April 2005
Volume 46, Issue 4
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Physiology and Pharmacology  |   April 2005
Time Course of Changes in Optic Nerve Head Circulation after Acute Reduction in Intraocular Pressure
Author Affiliations
  • Jun Takayama
    From the Eye Clinic, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan; and the
  • Atsuo Tomidokoro
    Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
  • Yasuhiro Tamaki
    Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
  • Makoto Araie
    Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
Investigative Ophthalmology & Visual Science April 2005, Vol.46, 1409-1419. doi:10.1167/iovs.04-1082
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      Jun Takayama, Atsuo Tomidokoro, Yasuhiro Tamaki, Makoto Araie; Time Course of Changes in Optic Nerve Head Circulation after Acute Reduction in Intraocular Pressure. Invest. Ophthalmol. Vis. Sci. 2005;46(4):1409-1419. doi: 10.1167/iovs.04-1082.

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      © 2015 Association for Research in Vision and Ophthalmology.

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Abstract

purpose. To study the time course of changes in circulation in the optic nerve head (ONH) after acute reduction in intraocular pressure (IOP) and to evaluate the effects of a calcium antagonist, a nitric oxide synthetase (NOS) inhibitor, indomethacin, and sympathetic nerve amputation on the changes in ONH circulation after reduction of IOP.

methods. In anesthetized albino rabbits, acute reduction of IOP (acute increase in ocular perfusion pressure [OPP]) was manometrically achieved and normalized blur (NB), a quantitative index of tissue blood velocity obtained with the laser speckle method, was serially monitored for 30 seconds and 60 minutes. The effects of systemic administration of 1 μg/kg per hour nilvadipine (a calcium antagonist), 300 μg/kg Nω-nitro-l-arginine (l-NAME, a nonselective NOS inhibitor), and 5 mg/kg indomethacin or sympathetic nerve amputation on the changes in NB after reduction of IOP were studied.

results. During changes in IOP from 10 to 40 mm Hg and then back to 10 mm Hg, NB exhibited no significant change. During changes in IOP from 10 to 60 mm Hg and then back to 10 mm Hg, NB initially decreased with an increase in IOP to 60 mm Hg and then increased to baseline level when IOP was returned to 10 mm Hg. In the nilvadipine-treated rabbits, during changes in IOP from 10 to 40 mm Hg and back to 10 mm Hg and during the changes from 10 to 60 mm Hg and back to 10 mm Hg, NB decreased with increase in IOP to 40 or 60 mm Hg and then increased to slightly above the baseline when IOP returned to 10 mm Hg. l-NAME, indomethacin, and sympathetic nerve amputation each had little effect on the time course of change in NB.

conclusions. ONH circulation was stably maintained after reduction of IOP from 40 to 10 mm Hg but not after that from 60 to 10 mm Hg. The changes in NB after reduction of IOP occurred quickly and were partially impaired with a calcium antagonist, but not with the NOS inhibitor, indomethacin, or sympathetic nerve amputation. These findings suggest the importance of vascular smooth muscle in maintaining stable ONH circulation against reduction of IOP in a fashion nearly independent of NO, endogenous prostaglandins, and the sympathetic nervous system.

