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Purpose: To investigate the vasorelaxation effect of ripasudil (K-115), a novel Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, on isolated retinal arterioles. We determined whether the actions of ripasudil on the retinal microvascular diameter were dependent on the endothelium and/or potassium channels in the smooth muscle, with the goals of uncovering the signaling mechanisms required for this vasomotor activity and inhibiting the action of endothelin-1 (ET-1). Methods: In this in vitro study, we isolated porcine retinal arterioles, which were cannulated and pressurized without flow. We recorded diametric changes using videomicroscopic techniques. Results: In a dose-dependent (10 nM-30 µM) manner, retinal arterioles were relaxed in response to ripasudil [maximum % resting diameter, 160.3% ± 7.7% (mean ± standard error of the mean)]. The ripasudil-induced vasorelaxation was unaffected by endothelium removal, using nonselective potassium channel blocker tetraethylammonium, Ca2+-activated large-conductance potassium channel blocker iberiotoxin, voltage-gated potassium channel blocker 4-AP, ATP-sensitive potassium channel blocker glibenclamide, and inward rectifier potassium channel blocker BaCl2. Ripasudil prevented ET-1-caused vasoconstriction of the retinal arterioles regardless of the presence of endothelium to a similar extent. Conclusion: The ROCK inhibitor ripasudil elicits endothelium-independent relaxation and inhibits the action of ET-1 on the retinal arterioles. Determining the relaxation properties of ripasudil on the retinal microvasculature will likely support the development of potential therapies for glaucoma.

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Purpose: We aimed to observe longitudinal changes in retinal blood flow (RBF) and structural transformations in capillaries using Doppler optical coherence tomography (DOCT) and optical coherence tomography angiography (OCTA) in a feline retinal blood occlusion (RVO) model. Methods: RVO was induced by argon green laser photocoagulation (PC) in six eyes of six cats. RBF was measured at a first-order retinal artery and vein by a DOCT flowmeter, and structural changes in the capillaries around the occluded vessels (12 × 12 and 3 × 3 mm) were assessed by OCTA before (at baseline); immediately after PC; and on days 1, 4, 7, and 14 thereafter. Systemic and ocular parameters were monitored during the observation period. Results: There were no significant differences in any systemic or ocular parameters before and after PC. Arterial RBF increased significantly on day 1 (160.6 ± 8.6% vs. baseline, P < 0.001) and decreased below baseline after day 1 through 14. Venous RBF decreased immediately after PC (17.4 ± 9.6% vs. baseline, P = 0.001) and then gradually increased afterwards, but did not return to baseline. OCTA showed dilatation of retinal venules immediately after PC to day 1. Collateral vessels began to form on day 4, had matured by day 7, and were pruned on day 14, which formed as mature as normal retinal venule diameters. Conclusions: With increasing arterial RBF within 1 day after inducing RVO, venules gradually expanded to form collateral vessels, suggesting that collateral vessels originate from existing capillary networks, not neovascularization.

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BACKGROUND: Studies identifying modifiable lifestyle risk factors related to open-angle glaucoma (OAG) are limited, especially from Asian countries. This study aimed to identify lifestyle risk factors for OAG in a Japanese population. METHODS AND FINDINGS: This population-based, cross-sectional study recruited Japanese participants aged 40 years or older from January 2013 to March 2015. We took fundus photographs for OAG screening, determined lifestyle and health characteristics through a questionnaire and performed physical examinations. The participants who had suspect findings in the fundus photographs were sent for a detailed ophthalmic examination to diagnose OAG. Lifestyle and heath characteristics were statistically compared between the OAG and non-OAG participants. A total of 1583 participants were included in the study, of which 42 had OAG and 1541 did not have OAG. The number of days per week that the female participants consumed meat (mean±SD; OAG: 1.7±1.2 days, non-OAG: 2.7±1.5 days) was negatively associated with OAG (OR = 0.61; 95% CI: 0.43-0.88; p = 0.007). Higher intraocular pressure was positively associated with OAG in men (OR = 1.20; 95% CI: 1.05-1.38, p = 0.009). No significant difference between participants with and without OAG was observed for a range of other lifestyle factors and health criteria including self-report of diabetes, number of family living together, body mass index, blood pressure, pulse rate, coffee drinking, tea drinking, alcohol drinking, number of fruits consumed per day and days of fish consumption per week. CONCLUSIONS: A higher weekly consumption of meat appears to be negatively associated with OAG in Japanese women. Increasing the dietary intake of meat can contribute to reducing the risk of developing OAG.

