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Purpose: To investigate optic nerve head (ONH) blood flow changes resulting from intraocular pressure (IOP) elevation in subjects without systemic disorders. Materials and Methods: Eighteen eyes of 18 patients who underwent vitrectomy to treat an epiretinal membrane or macular hole at Toho University Sakura Medical Center were included. Following standard 25-gauge microincision vitreous surgery, mean blur rate (MBR) in tissue (MT), an index of ONH blood flow, was measured using laser speckle flowgraphy. Measurements were taken before and 5 and 10 minutes after a 15 mmHg IOP elevation. Results: The ONH blood flow was initially lower than baseline (P= 0.001) after elevating IOP from 14.8 ± 2.8 mmHg to approximately 30 mmHg. Between 5 and 10 minutes after elevating IOP, ONH blood flow partially recovered (P= 0.004), even though ocular perfusion pressure was 20.2% lower than at baseline. Conclusions: The ONH blood flow in subjects without systemic disorders was initially lower, but began to recover 5–10 minutes after a 15 mmHg elevation in IOP. These results indicate that autoregulatory mechanisms of ONH blood flow may help to minimize the effects of IOP elevations and fluctuations during vitreous surgery. [ABSTRACT FROM PUBLISHER]

Purpose: To clarify the involvement of angiotensin II-dependent vascular endothelial growth factor (VEGF) via NADPH oxidase in the retina in spontaneously diabetic Torii (SDT) rats, a type 2 diabetic rat model. In SDT rats, the plasma glucose level and angiotensin-converting enzyme (ACE) levels were measured, and effects of angiotensin II receptor blocker (ARB) and angiotensin II were also studied. Materials and Methods: We evaluated the age-dependent changes in the peripheral and ocular angiotensin II-forming systems in SDT rats at 15 (n = 8), 20 (n = 8), 30 (n = 7), and 50 weeks of age (n = 8). We also evaluated the effect of an ARB (2.5 mg/kg/day candesartan) or angiotensin II (500 ng/kg/min) on retinal gene expressions of VEGF and p22phox, a subunit of NADPH oxidase. Results: The plasma glucose level was significantly increased from 20 weeks of age. No significant changes in ACE activities in the plasma, aorta, and eye were observed until 30 weeks of age. At 50 weeks, ACE activity in the eyes was significantly increased, whereas ACE activities in the plasma and aorta were not. At 50 weeks, significant increases in VEGF and p22phox, an NADPH oxidase subunit, were significantly reduced by candesartan. Angiotensin II infusion resulted in significant increases in VEGF and p22phox levels. Conclusions: Angiotensin II is involved in the gene expression of VEGF via NADPH oxidase in the retina of SDT rats. [ABSTRACT FROM AUTHOR]

Purpose: To determine the alterations in the expression of endothelin-1 (ET-1) and its specific receptors in the sensory retina after optic nerve injury. Methods: The optic nerve of the right eye of Wistar rats was crushed. The sensory retinas were removed 1, 2, 4, 7, and 14 days after the surgery, and the amount of ET-1 in the retinas was measured by radioimmunoassay, and the mRNA levels of ETA and ETB receptors were determined by real-time PCR. Results: The ET-1 levels in the sensory retinas following the optic nerve crush were 8.83 ± 2.23 and 9.99 ± 4.83 pg/mg protein on days 7 and 14 after the injury, while those in the sham controls were 4.55 ± 1.36 and 4.85 ± 1.57 pg/mg protein, respectively. The increase was significant on day 7 (p = 0.003, ANOVA followed by t- test), but not on day 14 (p = 0.054). The mRNA levels of the ETA and ETB receptors in the retina after the optic nerve crush was significantly increased on day 7. A two-fold increase was recognized in ETB receptors. Immunohistochemical analyses revealed that the ET-1 expression was increased mainly in the inner retinal layers, including the nerve fiber layer and ganglion cell layer (GCL). The increased immunoreactivity of the ETB receptor was seen in the GCL cells and also in the outer nuclear layer. Conclusion: An increase in the intraretinal ET-1 may be involved in the retinal remodeling after the optic nerve is crushed. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of bunazosin hydrochloride, an α 1 -adrenergic blocker, on the impairment of optic nerve head (ONH) blood flow and depression of visual function induced by repeated intravitreal injections of endothelin-1 (ET-1) in rabbits. Method: We injected ET-1 (20 pmol) into the right posterior vitreous of rabbits twice a week for 4 weeks, and the observation period was set at 8 weeks (starting from the first injection). The animals that received ET-1 were divided into two groups: twice a day for 8 weeks, one group received topical 0.01% bunazosin, while the second received the vehicle for bunazosin. The ONH blood flow was monitored using the laser speckle method, and visual function was assessed by examining visually evoked potentials (VEPs). Changes in the ONH cup/disk area and in the number of cells in the retinal ganglion cell layer (GCL) were also determined.Results: Repeated injections of ET-1 decreased the ONH blood flow, prolonged the VEP implicit time, enlarged the optic cup, and decreased the number of GCL cells. Topical bunazosin significantly decreased these impairments. Conclusions: These results indicate that in rabbits, topical bunazosin suppresses the changes in ONH circulation and function induced by intravitreal ET-1. [ABSTRACT FROM AUTHOR]

