response to changes in perfusion pressure were measured by means of a fundus camera in 65 normal subjects. A reduction of effective MABP was induced by a postural change from a recumbent to an erect position. A small but significant increase in retinal arterial diameter was observed by reduction of the perfusion pressure in all subjects. The reduction of retinal arterial reactivity in response to blood pressure changes (-% change in diameter/delta effective MABP) was significantly correlated with advancing age (p less than 0.01). No significant correlations were observed between the retinal arterial reactivity, magnitude of the retinal arterial diameter (range: 60-140 mu), and systemic blood pressure (range of MABP: 75-110 mmHg). These results indicate that the retinal artery has an autoregulatory mechanism which is influenced by aging.