Effects of nilvadipine, a calcium antagonist, on rabbit ocular circulation and optic nerve head circulation in NTG subjects

PURPOSE: To study the effects of nilvadipine, a Ca2+ antagonist, on tissue circulation in the optic nerve head (ONH), choroid, and retina in rabbits and on the ONH circulation in normal tension glaucoma (NTG) patients. METHODS: Nilvadipine (3.2 microg/kg) or vehicle solution was injected intravenously into urethane-anesthetized rabbits, and the normalized blur value (NB), a quantitative index of in vivo tissue blood velocity, was measured in the choroid and in an area of the ONH and retina free of visible surface vessels before and for 90 minutes after injection, using the laser speckle method. The effects of nilvadipine on the ONH circulation was also studied using the H2 gas clearance method in separate groups of rabbits. Oral nilvadipine (4 mg/d) or placebo was administered to NTG patients in a double-masked manner, and NB in an area of the ONH rim free of visible surface vessels was measured by the same method before and 2, 4, 8, and 12 weeks after administration. RESULTS: The NB obtained from the ONH, choroid, or retina during the experimental period was increased by approximately 10% to 25% in the nilvadipine group compared with the NB in the control group (P < 0.0001, ANOVA), although systemic condition parameters and intraocular pressure (IOP) showed no significant intergroup difference except for a transient decrease in blood pressure in the nilvadipine groups. Blood flow rate in the ONH determined by the H2 gas clearance method also showed an approximately 25% increase in the nilvadipine group. The NB in the ONH of the oral nilvadipine-treated patients was significantly increased, by approximately 20% compared with the placebo-treated patients throughout the follow-up period. No significant intergroup difference was seen in blood pressure, pulse rate, or IOP. CONCLUSIONS: Nilvadipine increased blood velocity and, probably, blood flow in the ONH, choroid, and retina of rabbits. It also increased blood velocity in the ONH of NTG patients.     

Effects of pranidipine, a new calcium antagonist, on circulation in the choroid, retina and optic nerve head.

PURPOSE. To study the effects of pranidipine, a newly developed Ca(2+)-antagonist, on tissue circulation in the optic nerve head (ONH), choroid, and retina in rabbits. METHODS. Pranidipine (5 microg/kg) or vehicle solution was injected intravenously in urethane-anesthetized rabbits and the normalized blur value (NB), a quantitative index of in vivo tissue blood velocity, was measured in the choroid and in an area of the ONH and retina free of visible surface vessels before and for 90 min after injection, using the laser speckle method. Measurements in the ONH and choroid were performed in the same albino rabbit eyes (pranidipine group, n = 10; control group, n = 10) and those in the retina in another group of Dutch rabbits (pranidipine group, n = 10; control group, n = 10). RESULTS. Between 30 and 90 min after injection, the NB in the pranidipine group increased by 24% in the ONH, 19% in the choroid, and 17% in the retina on an average compared to baseline, and was significantly different from that in the control group (P < 0.0001, ANOVA). There were no significant inter-group differences in the systemic parameters, except for a transient decrease in blood pressure in the pranidipine groups. CONCLUSIONS. Pranidipine increased blood velocity and probably blood flow in the ONH, choroid, and retina of rabbits.     

In vivo measurement of ocular circulation with the laser speckle method--development of apparatus and application in ophthalmological research