Purpose. To determine whether adenosine can protect cultured retinal neurons, consisting mainly of amacrine cells. from N-methyl-D-aspartate (NMDA)-induced neurotoxicity, and to determine whether agonists and antagonists of adenosine receptors also have a protective effect. Methods. Cultured retinal neurons obtained from fetal Wistar rats (gestational age 18-19 days) were maintained for 10-11 days. Neurons were exposed to NMDA (1.0 mM) for 10 min with or without adenosine or to NMDA with adenosine receptor agonists or antagonists. Neuronal death was assessed by the trypan-blue exclusion method 24 hr alter the exposure. Results. Adenosine at doses of 0.01 μM and higher significantly protected (p < 0.05, Dunnett) primary cultured fetal rat retinal neurons from apoptotic and/or necrotic death induced by NMDA (1.0 μM). The protective effect of adenosine (10 μM) against NMDA-induced neuronal death was lost by simultaneous exposure to selective A1 receptor antagonist but not to A2a receptor antagonist. Selective A1 receptor agonists had similar effects as adenosine, but A2a receptor agonists and 8-Br-cyclic AMP bad no effect on cell viability. Conclusions. Adenosine can protect cultured retinal neurons against NMDA-induced cell death via the A1 receptor. [ABSTRACT FROM AUTHOR]

Purpose. Excessive activation of poly(ADP-ribose) polymerase (PARP). a nuclear enzyme that is activated by DNA damage, leads to neuronal cell death through depletion of ATP The purpose of this study was to determine whether inhibition of PARP has some neuroprotective effects on the N-methyl- D-aspartate (NMDA)-induced functional and morphological injury to the rabbit retina. Methods. Visually evoked potentials (VEPs) were recorded at different times after an intravitreal injection of NMDA (200. 660. and 2000 nmol) alone, or NMDA with 3- aminobenzamide (ABA. 200 nmol). a PARP inhibitor, or with MK-801 (200 nmol), an NMDA antagonist. The physiological changes were followed for 2 weeks, after which the eyes were enuculeated and prepared for histological examinations. Results. Intravitreal injections of NMDA reduced the amplitudes of rabbit VEPs and the number of cells in the retinal ganglion cell layer in a dose-dependent manner. No significant changes could be detected in the bright-flash electroretinograms (ERGs). Simultaneous injection of MK-801 (200 nmol) significantly diminished the changes induced by intravitreal NMDA. 3-Aminoben7amide (ABA) (200 nmol) also suppressed these changes, but its effects were less than those of MK-801 Conclusions. NMDA-induced retinal damage can be detected by VEPs, and PARP inhibition has some neuroprotective effects on the NMDA-induced retinal damage. [ABSTRACT FROM AUTHOR]

Purpose. Two pathways for the formation of angiotensin II (Ang II) in local tissues are known to exist, one involving angiotensin-converting enzyme (ACE), and the other in which chymase plays a role. It has been shown that chymase activity is present in monkey, dog, and hamster eyes. Because chymase activates various cytokines by increasing Ang II formation, thereby promoting the production of extracellular matrix, the role of Ang II in wound healing has attracted much interest. In this work, we created sclerocorneal wounds in hamster eyes and measured the levels of ACE and chymase activities in the eye during the wound healing process. Methods. Sclerocorneal wounds were made at 6 locations on the corneal limbus of one eye in each of 36 hamsters. Using the contralateral eyes as controls, we measured levels of chymase and ACE activities in the overall eye at 3, 7, and 21 days postoperatively. Histopathological evaluations of the sclerocorneal wounds in the treated eyes were also carried out for samples stained with toluidine blue. Results. Chymase activity in the treated eyes tended to be higher than that in the control at 21 days. ACE activity in the treated eyes was significantly higher than that in the control at 3, 7, and 21 days postoperatively. Histopathological examination revealed increased mast cells in the subconjunctival tissue and around the tunnel opening in the sclerocornea. Conclusions. These findings show that not only ACE but also chymase contributes to the formation of Ang II in the healing of sclerocorneal wounds in hamster eyes. This leads to the suggestion that ACE inhibitors or chymase inhibitors could potentially inhibit scarring in glaucoma filtering surgery. [ABSTRACT FROM AUTHOR]

