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(Investigative Ophthalmology and Visual Science. 2007;48:4215-4219.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0176
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Role of Nitric Oxide in Choroidal Blood Flow Regulation during Light/Dark Transitions

Karl-Heinz Huemer,1,2 Gerhard Garhofer,1 Tina Aggermann,1 Julia Kolodjaschna,1 Leopold Schmetterer,1,3 and Gabriele Fuchsjäger-Mayrl1,4

1From the Department of Clinical Pharmacology, the 2Center for Physiology and Pathophysiology, the 3Department of Biomedical Engineering and Physics, and the 4Department of Ophthalmology, Medical University of Vienna, Vienna, Austria.


   Abstract
Top
 Abstract
Subjects, Materials, and Methods
 Results
 Discussion
 References
 
PURPOSE. Several studies have recently shown that a transition from light to dark is associated with a reduction in choroidal blood flow. The mechanism underlying this effect is unclear but may be related to changes in neural input. In the present study, the authors hypothesized that either the {alpha}-receptor agonist phenylephrine or the nitric oxide synthase (NOS) inhibitor L-NMMA may alter the choroidal blood flow response during a transition from light to dark.

METHODS. In 15 healthy male nonsmoking subjects, the response of choroidal perfusion was studied in a randomized placebo-controlled three-way crossover study. Phenylephrine, L-NMMA or placebo was administered on different study days, and the effect of a light/dark transition on choroidal perfusion parameters was studied. Subfoveal choroidal blood flow and fundus pulsation amplitude were assessed with laser Doppler flowmetry and laser interferometry, respectively.

RESULTS. Before drug administration, a transition from light to dark reduced both choroidal hemodynamic parameters by 11% to 20%. Neither phenylephrine nor placebo altered basal choroidal blood flow or choroidal blood flow responses to the light/dark transitions. By contrast, the NOS inhibitor L-NMMA significantly reduced basal choroidal blood flow by 20.5% ± 5.9% (P < 0.001) and basal fundus pulsation amplitude by 21.5% ± 4.8% (P < 0.001). In addition, the response of subfoveal choroidal blood flow (–6.2% ± 3.2%; P = 0.008) and fundus pulsation amplitude (–4.2% ± 2.4%; P < 0.001) to the light/dark transition was significantly diminished.

CONCLUSIONS. The present study indicates that NO plays a role in the choroidal blood flow decrease during a transition from light to dark. Given that L-NMMA is a nonspecific inhibitor of NOS, the present study does not clarify whether this NO is from endothelial or neural sources.

Evidence indicates that the perfusion level in the choroid is dependent on fundus illumination. This was first shown in the pigeon, in which some mechanisms involved in this regulatory process were identified.1 More recently, it has been shown, through confocal laser Doppler flowmetry, that this also holds true for the human choroid.2 We have shown in an earlier study that there is evidence for a neural mechanism behind this effect,3 but neither ß-receptor blockade with propranolol nor muscarinic receptor blockade with atropine altered the response of choroidal blood flow to a light/dark transition.4

Nitric oxide (NO) is a major determinant of choroidal blood flow, as evidenced from numerous animal and human studies.5 6 NO plays a role in basal choroidal tone in rats5 , cats,7 and humans8 and in choroidal blood flow regulation in response to changes in ocular perfusion pressure.9 10 NO also mediates the vascular responses of hypercapnia,11 insulin,12 and other vasodilator substances.13

In the present study, we hypothesized that NO may also be involved in the choroidal blood flow response to light/dark transitions. For this purpose, we compared the choroidal hemodynamic response during light/dark transitions in the absence and presence of the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA). To account for the systemic hypertensive response to L-NMMA, we chose phenylephrine as a control substance in a dosage that induced a comparable increase in blood pressure. To assess choroidal blood flow, we used two independent methods, laser Doppler flowmetry with the confocal device14 15 and laser interferometric measurement of fundus pulsation.16


   Subjects, Materials, and Methods
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 Abstract
 Subjects, Materials, and Methods
Results
 Discussion
 References
 
