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(Investigative Ophthalmology and Visual Science. 2001;42:1499-1504.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Comparison of the Vasoactive Effects of the Docosanoid Unoprostone and Selected Prostanoids on Isolated Perfused Retinal Arterioles

Dao-Yi Yu1,2, Er-Ning Su1, Stephen J. Cringle1, Christian Schoch3, Christine P. Percicot3 and George N. Lambrou3,4

1 From the Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth; 2 Lions Eye Institute, Nedlands, Perth, Western Australia; 3 Ciba Vision, Basel, Switzerland; and the 4 University Eye Clinic, Strasbourg, France.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
PURPOSE. To compare the vasoactive properties of the docosanoid unoprostone, its free acid, and different members of the prostanoid family on isolated perfused pig retinal arterioles to assess their potential to modulate retinal blood flow.

METHODS. Segments of porcine retinal arterioles were dissected, cannulated, and perfused, and their diameter monitored during either intraluminal or extraluminal application of increasing doses (10-10–10-4 M) of either the docosanoid unoprostone isopropyl and its free acid or of selected prostanoids: prostaglandin (PG) F2{alpha} and thromboxane A2 analogue (U46619). Studies were performed on arterioles in their uncontracted state, and also during precontraction with endothelin-1 (10-9 M). The significance of any induced change in vessel diameter was assessed in relation to the initial vessel diameter or, in the case of endothelin-1 administration, to the contracted diameter with endothelin-1 alone.

RESULTS. In normal-tone arterioles without endothelin-1 contraction, PGF2{alpha} and U46619 both produced a potent dose-dependent contraction, but neither unoprostone isopropyl nor unoprostone free acid had a significant vasoactive effect. In endothelin-1–contracted arterioles, U46619 produced further contraction, PGF2{alpha} produced a slight vasodilatation, and unoprostone isopropyl and its free acid produced a pronounced dilatation.

CONCLUSIONS. Of the agents tested, unoprostone isopropyl and its free acid were the most potent vasodilators of endothelin-1–contracted pig retinal arterioles. Members of the prostanoid family demonstrated a different effect on the diameter of isolated retinal arterioles compared with the docosanoids. The potential therefore exists for the docosanoid unoprostone to have a beneficial effect on retinal blood flow in addition to any reduction in intraocular pressure.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Unoprostone isopropyl is a docosanoid that has been introduced recently for the treatment of glaucoma, under the trade name Rescula (Ciba Vision, Basel, Switzerland). Being a compound with a 22-carbon chain, it resembles the naturally occurring oxygenated metabolites of the docosahexaenoic and the docosatetraenoic acids. The latter are 22-carbon polyunsaturated fatty acids, which are abundant in brain and retina.1 2 Although these fatty acids have been known for several decades, only some of their particular functions and no specific receptors have been identified. As a synthetic docosanoid, unoprostone isopropyl has been shown to lower intraocular pressure (IOP) in various animal species3 4 and humans,5 6 7 8 probably by increasing aqueous humor outflow.9 10

Glaucoma remains the second most common cause of blindness in the world.11 Although lowering of IOP has been the mainstay of glaucoma treatment for many years, more scientific evidence has emerged recently that vascular factors are probably also involved in the pathogenesis of glaucomatous optic neuropathy.12 Patients with normal-tension glaucoma (NTG) or high-tension glaucoma, in whom disease progresses despite normal or normalized IOP, have been shown, for example, to have slower blood flow velocity in the retina,13 the choroid,14 15 and the optic nerve head.16 Increased plasma levels of endothelin (ET)-1, the most potent physiologic vasoconstrictor presently known,17 18 have also been reported in patients with NTG.19 20

Because the causative factors in impaired ocular blood flow (OBF) in glaucomatous eyes are still not well defined, the accumulating evidence of the hemodynamic effects of existing IOP-lowering medications is still contradictory and uncertain. Although some investigators have suggested that certain topical IOP-lowering medications may have a beneficial effect on the OBF with an unclear mechanism and clinical relevance,21 22 others have focused on the importance of the nondetrimental effects of topical IOP-lowering drugs on ocular circulation.23 24 25 In glaucoma therapy, any vasoactive effects on the retinal vasculature may be particularly relevant, given the increasing acceptance of an ischemic component to the pathophysiology of glaucoma.18 26 Thus, it is clear that identifying and abolishing the causative factors in impaired OBF in glaucomatous eyes may lead to a slowing down of the disease’s progress and ultimately to preservation of the visual field.