Blood flow in the optic nerve head (ONH) as well as the optic nerve and retina is stably maintained despite certain changes in ocular perfusion pressure (OPP), by a function referred to as autoregulation. 1 2 3 4 5 6 7 8 9 10 Insufficient blood supply to the optic nerve and ONH is thought to play at least some role in the development and progression of glaucoma. 11 12 13 14 15 Autoregulation probably plays a key role in determining the relationship between intraocular pressure (IOP) and ONH circulation in glaucoma. 
In previous studies of autoregulation in the ONH, OPP was altered by changing systemic blood pressure 3 4 9 or by increasing IOP. 1 2 5 6 7 8 10 11 However, because artificial changes in systemic blood pressure may influence regulation of ONH circulation, interpretation of these results requires caution. Other investigators have studied ONH autoregulation when IOP was increased. 1 2 5 6 7 8 10 11 To our knowledge, however, there have been no studies in which researchers have examined it when IOP is decreased. It is difficult to extend results obtained with the former approach to the latter, because the resting and reactive phases of ONH circulation are regulated in complex fashion by various vasodilatative or vasoconstrictive factors. Clinically, determination of the changes in ONH circulation after decrease in IOP is important for understanding the effects of IOP reduction with surgery or medical treatment in patients with glaucoma. 
The laser speckle method has recently been developed for noninvasive assessment of tissue circulation in living eyes. It yields a quantitative index of blood flow velocity, normalized blur (NB), which has been confirmed to correlate well with blood flow determined with the hydrogen gas clearance method in the ONH. 10 16 17 18 19 With this method, continuous monitoring of ONH circulation can be performed with high temporal resolution. 20 In the present study, using the laser speckle method, we examined the time course of changes in ONH circulation after acute reduction of IOP in rabbit eyes. We also examined the effects of a calcium antagonist, a nitric oxide synthetase (NOS) inhibitor, indomethacin, and sympathetic nerve amputation on the changes in ONH circulation after acute reduction of IOP. 
Methods
Animals
In this series of experiments, albino rabbits weighing 2.0 to 2.5 kg were used and handled in accordance with the ARVO Statement for 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, Po 2, Pco 2, and pH of arterial blood. The mean femoral arterial blood pressure (FABPm) was calculated as  
\[\mathrm{FABP}_{\mathrm{m}}\ {=}\ \mathrm{FABP}_{\mathrm{d}}\ {+}\ 1/3(\mathrm{FABP}_{\mathrm{s}}\ {-}\ \mathrm{FABP}_{\mathrm{d}})(\mathrm{mm\ Hg})\]
where FABPd and FABPs are the diastolic and systolic femoral arterial blood pressures, respectively. OPP was calculated as  
\[\mathrm{OPP}\ {=}\ \mathrm{FABP}_{\mathrm{m}}\ {-}\ \mathrm{IOP}\ {-}\ 14(\mathrm{mm\ Hg})\]
where −14 compensates for the discrepancy in pressures between the femoral artery and the ophthalmic artery in a rabbit in prone position. 21 22  
The animal was placed in a stereotaxic device equipped with a heating pad, and body temperature was monitored rectally. In both eyes, the pupil was dilated with 1 drop of 0.4% tropicamide at least 20 minutes before measurements. In a randomly chosen eye of each rabbit, 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 humor (Opeguard MA; Senju Pharmaceutical Co., Osaka, Japan), which were mounted at different heights. By alternating the reservoirs using the turncock, we could change IOP acutely while keeping the water surface placid in the bottles. The other needle was connected to a pressure transducer to monitor the actual IOP continuously (Fig. 1) . Rabbits that exhibited systemic parameters outside the normal ranges for healthy rabbits 23 after general anesthesia were excluded for the experiments described below. 
Evaluation of ONH Circulation
Circulation in the ONH was evaluated using the laser speckle method, details of which have been described previously 6 24 25 and are briefly summarized herein. The apparatus used for 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 of speckle intensity and the speckle intensity of successive scannings was calculated, and the ratio of average speckle intensity to this difference was defined as NB. The average NB level in the widest available rectangular area free of visible vessels is calculated as NBav. An NBav measurement took 0.125 second, and successive results for 1 second were averaged and the result referred to as NBONH
The coefficients of reproducibility of repeated measurements of NBONH at 5-minute and 24-hour intervals were reported to be 7.5% ± 2.0% (mean ± SEM, n = 12 eyes) and 11.8% ± 3.1%, respectively, 6 and the coefficient of reproducibility between two examiners was 7.8% ± 1.0% (n = 12 eyes; Takayama J, unpublished data, 2004). 
Time Course of Change in NB after IOP Reduction
The time course of changes in NBav for 30 seconds or in NBONH for 60 minutes after reduction of IOP from 40 or 60 to 10 mm Hg was studied. After IOP was initially set at 10 mm Hg and NBONH was measured, IOP was adjusted at 40 mm Hg for 10 minutes to confirm that stable NBONH results were obtained at 1-minute intervals. 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 decreased from 40 to 10 mm Hg by changing the reservoirs and NBav recording was continued for the next 25 seconds. 
In a separate group of rabbits, after IOP was initially set at 10 mm Hg and NBONH was measured, IOP was adjusted to 40 mm Hg and NBONH was serially monitored for 10 minutes. Subsequently, the IOP was decreased to 10 mm Hg by changing the reservoirs. NBONH was serially monitored at 1-minute intervals for the first 15 minutes and 30, 45, and 60 minutes after the IOP change. As a control, NBONH was serially measured at a constant IOP of 40 mm Hg over 60 minutes at the same intervals. The same protocol was performed in other rabbits, but IOP was reduced from 60 to 10 mm Hg or kept constant at 60 mm Hg. 
Effects of a Calcium Antagonist on NB
