September 2003
Volume 44, Issue 9
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Physiology and Pharmacology  |   September 2003
Time Course of the Change in Optic Nerve Head Circulation after an Acute Increase in Intraocular Pressure
Author Affiliations
  • Jun Takayama
    From the Eye Clinic, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan; the
  • Atsuo Tomidokoro
    Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan; the
  • Kiyoshi Ishii
    Eye Clinic, Omiya Red Cross Hospital, Saitama, Japan; and the
  • Yasuhiro Tamaki
    Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan; the
  • Yasuhiro Fukaya
    Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan; the
  • Tomokazu Hosokawa
    Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
  • Makoto Araie
    Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan; the
Investigative Ophthalmology & Visual Science September 2003, Vol.44, 3977-3985. doi:10.1167/iovs.03-0024
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      Jun Takayama, Atsuo Tomidokoro, Kiyoshi Ishii, Yasuhiro Tamaki, Yasuhiro Fukaya, Tomokazu Hosokawa, Makoto Araie; Time Course of the Change in Optic Nerve Head Circulation after an Acute Increase in Intraocular Pressure. Invest. Ophthalmol. Vis. Sci. 2003;44(9):3977-3985. doi: 10.1167/iovs.03-0024.

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      © 2015 Association for Research in Vision and Ophthalmology.

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Abstract

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 μg/kg per hour nilvadipine (a calcium antagonist), 30 mg/kg N ω-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.