Although the vasoactive properties of some of the older generation glaucoma medications have been extensively studied, the vasoactive properties of the newer generation drugs, such as the prostaglandin (PG) analogues and docosanoids have received little attention.

Since its launch in Japan in 1994, unoprostone isopropyl has been reported to increase OBF both in animals27 28 and in humans.29 We wanted to elucidate the mechanisms by which it exerts its beneficial effects on OBF.

PGs are known to have vasoactive effects in many organs. In ocular tissues, the vasoactive effects of closely related members of the prostaglandin family can vary significantly depending on the specific vessels involved.30 PGF2{alpha} is known to have contractile effects on the feeder vessels to the eye31 32 33 34 and also in bovine retinal arteries.35 36 Comparatively little is known, however, about the vasoactive effect of PGF2{alpha} and other prostanoids on retinal arterioles.

Because the development of IOP-lowering agents that also improve OBF is an attractive prospect in the clinical management of glaucoma, we attempted to determine the vasoactive properties of the new docosanoid agent Rescula on isolated perfused pig retinal arterioles, a preparation that has been shown to demonstrate vasoactive properties similar to those of human retinal arterioles.37 Although clinical trials have shown that unoprostone is pharmacologically different from the PG analogues, we decided to compare its vasoactive properties with those of some of the PGs. The selected agents were PGF2{alpha}, thromboxane A2 analogue U46619, unoprostone isopropyl, and its metabolite, unoprostone free acid. The thromboxane A2 analogue U46619 was chosen because of its highly potent vasoactive effects in the cardiovascular system. PGF2{alpha} was selected because it is the head of the PGF family. Using the diameter of the retinal artery as a measure of vasoactivity, the potency of intraluminal and extraluminal drug delivery38 was compared, as was the action of each agent on arterioles in their uncontracted state and during ET-1–induced contractions.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
General
The dissection, cannulation, perfusion, monitoring, and vessel diameter measuring system are described elsewhere37 38 39 40 41 and will be only briefly described herein. Pig eyes were obtained from a local abattoir. After enucleation, the eyes were placed in a sealed bottle of oxygenated Krebs solution and kept on ice during transfer to the laboratory (30–45 minutes). All procedures conformed to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Dissection and Cannulation of Vessels
The eyes were sectioned at the pars plana ciliaris, separating the anterior segment and adherent vitreous body from the posterior pole with the aid of a dissecting microscope. The retina, choroid, and sclera were divided into quadrants. The retina was then separated from the underlying choroid and sclera. A quadrant of retina was then placed on a hollowed glass slide containing Krebs solution. Individual first-order retinal arterioles were dissected from the retinal tissue with a micropipette. A segment of retinal artery approximately 100 µm in diameter, 800 to 1500 µm long, and containing only one relatively large side branch was selected. This arterial segment was then relocated to an incubation chamber (PDMI-2, Medical System Corp., Great Neck, NY) mounted on the stage of an inverted microscope (Diaphot-TMD; Nikon, Tokyo, Japan). The chamber contained 5 ml Krebs solution. Temperature was maintained at 37°C, and the incubating solution equilibrated with 95% O2-5% CO2, to maintain PaO2, PaCO2, and pH of the incubating solution.

The arterial segment was then cannulated at both ends, by using a customized pipette and manipulating system.39 The vessel was perfused through the proximal end in the orthograde direction at a constant flow of 5 µl/min. The vessel was visualized on video, and a preprogrammed computer algorithm was used to measure the external vessel diameter at user-selected locations from a frame-grabbed image at 2-second intervals. The vessel was left to stabilize for 30 minutes before any drug study.

Intraluminal and Extraluminal Drug Delivery
Intraluminal drug delivery was administered as a 5-µl bolus into the perfusate stream through an HPLC-type sample injector valve. This system allowed the bolus to enter the perfusate stream without pressure artifacts. The size, and therefore the duration, of the bolus was sufficient for vasoactive responses of the vessel to stabilize. Extraluminal drug delivery was accomplished by direct pipetting into the incubating solution to achieve the required concentration. This was done with cumulatively increasing doses, without washing out the bath between successive applications of the same agent. The dosage range used was 10-10 to 10-4 M. All data are presented as the normalized percentage of vessel diameter, where the data are normalized to the diameter of the vessel before any drug administration. When extraluminal application of ET-1 was used to precontract the vessels, the ET-1 remained in the bath during all subsequent drug administrations.