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To compare the intraocular pressure (IOP) variability measured by multiple clinicians with those by one clinician. Forty-seven of 227 consecutive patients with glaucoma who had been examined routinely for over 12 months without changes in antiglaucoma medications at Asahikawa Medical University were included. Patients were assigned to one of two groups based on whether they had been followed by multiple or one clinician. One eye of each patient was evaluated. The IOPs obtained using Goldmann applanation tonometry were evaluated. We used the IOP standard deviation (SD, mmHg) and coefficient of variation (CV, %) as parameters of IOP variability. The main outcome measures were the differences in SD and CV between the groups. Multiple linear regression analysis evaluated factors associated with the SD and CV. Twenty-four (51.1 %) patients were assigned to the multiple-clinicians group and 23 (48.9 %) to the single-clinician group. The mean ± SD and CV were higher in the former (1.9 ± 0.5 and 12.0 ± 3.7, respectively) than in the latter group (1.4 ± 0.3 and 10.1 ± 2.5; P = 0.0005 and 0.044, respectively). The number of treating clinicians was the factor most associated with the SD and CV (ß = 0.455, P = 0.002 and ß = 0.387, P = 0.008, respectively). The variability in the IOP measurements of patients who had been monitored by multiple clinicians was higher than in patients followed by one clinician. The factor most associated with IOP variability was the number of clinicians involved.

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PURPOSE: To investigate the role of endothelin-1 (ET-1) in retinal glial cells in regulating retinal blood flow (RBF) during hyperoxia in cats. METHODS: We measured the vessel diameter (D), blood velocity (V), and blood flow (F) simultaneously in first-order retinal arterioles using a laser Doppler velocimetry system. The animals were under general anesthesia during hyperoxia (100% oxygen) for 10 minutes 24 hours after intravitreal injection of L-2-aminoadipic acid (LAA), a gliotoxic compound, or diluted hydrochloric acid (0.01 N) used as the vehicle control. We also measured the changes in the RBF after intravitreal injection of BQ-123, a specific ET type A receptor antagonist, in LAA-treated eyes. To examine if endothelin-converting enzyme-1 (ECE-1), as an ET-1-generating enzyme located in retinal glial cells, immunohistochemical examinations with costaining of antiglial fibrillary acidic protein (GFAP) antibody and anti-ECE-1 antibody were performed in whole-mount retinas. RESULTS: During hyperoxia, the decreases in D, V, and F in response to hyperoxia were attenuated significantly (P < 0.01 for all comparisons) in the LAA-treated eyes compared with the vehicle control (LAA, D, -8.5 ± 1.5%; V, -13.8 ± 1.5%; F, -27.8 ± 3.0% versus vehicle control, D, -16.8 ± 1.3%; V, -26.3 ± 2.0%; F, -48.9 ± 2.4%). In LAA-treated eyes, intravitreal injections of BQ-123 did not change the rate of hyperoxia-induced RBF compared to LAA-treated eyes. The anti-ECE-1 antibody was costained with anti-GFAP antibody in the whole-mount retinas. CONCLUSIONS: The current findings suggest that retinal glial ET-1 may play an important role in regulating RBF during hyperoxia in cats.

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PURPOSE: To study retinal blood flow (RBF) measurement reproducibility using segmental-scanning Doppler optical coherence tomography (DOCT) in vitro in glass capillaries and in vivo in anesthetized cats. METHODS: As a preliminary study, the flow rates of human blood through glass capillaries were changed by using an infusion pump and measured at 13 preset velocities by DOCT. For in vivo measurement, the cats were anesthetized using sevoflurane. The flow in the parent vessel was compared with the sum of the flow values in the two daughter vessels. The RBF was measured using two different instruments: bidirectional laser Doppler velocimetry (LDV) and DOCT. The reproducibility of the measurements was assessed by calculating the coefficients of variation (CVs) for repeated measurements of RBF at the superior retinal arterioles and venules. RESULTS: In vitro, the flow velocities measured by DOCT agreed well with the preset velocities. In vivo, the flow in the parent vessel agreed with the sum of the flow values in the two daughter vessels. In addition, there were no significant differences in the mean averaged CVs of the RBF in both the arterioles and venules between LDV and DOCT. CONCLUSIONS: The newly developed segmental-scanning DOCT revealed the accuracy of the measurement in in vitro glass capillaries and reproducibility of the measurements of blood velocity in both the retinal arterioles and venules in anesthetized cats.