It is suggested that blood flow in the retina and optic nerve head (ONH) is stably maintained despite certain changes in ocular perfusion pressure (OPP), and this ability is recognized as a function of autoregulation. 1 2 3 4 5 6 7 8 9 10 Because vascular insufficiency, including inadequate response to changes in perfusion pressure in the ONH, may play a role in the pathogenesis of glaucoma 11 12 13 14 15 and acute ischemic optic neuropathy, 16 17 it is of clinical importance to investigate how ONH circulation reacts to the changes in OPP. 
Previous studies have mainly focused on the presence of autoregulation or its functional range of OPP. Because most of the studies evaluated the changes in ocular blood flow after certain time intervals (at least 20 minutes) after changes in OPP, 1 3 6 7 the time course of circulatory response has not been fully investigated. In recent years, using laser Doppler flowmetry, Riva et al. 8 continuously monitored relative changes in blood flow in the cat ONH during stepwise or continuous elevations of intraocular pressure (IOP). Although their results suggest a quick recovery of blood flow within 1 minute after elevation of IOP up to 50 mm Hg, the flow change during the first minute, in which the blood flow was reduced and then recovered, was not recorded. In humans, laser Doppler flowmetry was also used to assess autoregulation in the ONH after stepwise elevations 10 or continuous increase 9 of IOP by scleral suction cup, and it was suggested that restoration of ONH circulation after increase of IOP (i.e., OPP decrease) is achieved very quickly. Our knowledge about the time course of changes in the ONH circulation just after the IOP alteration, however, is limited, and physiological or pharmacological properties included in it have not been investigated. 
The laser speckle method has been developed recently for noninvasive assessment of tissue circulation in living eyes and gives a quantitative index of blood flow velocity and the normalized blur (NB) index, which also has been confirmed to correlate well linearly with the blood flow determined with microsphere technique in the iris 18 choroid, 19 and retina 20 and the blood flow determined with the hydrogen gas clearance method in the ONH. 21 22 Using this method, continuous monitoring of ONH circulation can be obtained with a high time resolution. 23 In this study, we investigated the time course of changes in the ONH circulation after an acute increase in IOP with a high-time-resolution analysis by the laser speckle method. Further, we studied the effects of a calcium antagonist, the nitric oxide synthetase (NOS) inhibitor, indomethacin, and sympathetic nerve amputation on the time course of the change. 
Methods
Animals
In this series of experiments, Japanese albino rabbits weighing 2.0 to 2.5 kg were used and handled in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. After induction of general anesthesia (0.9–1.1 g/kg urethane, intravenously), the femoral artery was cannulated for monitoring of blood pressure, pulse rate, Po 2, Pco 2, and pH of the arterial blood. The mean femoral arterial blood pressure (FABPm; in mm Hg) was calculated as  
\[\mathrm{FABP}_{\mathrm{m}}\ {=}\ \mathrm{FABP}_{\mathrm{d}}\ {+}\ 1/3(\mathrm{FABP}_{\mathrm{s}}\ {-}\ \mathrm{FABP}_{\mathrm{d}})\]
where FABPd and FABPs were the diastolic and systolic femoral arterial blood pressures, respectively. OPP (in mm Hg) was calculated as  
\[\mathrm{OPP}\ {=}\ \mathrm{FABP}_{\mathrm{m}}\ {-}\ \mathrm{IOP}\ {-}\ 14\]
where −14 was the compensator for the discrepancy in pressures between the femoral artery and the ophthalmic artery in a prone positioned rabbit. 24 25 The animal was placed in a stereotaxic device equipped with a heating pad, and the body temperature was monitored rectally. In both eyes, the pupil was dilated with 1 drop of 0.4% tropicamide at least 20 minutes before the experiment began. Rabbits that showed abnormal systemic parameters 26 after general anesthesia were excluded from the experiments. 
Evaluation of ONH Circulation
Circulation in the ONH was evaluated using the laser speckle method, details of which have been described previously 18 19 20 and are briefly summarized herein. An apparatus used for the measurements included a fundus camera with a diode laser (wavelength: 808 nm; power: 2 mW), an image sensor, and a personal computer. The laser beam was focused on the surface of the ONH, which was illuminated by a halogen lamp. The scattered light was imaged on an image sensor of 100 × 100 pixels, corresponding to a field of 0.62 × 0.62 mm2 in the rabbit fundus, where the speckle pattern appeared. The difference between an average speckle intensity and the speckle intensity of successive scans was calculated. The ratio of the average speckle intensity to this difference was defined as normalized blur (NB). The average NB level in the most widely available rectangular area free of visible vessels in the ONH was calculated and termed NBav. An NBav measurement took 0.125 second, and successive results for 1 second were averaged and refereed to as NBONH
Blood flow rate in the ONH was determined with a hydrogen clearance flowmeter (RBF-222; Biomedical Science, Kanazawa, Japan). A hydrogen needle electrode (diameter: 0.1 mm) was inserted through the vitreous body into the lower portion of the ONH (depth: approximately 0.7 mm), guided by viewing with a vitrectomy lens. A reference electrode was fixed in the subcutaneous tissue of the head. Capillary blood flow was calculated with hydrogen density half-life, after the inhalation of 10% hydrogen gas by mask at 0.5 L/min for 5 minutes. 21 22 After this experiment, some of the rabbits were killed immediately, and the eyes were enucleated to evaluate the histopathology around the ONH in which the hydrogen needle was inserted. 
Correlation between NBONH and ONH Blood Flow Measured by the Hydrogen Gas Clearance Method
A randomly chosen eye of each rabbit (n = 20) was prepared for ONH blood flow measurement by the hydrogen gas clearance method, and two 25-gauge needles were inserted into the anterior chamber from the limbus. The connecting tube from one of the needles was branched through a turncock into two reservoirs of commercially available artificial aqueous (Opeguard MA; Senju Pharmaceutical Co., Osaka, Japan), which were mounted at different heights. By alternating the reservoirs using the turncock, the IOP could be acutely changed, keeping the water surface placid in the bottles. The other needle was connected to a pressure transducer for continuous monitoring of the actual IOP. Ten minutes after IOP was adjusted at 20 mm Hg, ONH blood flow was obtained by the hydrogen gas clearance method, and NBONH was immediately measured in the same eye after confirming no change in the electrode’s positioning and no visible bleeding. Thereafter, IOP was retained at 20 mm Hg (n = 4) or was changed to 40, 50, or 60 mm Hg (n = 4, each). After a 10-minute interval, the hydrogen gas clearance method and NBONH measurement were repeated. 
Time Course of NB Change for 60 Minutes and 25 Seconds after Acute Increase in IOP
IOP was adjusted at 20 mm Hg and NBONH was serially monitored at 1-minute intervals for 10 minutes. Subsequently, the IOP was changed from 20 mm Hg to 40, 50, or 60 mm Hg (n = 6, each). NBONH was serially monitored at 1-minute intervals for the first 15 minutes and then at 30 and 60 minutes after the change in IOP. For comparison, the time course of changes in NB in the posterior choroid (NBcho) was also studied (n = 4). After IOP was adjusted to 20 mm Hg and held for 10 minutes, the IOP was manometrically increased to 50 mm Hg by changing the reservoirs. NBcho was serially monitored at 5- or 15-minute intervals for 60 minutes after the change in IOP. NBcho was measured at the posterior choroid one pupillary diameter below the ONH with the same-sized measurement fields as for the NBONH. 19  
In a separate group of rabbits, the changes in NBav in the ONH for approximately 25 seconds after the acute increase in IOP from 20 to 50 or 60 mm Hg was studied with much higher time resolution. IOP was adjusted at 20 mm Hg for at least 10 minutes to confirm that stable NBONH results were obtained. Then, continuous recording of NBav at 0.125-second intervals was started. Approximately 5 seconds after the start of serial NBav measurement, the IOP was increased to 50 or 60 mm Hg by changing the reservoirs, and NBav recording was continued for the next 25 seconds (n = 10 or 6, respectively). Changes in NBav in the choroid for 25 seconds after the increase in IOP from 20 to 50 mm Hg was measured in the same manner (n = 6). 
Effects of a Calcium Antagonist
Nilvadipine (Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan), a dihydropyridine calcium antagonist, was continuously administrated at the rate of 1 μg/kg per hour through the auricle vein of rabbits similarly prepared. 
Before nilvadipine administration was started, IOP was adjusted at 20 mm Hg and NBONH and systemic parameters were determined as described earlier. Twenty minutes after nilvadipine administration was started, because blood pressure was reduced by the nilvadipine, IOP was readjusted to keep OPP unchanged from its level before the administration of nilvadipine in each rabbit (IOP1). After confirming that NBONH was stable, IOP was increased from IOP1 to the second level (IOP2), which was 30 mm Hg higher than IOP1. NBONH was serially measured just before and at 30 seconds, 1, 5, 10, 20, 30, 40, 50, and 60 minutes after the increase in IOP (n = 6). As a control, the same protocol was performed with the same volume of the vehicle solution instead of nilvadipine in a separate group of rabbits (n = 6). 
Using other rabbits, changes in NBav for 25 seconds after the change in IOP from IOP1 to IOP2 were measured with high-time-resolution analysis according to the protocol described earlier, during the continuous administration of 1 μg/kg per hour nilvadipine (n = 6) or the vehicle solution (n = 6, control). 
In these experiments, one investigator measured NBONH and NBav and another monitored IOP and systemic blood pressure. Both of them were masked to the treatment with nilvadipine or vehicle in each rabbit, and each was masked to the results obtained by the other. 
Effects of an NOS Inhibitor or Indomethacin
