Regulation of retinal oxygen metabolism in humans during graded hypoxia.

Animal experiments indicate that the inner retina keeps its oxygen extraction constant despite systemic hypoxia. For the human retina no such data exist. In the present study we hypothesized that systemic hypoxia does not alter inner retinal oxygen extraction. To test this hypothesis we included 30 healthy male and female subjects aged between 18 and 35 years. All subjects were studied at baseline and during breathing 12% O2 in 88% N2 as well as breathing 15% O2 in 85% N2. Oxygen saturation in a retinal artery (SO2art) and an adjacent retinal vein (SO2vein) were measured using spectroscopic fundus reflectometry. Measurements of retinal venous blood velocity using bidirectional laser Doppler velocimetry and retinal venous diameters using a Retinal Vessel Analyzer (RVA) were combined to calculate retinal blood flow. Oxygen and carbon dioxide partial pressure were measured from earlobe arterialized capillary blood. Retinal blood flow was increased by 43.0 ± 23.2% (P < 0.001) and 30.0 ± 20.9% (P < 0.001) during 12% and 15% O2 breathing, respectively. SO2art as well as SO2vein decreased during both 12% O2 breathing (SO2art: -11.2 ± 4.3%, P < 0.001; SO2vein: -3.9 ± 8.5%, P = 0.012) and 15% O2 breathing (SO2art: -7.9 ± 3.6%, P < 0.001; SO2vein: -4.0 ± 7.0%, P = 0.010). The arteriovenous oxygen difference decreased during both breathing periods (12% O2: -28.9 ± 18.7%; 15% O2: -19.1 ± 16.7%, P < 0.001 each). Calculated oxygen extraction did, however, not change during our experiments (12% O2: -2.8 ± 18.9%, P = 0.65; 15% O2: 2.4 ± 15.8%, P = 0.26). Our results indicate that in healthy humans, oxygen extraction of the inner retina remains constant during systemic hypoxia.

Role of endothelin-A receptors in optic nerve head red cell flux regulation during isometric exercise in healthy humans.

Endothelin-1 (ET-1) is an important regulator of vascular tone in the eye. It appears to play a role in ocular disease because of its strong vasoconstrictor action, its role in intraocular pressure homeostasis, and its neurotoxic potential. We have previously shown that ET-1 is involved in choroidal red cell flux (RCF) regulation during isometric exercise in healthy humans. In the present study we hypothesized that ET-1 also plays a role in optic nerve head (ONH) RCF regulation during isometric exercise. To test this hypothesis, we performed a randomized, double-masked, placebo-controlled, two-way crossover study in 15 healthy volunteers. Subjects were randomized to receive intravenous infusions of the specific endothelin type A receptor antagonist BQ-123 and placebo on two different study days. During these infusion periods, subjects performed squatting for 6 min to increase ocular perfusion pressure (OPP). ONH RCF was assessed with laser-Doppler flowmetry, and OPP was calculated from mean arterial pressure and intraocular pressure. BQ-123 did not change OPP or ONH RCF at baseline. The relative increase in OPP during isometric exercise was comparable between both groups (between 84 and 88%, P = 0.76 between groups; P < 0.001 vs. baseline). Isometric exercise increased ONH RCF during placebo and BQ-123, but the increase was more pronounced when the endothelin type-A receptor antagonist was administered (placebo, 27.3 ± 5.4%; and BQ-123, 39.2 ± 4.4%; P = 0.007 between groups). The present data indicate that ET-1 regulates red cell flux in the ONH beyond the autoregulatory range.

Effects of orally administered moxaverine on ocular blood flow in healthy subjects.