Solutions
Vessels were usually bathed and perfused with normal Krebs solution composed of (in mM) NaCl 119, KCl 4.6, CaCl2 1.5, MgCl2 1.2, NaHCO3 15, NaH2PO4 1.2, glucose 6. Solutions were equilibrated with 95% O2-5% CO2.

Drugs
All chemicals and vasoactive agents used, including PGF2{alpha} and the thromboxane A2 analogue U46619, were obtained from Sigma Chemical Co. (St Louis, MO), except for human-porcine ET-1 (Auspep, Sydney, Australia), unoprostone isopropyl, and unoprostone free acid (Ueno Fine Chemicals Industry, Ltd., Osaka, Japan). All vasoactive agents were dissolved and diluted in distilled water, except unoprostone isopropyl and unoprostone free acid, which were made up as a stock in absolute ethanol and diluted in water. Stock solutions of all drugs were stored at -70°C, and fresh dilutions were made daily.

Experimental Protocol
After equilibration, either an intraluminal injection of 124 mM K+ Krebs, or extraluminal application of ET-1 (10-9 M), was administered to confirm vessel viability. Vessels were rejected if the contraction response did not result in a diameter of less than 85% of the uncontracted baseline diameter.

The effect of intraluminal and extraluminal delivery of increasing doses of each agent on the diameter of pig retinal arterioles was assessed in vessels in their normal state and after precontraction with ET-1 (10-9 M).

Statistics
All statistical testing was performed with a statistics software program (SigmaStat; SPSS, Chicago, IL). The significance of any drug-induced, concentration-dependent changes was tested using repeated-measures one-way ANOVA, with a significance acceptance level of P < 0.05 for the F value. When comparing dose–response curves to test for differences between different drugs or between intraluminal and extraluminal administration, two-way ANOVA with drug concentration as the second factor was used with an acceptance level of P < 0.05. When appropriate, Student’s t-test was used. All mean data are expressed as mean ± SE, and all error bars on graphs in figures also indicate SE. All vessel diameters are expressed as a percentage of the baseline diameter prior to any drug administration.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Preliminary studies confirmed that the vehicle alone produced no significant vasoactive effect in normal-tone or ET-1–contracted pig retinal arterioles (P = 0.11). Both intraluminal and extraluminal administration of PGF2{alpha} (10-10–10-4 M) produced significant (P < 0.05) vasoactive effects on pig retinal arterioles (Fig. 1) . In normal-tone vessels, PGF2{alpha} produced a contraction at doses of 10-9 M and higher when delivered intraluminally (P < 0.05) and at doses of 10-5 M and higher when delivered extraluminally (P < 0.05). At 10-4 M the maximal PGF2{alpha}–induced contractions were 73.3% ± 2.1% of normal-tone diameter with intraluminal (n = 19) and 82.3% ± 1.5% with extraluminal (n = 22) delivery. In ET-1–contracted vessels PGF2{alpha} induced a significant dilatation at 10-8 M and higher with both intraluminal and extraluminal application (P < 0.05). At 10-4 M PGF2{alpha}, the arterial diameters were 72.8% ± 2.3% for intraluminal (n = 19) and 73.4% ± 1.7% for extraluminal (n = 17) delivery. The magnitudes of the ET-1–induced contractions were not significantly different (P = 0.735) between the intraluminal and extraluminal groups (66.7% ± 2.2% and 67.7% ± 2.0%, respectively).



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  		Figure 1. Vasoactive response of pig retinal arterioles to intraluminal and extraluminal administration of PGF2{alpha} (10-10–10-4 M). The results from normal-tone vessels are shown in (A), where (*) indicates a significant contraction when compared with the starting diameter (P < 0.05). Data from ET-1–contracted vessels are shown in (B), where (*) indicates a significant dilatation from the ET-1–contracted diameter (P < 0.05).