After IOP was adjusted at 20 mm Hg and NBONH recorded as described for at least 10 minutes, serial recording of NBav at 0.125-second interval was started. Approximately 5 seconds after the NBav recording was started, IOP was increased to 50 mm Hg and NBav recording was continued for the next 25 seconds. When the NBav recording finished, the IOP was returned to 20 mm Hg again. Subsequently, 30 mg/kg N ω-nitro-l-arginine (l-NAME), a nonselective NOS inhibitor, was intravenously injected from the auricular vein (n = 10). Thirty minutes after administration, the same protocol of change in IOP and serial NBav measurements was repeated. Using the same experimental design, the effects of intravenous administration of 5 mg/kg indomethacin was also studied (n = 9). As a control, the same experiment was performed in a separate group of rabbits (n = 10), to which a similar amount of physiological saline was administrated instead of l-NAME or indomethacin. The investigator who measured NBav was masked to whether the rabbit had received l-NAME, indomethacin, or physiological saline. Because preliminary experiments revealed that the drugs given caused little effect on FABPm in Japanese albino rabbits, the second level of IOP was set at 50 mm Hg. 
To compare the time course of changes in NBav before and after l-NAME or indomethacin administration, a time-parameter analysis was applied to the time course obtained in each rabbit. For each of the NBav curves, two time parameters, such as descending time (T 1) and recovery time (T 2), were defined as follows (Fig. 1) . Serial NBav results obtained for 3 seconds just before the change in IOP from 20 to 50 mm Hg were averaged to obtain the baseline NBav. The difference between the baseline NBav and the minimum NBav was defined as NBreduction. If the minimum NBav was recorded at two or more different time points, the first time point was adopted. The time to obtain the minimum NBav from the change in IOP was defined as descending time. The time to recover the 90% of NBreduction from the minimum NBav was defined as recovery time. If the NBav showing the 90% of NBreduction was recorded at two or more different time points, the first time point was adopted. 
Effects of Sympathetic Nerve Amputation
After systemic preparation as described earlier, except pupillary dilation in six rabbits, the vagosympathetic nerve trunk was bilaterally exposed and confirmed with ipsilateral mydriasis induced with electric stimulation of the trunk. Thereafter, a randomly chosen side of the nerve trunk was sectioned with surgical scissors, while the contralateral nerve remained. Approximately 1 hour after these preparations, the pupil was dilated with tropicamide, and the anterior chamber was cannulated for controlling and monitoring IOP as described earlier in one randomly chosen eye of each rabbit. After IOP was kept at 20 mm Hg and NBONH measured for at least 10 minutes, serial recording of NBav at 0.125-second intervals was started. Approximately 5 seconds after the NBav recording was started, the IOP was increased to 50 mm Hg and recording of NBav was continued for the next 25 seconds. Subsequently, the same protocol was performed in the contralateral eye after confirming no significant changes in FABPm. The time parameter analysis of the time course changes in NBONH was performed in the same manner as described earlier. 
Results
Correlation between NBONH and ONH Blood Flow Measured by the Hydrogen Gas Clearance Method
Because NBONH is a relative value, the change in NBONH due to the increase in IOP was compared to the change in blood flow rate obtained by the hydrogen gas clearance method in each rabbit. There was a significant correlation between the change in NBONH and the change in blood flow rate (Spearman’s rank correlation coefficient, R s = 0.83, P < 0.001, Fig. 2 ). There were neither abnormal values nor significant changes in the systemic condition parameters. In a section of the ONH in which the hydrogen needle was inserted, neither major hemorrhage nor apparent destruction of the tissue structure was found. 
Time Course of NBONH Change before and after Acute Increase in IOP
Figure 3 shows the time course of NBONH and OPP for 60 minutes before and after the change in IOP in rabbits. Increasing IOP showed little effect on NBONH 1 minute after IOP was increased in the groups in which the IOP was elevated to 40 or 50 mm Hg, whereas NBONH was significantly decreased and showed no recovery to the initial value in the group in which the IOP was elevated to 60 mm Hg (Wilcoxon signed rank test, P < 0.05). There were neither abnormal levels nor significant changes in the systemic parameters during the experiment. Figure 4 shows the time course changes in NBcho and OPP for 60 minutes after change in IOP in rabbits. After the change in IOP, NBcho and OPP decreased by approximately 25% and 50%, respectively. 
Figure 5 shows an example of the recordings for 25 seconds of NBav and actual IOP before and after a change in IOP. NBav showed a transient decline and a rapid recovery to the initial level within several seconds. The mean change in NBav in the ONH after a change in IOP from 20 mm Hg to 50 or 60 mm Hg is shown in Figure 6 , in which the data are plotted at intervals of 0.625-second. NBav showed a transient decrease during the first 3 seconds after the change in IOP when IOP was increased to 50 mm Hg, whereas no apparent recovery, except a slight one immediately after the change in IOP, was found when IOP was increased to 60 mm Hg. The mean change in NBav in the choroid after a change in IOP from 20 to 50 mm Hg is shown in Figure 7 . Although a slight recovery was observed immediately after the change in IOP, no persistent recovery was found. 
Effects of a Calcium Antagonist
In the experiment in which there was a 60-minute observation after the increase in IOP, baseline NBONH, which was obtained just before the change in IOP, was 10.1 ± 0.9 in the nilvadipine-treated rabbits, which was significantly higher than that in the vehicle-treated rabbits (8.7 ± 0.4, Mann-Whitney test, P = 0.045). In the nilvadipine-treated rabbits, NBONH showed an acute reduction of approximately 20% and %NBONH (the relative NBONH versus baseline) was significantly smaller than that in the vehicle-treated rabbits at each time point after the change in IOP (Mann-Whitney test with Bonferroni correction; P = 0.016, Fig. 8 ). Although FABPm in the nilvadipine-treated rabbits was lower than that in the vehicle-treated rabbits at each time point, there was no significant difference in OPP, because IOP was set approximately 10 mm Hg lower in the nilvadipine-treated rabbits than in the vehicle-treated rabbits (Fig. 8) . Other systemic parameters were not significantly different between the two groups (Table 1)
In the experiment with the 25-second observation after the increase in IOP, the baseline NBav that was obtained just before the change in IOP was significantly higher in the nilvadipine-treated rabbits (10.1 ± 0.8) than in the vehicle-treated rabbits (9.0 ± 0.5, Mann-Whitney test, P = 0.014). NBav showed quick recovery after the change from IOP1 to IOP2 in the vehicle-treated rabbits, whereas the recovery was apparently restricted in the nilvadipine-treated rabbits (Fig. 9) . Systemic parameters were almost similar to those in the experiment with a 60-minute observation period. 
Effects of an NOS Inhibitor and Indomethacin
After treatment with l-NAME, the baseline NBav slightly but significantly decreased from 8.0 ± 0.3 to 7.4 ± 0.3 (Wilcoxon signed rank test, P = 0.028). The descending time did not significantly change after the administration of l-NAME (P > 0.1), whereas the recovery time was significantly prolonged compared with the pretreatment level (P = 0.012) and the increase was significantly greater than that in saline-treated rabbits (Mann-Whitney test, P = 0.023; Table 2 ). On the other hand, in the indomethacin and saline groups, neither baseline NBav, descending time, nor recovery time after the treatments was significantly different from that before the treatments (P > 0.1). FABPm and other systemic parameters did not significantly change before and after the treatment with l-NAME, indomethacin, or physiological saline (Table 3)
Effects of Sympathetic Nerve Amputation
The baseline NBav at IOP of 20 mm Hg in eyes in which the sympathetic nerve was amputated was significantly larger than that in the contralateral untreated eyes (9.6 ± 1.8 vs. 8.3 ± 1.0; Wilcoxon signed rank test, P = 0.027, Table 4 ). However, there was no significant difference in descending or recovery times in the time course changes of NBav between the eyes with sympathetic nerve amputation and the contralateral control eyes. Systemic parameters including FABPm did not significantly change during the experiment (Table 4)
Discussion
The NB index obtained by laser speckle tissue circulation analysis is primarily a quantitative index of tissue blood velocity. 20 27 However, it has also been found to correlates with the blood flow rate in the iris, retina, and choroid. 18 19 20 The rabbit NBONH had good correlation with the results obtained with the hydrogen gas clearance method, in which a needle electrode was inserted into the ONH to the depth of approximately 0.7 mm, regarding the changes after systemic administration of endothelin-1, 21 nilvadipine, 22 or inhalation of CO2. 21 In the present study, the change in NBONH and that in ONH blood flow measured by the hydrogen gas clearance method also correlated significantly (R s = 0.83, P < 0.001, Fig. 2 ). The blood flow rate in the rabbit ONH at the IOP of 20 mm Hg was estimated to be 115 mL/min per 100 g by the hydrogen gas clearance method in the present study, which is compatible with the previously reported ONH blood flow measured by the hydrogen gas clearance in normal rabbits (52–119 mL/min per 100 g). 21 28 29  
An infrared laser (wavelength: 808 nm; power: 2 mW) was used for NBONH measurements by the laser speckle method. Although it should be difficult to accurately decide how deep the laser penetrates into the rabbit ONH tissue, Koelle et al. 30 reported that infrared laser (wavelength: 811 nm; power: 2 mW) penetrated to a depth of approximately 1 mm in the cat optic nerve. On the contrary, Petrig et al. 31 reported that laser Doppler flowmetry (wavelength approximately 800 nm) is predominantly sensitive to blood flow changes in the superficial layers of the monkey ONH. In the present study, NBONH significantly correlated with the results obtained by the hydrogen gas clearance method in which the electrode was inserted to a depth of 0.7 mm in the ONH tissue. This finding suggests that the present NBONH data are likely to reflect blood flow changes in the rabbit ONH, not only from the superficial layers but also in layers beneath the lamina scleralis. 