We have developed an apparatus utilizing laser speckle phenomenon which can measure the peripheral circulation in the iris, choroid, retina and optic nerve head (ONH) and blood velocity through retinal vessels in the living eye non-invasively and quantitatively. A blue-component argon laser (wavelength 488 nm) was used for measurement of peripheral circulation in the retina and a diode laser (wavelength 808 nm) for measurements of peripheral circulation in the iris, posterior choroid and ONH, and measurement of centerline blood velocity through retinal vessels. A fundus camera (TRC-WT 3, Topcon) was equipped with a laser source and an image sensor where the speckle pattern from the fundus appears, and the data were analyzed with a personal computer to give a normalized blur (NB) value or a square blur rate (SBR) value, both quantitative indices of blood velocity. The NB value, whose computation requires much less time, was adopted to evaluate peripheral circulation because of non-linear correlation between the NB and actual blood velocity in the range above 20 mm/sec. The SBR value, whose computation requires a longer time, was adopted for measurement of blood velocity through retinal vessels. Measurement field in the living eye was 1.06 x 1.06 mm at its maximum and reproducibility index of the in vivo measurement in the rabbit iris, choroid, retina, and ONH was approximately 10%. When blood flow was changed by intraocular pressure (IOP) change in rabbit eyes, NB values obtained from the iris, choroid, and retina showed a significant correlation with the blood flow simultaneously determined with the colored microsphere technique in the same eye, and the NB obtained from the ONH also correlated with the blood flow determined with the H2 gas clearance method. Stepwise reduction in the ocular perfusion pressure (OPP) by stepwise increment of IOP resulted in proportional reduction in the iris- and choroid-NB. On the other hand, the retina- or ONH-NB remained almost unaltered at OPP levels above 50 mmHg, and decreased along with OPP at levels less than 50 mmHg. By monitoring NB values for 2 hours, presence or absence of autoregulatory mechanism against OPP change in the choroidal and ONH circulation was studied in rabbits. Throughout the experimental period of 2 hours, the choroidal NB was changed along with the OPP change, suggesting absence of blood flow autoregulation in this tissue. In the ONH, however, the NB returned to the baseline after its transient increase or decrease when the OPP was continuously increased or decreased, showing the presence of an autoregulatory mechanism in the ONH circulation. However, the time course of the NB resumption depended on the extent of OPP change. These results indicated that the laser speckle method can be useful in investigating the autoregulatory mechanism and processes of peripheral circulation in ocular tissues. Unilateral instillation of drugs with vasodilative activity (ifenprodil, betaxolol or nipradilol) in rabbit eyes significantly increased ONH and/or choroidal circulation. The extent in change in the ONH and/or choroidal circulation correlated with the number of doses, but not with the extent of IOP reduction, which suggested that the observed effects were attributable to the drug which penetrated locally. Intravenous administration of a Ca(2+)-antagonist (nicardipine, nilvadipine or pranidipine) significantly increased choroidal or retinal circulation in rabbits. The ONH circulation, however, was not affected by nicardipine, but affected by nilvadipine or pranidipine. Given the same effect on the ONH circulation, systemic hypotensive effect was stronger in pranidipine than in nilvadipine, which suggested that nilvadipine can be used in patients with ocular circulatory insufficiency. A modification of the laser speckle apparatus used for animal experiments was devised so that the NB or SBR values could be measured in human eyes every 0.12 sec on a real-time basis. (ABSTRACT TRUN     

Effects of scleral buckling and encircling procedures on human optic nerve head and retinochoroidal circulation

AIMS: To study the effects of segmental scleral buckling and encircling procedures on tissue circulation in the human optic nerve head (ONH) and choroid and retina. METHODS: Using the laser speckle method, the normalised blur (NB) value, a quantitative index of tissue blood velocity, was measured every 0.125 seconds and averaged over three pulses in the optic nerve head (NB(ONH)) and choroid and retina (NB(ch-ret)) in 10 patients with unilateral rhegmatogenous retinal detachment (mean age 52 (SD 17)). NB(ONH), NB(ch-ret), and intraocular pressure (IOP) in both eyes, and blood pressure (BP) were measured before, and 1, 4, and 12 weeks after the scleral buckling and encircling procedure. RESULTS: NB(ch-ret) on the buckled side was significantly reduced after surgery and smaller than that in the unoperated contralateral eye throughout the study period (ANOVA, p<0.0001). NB(ch-ret) on the unbuckled side, in the foveal area, NB(ONH), IOP, and BP showed no significant change. CONCLUSIONS: It was indicated that the segmental scleral buckling procedure with encircling elements decreased tissue blood velocity in the choroid and retina on the buckled side but caused no significant change on tissue circulation in other areas of the fundus or ONH.     

Effects of semotiadil, a novel calcium antagonist, on the retina and optic nerve head circulation.

