Katharina Karl

Correlation of flicker-induced and flow-mediated vasodilatation in patients with endothelial dysfunction and healthy volunteers.

OBJECTIVE Flicker-induced vasodilatation is reduced in patients with vascular-related diseases, which has at least partially been attributed to endothelial dysfunction of retinal vessels. Currently, the standard method to assess endothelial function in vivo is flow-mediated vasodilatation (FMD). Thus, the present study was performed to investigate whether a correlation exists between flicker-induced vasodilatation and FMD in patients with known endothelial dysfunction and healthy subjects. RESEARCH DESIGN AND METHODS In the present study, 20 patients with type 1 diabetes, 40 patients with systemic hypertension (systolic blood pressure 140–159 mmHg; diastolic blood pressure 90–99 mmHg) and/or serum cholesterol levels ≥0.65 mmol/l, and 20 healthy control subjects were included. The flicker response was measured using the Dynamic Retinal Vessel Analyzer. FMD was determined using a high-resolution ultrasound system, measuring brachial artery diameter reactivity during reperfusion after arterial occlusion. RESULTS The flicker response of both retinal arteries and veins was significantly reduced in the two patients groups. Likewise, FMD was significantly reduced in patients compared with healthy control subjects. However, only a weak correlation between flicker-induced vasodilatation and FMD was observed. CONCLUSIONS The study confirms that flicker responses and FMD are reduced in the selected patient groups. Whether the weak correlation between FMD and flicker is due to the different stimulation type, the different vascular beds measured, or other mechanisms has yet to be investigated.

Reduced Retinal Vessel Response to Flicker Stimulation but Not to Exogenous Nitric Oxide in Type 1 Diabetes

PURPOSE Various studies have shown that retinal vessels in patients with diabetes mellitus have a reduced capacity to adapt to changes in perfusion pressure and to stimulation with flickering light. Structural and functional changes in retinal vessels in diabetes could lead to a general reduction of vasodilator and/or vasoconstrictor capacity. To gain more insight into this topic, we compared the response of retinal vessel diameters to systemic glyceryl trinitrate (GTN) and stimulation with diffuse luminance flicker in patients with diabetes and healthy control subjects. METHODS Twenty patients with type 1 diabetes mellitus featuring no or mild nonproliferative diabetic retinopathy and 20 healthy, age-matched subjects were included in this study. A vessel analyzer was used for measurement of diameters of retinal arteries and veins. The response of diameters was measured continuously during stimulation with flickering light, as well as immediately after sublingual application of 0.8 mg GTN. RESULTS The response of retinal vessels to flickering light was significantly reduced in the patients with diabetes (arteries: 2.9% in diabetes versus 7.0% in control subjects, P < 0.002; veins: 4.6% in diabetes versus 6.8% in control subjects, P = 0.020). GTN-induced vasodilatation was not different between the patients with diabetes and the healthy control subjects (P >or= 0.70). CONCLUSIONS The present study confirmed reduced response of retinal vessels to stimulation with flickering light in diabetes. The response of retinal vessels to a direct NO-donor, however, was maintained. This result indicates that abnormal flicker-induced vasodilatation in diabetes is not a consequence of generally reduced retinal vascular reactivity (ClinicalTrials.gov number, NCT00432029).

Effect of Dual Endothelin Receptor Blockade on Ocular Blood Flow in Patients with Glaucoma and Healthy Subjects

