July 2003
Volume 44, Issue 7
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Physiology and Pharmacology  |   July 2003
Effects of Adenosine on Intraocular Pressure, Optic Nerve Head Blood Flow, and Choroidal Blood Flow in Healthy Humans
Author Affiliations
  • Elzbieta Polska
    From the Departments of Clinical Pharmacology and
  • Paulina Ehrlich
    From the Departments of Clinical Pharmacology and
  • Alexandra Luksch
    From the Departments of Clinical Pharmacology and
    Ophthalmology and the
  • Gabriele Fuchsjäger-Mayrl
    From the Departments of Clinical Pharmacology and
    Ophthalmology and the
  • Leopold Schmetterer
    From the Departments of Clinical Pharmacology and
    Institute of Medical Physics, University of Vienna, Vienna, Austria.
Investigative Ophthalmology & Visual Science July 2003, Vol.44, 3110-3114. doi:10.1167/iovs.02-1133
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      Elzbieta Polska, Paulina Ehrlich, Alexandra Luksch, Gabriele Fuchsjäger-Mayrl, Leopold Schmetterer; Effects of Adenosine on Intraocular Pressure, Optic Nerve Head Blood Flow, and Choroidal Blood Flow in Healthy Humans. Invest. Ophthalmol. Vis. Sci. 2003;44(7):3110-3114. doi: 10.1167/iovs.02-1133.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

purpose. There is evidence from a variety of animal studies that the adenosine system plays a role in the control of intraocular pressure (IOP) and ocular blood flow. However, human data on the effect of adenosine on IOP and choroidal and optic nerve blood flow are not available.

methods. The effect of stepwise increases in doses of adenosine (10, 20, and 40 μg/kg per minute, 30 minutes per infusion step) on optic nerve head blood flow, choroidal blood flow, and IOP was determined in a placebo-controlled double-masked clinical trial in 12 healthy male volunteers. Blood flow in the optic nerve head and choroid was measured with laser Doppler flowmetry. In addition, fundus pulsation amplitude in the macula (FPAM) and the optic nerve head (FPAO) were assessed with laser interferometry.

results. Adenosine induced a small but significant decrease in IOP (at 40 μg/kg per minute: 12% ± 13%), which was significant versus placebo (P = 0.046). In addition, adenosine induced a significant increase in choroidal blood flow (P < 0.001) and optic nerve head blood flow (P = 0.037), and FPAM (P = 0.0014) and tended to increase FPAO (P = 0.057). At the highest administered dose, the effect on choroidal hemodynamic parameters between 14% and 17%, whereas the effect on optic nerve hemodynamic parameters was between 3% and 11%.

conclusions. These data are consistent with adenosine inducing choroidal and optic nerve head vasodilatation and reducing IOP in healthy humans. Considering the neuroprotective properties of adenosine described in previous animal experiments the adenosine system is an attractive target system for therapeutic approaches in glaucoma.