BACKGROUND: To investigate the effect of orally administered moxaverine (Kollateral forte®) on ocular blood flow in young healthy subjects. METHODS: Sixteen healthy subjects (eight male/eight female) aged between 20 and 32 years were included in this placebo-controlled, double-masked, two-way crossover study. Volunteers received 900 mg moxaverine-hydrochloride administered orally in three equal doses or placebo identical in appearance on 2 study days. Outcome variables were measured at baseline and 5 h after first drug administration. Laser Doppler flowmetry was used to assess choroidal and optic nerve head blood flow. Blood velocities in the retrobulbar vessels were measured with color Doppler imaging. RESULTS: Neither moxaverine nor placebo changed mean arterial pressure or intraocular pressure. Neither moxaverine nor placebo had an effect on choroidal (moxaverine: by 9.5 ± 17.2 %, placebo 3.8 ± 18.8 %, p = 0.54 between groups) or optic nerve head blood flow (moxaverine: 4.8 ± 10.4 %, placebo: 1.8 ± 10.9 %, p = 0.52 between groups). Similarly, administration of moxaverine did not change blood flow velocities or calculated resistance index in the retrobulbar vessels compared to placebo. CONCLUSION: The data of the present study indicate that orally administered moxaverine does not increase ocular blood flow. This is in contrast to previous findings, where parenteral administration of moxaverine lead to a significant increase in choroidal blood flow and blood flow velocities in the retrobulbar vessels. The reason for these differing results is unclear, but may be related to the low bioavailability after oral administration.

Effects of increased white blood cell count on retinal perfusion during hyperoxia-induced vasoconstriction.

PURPOSE: Several studies have shown that administration of granulocyte-colony stimulating factor (G-CSF) is followed by an increase of white blood cell (WBC) count. There is evidence from other vascular beds that an increase in WBC count impairs blood flow regulation especially in the microcirculation. Whether this also holds true for the ocular circulation is yet unknown. In the following trial we investigated whether an increase in WBC count alters the oxygen induced vasoconstriction of retinal vessels. METHODS: The study design was randomized, double-masked, placebo-controlled with two parallel groups. 24 healthy, male subjects were included. Measurements of retinal white blood cell flux with the blue-field entoptic technique, red blood cell velocity using the laser Doppler velocimeter and retinal vessel diameter using a Retinal Vessel Analyzer, were assessed at baseline and after breathing of 100% oxygen over 20 min. Thereafter 300 µg of G-CSF or placebo was administered. Measurements were repeated after another inhalation of 100% oxygen 8h later. RESULTS: G-CSF did not show any influence on systemic hemodynamics. WBC count increased significantly from 5.7 ± 1.6 × 10(9)/L at baseline up to 19.5 ± 4.8 × 10(9)/L 8h after G-CSF administration. As expected, oxygen breathing induced a pronounced vasoconstriction and a decrease red and white cell flux in both, the placebo and the G-CSF group (p<0.01 for both groups). Administration of G-CSF increased WBC flux, but did not affect red blood cell flux. The response of red blood cell flux and retinal vessel diameters to hyperoxia was not altered by G-CSF administration. However, leukocytosis leads to a more pronounced oxygen induced reduction in red blood cell velocity compared to the placebo group (p=0.024). CONCLUSION: Our data indicate that increased WBC count as induced with G-CSF, leads to a more pronounced reduction in retinal red blood cell flux during states of vasoconstriction. This indicates that, as in other vascular beds, an increase in WBC leads to an altered blood flow regulation.

Effect of regular smoking on flicker induced retinal vasodilatation in healthy subjects.