The effects of semotiadil, a novel benzothiazine calcium antagonist, on the retinal and optic nerve head (ONH) tissue circulation were evaluated using the noninvasive laser speckle method. In urethane-anesthetized Dutch or albino rabbits, before and up to 90 min following intravenous injection of 400 microg/kg semotiadil fumarate (semotiadil group) or vehicle (control group), normalized blur value, a quantitative index of tissue blood velocity, in the retina (NB(retina)) or ONH (NB(onh)), was serially obtained with monitoring intraocular pressure (IOP) and systemic parameters: arterial pressure, pulse rate, arterial blood gas, and body temperature. There were no significant differences in IOP and the systemic parameters except arterial pressure between semotiadil and control groups during the experiments. Arterial pressure showed an acute and transient drop during the first 5 min after semotiadil administration. The time courses of the normalized blur value were significantly different between semotiadil and control groups in the retina (P = 0.0001, repeated measures two-way ANOVA), but not in the ONH (P = 0.6724). Changes in NB(retina) from the baseline in the semotiadil group was significantly greater than those in the control group 50 min or later after the administration (P < 0.0500, Mann-Whitney test). NB(onh) showed no significant differences between the two groups except during the first few min when arterial pressure acutely decreased in the semotiadil group. In conclusion, intravenously injected semotiadil increased the tissue blood velocity in the retina, but not in the ONH. This vascular selectivity in the ocular neural tissues differs from those of other calcium antagonists, such as nicardipine.     

Effects of kallidinogenase on ocular tissue circulation in rabbits.

The purpose of this study is to evaluate the effects of kallidinogenase, a tissue kallikrein, on tissue circulation in the optic nerve head (ONH), choroid and retina. Kallidinogenase (1.0 IU/kg) or saline was injected intravenously into urethane-anesthetized rabbits, and the normalized blur value (NB), a quantitative index of in vivo tissue blood velocity, was measured in the ONH, choroid and retina before and for 90 minutes after injection, using the laser speckle method. The difference in NB values in the kallidinogenase group was significantly higher compared with that in the control group in the choroid (p < 0.05) and retina (p < 0.05, ANOVA of repeated measurements). In the ONH, however, there was no significant difference between the kallidinogenase group and the control group except transient increment 10 min after drug administration (p < 0.01, unpaired t-test). On the other hand, systemic condition parameters and intraocular pressure showed no intergroup difference significantly except for a transient decrease in blood pressure and increase in pulse rate in the kallidinogenase groups. Kallidinogenase increased blood velocity, and probably blood flow, in the choroid and retina of rabbits.     

Effects of topical latanoprost on optic nerve head circulation in rabbits, monkeys, and humans.

PURPOSE: To evaluate the effect of topically administrated latanoprost on optic nerve head (ONH) circulation in Dutch rabbits, cynomolgus monkeys, and normal humans. METHODS: The ONH tissue blood velocity (NB(ONH)) was determined using the laser speckle method. Latanoprost (0.005%, 30 microl) was instilled into one eye, and vehicle into the other eye as a control. In rabbits, NB(ONH) was measured for 90 minutes after a single instillation and before and after a 7-day once-daily instillation regimen. In monkeys, NB(ONH) was measured before and after 1, 4, and 7 days of a once-daily instillation regimen. The effect of intravenous indomethacin on the latanoprost-induced NB(ONH) change was also studied in rabbits and monkeys. In humans, the time-course changes in NB(ONH) were measured for 4.5 hours before and after a 7-day once-daily instillation regimen. Intraocular pressure (IOP) and systemic parameters were simultaneously studied in each experiment. All measurements were performed by investigators masked to the experimental condition. RESULTS: Latanoprost significantly increased NB(ONH) 10% to 19% in treated eyes after a single instillation (P = 0.035) or 7-day instillation regimen (P = 0.035) in rabbits, after a 4-day (P = 0.035) or 7-day (P = 0.035) instillation regimen in monkeys, and after a 7-day (P = 0.013) instillation regimen in humans, whereas there were no significant changes in the vehicle-treated eyes in any of the experiments (P > 0.5). Pretreatment with indomethacin (5 mg/kg) abolished the NB(ONH) increase but not the IOP reduction in latanoprost-treated eyes in rabbits and monkeys. IOP remained unchanged in both eyes in rabbits (P > 0.4), whereas it significantly decreased only in latanoprost-treated eyes in monkeys (P < 0.05) and humans (P < 0.05). CONCLUSIONS: Topical latanoprost significantly increased ONH blood velocity only in treated eyes in rabbits, monkeys, and humans. This effect was independent of the IOP-reducing effect of latanoprost and probably was associated with local penetration of the drug and the production of endogenous prostaglandins.     

Effect of lomerizine, a new Ca(2+)channel blocker, on the microcirculation in the optic nerve head in conscious rabbits: a study using a laser speckle technique.