 
Both intraluminal and extraluminal administration of U46619 (10-10–10-4 M) produced significant vasoactive effects (P < 0.05) on pig retinal arterioles (Fig. 2) . In normal-tone vessels, U46619 produced a contraction at doses of 10-7 M and higher when delivered intraluminally or extraluminally (P < 0.05). At 10-4 M the maximal U46619-induced contractions were to 65.2% ± 2.6% for intraluminal (n = 18) and 64.5% ± 4.1% for extraluminal (n = 14) delivery. In ET-1–contracted vessels, U46619 induced a further significant contraction at 10-9 M and higher with intraluminal application and 10-8 M and higher with extraluminal application (P < 0.05). At 10-4 M U46619 the arterial diameters were 53.9% ± 1.6% with intraluminal (n = 18) and 54.4% ± 2.0% with extraluminal (n = 34) delivery. The magnitudes of the ET-1–induced contractions were not significantly different (P = 0.069) between the intraluminal and extraluminal groups (66.8% ± 1.7% and 68.8% ± 1.8%, respectively).



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  		Figure 2. Vasoactive response of pig retinal arterioles to intraluminal and extraluminal administration of U46619 (10-10–10-4 M). The results from normal-tone vessels are shown in (A), where (*) indicates a significant contraction with respect to the starting diameter (P < 0.05). Data from ET-1–contracted vessels are shown in (B), where (*) indicates a significant contraction from the ET-1–contracted diameter (P < 0.05).

 
Neither intraluminal (P = 0.076) nor extraluminal (P = 0.22) administration of unoprostone isopropyl (10-10–10-4 M) produced a significant vasoactive effect on normal-tone pig retinal arterioles (Fig. 3) . In ET-1–contracted vessels, unoprostone isopropyl induced a significantly pronounced dilatation at 10-9 M and higher with intraluminal application and 10-5 M and higher with extraluminal application (P < 0.05). At 10-4 M unoprostone isopropyl, the arterial diameters were 89.7% ± 1.4% with intraluminal (n = 39) and 83.8% ± 2.1% with extraluminal (n = 36) delivery. The magnitudes of the ET-1–induced contractions were not significantly different (P = 0.80) between the intraluminal and extraluminal groups (69.7% ± 1.9% and 70.4% ± 2.0%, respectively).



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  		Figure 3. Vasoactive response of pig retinal arterioles to intraluminal and extraluminal administration of unoprostone isopropyl (10-10–10-4 M) in normal-tone vessels (A). Data from ET-1–contracted vessels are shown in (B), where (*) indicates a significant dilatation from the ET-1–contracted diameter (P < 0.05).

 
Neither intraluminal (P = 0.145) nor extraluminal (P = 0.469) administration of unoprostone free acid (10-10–10-4 M) produced a significant vasoactive effect on normal-tone pig retinal arterioles (Fig. 4) . In ET-1–contracted vessels, unoprostone free acid induced a significantly pronounced dilatation at 10-8 M and higher with intraluminal application and 10-9 M and higher with extraluminal application (P < 0.05). At 10-4 M unoprostone free acid, the arterial diameters were 92.6% ± 4.5% with intraluminal (n = 22) and 85.7% ± 4.0% with extraluminal (n = 17) delivery. The magnitudes of the ET-1–induced contractions were not significantly different (P = 0.444) between the intraluminal and extraluminal groups (71.9% ± 4.5% and 69.4% ± 2.3%, respectively).



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  		Figure 4. Vasoactive response of pig retinal arterioles to intraluminal and extraluminal administration of unoprostone free acid (10-10–10-4 M) in normal-tone vessels (A). Data from ET-1–contracted vessels are shown in (B), where (*) indicates a significant dilatation from the ET-1–contracted diameter (P < 0.05).

 
Both intraluminal and extraluminal administration of unoprostone isopropyl and unoprostone free acid produced significantly more dilatation in ET-1–contacted vessels than did PGF2{alpha} (P < 0.05).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
According to our results, docosanoid unoprostone isopropyl and its metabolite had different vasoactive effects on both contracted and uncontracted pig retinal arterioles than did related members of the PG family. Although the docosanoid had no impact on normal, uncontracted vessels, it had a pronounced vasorelaxing effect on ET-1–contracted vessels. In contrast, PGF2{alpha} and the thromboxane analogue U46619 demonstrated powerful vasoconstrictive effects in normotensive vessels. PGF2{alpha} had a relaxing effect on ET-1–preconstricted vessels that was far less pronounced than the effect of the docosanoid. The thromboxane analogue led to a further constriction of the already precontracted vessels.