BACKGROUND: Habitual smoking is a risk factor for a variety of vascular diseases, including ocular pathologies. In the current study, we set out to investigate whether the regulation of retinal vascular tone is impaired in habitual smokers. For this purpose, vascular reactivity was tested during flicker light induced vasodilatation in smokers and in a non-smoking control group. METHODS: In this prospective, balanced, parallel group study 24 chronic smokers (28.1 ± 3.3 years) and 24 age-matched never-smoking volunteers (28.2 ± 4.0 years) were included. Flicker induced vasodilatation was measured in major retinal arteries and veins using a retinal vessel analyzer and flicker induced changes in retinal blood velocities were assessed in retinal veins by laser Doppler velocimetry. Three flicker periods of 60s were scheduled. Blood cotinine concentration was determined and a Fagerstrom questionnaire was performed to evaluate nicotine dependency. RESULTS: In non-smoking subjects, stimulation with flicker light increased retinal venous diameter by +7.7 ± 3.1%, +6.9 ± 2.9% and +7.1 ± 2.8% during the three flicker periods, respectively. Flicker induced vasodilatation in veins was significantly diminished in chronic smokers (+4.9 ± 2.4%, +6.3 ± 3.1% and +5.7 ± 3.4%, ANOVA between groups, p=0.032) as compared to the non-smoking control group. Calculated retinal blood flow in the measured veins increased by a maximum of +54 ± 21%, +43 ± 18% and +46 ± 19% during the three stimulation periods in the non-smoking subjects, respectively. The flicker induced increase in retinal blood flow as assessed in the veins was significantly reduced in chronic smokers as compared to the non-smoking control group (+19 ± 16%, +26 ± 14%, +24 ± 13%, ANOVA between groups, p=0.013). In retinal arteries, flicker stimulation increased retinal arterial diameters by 5.2 ± 3.8%, 5.8 ± 4.8% and 5.5 ± 5.6% during the three flicker periods in the non-smoking group. In smokers, the flicker induced arterial vasodilatation was not significantly different compared to non-smokers (4.6 ± 4.1%, 3.8 ± 3.7% and 4.8 ± 3.4%, ANOVA between groups, p=0.4). CONCLUSION: Our data indicate that the flicker induced hemodynamic response of retinal veins is reduced in chronic smokers as compared to age matched healthy volunteers. This supports the hypothesis that chronic smoking leads to vascular dysfunction in the eye.

Reactivity of retinal blood flow to 100% oxygen breathing after lipopolysaccharide administration in healthy subjects.

Administration of low doses of Escherichia coli endotoxin (LPS) to humans enables the study of inflammatory mechanisms. The purpose of the present study was to investigate the retinal vascular reactivity after LPS infusion. In a randomized placebo-controlled cross-over study, 18 healthy male volunteers received 20 IU/kg LPS or placebo as an intravenous bolus infusion. Outcome parameters were measured at baseline and 4h after LPS/placebo administration. At baseline and at 4h after administration a short period of 100% oxygen inhalation was used to assess retinal vasoreactivity to this stimulus. Perimacular white blood cell velocity, density and flux were assessed with the blue-field entoptic technique, retinal branch arterial and venous diameters were measured with a retinal vessel analyzer and red blood cell velocity in retinal branch veins was measured with laser Doppler velocimetry. LPS is associated with peripheral blood leukocytosis and increased white blood cell density in ocular microvessels (p<0.001). In addition, retinal arterial (p=0.02) and venous (p<0.01) diameters were increased. All retinal hemodynamic parameters showed a decrease during 100% oxygen breathing. This decrease was significantly blunted by LPS for all retinal outcome parameters except venous diameter (p=0.04 for white blood cell velocity, p=0.0002 for white blood cell density, p<0.0001 for white blood cell flux, p=0.01 for arterial diameter, p=0.02 for red blood cell velocity and p=0.006 for red blood cell flux). These data indicate that LPS-induced inflammation induces vascular dysregulation in the retina. This may provide a link between inflammation and vascular dysregulation. Further studies are warranted to investigate whether this model may be suitable to study inflammation induced vascular dysregulation in the eye.

Comparison of Two Toric IOLs with Different Haptic Design: Optical Quality after 1 Year.

BACKGROUND: The purpose of this prospective, randomised study was to interocularly compare the visual performance after implantation of two different toric IOLs with different haptic design. METHODS: 59 subjects with corneal astigmatism greater than 1.25 diopter (D) were implanted with an AT TORBI 709M IOL (Carl Zeiss Meditec AG) in one eye and with a Tecnis toric aspheric IOL (Abbot Medical Optics) in the other eye. Observation procedure was performed 12 months postoperatively. Main outcome measures included uncorrected distance visual acuity (UDVA), manifest refraction, IOL rotation, and IOL position. RESULTS: Mean UCDVA was 0.04 ± 0.14 logMAR for AT TORBI eyes and 0.06 ± 0.15 logMAR for Tecnis eyes (p = 0.3). The postoperative spherical equivalent values were significantly lower in the AT TORBI group. Mean toric IOL axis rotation was 3.0 ± 2.26 degrees for AT TORBI eyes and 3.27 ± 2.37 for Tecnis eyes (p = 0.5). The mean vertical IOL tilt and vertical decentration values measured with the Visante OCT were significantly larger in the AT TORBI group (p < 0.05). CONCLUSIONS: Both the Tecnis and the AT TORBI toric IOLs successfully reduced ocular astigmatism. Emmetropia could be better achieved with the AT TORBI IOL, whereas the Tecnis showed better positional stability. This trial is registered with ICMJE NCT03371576.