Subjects
After approval was obtained from the Ethics Committee of the Vienna Medical School, the study was performed in adherence to the tenets of the Declaration of Helsinki. Fifteen healthy male nonsmoking volunteers were included in the trial (age range, 20–31 years; mean, 24 years). The nature and possible consequences of the study were explained, and all subjects gave written informed consent to participate. Each subject passed a screening examination that included medical history and physical examination, 12-lead electrocardiogram, complete blood count, activated partial thromboplastin time, thrombin time, fibrinogen, clinical chemistry (sodium, potassium, creatinine, uric acid, glucose, cholesterol, triglycerides, alanine aminotransferase, aspartate transcarbamylase, {gamma}-glutamyltransferase, alkaline phosphatase, total bilirubin, total protein), hepatitis A, B, C and HIV serology, urine analysis, and urine drug screening. Furthermore, an ophthalmic examination, including slit lamp biomicroscopy and indirect funduscopy, was performed. Inclusion criteria were normal ophthalmic findings and ametropia <3 D. Subjects were excluded if any abnormality was found as part of this pretrial screening unless the investigators considered an abnormality to be clinically irrelevant.

Study Design
Before the study a sample size calculation was performed. The reproducibility of choroidal blood flow changes during light/dark transition using laser Doppler flowmetry was calculated based on the results of our previous study.3 These data were used for the sample size calculation selecting a double-sided {alpha}-level of 0.05 and a ß-level of 0.2. The sample size of 15 subjects was chosen to allow detection of choroidal blood flow changes greater than 8%. Fundus pulsation measurements were not considered for the sample size calculation because the reproducibility was better than with laser Doppler flowmetry.17

The study followed a randomized, double-masked, placebo-controlled, three-way crossover design with L-NMMA (nonselective NOS inhibitor), phenylephrine ({alpha}-adrenoceptor agonist), or placebo (physiological saline solution) on separate study days. The washout period between study days was at least 5 days. The dose of L-NMMA and phenylephrine was based on our previous trials in healthy humans. L-NMMA (Clinapha, Läufelfingen, Switzerland) was administered as an intravenous bolus infusion at a dose of 6 mg · kg–1 over 5 minutes followed by a continuous infusion of 60 µg · kg–1 · min–1 over 65 minutes.8 10 Phenylephrine (Neo-Synephrine; Winthrop Breon Laboratories, New York, NY) was administered at a dose of 1 µg · kg–1 · min–1 over an infusion period of 70 minutes.10 On the phenylephrine and the placebo study day, syringes with the respective medication were prepared by an unblinded nurse to allow for double-masked conditions with regard to the L-NMMA study day.

After a resting period of at least 20 minutes, baseline measurements of ocular and systemic hemodynamics were performed. Subjects were then kept in room light for 20 minutes. The room light consisted of neon lamp illumination with a radiance of approximately 115 µW · cm–2 · sr–1 (approximately 100 lux). At the end of this 20-minute period, baseline measurements of choroidal hemodynamic parameters were repeated. Thereafter, the room light was turned off for 20 minutes. During this period of darkness, the radiance was kept below 0.5 µW · cm–2 · sr–1. At the end of this 20-minute period in darkness, ocular hemodynamic parameters were assessed again. Finally, the light was turned on and subjects were measured again after 10 minutes. This pretreatment part of the experiment was concluded with a 30-minute resting period. Then the respective drugs were administered and another light/dark transition cycle was performed during the last 50 minutes of drug administration, which was identical to the pretreatment period. Intraocular pressure was measured at the beginning and at the end of each period.

Measurements
Blood Pressure and Pulse Rate.
Systolic, diastolic, and mean arterial pressure (SBP, DBP, MAP) were measured on the upper arm by an automated oscillometric device (HP-CMS patient monitor; Hewlett-Packard, Palo Alto, CA). Pulse rate (PR) was automatically recorded from a finger pulse-oximetric device (HP-CMS patient monitor; Hewlett-Packard).

