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Partial Antagonism of Endothelin 1–Induced Vasoconstriction in the Human Choroid by Topical Unoprostone Isopropyl
Elzbieta Polska, MD;
Arno Doelemeyer, MSc;
Alexandra Luksch, MD;
Paulina Ehrlich, MD;
Nils Kaehler, MD;
Christine L. Percicot, MD;
George N. Lambrou, MD;
Leopold Schmetterer, PhD
Arch Ophthalmol. 2002;120:348-352.
ABSTRACT
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Background There is increasing evidence that reduced ocular blood flow plays a
role in the pathogenesis of glaucoma. In patients with normal-tension glaucoma,
ocular blood flow abnormalities may be associated with dysfunction of the
endothelin 1 (ET-1) regulation system.
Objective To test the hypothesis that unoprostone, a topical docosanoid, may affect
ET-1–induced vasoconstriction in the human choroid.
Methods In a placebo-controlled, randomized, double-masked, 2-way crossover
design, ET-1 (2.5 ng/kg per minute for 150 minutes) was administered intravenously
to 24 healthy individuals. Thirty minutes after the start of ET-1 infusion,
1 drop of unoprostone or placebo was instilled into the right eye. After another
30 minutes, 2 drops of unoprostone or placebo was topically administered.
This procedure was continued and the dose was increased further until 4 drops
of unoprostone or placebo was reached. Subfoveal and pulsatile choroidal blood
flow were assessed using laser Doppler flowmetry and laser interferometric
measurement of fundus pulsation amplitude, respectively.
Results Administration of exogenous ET-1 decreased choroidal blood flow (mean
± SEM, 17% ± 2%; P<.001) and fundus pulsation
amplitude (mean ± SEM, 19% ± 2%; P<.001).
This effect was significantly blunted when topical unoprostone was coadministered
(mean ± SEM decrease in choroidal blood flow, 7% ± 2%; P = .04 vs placebo; mean ± SEM decrease in fundus
pulsation amplitude, 12% ± 2%; P<.001 vs
placebo).
Conclusion There is a functional antagonism between ET-1 and topical unoprostone
in the choroidal vasculature.
Clinical Relevance Our findings of a functional antagonism between ET-1 and topical unoprostone
in the choroidal vasculature may be important in vascular eye diseases associated
with increased ET-1.
INTRODUCTION
SIGNIFICANT EVIDENCE has been accumulated recently indicating that abnormal
ocular blood flow plays a role in the pathogenesis of glaucoma.1-4
Reduced ocular perfusion as observed in patients with primary open-angle glaucoma
and normal-tension glaucoma is hypothesized to be related to an altered nitric
oxide and endothelin system.5
Endothelin 1 (ET-1) is the most potent vasoconstrictor known, and it
affects vascular tone in ocular vessels. Systemic and topical administration
of ET-1 in rabbits reduced capillary blood flow in the optic nerve head (ONH)
and the choroid.6 Intravitreal injection of
ET-1 in rat eyes induced dose-dependent vasoconstriction of major retinal
vessels as well as pericyte contraction and significantly prolonged retinal
circulation times.7 The ET-1–induced
contraction of retinal arteries depends on the influx of extracellular Ca2+ through membrane potential–operated calcium channels, also
suggesting that ET-1 may participate in the regulation of retinal artery tone.8
Unoprostone isopropyl is a docosanoid therapeutic agent used for glaucoma
and ocular hypertension. Its structure resembles the 22-carbon structure of
the naturally occurring metabolites of docosahexaenoic acid (DHA).9-10 Twenty percent to 60% of the phospholipid
fatty acid content of the neural tissue is composed of DHA, which makes it
the most abundant endogenous polyunsaturated fatty acid in the retina and
brain.11-12 Thirty percent to
40% of the fatty acids of rod photoreceptor outer segments of the human retina
is DHA, which makes the photoreceptor cells the richest in DHA of all the
human cells.13
The synthetic docosanoid unoprostone reduces intraocular pressure (IOP)
by increasing the total aqueous outflow.14
Up to now, few investigators have examined the effect of unoprostone on ocular
blood flow. Topically administered unoprostone had no effect on the ONH circulation
in normal rabbit eyes.15 In humans, choroidal
blood flow (ChBF) was significantly increased after topical application of
unoprostone, but no changes in ONH circulation were observed.16
Intravitreal injection of unoprostone significantly inhibited an ET-1–induced
decrease in ONH blood flow, indicating a functional antagonism between unoprostone
and ET-1 in the rabbit eye.15
In the present study, a functional antagonism between ET-1 and unoprostone
was investigated in the human choroid. For this purpose, we administered exogenous
ET-1 to healthy individuals and investigated whether the vasoconstrictor effect
in the human choroid could be altered by topical application of unoprostone.