Effect of Spherical Aberration on the Optical Quality after Implantation of Two Different Aspherical Intraocular Lenses.

PURPOSE: To compare the effect of spherical aberration on optical quality in eyes with two different aspherical intraocular lenses. METHODS: 120 eyes of 60 patients underwent phacoemulsification. In patients' eyes, an aberration-free IOL (Aspira-aA; Human Optics) or an aberration-correcting aspherical IOL (Tecnis ZCB00; Abott Medical Optics) was randomly implanted. After surgery, contrast sensitivity and wavefront measurements as well as tilt and decentration measurements were performed. RESULTS: Contrast sensitivity was significantly higher in eyes with Aspira lens under mesopic conditions with 12 cycles per degree (CPD) and under photopic conditions with 18 CPD (p = 0.02). Wavefront measurements showed a higher total spherical aberration with a minimal pupil size of 4 mm in the Aspira group (0.05 ± 0.03) than in the Tecnis group (0.03 ± 0.02) (p = 0.001). Strehl ratio was higher in eyes with Tecnis (0.28 ± 0.17) with a minimal pupil size larger than 5 mm than that with Aspira (0.16 ± 0.14) (p = 0.04). In pupils with a minimum diameter of 4 mm spherical aberration had a significant effect on Strehl ratio, but not in pupils with a diameter less than 4 mm. CONCLUSIONS: Optical quality was better in eyes with the aberration-correcting Tecnis IOL when pupils were large. In contrast, this could not be shown in eyes with pupils under 4 mm or larger. This trial is registered with Clinicaltrials.gov NCT03224728.

Relation of retinal blood flow and retinal oxygen extraction during stimulation with diffuse luminance flicker.

Cerebral and retinal blood flow are dependent on local neuronal activity. Several studies quantified the increase in cerebral blood flow and oxygen consumption during activity. In the present study we investigated the relation between changes in retinal blood flow and oxygen extraction during stimulation with diffuse luminance flicker and the influence of breathing gas mixtures with different fractions of O2 (FiO2; 100% 15% and 12%). Twenty-four healthy subjects were included. Retinal blood flow was studied by combining measurement of vessel diameters using the Dynamic Vessel Analyser with measurements of blood velocity using laser Doppler velocimetry. Oxygen saturation was measured using spectroscopic reflectometry and oxygen extraction was calculated. Flicker stimulation increased retinal blood flow (57.7 ± 17.8%) and oxygen extraction (34.6 ± 24.1%; p < 0.001 each). During 100% oxygen breathing the response of retinal blood flow and oxygen extraction was increased (p < 0.01 each). By contrast, breathing gas mixtures with 12% and 15% FiO2 did not alter flicker-induced retinal haemodynamic changes. The present study indicates that at a comparable increase in blood flow the increase in oxygen extraction in the retina is larger than in the brain. During systemic hyperoxia the blood flow and oxygen extraction responses to neural stimulation are augmented. The underlying mechanism is unknown.

Retinal oxygen metabolism during normoxia and hyperoxia in healthy subjects.

PURPOSE: To characterize retinal metabolism during normoxia and hyperoxia in healthy subjects. METHODS: Forty-six healthy subjects were included in the present study, and data of 41 subjects could be evaluated. Retinal vessel diameters, as well as oxygen saturation in arteries and veins, were measured using the Dynamic Vessel Analyzer. In addition, retinal venous blood velocity was measured using bidirectional laser Doppler velocimetry, retinal blood flow was calculated, and oxygen and carbon dioxide partial pressures were measured from arterialized capillary blood from the earlobe. Measurements were done during normoxia and during 100% oxygen breathing. RESULTS: Systemic hyperoxia caused a significant decrease in retinal venous diameter (-13.0% ± 4.5%) and arterial diameter (-12.1% ± 4.0%), in retinal blood velocity (-43.4% ± 7.7%), and in retinal blood flow (-57.0% ± 5.7%) (P < 0.001 for all). Oxygen saturation increased in retinal arteries (+4.4% ± 2.3%) and in retinal veins (+19.6% ± 6.2%), but the arteriovenous oxygen content difference significantly decreased (-29.4% ± 19.5%) (P < 0.001 for all). Blood oxygen tension in arterialized blood showed a pronounced increase from 90.2 ± 7.7 to 371.3 ± 92.7 mm Hg (P < 0.001). Calculated oxygen extraction in the eye decreased by as much as 62.5% ± 9.5% (P < 0.001). CONCLUSIONS: Our data are compatible with the hypothesis that during 100% oxygen breathing a large amount of oxygen, consumed by the inner retina, comes from the choroid, which is supported by previous animal data. Interpretation of oxygen saturation data in retinal arteries and veins without quantifying blood flow is difficult. (ClinicalTrials.gov number, NCT01692821.).