The effects of nilvadipine (Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan), a dihydropyridine calcium antagonist, on the changes in NBONH after reduction of IOP from 40 to 10 mm Hg or from 60 to 10 mm Hg were studied. Nilvadipine was continuously administered at a rate of 1 μg/kg per hour through the auricle vein of rabbits prepared as described earlier. After IOP was initially set at 10 mm Hg and NBONH was measured, IOP was adjusted to 40 mm Hg and NBONH was serially monitored for 10 minutes. Subsequently, IOP was decreased to 10 mm Hg by changing the reservoirs. NBONH was then serially monitored at 1-minute intervals for the first 15 minutes and 30, 45, and 60 minutes after the change in IOP. As a control, the same protocol was performed using the same volume of vehicle solution in a separate group of rabbits. Since systemic arterial pressure decreased by approximately 10 mm Hg during nilvadipine treatment in a preliminary experiment, after IOP was initially set at 20 mm Hg and NBONH was measured, IOP was decreased from 50 to 20 mm Hg in the vehicle-treated rabbits to make OPP the same as in the nilvadipine-treated rabbits. In other groups of rabbits, the same protocol was performed with nilvadipine-treated rabbits in which IOP was decreased from 60 to 10 mm Hg and vehicle-treated rabbits in which IOP was decreased from 70 to 20 mm Hg. One investigator measured NBONH and another monitored IOP and systemic blood pressure. Both were masked to 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 on NB
The effects of l-NAME, a nonselective NOS inhibitor, and indomethacin on the changes in NBONH after reduction of IOP from 40 to 10 mm Hg or from 60 to 10 mm Hg were studied. 
Thirty minutes after a bolus injection of 30 mg/kg l-NAME, 5 mg/kg indomethacin, or physiological saline, after IOP was initially set at 10 mm Hg, NBONH was measured. IOP was adjusted to 40 mm Hg, and NBONH was serially monitored for 10 minutes. Subsequently, IOP was decreased to 10 mm Hg by changing the reservoirs, and NBONH was serially measured at 1-minute intervals for the first 15 minutes and at 30, 45, and 60 minutes after the change in IOP. The volumes of the solutions of l-NAME, indomethacin, and physiological saline were equal. In another group of rabbits, the same protocol was performed with reduction of IOP from 60 to 10 mm Hg. One investigator measured NBONH and another monitored IOP and systemic blood pressure. Both were masked to treatment with l-NAME, indomethacin, or physiological saline in each rabbit, and each was masked to the results obtained by the other. 
Effects of Sympathetic Nerve Amputation on NB
The effects of sympathetic nerve amputation on the changes in NBONH after IOP reduction from 40 to 10 mm Hg or from 60 to 10 mm Hg were studied. After systemic preparation the same as for the drugs but without pupillary dilation, the vagosympathetic nerve trunk was unilaterally exposed and confirmed by induction of ipsilateral miosis with electric stimulation of the trunk. Thereafter, the nerve trunk was sectioned with surgical scissors. Approximately, 1 hour later, the pupil was dilated with tropicamide, and the anterior chamber was cannulated to control and monitor IOP in the same fashion as described earlier. After IOP was initially set at 10 mm Hg and NBONH was measured, IOP was adjusted to 40 or 60 mm Hg, and NBONH was serially monitored for 10 minutes. Subsequently, IOP was decreased to 10 mm Hg and NBONH was serially measured at 1-minute intervals for the first 15 minutes and at 30, 45, and 60 minutes after the change in IOP. As a control, in other rabbits similarly prepared, the vagosympathetic nerve was exposed but not sectioned, and the same protocol regarding IOP reduction and NBONH measurements was performed. The investigator who measured NBONH was masked to whether the sympathetic nerve was or was not amputated. 
Results
Time Course of Change in NB after IOP Reduction
Typical recordings for 30 seconds of IOP and NBav after the changes in reservoirs from that corresponding to an IOP of 40 or 60 mm Hg (Fig. 2)to that corresponding to an IOP of 10 mm Hg are shown. IOP gradually decreased from 40 to 10 mm Hg over approximately 20 seconds, but NBav exhibited no change (Fig. 2 , top). IOP gradually decreased from 60 to 10 mm Hg over approximately 20 seconds, whereas NBav gradually increased by approximately 10% of the baseline (Fig. 2 , bottom). 
In the experiments performed for 60 minutes, NBONH was stable in rabbits in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg (Fig. 3 , n = 6 each). In rabbits in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg, NBONH decreased by approximately 20% when IOP was increased to 60 mm Hg and then recovered to a level slightly above the baseline NBONH (i.e., the value initially obtained at an IOP of 10 mm Hg) when IOP returned to 10 mm Hg (Fig. 4 , n = 4 each). An early part of these reactions in NBONH when IOP was increased was consistent with findings of our previous study. 10  
Effects of a Calcium Antagonist on NB
Baseline NBONH was significantly higher in the nilvadipine-treated rabbits (nilvadipine group, n = 10) than in the vehicle-treated rabbits (control group, n = 10; 14.1 ± 1.2 vs. 11.9 ± 2.1, P = 0.0147, Mann-Whitney test), whereas there was no difference in baseline OPP between these groups (35.3 ± 3.3 mm Hg vs. 35.4 ± 2.0 mm Hg, P > 0.7). 
In the experiment in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg in the nilvadipine group or from 20 to 50 to 10 mm Hg in the control group, in the nilvadipine group NBONH changed in accordance with the changes in OPP except for a slight overshoot after decrease in IOP from 10 to 40 mm Hg. In the control group, NBONH exhibited no remarkable change (Fig. 5)
In the experiment in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg in the nilvadipine group or from 20 to 70 mm Hg and then to 20 mm Hg in the control group, NBONH in both groups changed in accordance with the changes in OPP. When IOP was increased to 60 or 70 mm Hg, NBONH tended to be greater in the nilvadipine group than in the control group (12.84 ± 0.18 vs. 9.82 ± 0.47, P = 0.068), whereas the percentage of reduction from baseline tended to be greater in the nilvadipine group (Fig. 6 , top). When NBONH was normalized to the value obtained just before decrease of IOP from 60 to 10 mm Hg, the percentage of change in NBONH after decrease in IOP was significantly greater in the nilvadipine group (P = 0.0424, repeated-measures ANOVA; Fig. 6 , bottom). In both series of experiments, OPP did not differ significantly between the nilvadipine and control groups (Figs. 5 6 , top). 