PURPOSE Several lines of evidence indicate that altered blood flow regulation may contribute to the pathogenesis of glaucomatous optic neuropathy. Recent data support the hypothesis that the endothelin system is involved in the processes that lead to vascular dysregulation in glaucoma. This study was conducted to test the hypothesis that bosentan, a dual endothelin receptor antagonist, increases ocular blood flow in patients with glaucoma. METHODS Fourteen patients with primary open-angle glaucoma and 14 sex- and age-matched healthy volunteers were included. Both groups received bosentan 500 mg daily for 8 days. Ocular hemodynamics were assessed at baseline and on the last study day. Retinal vessel diameters and retinal red blood cell velocity were recorded with a retinal vessel analyser and laser Doppler velocimetry, respectively. Choroidal and optic nerve head blood flow were measured with laser Doppler flowmetry. RESULTS Retinal arteries and veins showed a significant dilatation after administration of bosentan in both groups (+5%-8%). Retinal blood velocity and retinal blood flow increased up to +45% after administration of bosentan in both patients and healthy subjects. Administration of bosentan increased choroidal (+12%-17%) and optic nerve head blood flow (+11%-24%) in both groups. The effect of bosentan on ocular blood flow parameters was comparable between the two groups. CONCLUSIONS The data from the present study indicate that dual inhibition of endothelin receptors increases ocular blood flow in patients with glaucoma and healthy subjects. Further studies are needed to study the dose-response relationship of this effect and to characterize the role of endothelin receptor subtypes.

Effects of antioxidants (AREDS medication) on ocular blood flow and endothelial function in an endotoxin-induced model of oxidative stress in humans.

PURPOSE The Age-Related Eye Disease Study (AREDS) has shown that supplementation of antioxidants slows the progression of age-related macular degeneration (AMD). The mechanism underlying this therapeutic effect may be related to a reduction of reactive oxygen species (ROS). The authors have recently introduced a model showing that the response of retinal blood flow (RBF) to hyperoxia is diminished by administration of lipopolysaccharide (LPS). In the present study, the hypothesis was that this response can be restored by the AREDS medication. METHODS Twenty-one healthy volunteers were included in this randomized, double-masked, placebo-controlled, parallel group study. On each study day, RBF and the reactivity of RBF to hyperoxia were investigated before and after infusion of 2 ng/kg LPS. Between the two study days, subjects took either the AREDS medication or placebo for 14 days. RESULTS After administration of LPS reduced retinal arterial vasoconstriction during hyperoxia (AREDS group: 12.5% +/- 4.8% pre-LPS vs. 9.4% +/- 4.6% post-LPS; placebo group: 9.2% +/- 3.3% pre-LPS vs. 7.1% +/- 3.5% post-LPS) and a reduced reactivity of RBF during hyperoxia (AREDS: 50.4% +/- 8.9% vs. 44.9% +/- 11.6%, placebo: 54.2% +/- 8.6% vs. 46.0% +/- 6.9%) was found. The reduced responses were normalized after 2 weeks of AREDS antioxidants but not after placebo (vasoconstriction: 13.1% +/- 4.5% vs. 13.1% +/- 5.0% AREDS, 11.2% +/- 4.2 vs. 7.4% +/- 4.2% placebo; RBF: 52.8% +/- 10.5% vs. 52.4% +/- 10.5% AREDS, 52.4% +/- 9.3% vs. 44.2% +/- 6.3% placebo). CONCLUSIONS The sustained retinal vascular reaction to hyperoxia after LPS in the AREDS group indicates that antioxidants reduce oxidative stress-induced endothelial dysfunction, possibly by eliminating ROS. The model may be an attractive approach to studying the antioxidative capacity of dietary supplements for the treatment of AMD (ClinicalTrials.gov number, NCT00431691).

Effect of systemic moxaverine on ocular blood flow in humans

Purpose:  A number of common eye diseases are associated with ocular perfusion abnormalities. The present study aimed to investigate whether systemically administered moxaverine improves ocular blood flow.

Effect of unspecific inhibition of cyclooxygenase by indomethacin on retinal and choroidal blood flow.