We examined the effect of a new Ca(2+)channel blocker, lomerizine (KB-2796), and compared it with that of nilvadipine, on the optic nerve head circulation in conscious rabbits using a laser speckle method. Lomerizine (0.03, 0.1 and 0.3 mg kg(-1), i.v.) and nilvadipine (0.003, 0.01 and 0.03 mg kg(-1), i.v.) each significantly increased the normalized blur values (an index of tissue blood velocity) in the optic nerve head in a dose-dependent manner. Neither lomerizine nor nilvadipine caused a significant change in intraocular pressure. Lomerizine produced no significant change in mean arterial blood pressure, although at 0.3 mg kg(-1), i. v. heart rate was significantly increased 5 min after its administration. In contrast, nilvadipine significantly decreased mean arterial blood pressure at 5 to 15 min after its administration and increased heart rate at 5-30 min after its administration (both effects being dose-dependent). Our results indicate that while lomerizine, like nilvadipine, increased tissue blood velocity in the optic nerve head, it did not affect mean arterial blood pressure at the doses that affected optic nerve head circulation, unlike nilvadipine. The plasma concentration of lomerizine (free base) obtained from rabbits at 15 min after administration at a dose of 0. 03 mg kg(-1)i.v., when time there was a significant increase in tissue blood velocity in the optic nerve head, was very similar to plasma concentration with healthy subjects receiving lomerizine at 10 mg (5 mgx2) day(-1), p.o., a dose that achieved a significant reduction in the frequency and mean duration of headache attacks but did not affect the blood pressure or heart rate. These results suggest that lomerizine may be clinically effective in favorably affecting the optic nerve circulation without producing systemic effects such as the hypotension seen during treatment with other Ca(2+)channel blockers.     

Changes in optic nerve head circulation in response to vasoactive agents: intereye comparison in monkeys with experimental unilateral glaucoma

Purpose. To investigate circulatory changes in the optic nerve head (ONH) in response to vasoactive agents including calcium antagonists, a substrate of nitric oxide (NO), and an inhibitor of NO synthase (NOS) in monkeys with unilateral experimental glaucoma. Methods. Argon laser cautery to the trabecular meshwork was used to create experimental unilateral glaucoma in nine monkeys. The effects of systemic lomerizine or nilvadipine (calcium-antagonists), L-arginine (a substrate of NO), and NG-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor) on the ONH tissue blood velocity (NB(ONH)) was studied by the laser speckle METHOD: Results. Lomerizine and nilvadipine significantly increased NB(ONH) in the untreated normal eyes (P = 0.039 and 0.008, respectively), while significant, less increases were found in the laser-treated experimental glaucomatous eyes with significant intereye differences (P = 0.036 and 0.011, respectively). L-arginine significantly increased NB(ONH) in both eyes without intereye difference (P = 0.71). L-NAME had no significant effects on NB(ONH) in the experimental glaucoma eyes; however, it produced a significant decrease in the nonlaser treated eyes (P = 0.036). Conclusions. In experimental glaucomatous eyes, the reactivity of ONH vessels to calcium antagonists was preserved, but was significantly reduced. The response to a NOS inhibitor was lost; however, reactivity to a substrate of NO was normal. These data indicate that in experimental glaucoma, vasodilator reactivity in the peripheral vasculature of the ONH is preserved, but functional alterations are likely to affect reactivity to the NO system. Japanese Abstract.     

Acute effects of cigarette smoking on tissue circulation in human optic nerve head and choroid-retina

OBJECTIVE: To study the acute effects of cigarette smoking on tissue circulation in the human optic nerve head (ONH) and choroid-retina. DESIGN: Nonrandomized, comparative trial (sequential self-controlled). PARTICIPANTS: Nine healthy habitual smokers (age, 28 +/- 4 years; number of cigarettes smoked per day, 27 +/- 10; length of smoking history, 10 +/- 4 years; mean +/- standard deviation). INTERVENTION: Using the laser speckle method, normalized blur (NB) value, a quantitative index of tissue blood velocity, was measured every 0.125 second and averaged over three pulses across an area located in the temporal site of the ONH free of visible surface vessels (NB(ONH)) and across an area located halfway between the macula and the ONH with no discrete vessels visible (NB(ch-ret)). NB(ONH), NB(ch-ret), and intraocular pressure (IOP) in one randomly chosen eye, and blood pressure (BP) and pulse rate (PR) were measured before and 1, 5, 10, 15, 20, 25, 30, 45, 60, and 90 minutes after sham smoking using a short drinking straw as a cigarette substitute (control). One week later, NB(ONH), NB(ch-ret), and IOP in the same eye, and BP and PR were measured after cigarette smoking according to the same time schedule as in the control experiment. MAIN OUTCOME MEASURES: NB(ONH) and NB(ch-ret). RESULTS: In the control experiment, all parameters examined showed no significant change during the experimental period. Differences in NB(ONH) and NB(ch-ret) before and after actual smoking were significantly greater than those in the control experiment (analysis of variance, P = 0.0000, 0.0000). BP and PR were significantly increased between 1 and 30 minutes after actual smoking as compared with control data, while IOP showed no significant change at any time of measurement. CONCLUSIONS: These results indicated that cigarette smoking increased tissue blood velocity in the ONH and possibly in the choroid in habitual smokers.     