Purpose. To evaluate the role of nitric oxide (NO) in the mechanism of the ocular hypotensive action of nipradilol, a β-blocker with α[sub 1]-blocking activity. Methods. Change in intraocular pressure (IOP) of albino rabbits was measured after a single application of carboxyPTIO (c-PTIO), an NO trapping agent. Next, IOP change was measured every hour for 5 hours after the instillation of 0.25% nipradilol into one of the eyes with and without cPTIO pretreatment of both eyes. IOP change induced by desnitro-nipradilol was also examined. The outflow facility and uveoscleral outflow were determined by two-level constant pressure and anterior chamber perfusion methods before and at 3 hours after the application of nipradilol with and without c-PTIO pretreatment. Results. Topical administration of c-PTIO showed no significant effect on IOP. Unilateral instillation of nipradilol reduced IOP significantly compared with control eyes with a maximum reduction of 3.6 mmHg and effect duration of 3 hours. Pretreatment with c-PTIO partially inhibited the reduction during an earlier period (1∼2 hours) and completely at 3 hours. IOP change by desnitro-nipradilol was similar to that by nipradilol with c-PTIO pretreatment. Nipradilol increased both outflow facility and uveoscleral outflow at 3 hours, whereas pretreatment with c-PTIO inhibited both of these outflows. Conclusions. Results indicate that ocular hypotensive action by nipradilol during the relatively late period may be mainly due to enhancement of aqueous humor outflow by NO at least in the rabbits. [ABSTRACT FROM AUTHOR]

Purpose. To study the effects of topically applied nipradilol, an α-B blocker recently developed in Japan as an ocular hypotensive drug, on retinal blood flow (RBF) in healthy volunteers. Methods. Seven healthy volunteers (mean age, 33 years) underwent measurement of RBF using a newly developed stabilized laser Doppler velocimetry system. In a double-blind trial, retinal arterial blood flow, intraocular pressure (IOP), and blood pressure (BP) were measured before and after the instillation of nipradilol or saline every hour for 5 hours. Results. Retinal arterial blood flow and the diameter of the retinal artery significantly (p < 0.05) increased at 4 hours after installation in nipradilol-treated eyes. Retinal blood velocity did not change in significantly. Nipradilol evoked a significant (p < 0.05) bilateral decrease in IOP. Mean BP decreased significantly (p < 0.05) 3 hours after installation. Ocular perfusion pressure (OPP), calculated from the mean BP and IOP, did not change significantly during the study. Conclusion. Topical nipradilol significantly increased retinal arterial blood flow in healthy volunteers, not through a secondary effect dependent on a change in OPP, but likely through the vasodilatory action of the drug. [ABSTRACT FROM AUTHOR]

Purpose. To assess the influence of the blood glucose level on ocular capillary circulation, we induced clinically significant hyperglycemia (200-300mg/dl) in rabbits and investigated the changes in the optic nerve head (ONH) circulation. Methods. Hyperglycemia was induced by injection of glucose (5.6mmol/kg) into an auricular vein of healthy albino rabbits and changes in the ONH circulation were measured by the laser speckle method. In order to examine the role of nitric oxide (NO), glucose was administered after intravenous injection of an NO synthetase inhibitor (N[sup G]nitro-L-arginine methyl ester, L-NAME, l mg/kg), then changes in the ONH circulation were measured. Results. The blood glucose level reached a peak at 30 min after glucose loading and returned to its initial level by 2 hours. ONH circulation showed a 60% increase compared with its initial level at 15 min after glucose loading and subsequently remained almost unchanged throughout the 2-hour observation period. There were no significant changes of the blood pressure, heart rate, or intraocular pressure. The glucose-induced increase of ONH circulation was completely inhibited by pretreatment with L-NAME. Conclusions. ONH circulation was increased by administration of glucose to healthy rabbits. A high blood glucose level seems to promote ocular capillary circulation and NO as well as insulin appear to have a role in this process. [ABSTRACT FROM AUTHOR]

PURPOSE. To investigate the effect of topical iganidipine,a new dihydropyridine derivative calcium channel blocker, on impairment ofthe ocular circulation caused by endothelin-1 (ET-1), we examined modificationof the effect of ET-1 on visual-evoked potential (VEP) in albino rabbits. METHODS. To clarify whether VEP could be used to indicate the extent ofocular circulatory impairment, we evaluated the dose dependency of changesin VEP over 2 hours after intravitreal injection of 3 ET-1 doses (1.0, 3.3,or 10 pmol) and the vehicle. Then modification of the effect of ET-1 on theVEP by iganidipine was examined. One hour after the topical instillation of0.1% iganidipine (20 μl) or its vehicle, 10 pmol of ET-1 was injected intothe vitreous in rabbits. The VEP was measured for 2 hours after ET-1 application,and the response was compared between the eyes with iganidipine and vehiclepretreatment. RESULTS. Intravitreal injection of ET-1 dose-dependently reduced the VEPamplitude. Topical administration of 0.1% iganidipine significantly suppressedthe reduction of VEP amplitude for the entire 2-hour monitoring period afterintravitreal injection of 10 pmol ET-1. There was no significant change ofthe systemic blood pressure as well as intraocular pressure after topicaladministration of iganidipine. CONCLUSIONS. Iganidipine eyedrops may be useful for the treatment of ischemicretinal and optic nerve disorders related to abnormal ET-1 production forthe maintenance of visual function. [ABSTRACT FROM AUTHOR]