Role of nitric oxide in optic nerve head blood flow regulation during isometric exercise in healthy humans.

PURPOSE: We determined whether administration of a nitric oxide synthase (NOS) inhibitor alters optic nerve head blood flow (ONHBF) regulation during isometric exercise in healthy subjects. METHODS: Our study was done in a randomized, placebo-controlled, double-masked, three-way crossover design. A total of 18 healthy subjects was randomized to receive either placebo, phenylephrine, or an inhibitor of NOS (L-NMMA) on three different study days. ONHBF was measured with laser Doppler flowmetry while the study participants performed isometric exercise (squatting). This was done before drug administration and during infusion of the study drugs. Mean arterial pressure (MAP) and IOP were measured noninvasively, and ocular perfusion pressure (OPP) was calculated as 2/3 MAP - IOP. RESULTS: The response in ONHBF to isometric exercise was less pronounced than the response in OPP, indicating for some autoregulatory capacity in the ONH. Administration of L-NMMA significantly decreased ONHBF at rest (P < 0.01). In contrast, inhibition of NOS did not alter the pressure-flow relationship in the ONH during an experimental increase in OPP compared to phenylephrine and placebo (P = 0.37 between groups). CONCLUSIONS: The data of our study support previous findings that ONHBF is autoregulated during an experimental increase in OPP. Nitric oxide has an important role in basal ONHBF regulation, but seems not to be involved in the autoregulatory response during an increase in OPP induced by isometric exercise. (ClinicalTrials.gov number, NCT00806741.).

Neurovascular dysfunction precedes neural dysfunction in the retina of patients with type 1 diabetes.

PURPOSE: A variety of studies have shown that flicker-induced vasodilatation is reduced in patients with diabetes. It is, however, unclear whether reduced neural activity or abnormal neurovascular coupling is the reason for this phenomenon. In the present study, we hypothesized that retinal neurovascular dysfunction precedes neural dysfunction in patients with early type 1 diabetes. METHODS: In the present study, 50 patients with type 1 diabetes without retinopathy and 50 healthy age- and sex-matched control subjects were included. The retinal vascular response to flicker stimulation was measured using the dynamic Retinal Vessel Analyzer. In addition, the response in retinal blood velocity to flicker stimulation as assessed with laser Doppler velocimetry was studied in a subgroup of patients. Pattern electroretinography (ERG) was used to measure neural retinal function. RESULTS: The flicker responses of both retinal arteries and veins were significantly reduced in patients with diabetes (veins in the diabetic group: 3.5 ± 2.3% versus healthy control group: 4.6 ± 2.0%; P = 0.022 between groups, whereas arteries in the diabetic group: 2.0 ± 2.7% versus healthy control group: 3.8 ± 1.7%; P < 0.001 between groups). Likewise, the response of retinal blood velocity was reduced in patients with diabetes, although adequate readings could only be obtained in a subgroup of subjects (diabetic group [n = 22]: 19 ± 7%; healthy control group [n = 24]: 43 ± 19% P < 0.001 between groups). The parameters of pattern ERG were not different between the two groups. CONCLUSIONS: The study confirms that flicker responses are reduced early in patients with type 1 diabetes. This is seen before alterations in pattern ERG indicating abnormal neurovascular coupling.

Measurement of retinal oxygen saturation in patients with chronic obstructive pulmonary disease.