Choroidal blood flow was assessed using 2 techniques: laser Doppler flowmetry
and laser interferometric measurement of fundus pulsation amplitude (FPA).
PARTICIPANTS AND METHODS
PARTICIPANTS
Before the study, a sample size calculation was performed using an 
level of .5 and a ß level of .2. Accordingly, 24 healthy, nonsmoking
men were studied (age range, 21-34 years; mean ± SD age, 26 ±
4 years) after approval from the ethics committee of the Vienna University
School of Medicine was obtained. We anticipated a 20% effect of exogenous
ET-1 on ChBF based on the results of a previous study.17
The reproducibility of measurements of ChBF using laser Doppler flowmetry
in our laboratory is comparable to that previously reported for measurements
of ONH blood flow using the same instrument.18
The reproducibility of laser interferometric measurement of FPA is higher19 and therefore is not critical. The sample size was
calculated to allow for detecting changes in ChBF of 8%. This means that the
present study had a power of detecting a 40% reduction in ET-1–induced
changes in ChBF.
The nature of the study was explained, and all participants gave written
consent to participate. All volunteers passed a prestudy screening during
the 4 weeks before the first study day, which included a physical examination
and medical history; a 12-lead electrocardiogram; a complete blood cell count;
measurement of activated partial thromboplastin time, thrombin time, and fibrinogen
levels; a clinical plasma histochemical analysis (measurement of sodium, potassium,
creatinine, uric acid, glucose, cholesterol, triglyceride, alanine aminotransferase,
aspartate aminotransferase,  -glutamyltransferase, alkaline phosphatase,
total bilirubin, and total protein levels); hepatitis A, B, and C testing;
human immunodeficiency virus serologic analysis; and urine analysis. Furthermore,
an ophthalmic examination, including slitlamp biomicroscopy and indirect funduscopy,
was performed in each participant before the first study day. Inclusion criteria
were normal findings in the screening examinations and ametropia of less than
3 diopters. Within 1 week of completion of the study, a follow-up safety investigation
was scheduled, which included a physical examination; a complete blood cell
count; measurement of activated partial thromboplastin time, thrombin time,
and fibrinogen concentration; measurement of sodium, potassium, creatinine,
uric acid, glucose, cholesterol, triglyceride, alanine aminotransferase, aspartate
amino transferase, -glutamyltransferase, alkaline phosphatase, total
bilirubin, and total protein levels; and a urine analysis.
EXPERIMENTAL DESIGN
The study was performed in a randomized, placebo-controlled, double-masked,
2-way crossover design. All participants were asked to refrain from alcohol
and caffeine intake for at least 12 hours before trial days. After a 20-minute
resting period in a sitting position, patients underwent baseline measurement
of ChBF using laser Doppler flowmetry, FPA in the macula using laser interferometry,
IOP (applanation tonometry), blood pressure, and pulse rate.
Thereafter, participants received a continuous intravenous infusion
of ET-1 (Clinalfa AG, Läufelfingen, Switzerland) in a dose of 2.5 ng/kg
per minute for 150 minutes. Thirty minutes after initiating ET-1 administration,
1 drop (35 µL using a micropipette) of unoprostone isopropyl (0.12%)
(Rescula; CIBA-Vision, Basel, Switzerland) or placebo (physiologic saline
solution) was instilled into the right eye. After another 30 minutes, 2 drops
of unoprostone or placebo was topically administered. The dose was further
increased every 30 minutes until 4 drops of unoprostone or placebo was instilled.