Intraocular Pressure.
A slit-lamp–mounted Goldmann applanation tonometer was used to measure intraocular pressure (IOP). Before each measurement, 1 drop of 0.4% benoxinate hydrochloride combined with 0.25% fluorescein sodium was used for local anesthesia of the cornea.

Laser Doppler Flowmetry.
Subfoveal choroidal blood flow was performed by laser Doppler flowmetry.18 In this technique, the vascularized tissue is illuminated by coherent laser light. Light scattered by the moving red blood cells (RBCs) undergoes a frequency shift. In contrast, static tissue scatterers do not change the light frequency but lead to randomization of light directions impinging on RBCs. Hence, RBCs receive light from numerous random directions. The frequency shift is dependent not only on the velocity of the moving RBCs but also on the angle between the wave vectors of the incident and scattered light; hence, scattering of the light in tissue broadens the Doppler shift power spectrum. From this spectrum, the following flow parameters are calculated19 : mean RBC velocity in Hz, blood volume and blood flow (FLOW) in arbitrary units.

In the present study, a compact laser Doppler flowmeter14 15 was used for the measurements of the choroidal blood flow parameters. The laser beam of a single-mode laser diode (785 nm, 90 µW at the cornea) is delivered to the eye through a confocal optical system. The beam diameter at the fundus is nominally 12 µm. The light is collected by a bundle of six fibers with a core diameter of 110 µm, which are arranged on a circle with a diameter of 180 µm (indirect detection). All measurements were performed in the fovea by asking the subject to directly fixate at the beam, which appeared as a small red dot.

Fundus Pulsation Measurement.
Pulse synchronous pulsations of the ocular fundus were recorded with a laser interferometric method.16 The method uses a single-mode laser beam with a wavelength of 780 nm for illumination of the subject's eye. The power of the laser beam is approximately 80 µW at a beam diameter of 1 mm. The light is reflected at the anterior surface of the cornea and at the fundus. The light from the front side of the cornea serves as a reference wave. Because of the high coherence length of the laser light, the interferences produced by the two waves can be observed. This permits calculation of the relative distance changes between cornea and retina during the cardiac cycle. These distance changes are in the order of several micrometers and are caused by the rhythmic filling of ocular vessels during systole and diastole. The distance between cornea and retina decreases during systole because the blood volume entering the eye through the arteries exceeds the blood volume, leaves the eye through the veins, and increases during diastole. The maximum distance change between the cornea and fundus during the cardiac cycle is called fundus pulsation amplitude (FPA) and yields information on the pulsatile component of ocular blood flow.17

Data Analysis
All responses in choroidal hemodynamic parameters during light/dark transitions were expressed as percentage change from baseline values. The effect of L-NMMA and phenylephrine on choroidal blood flow changes during light/dark transitions were assessed with a repeated-measure ANOVA model. The effect of the light/dark transition was calculated as the time effect. The effect of the administered drugs on these choroidal blood flow changes was calculated as the interaction between treatment and time. Post hoc analyses were performed using planned comparisons. All statistical analyses were performed with a software package (Statistica, version 4.5; StatSoft Inc., Tulsa, OK). Data are presented as mean ± SD. Two-tailed P < 0.05 was considered the level of significance.


   Results
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 Abstract
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 Results
Discussion
 References
 
Baseline hemodynamic parameters and baseline IOP on the three study days are presented in Table 1 . All outcome variables were comparable for the three study days.


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  		TABLE 1. Baseline Hemodynamic Parameters

 
No significant changes were observed in MAP, PR, or IOP during the light/dark transitions. As expected, L-NMMA and phenylephrine caused a significant increase in MAP, as shown in Table 2 (P < 0.001, ANOVA). This effect was significant for L-NMMA (P = 0.03) and for phenylephrine versus placebo (P < 0.001). The effect of L-NMMA and phenylephrine was, however, comparable (P = 0.15). These effects on MAP were paralleled by a significant decrease in PR with phenylephrine and L-NMMA (P < 0.001, ANOVA). Although both drugs induced significant reductions in PR compared with placebo (P = 0.03, L-NMMA; P < 0.001, phenylephrine), the effect of L-NMMA and phenylephrine were again comparable (P = 0.11). None of the administered drugs induced consistent effects on IOP.