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PURPOSE: To investigate how glial cells participate in retinal circulation during flicker stimulation in cats. METHODS: Using laser Doppler velocimetry, we measured the vessel diameter and blood velocity simultaneously and calculated the retinal blood flow (RBF) in feline first-order retinal arterioles. Twenty-four hours after intravitreal injections of L-2-aminoadipic acid (LAA), a gliotoxic compound, and the solvent of 0.01 N hydrochloric acid as a control, we examined the changes in RBF in response to 16-Hz flicker stimulation for 3 minutes. We also measured the changes in RBF 2 hours after intravitreal injection of Nω-propyl-L-arginine (L-NPA), a selective neuronal nitric oxide synthase inhibitor, in LAA-treated eyes. To evaluate the effects of LAA on retinal neuronal function, ERGs were monitored. Immunohistochemical examinations were performed. RESULTS: In LAA-treated eyes, histologic changes selectively occurred in retinal glial cells. There were no significant reductions in amplitude or elongation of implicit time in ERG after LAA injections compared with controls. In control eyes, the RBF gradually increased and reached the maximal level (53.5% ± 2.5% increase from baseline) after 2 to 3 minutes of flicker stimulation. In LAA-treated eyes, the increases in RBF during flicker stimulation were attenuated significantly compared with controls. In LAA-treated eyes 2 hours after injection of L-NPA, flicker-evoked increases in RBF decreased significantly compared with LAA-treated eyes. CONCLUSIONS: The current results suggested that increases in RBF in response to flicker stimulation were regulated partly by retinal glial cells.

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Ripasudil (K-115) is a novel Rho kinase inhibitor with a potent intraocular pressure-lowering effect. However, it is unclear whether ripasudil affects the retinal blood flow (RBF). We investigated the effect of ripasudil on feline retinal microcirculation. Ripasudil (5 µM, 50 µM or 5 mM; n = 5 each concentration) or vehicle (PBS; n = 5) was injected intravitreally. The vessel diameter (D) and blood velocity (V) were measured by laser Doppler velocimetry simultaneously in the first-order retinal arterioles and the RBF was calculated. The measurements started 5 min before the injection and were performed every 10 min for 120 min. After the intravitreal injection, the retinal circulatory parameters did not change significantly in PBS or 5 µM of ripasudil. The blood V and RBF increased significantly compared to baseline, whereas the vessel D did not change significantly in 50 µM and 5 mM of ripasudil. The V in 50 µM, and the V and RBF in 5 mM of ripasudil significantly increased compared to those in PBS. Intravitreal administration of ripasudil increased the blood V and RBF in cats, suggesting that ripasudil has the potential to improve the retinal blood flow.

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PURPOSE: To report a case of autologous transplantation of a free Tenon's graft to repair excessive bleb leakage after trabeculectomy. CASE REPORT: A 39-year-old Japanese woman presented with severe hypotony in her left eye. She had undergone trabeculectomy with mitomycin C 14 years ago. Slit-lamp examination showed an ischemic and ruptured bleb, excessive bleb leakage, and an extremely shallow anterior chamber. A large scleral defect was vaguely observed through the bleb conjunctiva. The hypotony was attributed to excessive bleb leakage. A surgical revision was required. First, the avascular bleb conjunctiva and the melted scleral flap were excised. A scleral defect was observed. Thick fibrotic tissue, i.e., the autologous Tenon's graft, was separated from the underlying sclera, cut to the desired size to cover the defect, and sutured to the sclera with 10-0 nylon sutures. Irrigation with balanced salt solution through the paracentesis confirmed deepening of the anterior chamber with no bleb leakage. In the current case, a layer of amniotic membrane was applied to cover the largely exposed sclera. Two weeks postoperatively, the surgical site was totally re-epi-thelialized with no aqueous leakage. Three months postoperatively, vascularization into the surgical site was observed. The intraocular pressure remained within normal levels without recurrent bleb leakage. CONCLUSIONS: Autologous transplantation of a free Tenon's graft successfully repaired excessive bleb leakage through a scleral defect after trabeculectomy. This technique is easier, safer, and may be more cost effective for repairing excessive bleb leakage after trabeculectomy than conventional management techniques.