PURPOSE: There is growing evidence that disturbances in retinal oxygenation may trigger ocular diseases. New instruments allow for the noninvasive measurement of retinal oxygen saturation in humans. The present study was designed to investigate the retinal oxygen saturation in patients with chronic obstructive pulmonary disease (COPD). This was also done in an effort to test the validity of retinal oxygenation measurements with a retinal vessel analyzer. METHODS: In all, 16 patients with severe COPD grade 4 who were on long-term oxygen treatment were included in the study. For each patient two identical study days were scheduled. Measurements of retinal arterial and venous oxygen saturation were done using a commercially available instrument for retinal oxygen analysis. Peripheral arterial oxygen saturation values were analyzed with pulse oximetry and via a capillary blood sample drawn from the earlobe. Measurements were performed during oxygen treatment and during a period without oxygen supplementation. Analysis of all images for retinal oxygen saturation quantification was done by a masked investigator. Analysis was done using Pearson's correlation and a multivariate regression model. RESULTS: Arterial and venous retinal oxygen saturation decreased significantly after the cessation of the oxygen therapy. The arteriovenous oxygen difference was unchanged while breathing ambient air or pure oxygen-enriched air. With both Pearson's correlation and the multivariate model, we found significant positive correlation coefficients between retinal arterial and peripheral arterial oxygen saturation as assessed with pulse oximetry as well as between retinal arterial and peripheral arterial oxygen saturation measured in blood samples. The change of oxygen saturation after discontinuation of oxygen supplementation showed a good correlation between retinal arterial oxygen saturation and peripheral arterial oxygen saturation (r = 0.53, P < 0.05). Reproducibility on the two study days was high. DISCUSSION: The present study shows a good correlation between retinal arterial and peripheral arterial oxygen saturation indicating good validity of the technique. (ClinicalTrials.gov number, NCT00999024.).

Alterations of choroidal blood flow regulation in young healthy subjects with complement factor H polymorphism.

A common polymorphism in the complement factor H gene (rs1061170, Y402H) is associated with a high risk of age-related macular degeneration (AMD). In the present study we hypothesized that healthy young subjects homozygous for the high-risk haplotype (CC) show abnormal choroidal blood flow (ChBF) regulation decades before potentially developing the disease. A total of 100 healthy young subjects were included in the present study, of which 4 subjects were excluded due to problems with genotyping or blood flow measurements. ChBF was measured continuously using laser Doppler flowmetry while the subjects performed isometric exercise (squatting) for 6 minutes. The increase in ChBF was less pronounced than the response in ocular perfusion pressure (OPP), indicating for some degree of choroidal blood flow regulation. Eighteen subjects were homozygous for C, 47 subjects were homozygous for T and 31 subjects were heterozygous (CT). The increase in OPP during isometric exercise was not different between groups. By contrast the increase in ChBF was more pronounced in subjects homozygous for the high risk C allele (p = 0.041). This was also evident from the pressure/flow relationship, where the increase in ChBF in homozygous C carriers started at lower OPPs as compared to the other groups. Our data indicate that the regulation of ChBF is abnormal in rs1061170 CC carriers. So far this polymorphism has been linked to age related macular degeneration (AMD) mainly via inflammatory pathways associated with the complement system dysfunction. Our results indicate that it could also be related to vascular factors that have been implicated in AMD pathogenesis.

Regulation of optic nerve head blood flow during combined changes in intraocular pressure and arterial blood pressure.

In the choroid, there is evidence that blood flow does not only depend on ocular perfusion pressure (OPP), but also on absolute mean arterial pressure (MAP) and intraocular pressure (IOP). The present study included 40 healthy subjects to investigate whether such behavior is also found in the optic nerve head (ONH). The ONH blood flow (ONHBF) was studied using laser Doppler flowmetry during a separate increase in IOP and MAP as well as during a combined elevation. Mean arterial pressure was increased by isometric exercise and IOP by the suction method. During both, the change in ONHBF was less pronounced than the change in OPP indicating autoregulation. Correlation analysis was performed for the combined experiments after pooling all data according to IOP and MAP values. A correlation between ONHBF and MAP was found at IOPs 25 mm Hg (P<0.001), but not at IOPs>25 mm Hg (P=0.79). Optic nerve head blood flow and IOP were significantly correlated (P<0.001), and ONHBF was only slightly dependent on MAP. The data of the present study indicate a complex regulation of ONHBF during combined changes in MAP and IOP. Our results may be compatible with myogenic mechanisms underlying autoregulation, and indicate better ONHBF regulation during an increase in MAP than during an increase in IOP.