Effects of topical carteolol and timolol on tissue circulation in the iris and choroid.

PURPOSE: To evaluate the effects of topical carteolol or timolol on tissue circulation in the iris and posterior choroid. METHODS: After a topical instillation of 20 microl of 2% carteolol, 0.5% timolol, or physiological saline (for control) into one eye, and physiological saline into the other eye of pentobarbital-anesthetized Dutch pigmented rabbits, normalized blur value; a quantitative index of tissue blood velocity in the iris (NB(iris)) and posterior choroid (NB(cho)) was obtained using the laser-speckle method. Intraocular pressure (IOP), blood pressure and pulse rate were serially monitored for 2 hours after instillation. Using separate groups of rabbits, NB(iris) and IOP were measured before and after 20-day twice-daily unilateral treatment of carteolol or timolol. RESULTS: After a single instillation of carteolol, NB(iris) was significantly greater only in the treated eyes than control eyes (P = 0.0050, repeated measures two-way ANOVA), while NB(cho) showed no significant change. IOP in the treated eyes significantly reduced (P = 0.0005). Bilateral reductions of tissue vascular resistance in the iris were found after carteolol instillation (P = 0.0183 approximately 0.0322). After timolol instillation, serial changes in NB(iris) and NB(cho) in the treated eyes were significantly different from those in control eyes (P = 0.0129, 0.0031), while there were no significant differences at any of time points (Mann-Whitney test); IOP in both eyes was significantly reduced (P = 0.0096 approximately 0.0005); tissue vascular resistance in the iris and posterior choroid showed no significant changes. After 20-day treatment, NB(iris) in the both eyes of carteolol-treated rabbits significantly increased from the baseline (P = 0.0280, 0.0425, Wilcoxon signed rank test) and NB(iris) in timolol-treated eyes significantly decreased (P = 0.0280). CONCLUSIONS: A single instillation of topical carteolol significantly increased the iris tissue blood velocity in the treated eye and reduced the tissue vascular resistance in both eyes. Topical timolol tended to decrease tissue blood velocity in the iris and choroid of the treated eye, but showed no significant effects on tissue vascular resistance in the both tissues.     

Time course of the change in optic nerve head circulation after an acute increase in intraocular pressure

PURPOSE: To investigate the time course of changes in optic nerve head (ONH) circulation after an acute increase in intraocular pressure (IOP), by using the laser speckle method, and to evaluate the effects of a calcium antagonist, the nitric oxide synthetase inhibitor, indomethacin, or sympathetic nerve amputation on the response in ONH circulation after an acute increase in IOP. METHODS: In rabbits, the normalized blur (NB) level, a quantitative index of tissue blood velocity in the ONH, was monitored for 60 minutes after an increase in IOP from 20 mm Hg to 40, 50, or 60 mm Hg and for 25 seconds after increase in IOP from 20 mm Hg to 50 or 60 mm Hg with high time resolution. The effects of systemic administration of 1 micro g/kg per hour nilvadipine (a calcium antagonist), 30 mg/kg N(omega)-nitro-L-arginine (L-NAME), or 5 mg/kg indomethacin, or those of sympathetic nerve amputation on the time course of the changes in NB were studied. RESULTS: NB showed a quick recovery within several seconds after increase in IOP to 40 or 50 mm Hg, whereas no or little recovery occurred after an increase to 60 mm Hg. The nilvadipine treatment significantly increased NB at IOP of 20 mm Hg (baseline NB, P = 0.045) and apparently impaired the recovery of NB after the increase in IOP. After L-NAME administration, baseline NB significantly decreased (P = 0.028), and the NB recovery time was slightly but significantly prolonged (P = 0.012). Indomethacin showed no effects on baseline NB or NB recovery. Sympathetic nerve amputation increased baseline NB (P = 0.027), but did not influence NB recovery. CONCLUSIONS: The current results showed a quick recovery response in the ONH circulation after an acute increase in IOP in rabbits. A calcium antagonist impaired the response. Production of nitric oxide or prostaglandins or the sympathetic nervous system is probably not mainly responsible for the reaction.     