Adenosine, a breakdown product of cellular adenosine triphosphate, is a modulator of synaptic transmission and a potent endogenous vasodilator in most vascular beds, including that of the retina. Its vasodilatory effects are primarily mediated by adenosine A1 and adenosine A2 receptors. 1 Activation of these receptors increases guanylate cyclase activity and the subsequent increased cyclic guanosine 3,5′-monophosphate (cGMP) levels relax vascular smooth muscle. 
The role of adenosine in the eye is still a matter of controversy. However, it has been shown that adenosine receptor agonists protect the retina from ischemia–reperfusion damage. 2 Although the mechanism behind this neuroprotective effect of adenosine agonists is incompletely understood, this class of drugs has been suggested as a potential antiglaucoma therapy. 
Our current understanding of the pathophysiology of glaucoma is still not complete. However, there is increasing evidence that loss of visual field is triggered by a cascade of processes, which is likely to be similar to ischemic pathophysiology. 3 One would therefore predict that the ideal drug to treat glaucoma would be a substance that lowers intraocular pressure (IOP), facilitates blood flow to the optic nerve head (ONH) to prevent ischemia, and prevents neural cell death. As mentioned, adenosine agonists may exert neuroprotection in the retina. There is evidence from several animal studies that adenosine causes retinal and choroidal vasodilation. 4 5 6 However, more recently Portellos et al. 7 have shown that intravenous adenosine does not influence retinal or optic nerve blood flow, but increases choroidal blood flow in the cat. The adenosine system has also been shown to contribute to IOP regulation. Activation of A1 receptors induces a reduction in IOP, whereas activation of A2 receptors induces an increase in IOP. 8 Data from human subjects showing the role of the adenosine system in the eye have not been published. We set out to investigate the effect of exogenous adenosine on IOP and optic nerve and choroidal blood flow in healthy humans. 
Methods
Subject
The present study conformed with the provisions of the Declaration of Helsinki and the Good Clinical Practice (GCP) guidelines. After approval of the study protocol by the Ethics Committee of the Vienna University School of Medicine and after written informed consent was obtained, 12 healthy nonsmoking male subjects were studied. All subjects were drug free for at least 3 weeks before inclusion and passed a prestudy screening during the 4 weeks before the first study day that included medical history and physical examination, 12-lead electrocardiogram, complete blood count, activated partial thromboplastin time, thrombin time, clinical chemistry (sodium, potassium, creatinine, alanine aminotransferase, γ-glutamyltransferase, total bilirubin, total protein), hepatitis (types A, B, and C) and HIV serology, urinanalysis, and an ophthalmic examination. Subjects were excluded if any abnormality was found as part of the pretreatment screening, unless the investigators considered an abnormality to be clinically irrelevant. In addition, subjects with ametropia of more than 3 D, anisometropia more than 1 D, or any evidence of eye disease that might interfere with the purpose of the present trial were excluded. During the week after completion of the study, a follow-up safety examination was scheduled for all participating subjects. This follow-up included physical examination, electrocardiogram, complete blood count, activated partial thromboplastin time, thrombin time, clinical chemistry (sodium, potassium, creatinine, alanine aminotransferase, γ-glutamyltransferase, total bilirubin, total protein), and urinanalysis. 
Sample Size Calculation
The reproducibility of data with laser Doppler flowmetry (LDF) in the ONH and the choroid in healthy subjects was calculated from previous placebo-controlled clinical trials that were performed in our laboratory. 9 10 Based on the variability of the data during placebo infusion and choosing an α error of 0.05 and a power of 0.80, we calculated a sample size of 12 for the present study. This number was calculated by setting the minimally detectable difference in adenosine-induced hemodynamic effects to 10%. Changes below 10% were considered clinically insignificant. Laser interferometric measurement of fundus pulsation was not considered for the present sample size calculation, because the reproducibility is better than that achieved with LDF. 11 12  
Experimental Design
The study was performed in a randomized, placebo-controlled, double masked, two-way crossover design. All subjects were asked to refrain from alcohol and caffeine for at least 12 hours before the trial day. After a resting period of at least 20 minutes in a sitting position a 30-minute infusion of physiologic saline solution was started. Baseline measurements were performed by LDF and laser interferometry and levels of IOP and blood pressure (BP) and pulse rate (PR) were determined during the last 15 minutes of this infusion. Thereafter, adenosine (Ebewe Arzneimittel, Unterach, Austria) was administered in stepwise increasing doses: 10, 20, and 40 μg/kg per minute on 1 day and placebo (physiologic saline solution) on the other study day. Each infusion step lasted for 30 minutes. Ocular hemodynamic and IOP measurements were performed during the last 15 minutes of each infusion step. Blood pressure was measured in 5-minute intervals during the study period. Pulse rate and a real-time electrocardiogram were monitored continuously. All measurements were performed with dilated pupil, using tropicamide (Mydriaticum; Agepha, Vienna, Austria). Two trial days were scheduled for each subject. The washout period between the study days was at least 3 days. 
Measurements
Systemic Hemodynamics.