In the present study, the time course of changes in ONH circulation was documented. NBONH quickly decreased and immediately recovered within several seconds after an acute increase in IOP from 20 mm Hg to 40 or 50 mm Hg (Figs. 3 and 6) . These findings were consistent with the previous works in which the ONH blood flow recovered within 1 minute after the change in OPP in cats. 8 Moreover, very short-term changes just after increase in IOP were also found in the present study. These results obtained in the ONH contrasted with those in the posterior choroid (Fig. 4) , in which NBcho was decreased and showed little recovery after the increase in IOP from 20 to 50 mm Hg (OPP decrease from 60 to 30 mm Hg). However, NBcho decreased by approximately 25% under the condition that OPP decreased by approximately 50%, and NBav in the choroid showed a slight recovery response immediately after the change in IOP in the 25-second experiment (Fig. 7) . These findings suggest that the choroidal circulation may not be completely passive against changes in OPP, 32 although its autoregulatory mechanism was apparently weaker than that in the ONH. In contrast, when IOP was increased to 60 mm Hg (OPP decreased to 20 mm Hg), no recovery was seen in NBONH (Fig. 3) . Decrease in NBONH was considerably smaller, however, than that in OPP (33% vs. 66%). Although change in NBONH tended to underestimate the IOP-induced reduction in the ONH blood flow (Fig. 2) , this finding may suggest that some autoregulatory mechanism still has effects. The current results were consistent with the previously reported ranges of OPP in which autoregulation of the rabbit ONH was observed. 19  
In the present study, NBONH in the nilvadipine-treated rabbits was significantly higher than that in the vehicle-treated rabbits, suggesting an increase in ONH blood flow velocity induced by nilvadipine treatment. However, response against the acute decrease of perfusion pressure (i.e., acute increase in IOP) was apparently impaired. Nilvadipine is a Ca2+ antagonist classified in the dihydropyridine group, blocks L-type calcium channels, and is relatively selective of cerebral arteries. 33 Calcium antagonists impair influx of Ca2+ into the vascular smooth muscles and usually increases peripheral circulation. Recent studies using isolated vessels including rabbit cerebral arteries 34 35 showed that many kinds of Ca2+ antagonists abolish or attenuate the stretch-induced contraction of vascular smooth muscles. An in vivo study revealed that a Ca2+ antagonist (nimodipine) inhibits autoregulation of cerebral blood flow against arterial pressure increase by 40 mm Hg in cats and monkeys. 36 To our knowledge, however, no studies have investigated the effects of Ca2+ antagonists on the time course of the change in ONH circulation after an acute increase in IOP (and decrease in OPP). 
The current results suggest that the Ca2+ antagonist reduces the basal tone of the vascular smooth muscle, as documented by an increase in the baseline NBONH, and attenuates the additive relaxation necessary for the quick recovery response of a decrease in OPP. To maintain a stable vasodilating effect of nilvadipine, the drug was continuously administrated at the rate of 1 μg/kg per hour in the present study. Because nilvadipine is a lipophilic agent and is easily and strongly bound to the receptors on the cell membrane, its effect on the peripheral vessels does not directly follow its concentration in the blood. In animal experiments, 37 the optimum concentration of a bolus intravenous nilvadipine for reducing systemic arterial pressure ranged between 0.1 and 10 μg/kg, and the effect continued for at least 1 hour. Thus, the continuous administration of 1 μg/kg nilvadipine per hour was adopted for the current experiments. Although direct comparison between bolus or continuous intravenous and oral administration is usually difficult, the maximum blood concentration after oral administration of a 4-mg tablet of nilvadipine in normal humans is 3.5 ng/mL, 38 which roughly corresponds to that after a bolus administration of nilvadipine at 0.3 μg/mL per kilogram in rabbits. 37 Because 2 or 4 mg oral nilvadipine is the clinical dose for the treatment of systemic hypertension, the current dosage in rabbits should roughly correspond to the ordinary clinical condition. 
In the nilvadipine-treated rabbits, NBONH decreased by approximately 20% after an increase in IOP from 20 to 50 mm Hg, corresponding to an OPP decrease from 65 to 32 mm Hg (approximately 50% decrease). The apparent dissociation between a 20% decrease in NBONH and a 50% decrease in OPP suggests that the vascular system in the ONH tissue is not completely passive against the change in OPP, even after nilvadipine treatment at the present dose, and that other factors also may be involved in the maintenance of constant ONH circulation against an acute decrease in OPP. Because many kinds of Ca2+ antagonists are commonly used for the treatment of cardiovascular or cerebral diseases, the possibility should be noted that response to OPP changes may be somewhat modified in patients taking those drugs. For example, the acute increase in IOP due to an episode of acute angle-closure glaucoma or secondary glaucoma may exert more unfavorable influences in patients who are taking systemic Ca2+ antagonists. 
NO and prostacyclin are released from the vascular endothelium according to the changes in the sheer stress 39 40 and play vital roles in local control of the vascular tone. Because complete inhibition of the endothelium function cannot be obtained in living animals, we tested the effects of l-NAME (a nonselective inhibitor of NO synthesis) and indomethacin (an inhibitor of synthesis of prostaglandins including prostacyclin) on the quick recovery response in the ONH circulation after the changes in OPP. l-NAME showed a slight but significant retarding effect on the quick recovery of the ONH circulation, whereas indomethacin showed no effect. The doses of l-NAME and indomethacin used in this study were equivalent or larger than those used in previous studies in which their vasoactive effects were certified in rabbits. 32 41 42 In the present study, baseline NBONH showed a slight, but significant reduction after administration of l-NAME, suggesting that NO synthesis was at least partly inhibited. However, no manifest change in the blood pressure may suggest only a partial inhibition of NO synthesis. The reduction in NBONH and the change in blood pressure after administration of l-NAME in the present study were apparently smaller than those obtained in conscious albino rabbits. 41 The anesthesia used in the present study may have some influence on the vascular basal tone or vasoactive reaction to l-NAME. 
Gidday et al. 43 reported that an NOS inhibitor (N G-monomethyl-l-arginine) showed no significant influences on the autoregulatory vasodilatation of the newborn pig retinal artery caused by systemic hypoxia, hypotension, or hypercapnia. In contrast, Buerk et al. 44 found that NO is important for functional hyperemia (vasodilatation) of the cat ONH circulation during increased neuronal activity with flickering light stimuli to the eye, but Buerk and Riva 45 found that it is not essential for vasomotion in unstressed conditions. Because the effect of the NOS inhibitor on the rapid recovery of ONH circulation after an acute increase in IOP (decrease in OPP) was found to be small under the current experimental conditions, it is suggested that NO is not a main mediator for the reaction, at least in this species of animal. However, there remains a possibility that Japanese albino rabbits are not a suitable animal species in which to study of the role of NO in ONH circulation. 
In the current experiment involving the amputation of the sympathetic nerve, the alteration of IOP and measurements of NBONH were performed approximately 1 hour after the nerve was severed. Therefore, it is supposed that neither the effect of the ganglionectomy, which manifests as a degenerating release of norepinephrine from adrenergic nerve fiber terminals and usually occurs at least 12 hours after ganglionectomy, 46 nor the denervation supersensitivity that occurs approximately 10 days after injury, 47 48 occurred during the experimental period. It has been concluded in earlier reports 49 50 that sympathetic nerves in mammalians innervate the central retinal artery up to the ONH, but not beyond, whereas all uveal vascular beds are innervated. However, recent study using electron microscopy and fluorescent examination has revealed that sympathetic nerve innervation is found in the retinal arteries beyond the lamina cribrosa in rabbit eyes. 51 Similar to the results of experiments using the microsphere technique, sympathetic stimulation reduces the uveal blood flow, but does not affect the blood flow in the retina and optic nerve of cats, 52 and monkeys. 52 Other investigators have reported that the cat retinal blood flow increases after sympathectomy. 53 Using the microsphere technique, Linder 54 showed that autoregulation against systemic hypotension is partly impaired by sympathetic stimulation in the rabbit retina, but not in the optic nerve. The results of the present study obtained using the laser speckle method suggest that cutting the cervical sympathetic chain has a small but significant accelerating effect on the basal level of ONH circulation, whereas it shows no significant effects on its quick recovery response after acute changes in IOP. 
We performed several experiments in the present study, and some of the systemic parameters such as Po 2 during the sympathetic nerve amputation experiment were different from those in other experiments (Tables 1 3 and 4) . Although we do not have a good explanation for this difference, a main reason would be the surgical procedures used in this experiment for amputation of the sympathetic nerve, and that the time intervals between the induction of general anesthesia and the NB experiments differed between this experiment and others because of this surgery. None of the systemic parameters, however, exceeded the normal ranges of healthy rabbits. 26  
In conclusion, the present series of experiments using the laser speckle method indicate that recovery in the ONH circulation is accomplished in the first several seconds after an acute increase in IOP, and that the influx of Ca2+-related vascular smooth muscle relaxation was confirmed to play a role in the response. The production of NO or prostaglandins, or sympathetic nervous system appeared to have slight effects on it. The laser speckle method was found to be suited to noninvasive monitoring of the changes in ONH circulation with high time resolution and its process after various stimulations and to investigate factors relating to them. There are differences regarding anatomy and blood supply in the ONH between rabbits and primates or humans, despite similarities in the arterial supply. 55 Therefore, the current results may not be directly applied to the ONH circulation of primates or humans, but should provide useful information for future laboratory studies and probably for clinical settings. 
 