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BACKGROUND: In patients with severe optic nerve damage, it is crucial to prevent the hypertensive phase that can develop after Baerveldt glaucoma drainage implant (BGI) surgery. We describe the combination of BGI surgery with surgical bleb revision to prevent the postoperative hypertensive phase. CASE REPORTS: We report two patients who underwent BGI surgery combined with surgical bleb revision. The combined surgery was performed in a 62-year-old man with open-angle glaucoma (patient 1) and a 37-year-old man with neovascular glaucoma (patient 2) at Asahikawa Medical University in 2013. Each patient had undergone a previous failed trabeculectomy and another trabeculectomy was expected to be unsuccessful. In patient 1, the early postoperative intraocular pressure (IOP) was well controlled due to a well-functioning bleb, despite development of a small amount of hyphema. In contrast, in patient 2 the postoperative IOP was higher with poor bleb formation; however, after bleb needling, the IOP was well controlled. Thus, the usual techniques used after trabeculectomy were also applicable in this combined surgery. For comparison, we also report the case of a 54-year-old woman with secondary glaucoma who underwent BGI surgery alone (patient 3). The postoperative IOP remained relatively high compared to patients 1 and 2. CONCLUSION: Combining BGI surgery with surgical bleb revision might be effective to prevent the hypertensive phase that can occur after BGI surgery.

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We report the case of a patient with recurrent acute angle-closure glaucoma who had undergone a previous laser iridotomy. Because the initial iridotomy was small, patency could not be determined by slit-lamp examination. Therefore, anterior-segment optical coherence tomography was used to evaluate the patency. Cross-sectional images showed the presence of a membrane with an anterior bowing configuration at the base of the iridotomy, suggesting that recurrent pupillary block was the causative mechanism. A repeat laser iridotomy was performed, with a resultant decrease in the intraocular pressure and widening of the anterior chamber angle. Anterior-segment optical coherence tomography may be helpful to confirm the status of a laser iridotomy, especially when the iridotomy is small.

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PURPOSE: To investigate the regulatory mechanisms responsible for autoregulation of retinal blood flow (RBF) during periods of decreased ocular perfusion pressure (OPP). METHODS: The effects of acute reductions in OPP on RBF were assessed using laser Doppler velocimetry in cats. The OPP decreased from 90 to 40 mm Hg by increasing the IOP (elevated IOP) or by decreasing the systemic blood pressure via exsanguination (systemic hypotension). The contributions of nitric oxide (NO), adenosine, and/or N-methyl-D-aspartic acid (NMDA) in regulation of the retinal arteriolar hemodynamics during decreased OPP was determined at 120 minutes after intravitreal injection of various inhibitors or PBS. RESULTS: Following PBS injection, the flow velocity decreased in proportion to the decrease in OPP; however, the retinal arteriolar diameter gradually increased. Consequently, the RBF was maintained near baseline levels when the OPP exceeded 70 mm Hg but decreased significantly (P < 0.01) when the OPP fell to less than or equal to 60 mm Hg due to elevated IOP or systemic hypotension. Adenosine receptor blocker 8-(p-sulfophenyl)theophylline, significantly (P < 0.01) enhanced decreases in RBF induced by elevated IOP and systemic hypotension at OPP from 80 to 40 mm Hg, whereas NO synthase inhibitor N(G)-nitro-L-arginine-methyl ester and NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid only significantly (P < 0.01) enhanced reductions in RBF induced by elevated IOP. CONCLUSIONS: These results indicate that adenosine contributes to autoregulation of RBF during systemic hypotension, whereas adenosine, NO, and NMDA receptors autoregulate the RBF after elevated IOP. Different vasoregulatory factors might contribute to autoregulation of RBF after decreases in OPP induced by elevated IOP and systemic hypotension.

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PURPOSE: To evaluate systemic endothelial function in patients with branch retinal vein occlusion (BRVO). METHODS: Twenty-seven patients with BRVO (BRVO group, 8 men, 19 women; mean age, 65.4 ± 1.3), 10 patients with systemic hypertension and no other systemic or ocular disease (hypertension group, 6 men, 4 women; mean age, 70.4 ± 2.2), and 10 healthy volunteers (healthy group, 3 men, 7 women; mean age, 63.8 ± 2.1) were enrolled. We excluded patients with diabetes mellitus and current smokers. Using high-resolution ultrasonographic imaging, we evaluated the brachial artery (mm) to evaluate the flow-mediated vasodilation (FMD) by measuring the diameter of the brachial artery during reperfusion after arterial occlusion. RESULTS: There were no significant differences among the three groups in age (p = 0.98), sex (p = 0.21), or the baseline diameter of the brachial artery (p = 0.11). The group-averaged FMD value decreased significantly in the BRVO group (4.6 ± 0.4%) compared to the hypertension group (8.0 ± 0.8%, p < 0.01) and the healthy group (6.9 ± 0.6%, p < 0.05). Multiple logistic regression analysis identified lower FMD as an independent risk factor for BRVO. CONCLUSIONS: The results suggested that BRVO is associated with generalized endothelial dysfunction and that impaired systemic endothelial function may be associated with BRVO.