All hemodynamic measurements were performed in 30-minute intervals after
the start of ET-1 infusion. Blood pressure was measured at 5-minute intervals
during the entire study. Pulse rate and real-time electrocardiograms were
monitored continuously. Participants were monitored throughout infusion until
variables returned to baseline values. All measurements were performed with
the pupil dilated using tropicamide (Mydriaticum; Agepha, Vienna). Two trial
days were scheduled for each participant. The washout period between study
days was at least 2 days.
METHODS
Systemic Hemodynamics
Mean brachial artery blood pressure was monitored on the upper arm using
an automated oscillometric device. Pulse rate was automatically recorded from
a finger pulse-oxymetric device (HP-CMS patient monitor; Hewlett Packard,
Palo Alto, Calif).
Intraocular Pressure
A slitlamp-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 of the cornea.
Laser Doppler Flowmetry
Using this technique,20 the vascularized
tissue is illuminated by coherent laser light, avoiding visible vessels in
directing the laser beam. Scattering on moving red blood cells leads to a
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 red blood cells. 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 red blood cell velocity, blood volume, and blood
flow can be calculated in relative units.21
In the present study, laser Doppler flowmetry was performed in the fovea to
assess ChBF. For this purpose, a fundus camera–based system was used
(Oculix 4000; Oculix Sarl, Arbaz, Switzerland).
Laser Interferometry
The eye is illuminated by the beam of a single-mode laser diode (
= 783 nm) along the optical axis.22 The light
is reflected at the front side of the cornea and at the retina. The 2 reemitted
waves produce interference fringes from which the distance changes between
the cornea and the retina during a cardiac cycle can be evaluated. The FPA,
which is the maximum distance change between the cornea and the retina during
the cardiac cycle, is an estimate of pulsatile ChBF.23
Again, measurements were performed in the fovea.
DATA ANALYSIS
Statistical analysis was carried out using a statistical software program
(CSS Statistica for Windows; Statsoft, Inc, Tulsa, Okla). For data description,
outcome variables are expressed as percentage change from baseline. A 2-way
analysis of variance model was used to analyze the data. For comparison vs
baseline, we used the time effect to calculate the P
value. The effect vs baseline is given as the maximum percentage change over
the trial period. P values comparing the effect of
exogenous ET-1 in the absence or presence of topical unoprostone were calculated
from the interaction of time by treatment. Data are presented as mean ±
SEM. P<.05 was considered statistically significant.
RESULTS
Baseline values of mean brachial artery pressure, pulse rate, and IOP
are given in Table 1. Changes
in these variables during the study are illustrated in Figure 1. Mean brachial artery blood pressure was slightly elevated
on both study days vs baseline (placebo day: 6% ± 2%, P = .007; unoprostone day: 9% ± 2%; P<.001),
but this increase was not significantly different between study days. Pulse
rate decreased by 11% ± 4% vs baseline on the placebo day (P = .004) and by 10% ± 3% vs baseline on the day of administration
of unoprostone (P<.001). Again, the effect of
ET-1 on pulse rate was not different between study days. Intraocular pressure
decreased significantly by 7% ± 3% and 14% ± 4% vs baseline
on the placebo and unoprostone days, respectively (P<.001
for both). The IOP-lowering effect was more pronounced on the unoprostone
study day than on the placebo study day (P = .01).
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Baseline Values of Systemic Hemodynamic Variables and Intraocular Pressure
in 24 Healthy Individuals*
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Figure 1. Effects of unoprostone or placebo
administration on mean brachial artery blood pressure (A), pulse rate (B),
and intraocular pressure (C) in the presence of exogenous endothelin 1 (2.5
ng/kg per minute) in 24 patients. Asterisk indicates significant treatment
effects vs placebo, as calculated using repeated-measures analysis of variance.