Figure 1.
 
Time parameter analysis of NBav in l-NAME and indomethacin experiments. Approximately 5 seconds after the NBav recording was started, the IOP was increased to 50 mm Hg (arrow) and the recording continued for the next 25 seconds. NBav is plotted every 0.5 second in this example. For explanation of descending time (T 1) and recovery time (T 2), see the Methods section.
Figure 1.
 
Time parameter analysis of NBav in l-NAME and indomethacin experiments. Approximately 5 seconds after the NBav recording was started, the IOP was increased to 50 mm Hg (arrow) and the recording continued for the next 25 seconds. NBav is plotted every 0.5 second in this example. For explanation of descending time (T 1) and recovery time (T 2), see the Methods section.
Figure 2.
 
Relation between change in NBONH and that in ONH blood flow rate measured by the hydrogen gas clearance method. A significant correlation was found (Spearman’s rank correlation coefficient, R s = 0.83, P < 0.001).
Figure 2.
 
Relation between change in NBONH and that in ONH blood flow rate measured by the hydrogen gas clearance method. A significant correlation was found (Spearman’s rank correlation coefficient, R s = 0.83, P < 0.001).
Figure 3.
 
Time course of changes in the relative NBONH (A) compared with the baseline value (% NBONH) and OPP (B) for 60 minutes after change in IOP from 20 mm Hg to 40, 50, or 60 mm Hg in rabbits. Data are expressed as the average ± SE (n = 6, each). Increasing IOP showed little effect on NBONH in the groups in which IOP2 was 40 or 50 mm Hg, whereas NBONH was significantly decreased compared with the initial value in rabbits in which IOP was increased to 60 mm Hg (Wilcoxon signed rank test, P < 0.05).
Figure 3.
 
Time course of changes in the relative NBONH (A) compared with the baseline value (% NBONH) and OPP (B) for 60 minutes after change in IOP from 20 mm Hg to 40, 50, or 60 mm Hg in rabbits. Data are expressed as the average ± SE (n = 6, each). Increasing IOP showed little effect on NBONH in the groups in which IOP2 was 40 or 50 mm Hg, whereas NBONH was significantly decreased compared with the initial value in rabbits in which IOP was increased to 60 mm Hg (Wilcoxon signed rank test, P < 0.05).
Figure 4.
 
Time course of changes in the relative NBcho (A) compared with baseline (% NBcho) and OPP (B) for 60 minutes after change in IOP from 20 to 50 mm Hg. Data are expressed as the average ± SE (n = 4).
Figure 4.
 
Time course of changes in the relative NBcho (A) compared with baseline (% NBcho) and OPP (B) for 60 minutes after change in IOP from 20 to 50 mm Hg. Data are expressed as the average ± SE (n = 4).
Figure 5.
 
An example of the recordings for 25 seconds of NBav and IOP before and after change in IOP from 20 to 50 mm Hg (arrow).
Figure 5.
 
An example of the recordings for 25 seconds of NBav and IOP before and after change in IOP from 20 to 50 mm Hg (arrow).
Figure 6.
 
Time course of changes for 25 seconds in the relative NBav compared with baseline (% NBav) in the ONH. The NBav is expressed at intervals of 0.625 second ± SE. IOP was changed from 20 mm Hg to 50 (A) or 60 (B) mm Hg at time 0 (arrow).
Figure 6.
 
Time course of changes for 25 seconds in the relative NBav compared with baseline (% NBav) in the ONH. The NBav is expressed at intervals of 0.625 second ± SE. IOP was changed from 20 mm Hg to 50 (A) or 60 (B) mm Hg at time 0 (arrow).
Figure 7.
 
Time course of changes for 25 seconds in the relative NBav compared with baseline (% NBav) in the choroid. The NBav ± SE is shown at intervals of 0.625 second. IOP was changed from 20 to 50 mm Hg at time 0 (arrow).
Figure 7.
 
Time course of changes for 25 seconds in the relative NBav compared with baseline (% NBav) in the choroid. The NBav ± SE is shown at intervals of 0.625 second. IOP was changed from 20 to 50 mm Hg at time 0 (arrow).
Figure 8.
 
Time course of changes in the relative NBONH compared with (A) baseline (%NBONH), (B) FABPm, and (C) OPP for 60 minutes after change in IOP from IOP1 to IOP2 in nilvadipine-treated and vehicle-treated rabbits. Data are expressed as the average ± SE (n = 6, each).
Figure 8.
 
Time course of changes in the relative NBONH compared with (A) baseline (%NBONH), (B) FABPm, and (C) OPP for 60 minutes after change in IOP from IOP1 to IOP2 in nilvadipine-treated and vehicle-treated rabbits. Data are expressed as the average ± SE (n = 6, each).
Table 1.
 
IOP and Systemic Parameters in the Nilvadipine- or Vehicle-Treated Rabbits during a 60-Minute Change in NBONH after an Increase in IOP from IOP1 to IOP2
Table 1.
 
IOP and Systemic Parameters in the Nilvadipine- or Vehicle-Treated Rabbits during a 60-Minute Change in NBONH after an Increase in IOP from IOP1 to IOP2
Nilvadipine Vehicle
IOP1 (mm Hg) 10.1 ± 0.1* 20.1 ± 0.2
IOP2 (mm Hg) 40.3 ± 0.4* 50.2 ± 0.3
FABPm (mm Hg) 87.9 ± 1.2 98.1 ± 2.5
Pulse rate (min) 271 ± 7 270 ± 4
pH 7.42 ± 0.01 7.43 ± 0.01
Pco 2 (mm Hg) 38.6 ± 0.4 40.2 ± 0.6
Po 2 (mm Hg) 87.2 ± 1.3 86.5 ± 2.1
Body temperature (°C) 37.1 ± 0.1 37.2 ± 0.1
Figure 9.
 
Time course of changes in the relative NBav compared with baseline (%NBav) obtained for 25 seconds after change in IOP from IOP1 to IOP2, in nilvadipine-treated rabbits and vehicle-treated rabbits. Data are expressed as the average ± SE (n = 6, each).
Figure 9.
 
Time course of changes in the relative NBav compared with baseline (%NBav) obtained for 25 seconds after change in IOP from IOP1 to IOP2, in nilvadipine-treated rabbits and vehicle-treated rabbits. Data are expressed as the average ± SE (n = 6, each).
Table 2.
 
Baseline NBav, Descending Time, and Recovery Time before and after the Administration of l-NAME, Indomethacin, or Physiological Saline
Table 2.
 
Baseline NBav, Descending Time, and Recovery Time before and after the Administration of l-NAME, Indomethacin, or Physiological Saline
l-NAME Indomethacin Saline
Number of rabbits 10 9 10
Baseline-NBav
 Pre 8.0 ± 0.3 7.9 ± 0.5 8.0 ± 0.4
 Post 7.4 ± 0.3* 7.5 ± 0.5 8.2 ± 0.5
 Change −0.5 ± 0.3 −0.3 ± 0.6 0.2 ± 0.5
Descending Time (sec)
 Pre 1.69 ± 0.19 1.88 ± 0.17 1.75 ± 0.40
 Post 1.93 ± 0.24 2.03 ± 0.16 1.44 ± 0.19
 Change 0.25 ± 0.25 0.14 ± 0.17 −0.31 ± 0.50
Recovery Time (sec)
 Pre 2.56 ± 0.33 2.18 ± 0.31 2.00 ± 0.20
 Post 3.69 ± 0.51 2.27 ± 0.20 2.38 ± 0.24
 Change 1.13 ± 0.33, ‡ 0.07 ± 0.22 0.38 ± 0.28
Table 3.
 
Systemic Parameters before and after the Administration of l-NAME, Indomethacin, or Saline
Table 3.
 
Systemic Parameters before and after the Administration of l-NAME, Indomethacin, or Saline
l-NAME Indomethacin Saline
FABPm (mm Hg)
 Pre 92.2 ± 2.8 96.4 ± 2.2 95.6 ± 3.4
 Post 96.3 ± 3.2 101.5 ± 4.9 102.3 ± 3.2
Pulse Rate (min)
 Pre 247 ± 8 250 ± 6 259 ± 8
 Post 250 ± 10 257 ± 8 240 ± 8
pH
 Pre 7.38 ± 0.01 7.41 ± 0.02 7.39 ± 0.01
 Post 7.38 ± 0.01 7.38 ± 0.02 7.44 ± 0.02
Pco 2 (mm Hg)
 Pre 36.2 ± 1.1 35.1 ± 1.4 35.4 ± 1.2
 Post 35.2 ± 1.2 37.1 ± 1.1 34.0 ± 1.5
Po 2 (mm Hg)
 Pre 83.8 ± 2.1 84.5 ± 3.6 80.6 ± 2.0
 Post 88.5 ± 2.2 82.6 ± 2.5 87.8 ± 4.1
Body temperature (°C)
 Pre 38.1 ± 0.1 38.0 ± 0.2 38.1 ± 0.1
 Post 37.4 ± 0.2 38.0 ± 0.1 38.1 ± 0.2
Table 4.
 