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The purpose of this study was to investigate the roles of endothelium-derived factors in the retinal arteriolar responses to acute severe elevation in systemic blood pressure (BP) in cats. Acute elevation of mean arterial BP by 60% for 5 min was achieved by inflating a balloon-tipped catheter in the descending aorta. The retinal arteriolar diameter, flow velocity, wall shear rate (WSR) and blood flow (RBF) changes during BP elevation were assessed with laser Doppler velocimetry 2 h after intravitreal injections of nitric oxide (NO) synthase inhibitor l-NAME, cyclooxygenase inhibitor indomethacin, endothelin-1 receptor antagonists (BQ-123 for type A and BQ-788 for type B), or Rho kinase inhibitor fasudil. BP elevation caused a marked increase in retinal arteriolar flow velocity and WSR with slight vasoconstriction, resulting in an increase in RBF. The increases in velocity, WSR and RBF, but not diameter, were correlated with the increase in ocular perfusion pressure. With l-NAME or indomethacin, the increase in RBF upon BP elevation was significantly attenuated due to enhanced retinal arteriolar vasoconstriction. In contrast, BQ-123 and fasudil potentiated the increased RBF. BQ-788 had no effect on arteriolar diameter and hemodynamics. Our data suggest that acute elevation of BP by 60% leads to an increase in RBF due to the release of NO and prostanoids probably through a shear stress-induced vasodilation mechanism. The release of endothelin-1 and Rho kinase activation help to limit RBF augmentation by counteracting the vasodilation. It appears that the retinal endothelium, by releasing vasoactive substances, contributes to RBF regulation during acute severe elevation of systemic blood pressure.

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OBJECTIVE: Retinal endothelial dysfunction is a key in the etiogenesis of diabetic retinopathy (DR), in patients with type 2 diabetes mellitus (DM). Brachial artery flow-mediated vasodilation (FMD) is a marker of endothelial function associated with production of endogenous nitric oxide. Using FMD, we investigated the relationship between macrovascular function and DR. METHODS: We studied 74 patients with type 2 DM, including non-DR (NDR) (n = 30); mild nonproliferative DR (NPDR) (n = 16); moderate NPDR (n = 10); severe NPDR (n = 10); and proliferative DR (PDR) (n = 8); and 21 age-matched controls. We measured FMD in each group. Retinal blood flow and pulsatility ratios were measured using laser Doppler velocimetry. RESULTS: FMD decreased significantly in patients with DM compared with healthy control subjects. No significant differences were found in FMD among the NDR, mild NPDR, and moderate NPDR groups. FMD decreased significantly in the severe NPDR and PDR groups compared with the NDR group. FMD was significantly and negatively correlated with duration of DM and pulsatility ratio. CONCLUSION: Systemic endothelial dysfunction appears to be associated with DR and vascular abnormalities in patients with type 2 DM.

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PURPOSE: To investigate the effects of acute hyperglycemia on retinal microcirculation and endothelial function in cats and removal of superoxide to prevent retinal endothelial dysfunction from hyperglycemia. METHODS: Hyperglycemia was induced by intravenous injection of 25% glucose to maintain the plasma glucose concentration at 30 mM. Laser Doppler velocimetry was used to measure the vessel diameter (D) and blood velocity (V) simultaneously and calculated retinal blood flow (RBF) in second-order retinal arterioles in cats. Intravitreous, endothelial-dependent vasodilator bradykinin (BK) and endothelium-independent vasodilator sodium nitroprusside (SNP) were administered into the vitreous cavity to evaluate endothelial function in the retinal arterioles. To control osmolality, 25% mannitol was administered the same way. Systemic hyperoxia was induced to noninvasively examine endothelial function during hyperglycemia. To determine the effect of the superoxide on the hyperglycemia-induced changes in the retinal circulation, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) was administered in drinking water for 14 days before the experiment. RESULTS: The D, V, and RBF increased with acute hyperglycemia and mannitol compared with baseline. BK-induced increases in D, V, and RBF significantly declined, whereas SNP-induced increases were unattenuated during acute hyperglycemia. Return of the decreased RBF to baseline after cessation of systemic hyperoxia was significantly (P < 0.05) inhibited by acute hyperglycemia. TEMPOL significantly (P < 0.05) prevented a decrease in the BK-induced increase in RBF during hyperglycemia. CONCLUSIONS: The results suggest that acute hyperglycemia increases RBF via increased osmolality and may cause retinal endothelial dysfunction partially via increased oxidative stress. Systemic hyperoxia can be used to noninvasively evaluate retinal endothelial function during hyperglycemia.

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