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  		TABLE 2. Systemic Hemodynamic Parameters and IOP during the Three Study Days

 
As expected, a transition from light to dark caused a decrease in choroidal blood flow and FPA at the pretreatment period (Figs. 1 and 2 ). This decrease was between 16% ± 4% and 20% ± 5% (P < 0.001) for choroidal blood flow and between 11% ± 3% and 13% ± 4% for FPA (P < 0.001). The reduction in ocular hemodynamic parameters was comparable for the three study days (choroidal blood flow, P = 0.39; FPA, P = 0.70). After the room light was switched on, all ocular hemodynamic parameters returned to baseline values within –4.5% to 0.1%.


Figure 1
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  		FIGURE 1. Time course of choroidal blood flow during light/dark transition periods. On each study day, the first light/dark transition period was scheduled before drug administration, and the second light/dark transition period was scheduled during infusion of L-NMMA (solid squares), phenylephrine (solid triangles), or placebo (open circles). Dark periods lasted from 21 to 41 minutes and from 121 to 141 minutes, respectively (indicated by boxes). Drug was administered at 80 minutes (boxes). Data are presented as mean ± SD (n = 15).

 

Figure 2
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  		FIGURE 2. Time course of FPA during light/dark transition periods. On each study day, the first light/dark transition period was scheduled before drug administration, and the second light/dark transition period was scheduled during infusion of L-NMMA (solid squares), phenylephrine (solid triangles), or placebo (open circles). Dark periods lasted from 21 to 41 minutes and from 121 to 141 minutes, respectively (boxes). Drug was administered at 80 minutes (indicated by boxes). Data are presented as mean ± SD (n = 15).

 
After the light was switched on, neither phenylephrine nor placebo changed choroidal blood flow or FPA (Figs. 1 2) . By contrast, L-NMMA significantly reduced basal choroidal blood flow by 20.5% ± 5.9% and FPA by 21.5% ± 4.8%. These effects were highly significant (P < 0.001 each). The response of choroidal blood flow during changes in light/dark conditions was comparable with phenylephrine (–15.1% ± 5.3%) and placebo (–15.5% ± 6.1%) and was not significantly different from baseline conditions. By contrast, the response of choroidal blood flow to the light/dark transition was significantly diminished with L-NMMA (–6.2% ± 3.2%; P = 0.008 vs. placebo). A similar pattern was seen for FPA. The response of FPA to a change in light/dark conditions was comparable to that for baseline when phenylephrine (–10.6% ± 3.3%) or placebo (–10.0% ± 3.1%) was administered and there was no difference between the two treatments. The decrease in FPA when the light was switched off was, however, significantly diminished when L-NMMA was administered (–4.2% ± 2.4%; P < 0.001 vs. placebo).


   Discussion
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 Abstract
 Subjects, Materials, and Methods
 Results
 Discussion
References
 
The present study indicates that NO plays a role in choroidal blood flow decrease during a transition from light to dark. This is well compatible with previous studies in the pigeon, in which retinal illumination increases choroidal blood flow by a mechanism that includes the suprachiasmatic nucleus and the Edinger-Westphal nucleus.1 The Edinger-Westphal nucleus innervates the choroidal neurons of the ipsilateral ganglion and provides cholinergic innervation in choroidal blood vessels.20 In a previous study from our group, the muscarinic receptor antagonist atropine did not alter the choroidal blood flow response to light/dark transitions in healthy subjects.4 This does not necessarily exclude an involvement of the cholinergic system in the choroidal blood flow changes with retinal illumination. In the pigeon, atropine had a small effect on Edinger-Westphal nucleus-induced choroidal vasodilatation.21 A more pronounced effect was seen with the selective M3 type muscarinic antagonist 4-diphenyl-acetoxy-N-methylpiperedine, which dose dependently reduced Edinger-Westphal–evoked responses.21