Effects of Severing the Sympathetic Nerve on Baseline NBav, the Descending and Recovery Times, and Systemic Conditions
Table 4.
 
Effects of Severing the Sympathetic Nerve on Baseline NBav, the Descending and Recovery Times, and Systemic Conditions
Sympathetic Nerve Severed
(+) (−)
Baseline-NBav 9.6 ± 1.8* 8.3 ± 1.0
Descending Time (sec) 1.88 ± 0.51 1.72 ± 0.30
Recovery Time (sec) 2.03 ± 0.29 2.19 ± 0.18
FABPm (mm Hg) 92.5 ± 2.1 92.6 ± 2.3
Pulse Rate (/min) 272 ± 6 275 ± 7
pH 7.43 ± 0.01 7.42 ± 0.01
Pco 2 (mm Hg) 38.7 ± 1.2 39.4 ± 0.9
Po 2 (mm Hg) 96.1 ± 2.9 95.4 ± 2.3
Body temperature (°C) 37.0 ± 0.1 37.0 ± 0.1
Alm, B, Bill, A. (1972) The oxygen supply to the retina, II. Effects of high intraocular pressure and of increased arterial carbon dioxide tension on uveal and retinal blood flow in cats Acta Physiol Scand 84,306-319 [CrossRef] [PubMed]
Loebl, R, Loebl, M. (1977) Autoregulation of blood flow in the capillaries of the human macula Invest Ophthalmol Vis Sci 16,568-571 [PubMed]
Geijer, C, Bill, A. (1979) Effects of raised intraocular pressure on retinal, prelaminar, laminar, and retrolaminar optic nerve blood flow in monkeys Invest Ophthalmol Vis Sci 18,1030-1042 [PubMed]
Riva, CE, Sinclair, SH, Grunwald, JE. (1981) Autoregulation of retinal circulation in response to decrease of perfusion pressure Invest Ophthalmol Vis Sci 21,34-38 [PubMed]
Grunwald, JE, Sinclair, SH, Riva, CE. (1982) Autoregulation of the retinal circulation in response to decrease of intraocular pressure below normal Invest Ophthalmol Vis Sci 23,124-127 [PubMed]
Weinstein, JM, Funsch, D, Page, RB, et al (1982) Optic nerve blood flow and its regulation Invest Ophthalmol Vis Sci 23,640-645 [PubMed]
Sossi, N, Anderson, D. (1983) Effect of elevated intraocular pressure on blood flow: occurrence in cat optic nerve head studied with iodoantipyrine I 125 Arch Ophthalmol 101,98-101 [CrossRef] [PubMed]
Riva, CE, Cranstoun, SD, Petrig, BL. (1996) Effect of decreased ocular perfusion pressure on blood flow and the flicker-induced flow response in the cat optic nerve head Microvasc Res 52,258-269 [CrossRef] [PubMed]
Riva, CE, Hero, M, Titze, P, et al (1997) Autoregulation of human optic nerve head blood flow in response to acute changes in ocular perfusion pressure Graefes Arch Clin Exp Ophthalmol 235,618-626 [CrossRef] [PubMed]
Pillunat, LE, Anderson, DR, Knighton, RW, et al (1997) Autoregulation of human optic nerve head circulation in response to increased intraocular pressure Exp Eye Res 64,737-744 [CrossRef] [PubMed]
Pillunat, LE, Stodtmeister, R, Wilmanns, I. (1987) Pressure compliance of the optic nerve head in low tension glaucoma Br J Ophthalmol 71,181-187 [CrossRef] [PubMed]
Langham, ME. (1994) Ocular blood flow and vision in healthy and glaucomatous eyes Surv Ophthalmol 38(suppl),S161-S168 [CrossRef] [PubMed]
Tielsch, JM, Katz, J, Sommer, A, et al (1995) Hypertension, perfusion pressure, and primary open-angle glaucoma: a population-based assessment Arch Ophthalmol 113,216-221 [CrossRef] [PubMed]
Anderson, DR. (1996) Glaucoma, capillaries and pericytes. 1. Blood flow regulation Ophthalmologica 210,257-262 [CrossRef] [PubMed]
Prunte, C, Orgul, S, Flammer, J. (1998) Abnormalities of microcirculation in glaucoma: facts and hints Curr Opin in Ophthalmol 9,50-55
Landau, K, Winterkorn, JM, Mailloux, LU, et al (1996) 24-hour blood pressure monitoring in patients with anterior ischemic optic neuropathy Arch Ophthalmol 114,570-575 [CrossRef] [PubMed]
Potarazu, SV. (1997) Ischemic optic neuropathy: models for mechanism of disease Clin Neurosci 4,264-269 [PubMed]
Tomidokoro, A, Araie, M, Tamaki, Y, et al (1998) In vivo measurement of iridial circulation using laser speckle phenomenon Invest Ophthalmol Vis Sci 39,364-371 [PubMed]
Tamaki, Y, Araie, M, Kawamoto, E, et al (1995) Non-contact, two-dimensional measurement of tissue circulation in choroid and optic nerve head using laser speckle phenomenon Exp Eye Res 60,373-383 [CrossRef] [PubMed]
Tamaki, Y, Araie, M, Kawamoto, E, et al (1994) Noncontact, two-dimensional measurement of retinal microcirculation using laser speckle phenomenon Invest Ophthalmol Vis Sci 35,3825-3834 [PubMed]
Sugiyama, T, Utsumi, T, Azuma, I, et al (1996) Measurement of optic nerve head circulation: comparison of laser speckle and hydrogen clearance methods Jpn J Ophthalmol 40,339-343 [PubMed]
Tomita, K, Araie, M, Tamaki, Y, et al (1999) Effects of nilvadipine, a calcium antagonist, on rabbit ocular circulation and optic nerve head circulation in NTG subjects Invest Ophthalmol Vis Sci 40,1144-1151 [PubMed]
Tamaki, Y, Araie, M, Tomita, K, et al (1997) Real-time measurement of human optic nerve head and choroid circulation, using the laser speckle phenomenon Jpn J Ophthalmol 41,49-54 [CrossRef] [PubMed]
Bill, A. (1963) Blood pressure in the ciliary arteries of rabbits Exp Eye Res 2,20-24 [CrossRef] [PubMed]
Cioffi, G, Granstam, E, Alm, A. (2003) Ocular circulation Kaufman, P Alm, A eds. Adler’s Physiology of the Eye 10th ed. ,747-784 Mosby, Inc. St. Louis.
Kozma, C, Macklin, W, Cumminus, L, Mauer, R. (1974) Anatomy, physiology, and biochemistry of the rabbit Weisbroth, S Flatt, R Kraus, A eds. The Biology of the Laboratory Rabbit ,50-72 Academic Press New York.
Briers, J, Fercher, A. (1982) Retinal blood-flow visualization by means of laser speckle photography Invest Ophthalmol Vis Sci 22,255-259 [PubMed]
Hatta, S. (1993) Effects of intraocular pressure on the optic nerve head in albino rabbits [in Japanese] Nippon Ganka Gakkai Zasshi 97,181-189 [PubMed]
Takahashi, Y. (1995) Optic nerve head circulation in alloxan-induced diabetic rabbits [in Japanese] Nippon Ganka Gakkai Zasshi 99,166-172 [PubMed]
Koelle, J, Riva, C, Petrig, B, et al (1993) Depth of tissue sampling in the optic nerve head using laser Doppler flowmetry Laser Med Sci 8,49-54 [CrossRef]
Petrig, B, Riva, C, Hayreh, S. (1999) Laser Doppler flowmetry and optic nerve head blood flow Am J Ophthalmol 127,413-425 [CrossRef] [PubMed]
Kiel, JW. (1999) Modulation of choroidal autoregulation in the rabbit Exp Eye Res 69,413-429 [CrossRef] [PubMed]
Rosenthal, J. (1994) Nilvadipine: profile of a new calcium antagonist: an overview J Cardiovasc Pharmacol 24,S92-S107 [CrossRef] [PubMed]
Nakayama, K, Suzuki, S, Sugi, H. (1986) Physiological and ultrastructural studies on the mechanism of stretch-induced contractile activation in rabbit cerebral artery smooth muscle Jpn J Physiol 36,745-760 [CrossRef] [PubMed]
Coombes, JE, Hughes, AD, Thom, SA. (1999) Intravascular pressure-evoked changes in intracellular calcium [Ca2+]i and tone in rat mesenteric and rabbit cerebral arteries in vitro J Hum Hypertens 13,855-858 [CrossRef] [PubMed]
Haws, CW, Heistad, DD. (1984) Effects of nimodipine on cerebral vasoconstrictor responses Am J Physiol 247,H170-H176 [PubMed]
Tokuma, Y, Sekiguchi, M, Niwa, T, et al (1988) Pharmacokinetics of nilvadipine, a new dihydropyridine calcium antagonist, in mice, rats, rabbits and dogs Xenobiotica 18,21-28 [CrossRef]
Terakawa, M, Tokuma, Y, Shishido, A, et al (1987) Pharmacokinetics of nilvadipine in healthy volunteers J Clin Pharmacol 27,111-117 [CrossRef] [PubMed]
Koller, A, Huang, A, Sun, D, et al (1995) Exercise training augments flow-dependent dilation in rat skeletal muscle arterioles: role of endothelial nitric oxide and prostaglandins Circ Res 76,544-550 [CrossRef] [PubMed]
Ueeda, M, Silvia, SK, Olsson, RA. (1992) Nitric oxide modulates coronary autoregulation in the guinea pig Circ Res 70,1296-1303 [CrossRef] [PubMed]
Sugiyama, T, Oku, H, Ikari, S, et al (2000) Effect of nitric oxide synthase inhibitor on optic nerve head circulation in conscious rabbits Invest Ophthalmol Vis Sci 41,1149-1152 [PubMed]
Rees, DD, Palmer, RM, Moncada, S. (1989) Role of endothelium-derived nitric oxide in the regulation of blood pressure Proc Natl Acad Sci USA 86,3375-3378 [CrossRef] [PubMed]
Gidday, JM, Zhu, Y. (1995) Nitric oxide does not mediate autoregulation of retinal blood flow in newborn pig Am J Physiol 269,H1065-H1072 [PubMed]
Buerk, DG, Riva, CE, Cranstoun, SD. (1996) Nitric oxide has a vasodilatory role in cat optic nerve head during flicker stimuli Microvasc Res 52,13-26 [CrossRef] [PubMed]
Buerk, DG, Riva, CE. (1998) Vasomotion and spontaneous low-frequency oscillations in blood flow and nitric oxide in cat optic nerve head Microvasc Res 55,103-112 [CrossRef] [PubMed]
Treister, G, Barany, EH. (1970) Mydriasis and intraocular pressure decrease in the conscious rabbit after unilateral superior cervical ganglionectomy Invest Ophthalmol 9,331-342 [PubMed]
Sears, M, Sherk, T. (1963) Supersensitivity of aqueous outflow resistance in rabbits after sympathetic denervation Nature 167,387-388
Langham, ME. (1965) The response of the pupil and intraocular pressure of conscious rabbits to adrenergic drugs following unilateral superior cervical ganglionectomy Exp Eye Res 4,381-389 [CrossRef] [PubMed]
Ehinger, B. (1966) Adrenergic nerves to the eye and to related structures in man and the cynomolgus monkey Invest Ophthalmol 5,42-52
Laties, AM. (1967) Central retinal artery innervation: absence of adrenergic innervation to the intraocular branches Arch Ophthalmol 77,405-409 [CrossRef] [PubMed]
Furukawa, H. (1987) Autonomic innervation of preretinal blood vessels of the rabbit Invest Ophthalmol Vis Sci 28,1752-1760 [PubMed]
Alm, A, Bill, A. (1973) The effect of stimulation of the sympathetic chain on retinal oxygen tension and uveal, retinal and cerebral blood flow in cats Acta Physiol Scand 88,84-96 [CrossRef] [PubMed]
Weiter, J, Scachar, R, Ernest, J. (1973) Control of intraocular blood flow. II. Effects of sympathetic tone Invest Ophthalmol 12,332-334 [PubMed]
Linder, J. (1982) Effects of cervical sympathetic stimulation on cerebral and ocular blood flows during hemorrhagic hypotension and moderate hypoxia Acta Physiol Scand 114,379-386 [CrossRef] [PubMed]
Sugiyama, K, Bacon, DR, Morrison, JC, et al (1992) Optic nerve head microvasculature of the rabbit eye Invest Ophthalmol Vis Sci 33,2251-2261 [PubMed]
Figure 1.
 