Effect of topical dorzolamide on tissue circulation in the rabbit optic nerve head

PURPOSE: To examine the effect of 1% topical dorzolamide on tissue circulation in the optic nerve head (ONH) of Dutch rabbits. METHODS: A laser speckle tissue circulation analyzer was used. One eye of each rabbit received 1% topical dorzolamide twice daily for 20 days, and the fellow eye received the vehicle in a masked, randomized manner. Intraocular pressure (IOP) was measured every 5 days. The normalized blur (NB) value, a quantitative index of tissue blood flow velocity in the ONH, was measured before treatment and 2 hours after the last instillation on the 20th day. RESULTS: The IOP was lowered by about 2 mm Hg only in the dorzolamide-treated eyes (P < .01). The NB value showed no significant change in either dorzolamide-treated or vehicle-treated eyes. CONCLUSIONS: Long-term topical dorzolamide does not affect the ONH tissue circulation in dorzolamide- and vehicle-treated eyes of Dutch rabbits.     

Effect of topical amosulalol on tissue circulation in the optic nerve head.

The effect of topical 0.1% amosulalol on tissue circulation in the albino rabbit optic nerve head (ONH) was investigated using a laser speckle tissue circulation analyzer. Amosulalol was administered into one eye twice daily for 20 days, and vehicle was administered into the other eye in a masked, randomized manner. Intraocular pressure (IOP) was measured every 5 days. The normalized blur value (NB), a quantitative index of tissue blood flow velocity in the ONH, was measured before treatment and 2 hours after the last instillation on day 20. The IOP was also measured at 5-day intervals. Amosulalol decreased IOP by approximately 2 mmHg in the treated eyes (P < 0.01). There was no significant difference in NB between eyes before the first instillation, whereas NB was significantly greater (by approximately 16%) in the amosulalol-treated eye than in the control eye after completion of instillations (P < 0.01). The difference between NB after completion of instillations and that before the first instillation was significantly greater in the ONH of the amosulalol-treated eye than in the contralateral control eye (P < 0.01). Twice-daily instillation of 0.1% amosulalol for 20 days induced a significant increase in tissue blood velocity in the ipsilateral ONH in albino rabbits.     

Effect of topical unoprostone on circulation of human optic nerve head and retina.

The purpose of the present study was to study the effect of topical unoprostone on the circulation of human optic nerve head (ONH) and retina in normal subjects. Using laser-speckle tissue blood flow analysis, normalized blur (NB), a quantitative index of tissue blood velocity, was measured every 0.125 sec at a temporal ONH site, free of visible surface vessels. Measurements were averaged for 3 cardiac cycles (NB(ONH)). Color Doppler imaging (CDI) was also used to evaluate peak systolic blood velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) in the central retinal artery (CRA) and mean blood velocity (MV) in the central retinal vein (CRV). For baseline comparison (Day 0), recordings of bilateral NB(ONH) and intraocular pressure (IOP), blood pressure (BP), and pulse rate (PR) were recorded in healthy volunteers before, and 45, 90, 180, and 270 min after instillation of one drop of unoprostone vehicle. On Day 1 (the day after baseline measurements), and twice daily for 7 days, one drop of 0.12% unoprostone was instilled into one eye and its vehicle into the other in a double-blinded manner. Measurements as on Day 0 were recorded on Days 1 and 7. CDI measurements were performed before and at 45 and 180 min after morning instillation on Days 1 and 7. During baseline recordings, there were no significant changes in any parameters. After administration of topical unoprostone, IOP was significantly lower bilaterally with more reduction in the unoprostone-treated eyes on Day 7. On Day 7, the NB(ONH) of the unoprostone-treated eyes was significantly higher 45 min after instillation than baseline (P = 0.035 with Bonferroni's correction). Analysis of variance for repeated measurements also revealed significant difference between Day 0 and Day 7 (P = 0.0017). BP, PR, NB(ONH) in the eye that received only the vehicle, PSV, EDV, and RI in the CRA in both eyes, and MV in the CRV in both eyes changed little. Tissue blood velocity in the ONH increased, at least temporarily, following instillation of unoprostone twice daily for 7 days. Although the clinical implication of the increase is unclear, the effects of topical unoprostone on human ONH circulation deserve further consideration.     