Brachial artery BPs (systolic [SBP] and diastolic [DBP]) were monitored on the upper arm by an automated oscillometric device. PR was automatically recorded from a finger pulse oxymetric device (HP-CMS pulse monitor; Hewlett Packard, Palo Alto, CA). 
Intraocular Pressure.
A slit lamp–mounted Goldmann applanation tonometer was used to measure IOP. Before each measurement, 1 drop of 0.4% benoxinate hydrochloride combined with 0.25% sodium fluorescein was used for local anesthesia. 
Laser Doppler Flowmetry.
With this technique, the vascularized tissue is illuminated by coherent laser light, avoiding visible vessels in directing the laser beam. Scattering on moving red blood cells (RBCs) leads to a Doppler frequency shift in the scattered light. In contrast, static scatterers in tissue do not change light frequency, but lead to randomization of light directions impinging on RBCs. This serves as a reference signal. This diffusion of light in vascularized tissue leads to a broadening of the spectrum of scattered light, from which the mean RBC velocity, the blood volume, and the blood flow can be calculated in relative units. 13 In the present study, choroidal blood flow was measured, aiming the laser beam at the fovea. 14 ONH blood flow was assessed at the temporal neuroretinal rim. 15 For the measurements, a commercially available fundus camera–based system was used (Oculix 4000; Oculix Sarl, Arbaz, Switzerland). The incident laser beam had a wavelength of 670 nm. The scattered laser light emerging from the pupil was collected through an optical fiber aperture and detected by a photomultiplier. To reduce the variability of blood flow data as assessed with this technique, we used an approach that has recently been introduced by another group. 16 This approach takes into account that the signal obtained with LDF may depend on the absolute amount of re-emitted light, which affects the direct current (DC) level at the detector. Accordingly, the parameter yield, which is defined as DC/amplification, was calculated. 16 The influence of yield on the measurements was investigated by using a regression model (third-order polynomial equation) applied on the logarithmic values of yield and LDF data of flow in the choroid and the ONH. Using this approach, it was possible to omit partially the influence of yield on blood flow values obtained with the system. Choroidal blood flow (CHBF) and optic nerve head blood flow (ONHBF) were calculated in arbitrary units. 
Laser Interferometric Measurement of Fundus Pulsation.
With this technique, pulse synchronous distance changes between cornea and retina are assessed. For this purpose, the eye is illuminated by the beam of a single mode laser diode (λ = 783 nm) along the optical axis. 17 The light is reflected at both the front surface of the cornea and the retina. The two re-emitted waves produce interference fringes from which the change in distance between cornea and retina during a cardiac cycle can be evaluated. This change in distance occurs, because the volume of blood entering the eye through the arteries exceeds the volume of blood leaving the eye during systole. Hence, a reduction in corneoretinal distance occurs during systole, whereas the distance during diastole slightly increases. The fundus pulsation amplitude (FPA), which is the maximum distance change between cornea and retina during the cardiac cycle, provides an estimate of pulsatile blood flow. 12 Again, measurements were performed in the fovea (FPAM) to assess pulsatile choroidal blood flow and in the ONH (FPAO). 18  
Data Analysis
Statistical analysis was performed on computer (CSS Statistica for Windows; Statsoft, Inc., Tusla, OK). For data description, outcome parameters were expressed as the percentage change from baseline (Δ%). A two-way repeated-measures ANOVA was used to analyze the data, and probabilities for adenosine-induced hemodynamic effects are presented versus placebo. For post hoc comparisons, calculating the dose dependence of adenosine-induced effects, the paired t-test with application of the Bonferroni adjustment for multiple comparisons was used. For statistical analysis, absolute data were used. Data are presented as means ± SD. A two-tailed P < 0.05 was considered significant. 
Results
Twelve healthy men (mean age, 28 ± 3 years) were enrolled and randomized in the present study. The baseline values of all outcome variables in these subjects are shown in Table 1 . There were no significant differences in hemodynamic parameters or IOP on the two study days at baseline. 
Neither placebo nor exogenous adenosine induced any consistent change in systemic hemodynamic parameters (Fig. 1) . Adenosine caused a significant reduction in IOP (ANOVA: P = 0.046 versus placebo, Fig. 1 ), which was significant only at the highest dose (40 μg/kg per minute) of adenosine (12% ± 13% versus baseline, P = 0.009). On the placebo study day, no changes in IOP were observed. Figure 2 shows the effects of adenosine on ocular hemodynamic parameters. Infusion of adenosine significantly increased CHBF (ANOVA: P < 0.001 versus placebo). This effect was significant at doses of 20 μg/kg per minute (9% ± 5%; P = 0.005) and 40 μg/kg per minute (17% ± 7%; P < 0.001). This increase in choroidal perfusion was also reflected in the results obtained for FPAM. FPAM increased during administration of adenosine (ANOVA: P = 0.0014 versus placebo), but the effect was slightly less pronounced than that on CHBF. This effect of adenosine on FPAM was significant at doses of 20 μg/kg per minute (8% ± 11%; P = 0.01) and 40 μg/kg per minute (14% ± 11%; P = 0.006). 
Adenosine had a lesser effect on blood flow parameters in the ONH. Nevertheless, exogenous adenosine induced a significant increase in ONHBF (ANOVA: P = 0.037 versus placebo). This effect was significant, however, only at the highest dose of adenosine administered (11% ± 13%; P = 0.022). By contrast, FPAO showed a tendency toward increase only during administration of adenosine (P = 0.057). Even with the highest administered dose, no significant effect on FPAO was observed (40 μg/kg per minute: 3% ± 7%). 