Time parameter analysis of NBav in l-NAME and indomethacin experiments. Approximately 5 seconds after the NBav recording was started, the IOP was increased to 50 mm Hg (arrow) and the recording continued for the next 25 seconds. NBav is plotted every 0.5 second in this example. For explanation of descending time (T 1) and recovery time (T 2), see the Methods section.
Figure 1.
 
Time parameter analysis of NBav in l-NAME and indomethacin experiments. Approximately 5 seconds after the NBav recording was started, the IOP was increased to 50 mm Hg (arrow) and the recording continued for the next 25 seconds. NBav is plotted every 0.5 second in this example. For explanation of descending time (T 1) and recovery time (T 2), see the Methods section.
Figure 2.
 
Relation between change in NBONH and that in ONH blood flow rate measured by the hydrogen gas clearance method. A significant correlation was found (Spearman’s rank correlation coefficient, R s = 0.83, P < 0.001).
Figure 2.
 
Relation between change in NBONH and that in ONH blood flow rate measured by the hydrogen gas clearance method. A significant correlation was found (Spearman’s rank correlation coefficient, R s = 0.83, P < 0.001).
Figure 3.
 
Time course of changes in the relative NBONH (A) compared with the baseline value (% NBONH) and OPP (B) for 60 minutes after change in IOP from 20 mm Hg to 40, 50, or 60 mm Hg in rabbits. Data are expressed as the average ± SE (n = 6, each). Increasing IOP showed little effect on NBONH in the groups in which IOP2 was 40 or 50 mm Hg, whereas NBONH was significantly decreased compared with the initial value in rabbits in which IOP was increased to 60 mm Hg (Wilcoxon signed rank test, P < 0.05).
Figure 3.
 
Time course of changes in the relative NBONH (A) compared with the baseline value (% NBONH) and OPP (B) for 60 minutes after change in IOP from 20 mm Hg to 40, 50, or 60 mm Hg in rabbits. Data are expressed as the average ± SE (n = 6, each). Increasing IOP showed little effect on NBONH in the groups in which IOP2 was 40 or 50 mm Hg, whereas NBONH was significantly decreased compared with the initial value in rabbits in which IOP was increased to 60 mm Hg (Wilcoxon signed rank test, P < 0.05).
Figure 4.
 
Time course of changes in the relative NBcho (A) compared with baseline (% NBcho) and OPP (B) for 60 minutes after change in IOP from 20 to 50 mm Hg. Data are expressed as the average ± SE (n = 4).
Figure 4.
 