Systemic parameters in the rabbits were within the normal ranges for rabbits 23 and did not change significantly during the experiment (Table 1)
Effects of an NOS Inhibitor or Indomethacin on NB
Baseline NBONH and OPP during the experiment did not differ significantly among the l-NAME-treated, indomethacin-treated, and control rabbits (P > 0.6, ANOVA, n = 10 each; Table 2 , Figs. 7 8 ). 
In the experiment in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg, in each of the groups, NBONH exhibited little change, either when IOP was increased to 40 mm Hg or when it was returned to 10 mm Hg (Fig. 7) . In the experiment in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg, NBONH changed in accordance with the changes in OPP in each of the groups, and there were no differences in changes in NBONH among the three groups (P > 0.6, repeated-measures ANOVA; Fig. 8 ). 
Systemic parameters in the rabbits were within the normal ranges for rabbits 23 and did not change significantly during the experiment (Table 2)
Effects of Sympathetic Nerve Amputation
During the experiment, neither baseline NBONH nor OPP differed significantly between eyes with and without sympathetic nerve amputation (P > 0.6, ANOVA; Table 3 , Figs. 9 10 ). 
In the experiment in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg, NBONH exhibited little change during the 60-minute observation after reduction of IOP (Fig. 9) . In the experiment in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg, NBONH changed in accordance with the changes in OPP, and there were no differences in changes in NBONH between the eyes (P > 0.6, repeated-measures ANOVA; Fig. 10 ). 
Systemic parameters in the rabbits were within the normal ranges for rabbits 23 and did not change significantly during the experiment (Table 3)
Discussion
The laser speckle method has been developed for noninvasive evaluation of tissue blood flow in living eyes. 24 26 NB is determined by this method, primarily as a quantitative index of tissue blood velocity, but correlates well with the rate of blood flow in the iris, retina, and choroid, 6 24 25 since it reflects in part the total number of red blood cells in the tissues and “flow” parallels the fourth power of velocity if other conditions including vessel diameter are unchanged. 27 The rabbit NBONH exhibited a good correlation with rate of blood flow obtained using the hydrogen gas clearance method and noting the changes in NB and blood flow after inhalation of CO2 16 ; systemic administration of endothelin-1, 16 nilvadipine, 17 or lomerizine (a calcium antagonist) 19 ; or acute increase in IOP. 10  
In our previous study, in which experimental conditions were similar to those in the present study, 10 relative changes in NBONH and those in blood flow determined with the hydrogen gas clearance method correlated well when IOP was acutely increased from 20 to 40, 50, or 60 mm Hg. In the hydrogen gas clearance method, a needle electrode is inserted into the ONH tissue to a depth of approximately 0.7 mm, and Koelle et al. 28 reported that an infrared laser (wavelength 811 nm, power 2 mW) penetrated the cat optic nerve to a depth of approximately 1 mm. These findings suggest that the present NBONH results obtained by the laser speckle method probably reflect blood flow changes, not only in the superficial layers but also in the deeper layers, such as the lamina scleralis in the rabbit ONH. 
The time course of blood flow change in the rabbit ONH after reduction of IOP (i.e., OPP increase) has been documented for the first time in the present study. When OPP was increased from approximately 40 to 70 mm Hg by reduction of IOP from 40 to 10 mm Hg, NB was stable during 25-second (Fig. 2 , top) and 60-minute (Fig. 2 , bottom) follow-up periods after the change in OPP. No increase, not even a temporary one, was observed in NB just after reduction of IOP was observed in serial measurements at 0.125-second intervals (Fig. 2 , top). When the reservoirs were changed from that placed at a height corresponding to an IOP of 40 or 60 mm Hg to that corresponding to an IOP of 10 mm Hg (Fig. 1) , actual reduction of IOP required approximately 20 seconds (Fig. 2) , which suggests that autoregulatory response to OPP increase is completed within a short period (<20 seconds). 
In contrast, when OPP was increased from approximately 20 to 70 mm Hg by reduction of IOP from 60 to 10 mm Hg, NBONH significantly increased (∼20% of baseline; Fig. 4 ). Results in studies have indicated that circulation in rabbit ONH 6 10 and cat optic nerve 4 5 did not remain constant when IOP was increased to a level of 50 to 60 mm Hg, a finding confirmed in the present study. Moreover, the findings in the present study for the first time suggest that the upper limit of IOP for effective autoregulatory response in ONH circulation to an acute decrease in IOP can be estimated to be between 40 and 60 mm Hg in rabbit eyes, which is a phenomenon reciprocal to that against and acute increase in IOP. 
We investigated the effects of continuous administration of nilvadipine on ONH circulation after IOP reduction. Nilvadipine is a dihydropyridine calcium antagonist, blocks L-type calcium channels, and is relatively selective for the cerebral arteries. 29 Calcium antagonists reduce influx of Ca2+ into vascular smooth muscle and usually increase peripheral circulation. Many types of calcium antagonists abolish or attenuate stretch-induced contraction of isolated vascular smooth muscle, including that in rabbit cerebral arteries. 30 31 Autoregulation of cerebral blood flow against increase in arterial pressure of 40 mm Hg in cats and monkeys was attenuated by a calcium antagonist (nimodipine). 32 However, no previous studies have been undertaken to investigate the effects of calcium antagonists on the change in circulation after reduction of IOP or increase in OPP in the ONH or other ocular tissues. 