Error bars represent SEM.
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Figure 2 shows the effects
of ET-1 and unoprostone on ocular hemodynamic variables. Infusion of ET-1
led to a significant decrease in FPA. At 150 minutes, FPA was reduced by 19%
± 2% from baseline (P<.001) when placebo
was applied. Administration of unoprostone attenuated the FPA-lowering effect
of ET-1: FPA was reduced by a maximum of 12% ± 2% from baseline (P<.001). Thus, 150 minutes after the start of ET-1 infusion,
the effect on FPA was significantly blunted by coadministration of unoprostone
(P = .003 vs placebo).
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Figure 2. Effects of unoprostone or placebo
administration on fundus pulsation amplitude (A) and choroidal blood flow
(B) in the presence of exogenous endothelin 1 (2.5 ng/kg per minute) in 24
patients. Asterisks indicate significant treatment effects vs placebo, as
calculated using repeated-measures analysis of variance. Error bars represent
SEM.
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Measurement of ChBF exhibited comparable results; during administration
of ET-1, ChBF was significantly decreased vs baseline by 17% ± 2% (P<.001) on the placebo day. As with FPA, coadministration
of unoprostone diminished this effect: 90 minutes after the start of ET-1
administration, ChBF reached its lowest level (reduction of 11% ± 2%
from baseline) and slightly increased thereafter (P<.001
vs baseline). At the end of ET-1 infusion, the reduction in ChBF from baseline
was 7% ± 2% (P = .04 vs placebo).
COMMENT
Results of the present study indicate a functional antagonism between
ET-1 and unoprostone on the level of the human choroid. This was evidenced
from 2 independent measurements of ChBF using laser Doppler flowmetry and
of FPA using laser interferometry. At the highest administered dose, unoprostone
blunted the effect of ET-1 on FPA by more than 40% and on ChBF by more than
50%. The mechanisms underlying this functional antagonism are hitherto unidentified.
In the human choroid, the potent vasoconstrictor effects of ET-1 are primarily
mediated via the ET-A receptor,24 which is
located directly on the smooth muscle cells. No data, however, are currently
available, to our knowledge, to indicate that unoprostone has any affinity
to this ET receptor subtype. Preliminary data suggest rather that unoprostone
isopropyl does not bind to either ET-A or ET-B receptors (CIBA-Vision internal
report, MDS Panlabs Pharmacology Services; 1999).
Another possibility is that unoprostone interacts with the release of
cytoplasmic Ca2+, which is responsible for many cellular mechanisms
induced by ET-1.25 The effects of ET-1 on vascular
tone in a specific vascular bed depend on the relative expression of ion channels
and on the spatial and temporal pattern of the Ca2+ signals. It
is obvious from the present study results that in the human choroid, ET-1–induced
vasoconstriction predominates over vasodilatory effects of the peptide, which
may be due to activation of nonselective cation channels, Ca2+-activated
Cl-channels, and voltage-dependent L-type Ca2+
channels. This mechanism would be consistent with previous results,26 where it was shown that in the human ONH, effects
of ET-1 can be antagonized by administering low-dose nifedipine. Effects of
unoprostone on ET-1–induced changes in intracellular calcium concentration
in vascular smooth muscle cells, however, remain to be established.
In the present study, we cannot exclude effects on ocular perfusion
pressure during drug administration because we observed significant changes
in mean brachial artery blood pressure and IOP on both study days. However,
a systemic hypertensive effect of ET-1 administration was observed on both
study days and therefore does not limit the comparability of our ChBF variables
on the 2 study days. Intraocular pressure was reduced on the placebo and unoprostone
days, but this effect was more pronounced when unoprostone was coadministered
with exogenous ET-1. Therefore, ocular perfusion pressure may have been slightly
higher on the unoprostone day compared with the placebo day. The effect of
unoprostone on IOP at less than 2 mm Hg was, however, small in the present
study, and it is unlikely that this small effect had any detectable effect
on choroidal perfusion. In the present study, administration of unoprostone
blunted the ET-1–induced effect on ChBF by more than 50%, which cannot
be caused by changes in ocular perfusion pressure of a few millimeters of
mercury.