Effect of NO synthase inhibition on retinal vessel reaction to isometric exercise in healthy humans.

PURPOSE: It has been shown that retinal blood flow is autoregulated, meaning that flow is independent of perfusion pressure within a certain range. We tested the hypothesis that nitric oxide (NO) synthase inhibition alters the response of retinal arterial and venous vessels during isometric exercise. METHODS: In this study, nine healthy subjects were included. Each subject received the NO synthase inhibitor Ng-monomethyl-l-Arginine (l-NMMA, the α-receptor agonist phenylephrine or placebo intravenously on three study days. Retinal vessel diameter was assessed with the retinal vessel analyser (RVA), at baseline and during a squatting period of 6-7 min in absence or presence of l-NMMA, phenylephrine or placebo. RESULTS: Mean arterial pressure (MAP) and pulse rate (PR) increased significantly during all pretreatment squatting periods (p < 0.001) Retinal venous and arterial diameters showed a continuous decrease during squatting (p < 0.001). Phenylephrine increased MAP and PR but did not alter the retinal vessel diameter response to squatting. Administration of l-NMMA lead to a significant decrease in venous diameter before isometric exercise (p = 0.004). In addition, the retinal venous diameter response during administration of the NO synthase inhibitor was less pronounced than during phenylephrine or placebo (p < 0.001). CONCLUSION: Our study confirms that NO plays an important role in the control of retinal vascular tone at rest. In addition, the present data indicate a role of NO in retinal autoregulation, because the response of retinal venous diameters was altered after NO synthase inhibition. The nature of involvement, however, appears to be complex and requires further studies.

The effects of moxaverine on ocular blood flow in patients with age-related macular degeneration or primary open angle glaucoma and in healthy control subjects.

PURPOSE: The phosphodiesterase inhibitor moxaverine has been shown to increase choroidal blood flow (BF) in young healthy subjects. The present study was performed to investigate the effect of intravenously administered moxaverine on ocular BF in patients with age-related macular degeneration (AMD), primary open angle glaucoma (POAG) and in age-matched control subjects. METHODS: Twenty patients with AMD, 20 patients with POAG and 20 control subjects were included. Moxaverine 150 mg was applied intravenously over 30 min. BF was measured in the choroid and in the optic nerve head (ONH) using laser-Doppler flowmetry and in retinal vessels combining laser-Doppler velocimetry with retinal vessel analysis before and 30, 60 and 90 min after start of drug administration. BF velocities in the retrobulbar vessels were measured using colour Doppler imaging. RESULTS: Moxaverine increased choroidal BF by 9 ± 22% (p = 0.012), ONH BF by 13 ± 33% (p = 0.021), mean flow velocity in the ophthalmic artery by 23 ± 34% (p < 0.001) and in the posterior ciliary arteries by 25 ± 35% (p < 0.001). Moxaverine had no significant effect on retinal vessel diameters and retinal BF. There were no significant differences in any of the measured parameters between the three groups. CONCLUSION: The present study indicates that systemic administration of moxaverine increases choroidal and ONH BF in elderly patients with eye diseases associated with hypoperfusion and in age-matched controls. Further studies in patients are needed to investigate whether long-term treatment with moxaverine is clinically beneficial for patients with ocular diseases.

Reproducibility of retinal vessel oxygen saturation measurements in healthy young subjects.