In the present study, the changes in NBONH when OPP was changed from 65 to 35 and then returned to 65 mm Hg differed between the nilvadipine and control groups (Fig. 5) . NBONH changed by approximately 20% of baseline, corresponding to the changes in OPP between 35 and 65 mm Hg (∼45% change) in the nilvadipine group, suggesting that the vascular system in the ONH tissue behaves partly, but not completely, as a passive bed to change in OPP after administration of a calcium antagonist and that other factors also participate in maintenance of ONH circulation. Just after an increase in OPP from 35 to 65 mm Hg, NBONH in the nilvadipine group exhibited a slight overshoot of baseline, suggesting the presence of decreased vascular resistance due to use of a calcium antagonist. 
In the experiment in which OPP was changed from 60 to 10 mm Hg and then returned to 60 mm Hg, the trough level of %NBONH at an OPP of 10 mm Hg appeared to be lower in the nilvadipine group than in the control group (Fig. 6 , top). Because the baseline NBONH was higher in the nilvadipine group, however, the troughs of NBONH itself were similar in the two groups. When NBONH was normalized to the level obtained just before the increase in OPP to 60 mm Hg, the percentage change in NBONH after the increase in OPP was significantly greater in the nilvadipine-treated rabbits, also suggesting the presence of a partially passive vascular bed in the ONH (Fig. 6 , bottom). 
In the present study, nilvadipine was continuously administered through the auricle vein to maintain a stable vasodilatative effect. It is known that nilvadipine’s vasodilatative effect on the peripheral vessels does not directly follow its blood concentration, because it binds receptors tightly as a result of its high lipophilicity. Nilvadipine can decrease systemic arterial pressure with an optimum concentration between 0.1 and 10 μg/kg, and its effect persists for at least 1 hour in animal experiments. 33 We therefore used a continuous administration of 1 μg/kg per hour nilvadipine in the present study. Although direct comparison of results of continuous intravenous and oral administration is usually difficult, the maximum blood concentration after clinical oral administration of a 4-mg tablet of nilvadipine in normal humans is 3.5 ng/mL, 34 which corresponds roughly to that after a bolus administration of 0.3 μg/kg nilvadipine in rabbits. 33  
l-NAME, a nonselective inhibitor of NO synthesis, and indomethacin, an inhibitor of synthesis of prostaglandins including prostacyclin, had no significant effects on stable maintenance of ONH circulation against the increase in OPP induced by IOP reduction. NO and prostacyclin are released from the vascular endothelium when sheer stress changes, 35 36 and they play vital roles in local control of vascular tone. The doses of l-NAME and indomethacin used in this study were equivalent to or larger than those in previous studies in which vasoactive effects of these agents were found in rabbits. 18 37 38 The present findings suggest that production of NO and endogenous prostaglandins does not play a significant role in the response to the acute increase in OPP induced by reduction of IOP in rabbit ONH. 
Sympathetic nerves innervate the retinal arteries, not only before but also beyond the lamina scleralis in rabbit ONH. 39 However, the effects of sympathetic nerve amputation on blood flow in the ONH or retina are still unclear. A previous study suggested an increase in cat retinal blood flow after sympathectomy, 40 whereas others found no significant effects of this procedure on blood flow in the retina and optic nerve of cats 41 and monkeys. 42 In the present study, NBONH did not differ significantly between eyes with and without sympathetic nerve amputation, suggesting that sympathetic nerve amputation has no effect on rabbit ONH circulation, not only when IOP is increased but also when it is decreased. According to Linder, 43 autoregulation against systemic hypotension is partially attenuated by sympathetic stimulation in the rabbit retina, but not in the optic nerve. The present findings are consistent with Linder’s, suggesting that maintenance of constant blood flow against increase in OPP by reduction of IOP is achieved almost independently of sympathetic nervous system involvement in the ONH. 
Because differences in the anatomy and blood supply of the ONH exist between rabbits and primates/humans, despite several similarities, 44 and because, in this study, we evaluated the changes in ONH circulation after decrease in IOP after a 10-minute high-IOP phase, the present findings cannot be directly extended to ONH circulation in primates or humans, or to eyes with a long-standing increase in IOP, which may result in histologic changes in ONH tissue. However, our results that ONH circulation was not increased by reduction in IOP is consistent with findings obtained in patients with glaucoma. Filtrating surgeries did not affect ocular hemodynamics including blood velocity in the ONH tissue evaluated with the laser speckle method, 45 parameters of color Doppler imaging in the ophthalmic and central retinal arteries, and parameters of Heidelberg retinal flowmetry in the peripapillary and ONH tissue. 46 In contrast, after trabeculectomy, a significant increase in pulsatile ocular blood flow measured in subjects in a standing position has been reported. 47 It seems likely that reaction to an IOP decrease in humans varies among the central retinal, ciliary, and ophthalmic arteries. In fact, Harris et al. 48 reported that peak systolic and end diastolic velocities evaluated with the color Doppler imaging increase significantly after an acute IOP decrease from approximately 40 to 50 to 8 mm Hg in the central retinal artery of healthy human eyes, but not in the ophthalmic artery. 
In conclusion, tissue circulation in rabbit ONH was stable when IOP was decreased from a level in which autoregulation against IOP increase was effective, whereas ONH circulation increased (or recovered) when IOP was decreased from a level above the upper limit of effective autoregulation against IOP increase. This reaction was partially, but significantly, attenuated by systemic administration of a calcium antagonist, suggesting that vascular smooth muscle plays a significant role in maintaining ONH circulation constant against reduction of IOP. NO, prostaglandins, and sympathetic nervous system did not appear to be involved in the response to OPP change. Changes in ONH circulation after decrease in IOP deserve further investigation, especially in eyes with a long-standing increase in IOP, and determination of them will provide many findings useful in the treatment of glaucoma. 
 