Effect of topical carteolol on tissue circulation in the optic nerve head

The effect of topical 2% carteolol on tissue circulation in the albino rabbit optic nerve head (ONH) was investigated using a laser speckle tissue circulation analyzer. In the first experiment, the normalized blur (NB) value, a quantitative index of tissue blood flow velocity in the ONH, intraocular pressure (IOP), blood pressure (BP), and pulse rate were measured under general anesthesia before as well as 30, 60, 90, and 120 minutes after a 20-μL instillation of carteolol in one eye and the vehicle in the other eye in a masked, randomized manner. In the second experiment, one eye of a rabbit received carteolol twice daily for 20 days and the fellow eye received the vehicle in a masked, randomized manner. The IOP was measured every 5 days, and the NB in the ONH and IOP were measured before treatment and 2 hours after the last instillation on the 20th day. After a single instillation of carteolol, pulse rate showed a maximum reduction of 15%, and IOP in the carteolol-treated eyes showed a maximum decrease of 22%. The NB in the ONH and BP did not show any significant change during the experiment. After 20-day treatment with carteolol, IOP showed a maximum decrease of 25% in the carteolol-treated eyes and 21% in the vehicle-treated eyes. The NB showed a significant increase of 15% (P < 0.01) in the carteolol-treated eyes and 11% (P < 0.01) in the vehicle-treated eyes. It was indicated that long-term topical carteolol increased the blood velocity in the ONH tissue both in the carteolol- and vehicle-treated contralateral eyes in albino rabbits.     

Optic cup enlargement followed by reduced optic nerve head circulation after optic nerve stimulation.

PURPOSE: To investigate changes in optic nerve head (ONH) circulation, visual evoked potentials (VEPs), and ONH cupping after stimulation of the optic nerve. METHODS: Electrodes were fixed above the optic chiasma in rabbits under general anesthesia. Screw-type electrodes for VEP recording were fixed on the dura. ONH circulation, intraocular pressure (IOP), and blood pressure (BP) were measured after the passage of a current of 0.1 mA for 0.1 second (weak stimulation), 1 mA for 1 second (moderate), 5 mA for 10 seconds (strong), or 25 mA for 10 seconds (severe). Normalized blur (NB), indicative of tissue blood flow and velocity, was measured in the ONH after each stimulation, by using a laser speckle circulation analyzer. Changes in VEP and ocular fundus were also recorded. The ratio of cup area (CA) to disc area (DA) was measured before and 4 weeks after stimulation. After all experiments, the ONH was histologically examined. RESULTS: Weak stimulation increased NB in ONH for 10 minutes, whereas strong or severe stimulation significantly decreased NB for a longer time, in a dose-dependent manner. BP showed no significant change, except with severe stimulation. IOP was not significantly changed. VEP amplitude was reduced 30 minutes after strong stimulation. The CA-to-DA ratio was significantly increased 4 weeks after strong stimulation. In some rabbits, disc hemorrhage occurred, followed by enlargement of disc cupping, with slight gliosis. CONCLUSIONS: Electrical stimulation of the optic nerve changed ONH circulation and VEPs and increased disc cupping. This technique warrants further investigation as an experimental model for normal-tension glaucoma.     

Effect of ifenprodil on ocular tissue circulation in rabbits.

Ifenprodil tartrate has long been employed as a cerebral vasodilator with alpha and N-methyl-D-aspartate (NMDA) receptor antagonistic activities. The purpose of this study was to evaluate the effects of ifenprodil on ocular circulation in rabbits. Experiments were performed during the dark phase in Dutch rabbits conditioned to a schedule of alternating 12-hr periods of light and dark. Effects on ocular tissue blood velocity were estimated using the laser speckle method in the iris, posterior choroid, and optic nerve head (ONH). Measurements of tissue blood velocity were performed both after intravenous injection of ifenprodil at a dose of 0.2 mg/kg, 0.1 mg/kg, and the same volume of the vehicle, and after topical instillation of 0.5% ifenprodil (50 microl) twice daily for 1, 3 and 20 days unilaterally in a masked manner. Intraocular pressure (IOP) was also measured during the experimental period. Intravenous administration of ifenprodil caused a significant increase in blood velocity in the ONH, choroid, and iris, but ONH circulation was affected at a lower dose than uveal circulation. In the topical instillation experiment, IOP in the ifenprodil-treated eye was significantly lower, by approximately 2 mmHg, than that in the contralateral eye when the laser speckle measurement was performed. Twice-daily, unilateral 0.5% ifenprodil instillation significantly increased blood velocity in the iris after 3 days and that in the ONH and posterior choroid after 20 days in the treated eye. Topical 0.5% ifenprodil increased blood velocity in the iris, posterior choroid, and ONH after multiple dosings. After systemic administration, ONH circulation appeared to be influenced at a lower dose than was uveal circulation.     