Time course of changes in the relative NBcho (A) compared with baseline (% NBcho) and OPP (B) for 60 minutes after change in IOP from 20 to 50 mm Hg. Data are expressed as the average ± SE (n = 4).
Figure 5.
 
An example of the recordings for 25 seconds of NBav and IOP before and after change in IOP from 20 to 50 mm Hg (arrow).
Figure 5.
 
An example of the recordings for 25 seconds of NBav and IOP before and after change in IOP from 20 to 50 mm Hg (arrow).
Figure 6.
 
Time course of changes for 25 seconds in the relative NBav compared with baseline (% NBav) in the ONH. The NBav is expressed at intervals of 0.625 second ± SE. IOP was changed from 20 mm Hg to 50 (A) or 60 (B) mm Hg at time 0 (arrow).
Figure 6.
 
Time course of changes for 25 seconds in the relative NBav compared with baseline (% NBav) in the ONH. The NBav is expressed at intervals of 0.625 second ± SE. IOP was changed from 20 mm Hg to 50 (A) or 60 (B) mm Hg at time 0 (arrow).
Figure 7.
 
Time course of changes for 25 seconds in the relative NBav compared with baseline (% NBav) in the choroid. The NBav ± SE is shown at intervals of 0.625 second. IOP was changed from 20 to 50 mm Hg at time 0 (arrow).
Figure 7.
 
Time course of changes for 25 seconds in the relative NBav compared with baseline (% NBav) in the choroid. The NBav ± SE is shown at intervals of 0.625 second. IOP was changed from 20 to 50 mm Hg at time 0 (arrow).
Figure 8.
 
Time course of changes in the relative NBONH compared with (A) baseline (%NBONH), (B) FABPm, and (C) OPP for 60 minutes after change in IOP from IOP1 to IOP2 in nilvadipine-treated and vehicle-treated rabbits. Data are expressed as the average ± SE (n = 6, each).
Figure 8.
 
Time course of changes in the relative NBONH compared with (A) baseline (%NBONH), (B) FABPm, and (C) OPP for 60 minutes after change in IOP from IOP1 to IOP2 in nilvadipine-treated and vehicle-treated rabbits. Data are expressed as the average ± SE (n = 6, each).
Figure 9.
 
Time course of changes in the relative NBav compared with baseline (%NBav) obtained for 25 seconds after change in IOP from IOP1 to IOP2, in nilvadipine-treated rabbits and vehicle-treated rabbits. Data are expressed as the average ± SE (n = 6, each).
Figure 9.
 
Time course of changes in the relative NBav compared with baseline (%NBav) obtained for 25 seconds after change in IOP from IOP1 to IOP2, in nilvadipine-treated rabbits and vehicle-treated rabbits. Data are expressed as the average ± SE (n = 6, each).
Table 1.
 
IOP and Systemic Parameters in the Nilvadipine- or Vehicle-Treated Rabbits during a 60-Minute Change in NBONH after an Increase in IOP from IOP1 to IOP2
Table 1.
 
IOP and Systemic Parameters in the Nilvadipine- or Vehicle-Treated Rabbits during a 60-Minute Change in NBONH after an Increase in IOP from IOP1 to IOP2
Nilvadipine Vehicle
IOP1 (mm Hg) 10.1 ± 0.1* 20.1 ± 0.2
IOP2 (mm Hg) 40.3 ± 0.4* 50.2 ± 0.3
FABPm (mm Hg) 87.9 ± 1.2 98.1 ± 2.5
Pulse rate (min) 271 ± 7 270 ± 4
pH 7.42 ± 0.01 7.43 ± 0.01
Pco 2 (mm Hg) 38.6 ± 0.4 40.2 ± 0.6
Po 2 (mm Hg) 87.2 ± 1.3 86.5 ± 2.1
Body temperature (°C) 37.1 ± 0.1 37.2 ± 0.1
Table 2.
 
Baseline NBav, Descending Time, and Recovery Time before and after the Administration of l-NAME, Indomethacin, or Physiological Saline
Table 2.
 
Baseline NBav, Descending Time, and Recovery Time before and after the Administration of l-NAME, Indomethacin, or Physiological Saline
l-NAME Indomethacin Saline
Number of rabbits 10 9 10
Baseline-NBav
 Pre 8.0 ± 0.3 7.9 ± 0.5 8.0 ± 0.4
 Post 7.4 ± 0.3* 7.5 ± 0.5 8.2 ± 0.5
 Change −0.5 ± 0.3 −0.3 ± 0.6 0.2 ± 0.5
Descending Time (sec)
 Pre 1.69 ± 0.19 1.88 ± 0.17 1.75 ± 0.40
 Post 1.93 ± 0.24 2.03 ± 0.16 1.44 ± 0.19
 Change 0.25 ± 0.25 0.14 ± 0.17 −0.31 ± 0.50
Recovery Time (sec)
 Pre 2.56 ± 0.33 2.18 ± 0.31 2.00 ± 0.20
 Post 3.69 ± 0.51 2.27 ± 0.20 2.38 ± 0.24
 Change 1.13 ± 0.33, ‡ 0.07 ± 0.22 0.38 ± 0.28
Table 3.
 
Systemic Parameters before and after the Administration of l-NAME, Indomethacin, or Saline
Table 3.
 
Systemic Parameters before and after the Administration of l-NAME, Indomethacin, or Saline
l-NAME Indomethacin Saline
FABPm (mm Hg)
 Pre 92.2 ± 2.8 96.4 ± 2.2 95.6 ± 3.4
 Post 96.3 ± 3.2 101.5 ± 4.9 102.3 ± 3.2
Pulse Rate (min)
 Pre 247 ± 8 250 ± 6 259 ± 8
 Post 250 ± 10 257 ± 8 240 ± 8
pH
 Pre 7.38 ± 0.01 7.41 ± 0.02 7.39 ± 0.01
 Post 7.38 ± 0.01 7.38 ± 0.02 7.44 ± 0.02
Pco 2 (mm Hg)
 Pre 36.2 ± 1.1 35.1 ± 1.4 35.4 ± 1.2
 Post 35.2 ± 1.2 37.1 ± 1.1 34.0 ± 1.5
Po 2 (mm Hg)
 Pre 83.8 ± 2.1 84.5 ± 3.6 80.6 ± 2.0
 Post 88.5 ± 2.2 82.6 ± 2.5 87.8 ± 4.1
Body temperature (°C)
 Pre 38.1 ± 0.1 38.0 ± 0.2 38.1 ± 0.1
 Post 37.4 ± 0.2 38.0 ± 0.1 38.1 ± 0.2
Table 4.
 
Effects of Severing the Sympathetic Nerve on Baseline NBav, the Descending and Recovery Times, and Systemic Conditions
Table 4.
 
Effects of Severing the Sympathetic Nerve on Baseline NBav, the Descending and Recovery Times, and Systemic Conditions
Sympathetic Nerve Severed
(+) (−)
Baseline-NBav 9.6 ± 1.8* 8.3 ± 1.0
Descending Time (sec) 1.88 ± 0.51 1.72 ± 0.30
Recovery Time (sec) 2.03 ± 0.29 2.19 ± 0.18
FABPm (mm Hg) 92.5 ± 2.1 92.6 ± 2.3
Pulse Rate (/min) 272 ± 6 275 ± 7
pH 7.43 ± 0.01 7.42 ± 0.01
Pco 2 (mm Hg) 38.7 ± 1.2 39.4 ± 0.9
Po 2 (mm Hg) 96.1 ± 2.9 95.4 ± 2.3
Body temperature (°C) 37.0 ± 0.1 37.0 ± 0.1
Copyright 2003 The Association for Research in Vision and Ophthalmology, Inc.
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