Figure 1.
 
Manometric control and monitoring of IOP in a rabbit eye. 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 that were mounted at different heights. By altering the reservoirs using the turncock, the IOP could be acutely changed while keeping the water surface placid in the bottles. The other needle was connected to a pressure transducer to monitor the actual IOP continuously.
Figure 1.
 
Manometric control and monitoring of IOP in a rabbit eye. 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 that were mounted at different heights. By altering the reservoirs using the turncock, the IOP could be acutely changed while keeping the water surface placid in the bottles. The other needle was connected to a pressure transducer to monitor the actual IOP continuously.
Figure 2.
 
Typical recordings for 30 seconds of IOP and NBav, before and after IOP change from 40 (top) or 60 (bottom) to 10 mm Hg. IOP and NBav were plotted every 0.5 second.
Figure 2.
 
Typical recordings for 30 seconds of IOP and NBav, before and after IOP change from 40 (top) or 60 (bottom) to 10 mm Hg. IOP and NBav were plotted every 0.5 second.
Figure 3.
 
Time course of changes in NBONH and OPP in rabbits in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg (○) and those in rabbits in which IOP was changed from 10 to 40 mm Hg and maintained at 40 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline, with SE bars (n = 6 each).
Figure 3.
 
Time course of changes in NBONH and OPP in rabbits in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg (○) and those in rabbits in which IOP was changed from 10 to 40 mm Hg and maintained at 40 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline, with SE bars (n = 6 each).
Figure 4.
 
Time course of changes in NBONH and OPP in rabbits in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg (○) and those in rabbits in which IOP was changed from 10 to 60 mm Hg and maintained at 60 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline, with SE bars (n = 4 each).
Figure 4.
 
Time course of changes in NBONH and OPP in rabbits in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg (○) and those in rabbits in which IOP was changed from 10 to 60 mm Hg and maintained at 60 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline, with SE bars (n = 4 each).
Figure 5.
 
Time course of changes in NBONH and OPP in nilvadipine-treated rabbits in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg (○) and vehicle-treated rabbits in which IOP was changed from 20 to 50 mm Hg and then returned to 20 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline with SE bars (n = 6 each).
Figure 5.
 
Time course of changes in NBONH and OPP in nilvadipine-treated rabbits in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg (○) and vehicle-treated rabbits in which IOP was changed from 20 to 50 mm Hg and then returned to 20 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline with SE bars (n = 6 each).
Figure 6.
 
Time course of changes in NBONH and OPP in nilvadipine-treated rabbits in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg (○) and vehicle-treated rabbits in which IOP was changed from 20 to 70 mm Hg and then returned to 20 mm Hg (▴). NBONH is shown as the average %NBONH relative to the baseline (top) or the value obtained just before decrease of IOP from 60 to 10 mm Hg (bottom), with SE bars (n = 4 each).
Figure 6.
 
Time course of changes in NBONH and OPP in nilvadipine-treated rabbits in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg (○) and vehicle-treated rabbits in which IOP was changed from 20 to 70 mm Hg and then returned to 20 mm Hg (▴). NBONH is shown as the average %NBONH relative to the baseline (top) or the value obtained just before decrease of IOP from 60 to 10 mm Hg (bottom), with SE bars (n = 4 each).
Table 1.
 
Systemic Parameters in Nilvadipine- or Vehicle-Treated Rabbits
Table 1.
 
Systemic Parameters in Nilvadipine- or Vehicle-Treated Rabbits
Nilvadipine Vehicle
FABPm (mm Hg) 83.7 ± 4.5 93.2 ± 1.8
Pulse (beats/min) 292 ± 6 290 ± 4
pH 7.40 ± 0.01 7.41 ± 0.01
Pco 2 (mm Hg) 37.6 ± 0.2 37.3 ± 1.3
Po 2 (mm Hg) 87.0 ± 1.9 87.3 ± 2.1
Body temperature (°C) 37.1 ± 0.1 37.2 ± 0.2
Table 2.
 
Baseline NBONH and Systemic Parameters in Rabbits Treated with l-NAME, Indomethacin, or Physiological Saline
Table 2.
 
Baseline NBONH and Systemic Parameters in Rabbits Treated with l-NAME, Indomethacin, or Physiological Saline
l-NAME Indomethacin Saline
Baseline NBONH 13.4 ± 0.5 13.4 ± 0.3 13.0 ± 0.4
FABPm (mm Hg) 93.1 ± 1.5 92.1 ± 3.6 91.5 ± 1.8
OPP (mm Hg) 69.5 ± 3.8 68.1 ± 4.0 68.3 ± 3.1
Pulse (beats/min) 281 ± 13 282 ± 11 284 ± 13
pH 7.42 ± 0.01 7.40 ± 0.01 7.40 ± 0.01
Pco 2 (mm Hg) 34.9 ± 1.2 33.9 ± 0.7 35.0 ± 1.7
Po 2 (mm Hg) 87.2 ± 1.6 86.1 ± 2.6 86.5 ± 1.5
Body temperature (°C) 37.3 ± 0.1 37.4 ± 0.2 37.3 ± 0.2
Figure 7.
 