We observed a significant reduction in IOP on the placebo day when ET-1
was intravenously administered. Previous animal and in vitro studies on the
effect of exogenous ET-1 on IOP are contradictory, and reduced27-28
and increased29 IOPs have been reported. One
must be careful when interpreting the results of infusion of ET-1 on IOP in
the present study because no placebo control was used with respect to ET-1,
and a reduction in IOP could result from repeated applanation tonometry. On
the other hand, systemic administration of ET-1 may induce effects on ciliary
body blood flow, which in turn may decrease aqueous humor production. Our
data, therefore, do not contradict the view that ET-1 is an important factor
contributing to contraction of the trabecular meshwork.30
Our findings could be of interest in patients with glaucoma, in which
ET-1 is assumed to play a pathogenic role.31
This may be related not only to the role of ET-1 in the control of IOP but
also to the reduction in ONH blood flow as measured in patients with glaucoma2, 32-33 potentially mediated
by ET-1. The clinical significance of the results of the present trial, however,
remains to be investigated. A recent study in patients with normal-tension
glaucoma did not show an effect of topical unoprostone on ocular hemodynamic
variables.34 Although patients included in
this trial were tested for vasospastic diathesis, the local level of ET-1
in the eye was unknown. Moreover, short-term experiments applying high doses
of unoprostone are not necessarily comparable to long-term effects of unoprostone
in patients with glaucoma, and it is unclear whether a functional antagonism
may also be achieved with lower doses of the drug. Results of in vitro experiments,
however, indicate that already low doses of unoprostone exert vasodilation
in ET-1–contracted pig retinal arterioles.35
Endothelin 1 has also been implicated in the pathogenesis of other eye
diseases, including diabetic retinopathy,36-37
retinal vein occlusion,38 and human immunodeficiency
virus–related retinopathy.39 Hence, there
is significant need to further establish the potential role of drugs that
interfere with the ET-1 system in the treatment of ocular vascular disease.
The present study may establish unoprostone as a candidate for further investigations
in this direction.
A limitation of all studies investigating ocular blood flow responses
is that no technique is capable of directly quantifying perfusion in the eye.
Kiel40 provided an excellent overview of all
currently available techniques for the assessment of ocular blood flow. He
concluded that no gold standard method is available, neither in humans nor
in experimental animals. However, effects of unoprostone on ET-1–induced
vasoconstriction in the present study were evidenced with 2 independent methods.
In addition, results of previous studies indicate that the techniques used
provide consistent results with several different stimuli.41-42
In conclusion, our data indicate that unoprostone isopropyl applied
topically in the eye partially reverses the vasoconstrictor effect of infused
exogenous ET-1 in the human choroid. Whether this effect is of clinical relevance
for the treatment of patients with glaucoma remains to be shown.
AUTHOR INFORMATION
Submitted for publication March 6, 2001; final revision received November
7, 2001; accepted November 16, 2001.
Unoprostone isopropyl (0.12%) (Rescula; Novartis Ophthalmics, Basel,
Switzerland) was donated by Novartis Ophthalmics.
Corresponding author: Leopold Schmetterer, PhD, Department of Clinical
Pharmacology, Allgemeines Krankenhaus Wien, Waehringer Guertel 18-20, A-1090
Vienna, Austria (e-mail: leopold.schmetterer{at}univie.ac.at).
From the Department of Clinical Pharmacology (Drs Polska, Luksch, Ehrlich,
Kaehler, and Schmetterer and Mr Doelemeyer) and the Institute of Medical Physics
(Dr Schmetterer), Vienna University, Vienna, Austria; Novartis Ophthalmics,
Basel, Switzerland (Drs Percicot and Lambrou and Mr Doelemeyer); and University
Eye Clinic, Strasbourg, France (Dr Lambrou).
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