All subjects completed the study according to the protocol and without adverse events. At the follow-up examination, all findings were within the normal range. 
Discussion
In the present study, we observed a small but significant decrease of IOP during infusion of exogenous adenosine. This is the first study in humans to show that ocular hypotensive effects may be exerted through the adenosine system. Previous animal studies indicate that it is primarily the activation of the A1 receptor that is responsible for the ocular hypotensive effects of adenosine. This has been shown in several species including the rabbit, 19 20 21 the monkey, 22 and the mouse. 23 The mechanism underlying this ocular hypotensive effect is not entirely clear. A1 receptors have been identified prejunctionally on sympathetic nerves in the rat iris. 24 However, A1 receptor agonists do not evoke the release of [3H]-norepinephrine in the isolated iris-ciliary body, 25 indicating that prejunctional receptors play a minor role in the IOP-lowering effect of adenosine. The ocular hypotensive effect of A1 receptor agonists is more likely to be due to an effect on the postjunctional receptor, because activation of this receptor suppresses stimulated cAMP accumulation. 25 26 It has been shown, however, that the A1 receptor agonist cyclohexyladenosine reduces IOP by an early reduction in aqueous flow followed by a subsequent increase in outflow facility. 21  
In addition, the present study provided evidence that adenosine may exert choroidal and optic nerve vasodilation in healthy subjects. This is in keeping with results in a variety of animal studies indicating that adenosine plays a role in the control of ocular blood flow. Studies in newborn piglets have revealed that adenosine induces retinal vasodilation through the A2 receptor subtype, 6 plays a role in hypoxia-induced vasodilation, 27 and is involved in retinal autoregulation. 27 It should be emphasized, however, that the retina is differentially regulated in the newborn and the adult animal. 28 More important, for the results of the present trial adenosine agonists have been shown to reduce vascular resistance in the perfused cat eye. 29 In isolated rat retinal pericytes, adenosine activates a hyperpolarizing current, most likely caused by the opening of ATP-sensitive potassium channels. 30 Considering the high density of pericytes in the retina and the ONH this finding may explain why ocular vasodilator effects of adenosine occurred in the present study at doses that had little effect on systemic hemodynamics. 
In the cat, intravenous administration of adenosine induces a pronounced increase in choroidal blood flow, but has little effect on optic nerve blood flow, as evidenced by LDF. 7 The authors speculated that the blood ocular barrier prevents the vasodilator response in the ONH after intravenous adenosine administration. Obviously, there is either some species difference in the response to exogenous adenosine between cats and humans, or the two studies had different powers in detecting changes in ONHBF. As mentioned earlier, the increase in ONHBF observed in the present study may have been due to a direct effect on pericytes. In the brain, however, adenosine transport is regulated by the activity of the adenosine transporter located at the brain capillary endothelial wall. 31 32 Only a few studies have focused on such nucleoside transport sites in the retina, but a nucleoside transport system has been identified in a cultured human retinal cell line. 33 Hence, one may speculate that the vasodilator effect in the ONH as observed in the present study may be the result, at least partially, of an active transport through the blood–ocular barrier. 
Considering the limitations of all currently available systems for the assessment of ocular perfusion, we deem it important that the increase in choroidal perfusion was shown with two independent methods. The effect on fundus pulsation was less pronounced than that on blood flow, as assessed with LDF in both vascular beds under study. Whether this indicates that adenosine reduces flow pulsatility in the eye, as expected with local vasodilation, remains to be established. 
In this study we did not observe any significant systemic hemodynamic effects of adenosine. Previous investigations showed a dose-dependent increase in heart rate and SBP and a decrease in DBP. 34 35 However, an effect was seen only at doses of 80 μg/kg per minute and higher, which is in keeping with the results of the present study. With very high doses of adenosine (236–500 μg/kg per minute), an increase in cerebral blood flow has been reported. 35 Moreover, an accumulation of the applied doses (and a subsequent effect on systemic hemodynamic parameters) is very unlikely to be due to the short half-life of adenosine. 
Several studies indicate that adenosine may exert neuroprotective effects, mainly by activation of the A1 receptor. Ischemia–reperfusion injury, quantified by the b-wave of the electroretinogram, was largely prevented by an adenosine A1 receptor agonist. 2 More recently, it has been shown that the A1 receptor plays a key role in the inhibitory effect of ischemic preconditioning on leukocyte rolling during retinal ischemia–reperfusion in the rat. 36 This is in keeping with several studies in the brain, where adenosine is assumed to provide neuroprotection by counteracting Ca2+ overload and by reducing neurotoxic microglial functions. 37  
In conclusion, the present trial is the first human study to indicate vasodilation in the choroid and ONH after administration of adenosine. Moreover, exogenous adenosine induced a reduction in IOP. Considering the neuroprotective properties of adenosine, which have been shown in several animal models, our data indicate that the adenosine system is an attractive target for therapeutic approaches in glaucoma. 
 