Time course of changes in NBONH and OPP during change in IOP from 10 to 40 mm Hg and return to 10 mm Hg in rabbits treated with l-NAME (○), indomethacin (•), or physiological saline (▵). NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 6 each).
Figure 7.
 
Time course of changes in NBONH and OPP during change in IOP from 10 to 40 mm Hg and return to 10 mm Hg in rabbits treated with l-NAME (○), indomethacin (•), or physiological saline (▵). NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 6 each).
Figure 8.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 60 mm Hg and return to 10 mm Hg in rabbits treated with l-NAME (○), indomethacin (•), or physiological saline (▵). NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 4 each).
Figure 8.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 60 mm Hg and return to 10 mm Hg in rabbits treated with l-NAME (○), indomethacin (•), or physiological saline (▵). NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 4 each).
Table 3.
 
Baseline NBONH and Systemic Parameters in Rabbits with or without Sympathetic Nerve Amputation
Table 3.
 
Baseline NBONH and Systemic Parameters in Rabbits with or without Sympathetic Nerve Amputation
Sympathetic (+) Amputation (−)
Baseline NBONH 14.2 ± 0.2 13.9 ± 0.3
FABPm (mm Hg) 92.1 ± 1.4 91.4 ± 1.3
OPP (mm Hg) 68.0 ± 2.9 67.4 ± 2.5
Pulse (beats/min) 287 ± 4.4 284 ± 6.3
pH 7.40 ± 0.01 7.41 ± 0.01
Pco 2 (mm Hg) 34.7 ± 1.6 36.4 ± 1.3
Po 2 (mm Hg) 85.8 ± 2.9 86.4 ± 1.6
Body temperature (°C) 37.2 ± 0.2 37.4 ± 0.2
Figure 9.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 40 mm Hg and return to 10 mm Hg in eyes with (○) or without (▴) sympathetic nerve amputation. NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 6 each).
Figure 9.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 40 mm Hg and return to 10 mm Hg in eyes with (○) or without (▴) sympathetic nerve amputation. NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 6 each).
Figure 10.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 40 mm Hg and return to 10 mm Hg in eyes with (▴) or without (▵) sympathetic nerve amputation. NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 4 each).
Figure 10.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 40 mm Hg and return to 10 mm Hg in eyes with (▴) or without (▵) sympathetic nerve amputation. NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 4 each).
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Figure 1.
 
Manometric control and monitoring of IOP in a rabbit eye. 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 that were mounted at different heights. By altering the reservoirs using the turncock, the IOP could be acutely changed while keeping the water surface placid in the bottles. The other needle was connected to a pressure transducer to monitor the actual IOP continuously.
Figure 1.
 
Manometric control and monitoring of IOP in a rabbit eye. 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 that were mounted at different heights. By altering the reservoirs using the turncock, the IOP could be acutely changed while keeping the water surface placid in the bottles. The other needle was connected to a pressure transducer to monitor the actual IOP continuously.
Figure 2.
 
Typical recordings for 30 seconds of IOP and NBav, before and after IOP change from 40 (top) or 60 (bottom) to 10 mm Hg. IOP and NBav were plotted every 0.5 second.
Figure 2.
 
Typical recordings for 30 seconds of IOP and NBav, before and after IOP change from 40 (top) or 60 (bottom) to 10 mm Hg. IOP and NBav were plotted every 0.5 second.
Figure 3.
 
Time course of changes in NBONH and OPP in rabbits in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg (○) and those in rabbits in which IOP was changed from 10 to 40 mm Hg and maintained at 40 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline, with SE bars (n = 6 each).
Figure 3.
 
Time course of changes in NBONH and OPP in rabbits in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg (○) and those in rabbits in which IOP was changed from 10 to 40 mm Hg and maintained at 40 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline, with SE bars (n = 6 each).
Figure 4.
 
Time course of changes in NBONH and OPP in rabbits in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg (○) and those in rabbits in which IOP was changed from 10 to 60 mm Hg and maintained at 60 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline, with SE bars (n = 4 each).
Figure 4.
 
Time course of changes in NBONH and OPP in rabbits in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg (○) and those in rabbits in which IOP was changed from 10 to 60 mm Hg and maintained at 60 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline, with SE bars (n = 4 each).
Figure 5.
 
Time course of changes in NBONH and OPP in nilvadipine-treated rabbits in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg (○) and vehicle-treated rabbits in which IOP was changed from 20 to 50 mm Hg and then returned to 20 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline with SE bars (n = 6 each).
Figure 5.
 
Time course of changes in NBONH and OPP in nilvadipine-treated rabbits in which IOP was changed from 10 to 40 mm Hg and then returned to 10 mm Hg (○) and vehicle-treated rabbits in which IOP was changed from 20 to 50 mm Hg and then returned to 20 mm Hg (▴). NBONH is shown as the average (%NBONH) relative to the baseline with SE bars (n = 6 each).
Figure 6.
 