Topical latanoprost and optic nerve head and retinal circulation in humans.

The purpose of the present study was to study the effect of a single instillation of latanoprost on the human optic nerve head (ONH) and retinal circulation. Using laser-speckle tissue blood flow analysis, normalized blur (NB; a quantitative index of tissue blood velocity) was measured every 0.125 sec at a temporal ONH site free of visible surface vessels. Measurements were averaged for 3 cardiac cycles (NB(ONH)). Color Doppler Imaging (CDI) was also used to evaluate peak systolic blood velocity (PSV), endo-diastolic velocity (EDV), and resistive index (RI) in the central retinal artery (CRA) and mean blood velocity (MV) in the central retinal vein (CRV). One drop of 0.005% latanoprost was instilled into one eye and its vehicle into the other in eleven healthy volunteers in a double-blinded manner. Measurements of bilateral NB(ONH), CDI parameters, intraocular pressure (IOP), blood pressure (BP), and pulse rate (PR) were performed before, and 45, 90, 180, and 270 min after instillation. After a single instillation of latanoprost or the vehicle, there was no significant bilateral difference throughout the experimental period. The difference in NB(ONH) between that before and at each time point of measurement (delta NB(ONH)) in the latanoprost-treated eyes was significantly higher between 45 and 270 min after instillation than that in vehicle-treated eyes (P = 0.0003 to 0.0156); ANOVA for repeated measurements also revealed significant difference between both eyes (P < 0.00001). BP, PR, and NB(ONH) in the eye that received only the vehicle, PSV, EDV, and RI in the CRA in both eyes, and MV in the CRV in both eyes changed little. Tissue blood velocity in the ONH increased at least temporarily following a single instillation of topical latanoprost. Although the mechanism of the increase is unclear, the effects of latanoprost on ONH tissue circulation in humans may have clinical implications.     

Effect of topical betaxolol on tissue circulation in the human optic nerve head.

There have been no reports to date on long-term betaxolol instillation effects on the human optic nerve head (ONH) tissue circulation. The purpose of this study was to study the effect of topical 0.5% betaxolol on tissue blood velocity in the human ONH. Using a laser-speckle tissue blood flow analyzer, normalized blur (NB; a quantitative index of tissue blood velocity) was measured every 0.125 seconds at a temporal ONH site free of visible surface vessels. Measurements were averaged for 3 cardiac cycles (NB(ONH)). For baseline comparison (day 0), recordings of bilateral NB(ONH) and intraocular pressure (IOP), blood pressure (BP) and pulse rate (PR) were recorded in healthy volunteers before, and 2, 4.5, and 7 hr after, instillation of 30 microL of betaxolol vehicle, and again on day 21; IOP was also recorded on days 7 and 14. On day 1 (the day after baseline measurements), and twice daily for 3 weeks, 30 microL of 0.5% betaxolol into one eye and 30 microL vehicle was instilled into the other in a double-blind study. Measurements as on day 0 were again recorded on day 21; IOP was also recorded on days 7 and 14. During baseline recordings, no significant changes were noted in any parameters. After administration of topical betaxolol, IOP was significantly reduced, bilaterally, with greater reduction in the betaxolol-treated eyes on day 21. Also on day 21, the NB(ONH) of the betaxolol-treated eyes was significantly higher 4.5 hr after instillation than that of the comparable baseline recording (p = 0.035 with Bonferroni's correction); BP, PR, and NB(ONH) in the eye which received only the vehicle showed little change. Tissue blood velocity in the human ONH was increased at least temporarily by instillation of topical betaxolol twice daily for 3 weeks. Although the obtained increase is small and may be clinically insignificant, the potential of betaxolol that can affect the ONH tissue circulation in humans after 21 days of instillation is thought to deserve further investigation.