PURPOSE: An adequate oxygenation and perfusion is essential for the function of the inner retina. Recently, several techniques for the measurement of retinal oxygen saturation became available. We set out to evaluate reproducibility of the measurements using a modified Retinal Vessel Analyzer. METHODS: A total of 20 healthy female and male subjects aged between 18 and 35 years (22.9 ± 3.9; mean ± SD) were included. The measurement of retinal oxygen saturation with the retinal oximeter employed in this study is based on optical reflectometry using the different absorption characteristics of oxygenated and deoxygenated haemoglobin. The intraclass correlation coefficients and the coefficients of variation (CV) for test-retest, short-term as well as day-to-day measurements were calculated. RESULTS: The intraclass correlation coefficients were between 0.91 and 0.94 for retinal branch arteries and between 0.84 and 0.88 for retinal branch veins. In retinal arteries, we calculated a test-retest CV of 3.24 ± 3.18% for oxygen saturation measurements. In retinal veins, data were slightly less reproducible with a CV of 4.92 ± 3.57%. Short-term reproducibility of both measurement cycles on each study day was in the same range (CV in retinal arteries: 2.91 ± 2.42% and CV in retinal veins: 4.76 ± 3.14%). The day-to-day coefficient of variation was slightly higher (CV in retinal arteries: 3.97 ± 2.87% and CV in retinal veins: 6.18 ± 3.36%). CONCLUSION: The reproducibility of haemoglobin oxygen saturation measurements using the retinal oximeter is acceptable. Further studies on the validity of the obtained results are, however, required.

Comparison of choroidal and optic nerve head blood flow regulation during changes in ocular perfusion pressure.

PURPOSE: We compared the response of choroidal and optic nerve head blood flow (ChBF, ONHBF) in response to an increase in ocular perfusion pressure (OPP) during isometric exercise and during a decrease in OPP during an artificial increase in intraocular pressure (IOP). METHODS: We included 96 healthy subjects in our study. In 48 subjects OPP was increased by 6 minutes of squatting, and either ONHBF (n = 24) or ChBF (n = 24) was measured continuously. In 48 other healthy subjects either ONHBF (n = 24) or ChBF (n = 24) was measured continuously during a period of artificial increase in IOP using a suction cup. All blood flow measurements were done using laser Doppler flowmetry. RESULTS: During all experiments the response in blood flow was less pronounced than the response in OPP, indicating for flow regulation. During isometric exercise ChBF regulated better than ONHBF (P = 0.023). During artificial IOP increase ONHBF regulated better than ChBF (P = 0.001). Inter-individual variability in blood flow responses was high. During squatting ONHBF decreased considerably below baseline ONHBF when OPP fluctuated in 3 subjects, although OPP still was much higher than at baseline. This phenomenon was not observed in the choroid. CONCLUSIONS: Our data indicate that regulation of ChBF and ONHBF during changes in OPP is different and complex. In some subjects performing squatting, considerable ONHBF reductions were observed during OPP fluctuations, although OPP still was high. Whether this predisposes to ocular disease remains unclear.

Effect of latanoprost on choroidal blood flow regulation in healthy subjects.

PURPOSE: The present study tested the hypothesis that human choroidal blood flow (ChBF) regulation in the face of changes in ocular perfusion pressure (OPP) may be modified by a drug-induced decrease in intraocular pressure (IOP). METHODS: This hypothesis was tested in a double-masked, randomized, placebo-controlled, parallel-group trial in 24 healthy volunteers. OPP was manipulated by 6 minutes of squatting and a subsequent period of artificial increase in IOP induced with a suction cup. These interventions were repeated after 14 days of treatment with either latanoprost or placebo. ChBF was measured continuously with a portable laser Doppler flowmeter. RESULTS: As expected, latanoprost significantly reduced IOP compared with placebo (P = 0.008). The relative increases in OPP during squatting (P = 0.97) and an artificial IOP increase (P = 0.75), however, were comparable after placebo and latanoprost. The response of ChBF was, in contrast, different between the two treatment groups. During the squatting-induced elevation of OPP, ChBF increased less after latanoprost than after placebo treatment (P = 0.049). During the suction cup-induced increase in IOP, the decrease in ChBF was less pronounced after latanoprost than after placebo (P = 0.026). Latanoprost, however, did not modify baseline ChBF at rest (P = 0.30). CONCLUSIONS: The data indicate that latanoprost improves ChBF regulation during both an increase and a decrease in OPP. Since latanoprost did not affect baseline ChBF, the authors assume that this effect is related to the decrease in IOP. This finding has important implications for understanding the relation between IOP and vascular factors in glaucoma, because it indicates that a reduction in IOP itself improves ChBF regulation.