Time course of changes in NBONH and OPP in nilvadipine-treated rabbits in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg (○) and vehicle-treated rabbits in which IOP was changed from 20 to 70 mm Hg and then returned to 20 mm Hg (▴). NBONH is shown as the average %NBONH relative to the baseline (top) or the value obtained just before decrease of IOP from 60 to 10 mm Hg (bottom), with SE bars (n = 4 each).
Figure 6.
 
Time course of changes in NBONH and OPP in nilvadipine-treated rabbits in which IOP was changed from 10 to 60 mm Hg and then returned to 10 mm Hg (○) and vehicle-treated rabbits in which IOP was changed from 20 to 70 mm Hg and then returned to 20 mm Hg (▴). NBONH is shown as the average %NBONH relative to the baseline (top) or the value obtained just before decrease of IOP from 60 to 10 mm Hg (bottom), with SE bars (n = 4 each).
Figure 7.
 
Time course of changes in NBONH and OPP during change in IOP from 10 to 40 mm Hg and return to 10 mm Hg in rabbits treated with l-NAME (○), indomethacin (•), or physiological saline (▵). NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 6 each).
Figure 7.
 
Time course of changes in NBONH and OPP during change in IOP from 10 to 40 mm Hg and return to 10 mm Hg in rabbits treated with l-NAME (○), indomethacin (•), or physiological saline (▵). NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 6 each).
Figure 8.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 60 mm Hg and return to 10 mm Hg in rabbits treated with l-NAME (○), indomethacin (•), or physiological saline (▵). NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 4 each).
Figure 8.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 60 mm Hg and return to 10 mm Hg in rabbits treated with l-NAME (○), indomethacin (•), or physiological saline (▵). NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 4 each).
Figure 9.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 40 mm Hg and return to 10 mm Hg in eyes with (○) or without (▴) sympathetic nerve amputation. NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 6 each).
Figure 9.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 40 mm Hg and return to 10 mm Hg in eyes with (○) or without (▴) sympathetic nerve amputation. NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 6 each).
Figure 10.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 40 mm Hg and return to 10 mm Hg in eyes with (▴) or without (▵) sympathetic nerve amputation. NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 4 each).
Figure 10.
 
Time course of changes in NBONH and OPP during IOP change from 10 to 40 mm Hg and return to 10 mm Hg in eyes with (▴) or without (▵) sympathetic nerve amputation. NBONH is shown as the average %NBONH relative to the baseline, with SE bars (n = 4 each).
Table 1.
 
Systemic Parameters in Nilvadipine- or Vehicle-Treated Rabbits
Table 1.
 
Systemic Parameters in Nilvadipine- or Vehicle-Treated Rabbits
Nilvadipine Vehicle
FABPm (mm Hg) 83.7 ± 4.5 93.2 ± 1.8
Pulse (beats/min) 292 ± 6 290 ± 4
pH 7.40 ± 0.01 7.41 ± 0.01
Pco 2 (mm Hg) 37.6 ± 0.2 37.3 ± 1.3
Po 2 (mm Hg) 87.0 ± 1.9 87.3 ± 2.1
Body temperature (°C) 37.1 ± 0.1 37.2 ± 0.2
Table 2.
 
Baseline NBONH and Systemic Parameters in Rabbits Treated with l-NAME, Indomethacin, or Physiological Saline
Table 2.
 
Baseline NBONH and Systemic Parameters in Rabbits Treated with l-NAME, Indomethacin, or Physiological Saline
l-NAME Indomethacin Saline
Baseline NBONH 13.4 ± 0.5 13.4 ± 0.3 13.0 ± 0.4
FABPm (mm Hg) 93.1 ± 1.5 92.1 ± 3.6 91.5 ± 1.8
OPP (mm Hg) 69.5 ± 3.8 68.1 ± 4.0 68.3 ± 3.1
Pulse (beats/min) 281 ± 13 282 ± 11 284 ± 13
pH 7.42 ± 0.01 7.40 ± 0.01 7.40 ± 0.01
Pco 2 (mm Hg) 34.9 ± 1.2 33.9 ± 0.7 35.0 ± 1.7
Po 2 (mm Hg) 87.2 ± 1.6 86.1 ± 2.6 86.5 ± 1.5
Body temperature (°C) 37.3 ± 0.1 37.4 ± 0.2 37.3 ± 0.2
Table 3.
 
Baseline NBONH and Systemic Parameters in Rabbits with or without Sympathetic Nerve Amputation
Table 3.
 
Baseline NBONH and Systemic Parameters in Rabbits with or without Sympathetic Nerve Amputation
Sympathetic (+) Amputation (−)
Baseline NBONH 14.2 ± 0.2 13.9 ± 0.3
FABPm (mm Hg) 92.1 ± 1.4 91.4 ± 1.3
OPP (mm Hg) 68.0 ± 2.9 67.4 ± 2.5
Pulse (beats/min) 287 ± 4.4 284 ± 6.3
pH 7.40 ± 0.01 7.41 ± 0.01
Pco 2 (mm Hg) 34.7 ± 1.6 36.4 ± 1.3
Po 2 (mm Hg) 85.8 ± 2.9 86.4 ± 1.6
Body temperature (°C) 37.2 ± 0.2 37.4 ± 0.2
Copyright 2005 The Association for Research in Vision and Ophthalmology, Inc.
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