The results of the present study are compatible with previous results in the pigeon because neural NO appears to mediate Edinger-Westphal–nucleus evoked increases in choroidal blood flow.22 In this laser Doppler study, the selective blocker of NOS-1, 7-nitroindazole, did not affect baseline choroidal blood flow but attenuated the Edinger-Westphal–induced effect. In humans, no direct evidence indicates that the change in choroidal blood flow is also mediated through the suprachiasmatic nucleus and the Edinger-Westphal nucleus; obviously, experimental limitations in humans hamper the direct proof of this concept. We have, however, previously shown that unilateral light/dark transitions lead to a decrease in choroidal perfusion in the contralateral eye,4 indicating that a neural mechanism contributes to the change in choroidal vascular tone during the change in retinal illumination. Based on the results of the present study, it appears likely that the reduction of blood flow in the dark is related to reduced vasodilator tone associated with less NO production. Whether this NO is indeed from neural sources is unclear from the present trial because no selective inhibitor of NOS-1 is available for human use.

A large body of evidence indicates that arterioles and arteries of the choroid are richly innervated by NOS and vasoactive intestinal peptide–containing nerves. This has been shown in the human eye by several investigators showing staining for adenine dinucleotide phosphate-diaphorase.23 24 25 26 In addition, evidence from rabbit and cat experiments indicate that NO is a mediator of parasympathetic vasodilatation in the choroid.27 28 In both species, inhibition of NOS reduced facial nerve stimulation–evoked increases in choroidal blood flow, particularly at lower stimulation frequencies. It is unclear whether NO in these experiments was from neural sources because the dose of 7-nitroindazole used for the cat experiments was likely too small to inhibit NOS-1 to a relevant degree and, therefore, had no effect on facial stimulation–induced vasodilatation.28 Alternatively, one could hypothesize that nonspecific blockade of NOS, which attenuated facial stimulation–induced vasodilatation in the cat choroid,28 is effective because NO formed through NOS-3 in the vascular endothelium plays a role secondary to the neural release of acetylcholine and VIP. This could, of course, also apply to the results of the present trial, which provided no evidence of a direct release of NO from cholinergic nerves. The reduction in choroidal blood flow was less pronounced after NOS inhibition than after placebo administration. Hence, we cannot exclude that NO-independent mechanisms also contribute to the choroidal blood flow reduction in the dark.

A number of limitations applied to the present study. Laser Doppler flowmetry and laser interferometric measurement of fundus pulsation amplitude have a variety of limitations. These have been summarized in some detail,29 and further discussion is beyond the scope of this article. Most important, results were consistent with both techniques in the present study, indicating the validity of the results. One additional point—the effect of laser measurements on the process of dark adaptation—may require specific consideration. In both methods, red light is applied to the eye, which can hamper dark adaptation to some extent. Longo et al.,2 however, performed an experiment in which they measured choroidal blood flow for 3 minutes after 10 minutes of dark adaptation and found no detectable increase in choroidal blood flow, strongly indicating that the laser beam itself did not evoke a vasodilator response in the choroid.

One also must consider that L-NMMA increased systemic blood pressure because of its peripheral vasoconstrictor action. This effect appears not to have played a role in the observed effects in choroidal blood flow because phenylephrine, which caused a comparable effect on systemic hemodynamic parameters, did not alter the characteristics of choroidal blood flow during light/dark transition.

In conclusion, the present study indicates that NO plays a role in choroidal blood flow decrease during the transition from light to dark. The source of this NO is unclear because no selective inhibitors of NOS are available for human use. Further studies are required to elucidate the physiological role of blood flow decrease during a transition from light to dark.


   Footnotes
 
Submitted for publication February 12, 2007; revised April 3, 2007; accepted May 30, 2007.

Disclosure: K.-H. Huemer, None; G. Garhofer, None; T. Aggermann, None; J. Kolodjaschna, None; L. Schmetterer, None; G. Fuchsjäger-Mayrl, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Gabriele Fuchsjäger-Mayrl, Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria; astrid.fuchsjaeger-mayrl{at}meduniwien.ac.at.


   References
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 Abstract
 Subjects, Materials, and Methods
 Results
 Discussion
 References
 

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