PURPOSE Animal studies suggest that retinal and choroidal blood flow decrease after administration of indomethacin, a nonspecific cyclooxygenase inhibitor. Cyclooxygenase is the key enzyme involved in the arachidonic pathway and regulates the production of vasoactive substances such as prostaglandins and thromboxans. The aim of the present study was to investigate the short-term effects of indomethacin on ocular blood flow in healthy humans. METHODS A randomized, double-masked, placebo-controlled, two-way crossover study in 12 healthy, male, nonsmoking subjects was performed. Indomethacin was administered as a bolus injection of 0.4 mg/kg followed by continuous infusion of 0.4 mg/kg/h over 120 minutes. Ocular hemodynamic parameters were measured at baseline and up to 3 hours after start of the infusion. Subfoveal choroidal blood flow and fundus pulsation amplitude were measured with laser Doppler flowmetry and laser interferometry, respectively. Retinal vessel diameters were assessed using a retinal vessel analyzer. Retinal blood flow was calculated based on retinal vessel diameters, and red blood cell velocity was measured with laser Doppler velocimetry. RESULTS Administration of indomethacin decreased retinal arterial diameters up to -4.3% +/- 3.4% and reduced retinal blood velocity by a maximum of -29% +/- 20% (P < 0.05). Calculated retinal blood flow decreased by -27% +/- 21% (P < 0.05), reaching the maximal decrease 60 minutes after administration. Choroidal blood flow and fundus pulsation amplitude (FPA) also decreased during the infusion of indomethacin with maximum effects of -17% +/- 13% (P < 0.05, vs. placebo) and -7% +/- 4% (P < 0.05, vs. placebo), respectively. CONCLUSIONS Results showed a marked decrease in retinal and choroidal blood flow after short-term administration of indomethacin. Whether this decrease can be attributed to a reduced production of prostaglandins or an unknown mechanism has yet to be clarified. Further studies appear to be indicated to investigate whether the long-term intake of indomethacin is associated with an increased risk for vascular eye disease.

Effect of dual endothelin receptor blockade on ocular blood flow in patients with glaucoma and healthy subjects

PURPOSE. Several lines of evidence indicate that altered blood flow regulation may contribute to the pathogenesis of glaucomatous optic neuropathy. Recent data support the hypothesis that the endothelin system is involved in the processes that lead to vascular dysregulation in glaucoma. This study was conducted to test the hypothesis that bosentan, a dual endothelin receptor antagonist, increases ocular blood flow in patients with glaucoma. METHODS. Fourteen patients with primary open-angle glaucoma and 14 sex- and age-matched healthy volunteers were included. Both groups received bosentan 500 mg daily for 8 days. Ocular hemodynamics were assessed at baseline and on the last study day. Retinal vessel diameters and retinal red blood cell velocity were recorded with a retinal vessel analyser and laser Doppler velocimetry, respectively. Choroidal and optic nerve head blood flow were measured with laser Doppler flowmetry. RESULTS. Retinal arteries and veins showed a significant dilatation after administration of bosentan in both groups (5%‐ 8%). Retinal blood velocity and retinal blood flow increased up to 45% after administration of bosentan in both patients and healthy subjects. Administration of bosentan increased choroidal (12%‐17%) and optic nerve head blood flow (11%‐24%) in both groups. The effect of bosentan on ocular blood flow parameters was comparable between the two groups. CONCLUSIONS. The data from the present study indicate that dual inhibition of endothelin receptors increases ocular blood flow in patients with glaucoma and healthy subjects. Further studies are needed to study the dose‐response relationship of this effect and to characterize the role of endothelin receptor subtypes. (Invest Ophthalmol Vis Sci. 2009;50:358‐363) DOI: 10.1167/iovs.08-2460

Effect of antioxidants on ocular blood flow and endothelial function in an endotoxin-induced inflammatory model in humans

Background Oxidative stress, which refers to cellular damage caused by reactive oxygen species (ROS), has been implicated in many disease processes. The Age-Related Eye Disease Study (AREDS) showed that daily intake of a combination of the antioxidants beta carotene, vitamins C and E, zinc and copper may retard the progression of age related macular degeneration by reducing ROS [1]. We investigated the effect of the AREDS combination of antioxidants on retinal and choroidal blood flow and on retinal vascular reactivity under normal conditions and in a standardized experimental inflammatory model in humans.