Table 1.
 
Baseline Data
Table 1.
 
Baseline Data
Placebo Day Adenosine Day
SBP (mm Hg) 123 ± 8 124 ± 6
DBP (mm Hg) 61 ± 3 61 ± 5
PR (beats/min) 61 ± 6 62 ± 6
IOP (mm Hg) 12 ± 2 12 ± 2
CHBF (arbitrary units) 6.6 ± 1.2 6.5 ± 1.6
ONHBF (arbitrary units) 5.6 ± 1.0 5.4 ± 1.0
FPAM (μm) 4.1 ± 1.4 4.1 ± 1.2
FPAO (μm) 8.3 ± 1.6 8.1 ± 1.5
Figure 1.
 
Percentage change in systemic hemodynamic parameters (SBP, DBP, MAP, PR), IOP, and computed ocular perfusion pressure (OPP = 2/3MAP − IOP) during infusion of adenosine (▴) or placebo (▿). Data are presented as means ± SD (n = 12). *Significant effects of adenosine versus placebo, as calculated from the absolute values.
Figure 1.
 
Percentage change in systemic hemodynamic parameters (SBP, DBP, MAP, PR), IOP, and computed ocular perfusion pressure (OPP = 2/3MAP − IOP) during infusion of adenosine (▴) or placebo (▿). Data are presented as means ± SD (n = 12). *Significant effects of adenosine versus placebo, as calculated from the absolute values.
Figure 2.
 
Percentage change in CHBF and FPAM in the choroid, ONHBF, and FPAO during infusion of adenosine (▴) or placebo (▿). Data are presented as means ± SD (n = 12). *Significant effects of adenosine versus placebo, as calculated from the absolute values.
Figure 2.
 
Percentage change in CHBF and FPAM in the choroid, ONHBF, and FPAO during infusion of adenosine (▴) or placebo (▿). Data are presented as means ± SD (n = 12). *Significant effects of adenosine versus placebo, as calculated from the absolute values.
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Figure 1.
 
Percentage change in systemic hemodynamic parameters (SBP, DBP, MAP, PR), IOP, and computed ocular perfusion pressure (OPP = 2/3MAP − IOP) during infusion of adenosine (▴) or placebo (▿). Data are presented as means ± SD (n = 12). *Significant effects of adenosine versus placebo, as calculated from the absolute values.
Figure 1.
 
Percentage change in systemic hemodynamic parameters (SBP, DBP, MAP, PR), IOP, and computed ocular perfusion pressure (OPP = 2/3MAP − IOP) during infusion of adenosine (▴) or placebo (▿). Data are presented as means ± SD (n = 12). *Significant effects of adenosine versus placebo, as calculated from the absolute values.
Figure 2.
 
Percentage change in CHBF and FPAM in the choroid, ONHBF, and FPAO during infusion of adenosine (▴) or placebo (▿). Data are presented as means ± SD (n = 12). *Significant effects of adenosine versus placebo, as calculated from the absolute values.
Figure 2.
 
Percentage change in CHBF and FPAM in the choroid, ONHBF, and FPAO during infusion of adenosine (▴) or placebo (▿). Data are presented as means ± SD (n = 12). *Significant effects of adenosine versus placebo, as calculated from the absolute values.
Table 1.
 
Baseline Data
Table 1.
 
Baseline Data
Placebo Day Adenosine Day
SBP (mm Hg) 123 ± 8 124 ± 6
DBP (mm Hg) 61 ± 3 61 ± 5
PR (beats/min) 61 ± 6 62 ± 6
IOP (mm Hg) 12 ± 2 12 ± 2
CHBF (arbitrary units) 6.6 ± 1.2 6.5 ± 1.6
ONHBF (arbitrary units) 5.6 ± 1.0 5.4 ± 1.0
FPAM (μm) 4.1 ± 1.4 4.1 ± 1.2
FPAO (μm) 8.3 ± 1.6 8.1 ± 1.5
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