Maximal doses of PGF2{alpha} (10-4 M) caused the vessel diameter to reduce to 73% of preadministration diameter with intraluminal application and to 82% with extraluminal delivery. The thromboxane A2 analogue U46619 contracted the pig retinal arterioles more severely, down to 65% with intraluminal and 64% with extraluminal application. In contrast, neither unoprostone isopropyl nor its metabolite, unoprostone free acid, produced a significant vasoactive effect on pig retinal arterioles under spontaneous-tone conditions.

In retinal arterioles contracted with ET-1, U46619 produced a further contraction effect, reducing vessel diameter to approximately 54% of the normal-tone baseline. In contrast, PGF2{alpha} produced a modest dilatation of ET-1–contracted arterioles with both intraluminal (9%) and extraluminal (8.4%) application. Both unoprostone isopropyl and its metabolite, unoprostone free acid, had more dramatic vasodilatory effects on ET-1–contracted vessels. Unoprostone produced a diameter increase of 29% with intraluminal and 19% with extraluminal delivery, whereas the corresponding figures for unoprostone free acid were 29% and 24%, respectively.

Our finding of vasoconstrictive effects of PGF2{alpha} and U46619 in normal-tone arterioles agrees with earlier studies on isolated long posterior ciliary artery, ophthalmic artery, or bovine retinal arterioles.31 32 33 34 35 36 However, as far as we know, the finding of the dual effect of PGF2{alpha} in contracting normal-tone vessels but dilating ET-1–contracted vessels is novel.

Many factors may be involved in the diversity of vasoactive response of pig retinal arterioles, among which are the presence of specific PG receptors and the concentration of the PG used.42 43 44 45 46 47 48 The potent contractile effect of the thromboxane A2 analogue, U46619, and PGF2{alpha} may indicate the existence of TP and FP receptors in the porcine retinal arterioles.

Barrere et al.49 recently reported in vitro data from various animal tissues showing that unoprostone isopropyl has no affinity to any PG receptors (FP, DP, EP, TP, or IP), indicating that vasoactivity of unoprostone isopropyl may not be mediated by prostanoid receptors. The vasoactive effects of PGs on ocular vasculature may be changed by different physiological and pathologic conditions. We have reported that PGF2{alpha} produces a significant contractile effect in cat ophthalmic artery and that pH modulates this contractile effect.33 We also have studied the vasoactive effects of PGF2{alpha} on the ocular microvasculature in an isolated perfused rat eye preparation and found that PGF2{alpha} induces a net contractile effect in rats with streptozotocin (STZ)-induced diabetes that was significantly greater than that seen in normal rats.34

Increases in plasma ET-1 levels have been reported in patients with NTG19 20 and in the aqueous humor of patients with open-angle glaucoma.50 Reduced OBF may play an important role in the pathophysiology of glaucoma.12 Therapeutic agents that are able to counteract any vasoconstrictive effect of ET-1 on retinal vessels may therefore be of particular use in glaucoma management.

Direct vasoactivity of unoprostone isopropyl and unoprostone free acid on retinal arterioles has not been studied before, although a dilatory effect on potassium-contracted ciliary arteries has been reported.51 In vivo studies of optic nerve head blood flow in the rabbit eye suggest a vasodilatory effect of unoprostone isopropyl, because intravitreal injection inhibits the decrease in optic nerve head blood flow induced by ET-1.27 In monkey eyes, the use of unoprostone isopropyl to prevent ET-1–induced spasm of the choroidal arteries has recently been reported.52

In summary, in this in vitro experiment the newly developed IOP-lowering docosanoid unoprostone isopropyl antagonized the constrictive effects of ET-1 without affecting the tension of normal vessels. Taken together with the evidence for increased OBF with unoprostone isopropyl, it may be implied that unoprostone isopropyl has beneficial effects on OBF. This is a promising sign that this agent, whether used alone or in addition to other glaucoma medications, may produce improved outcomes in glaucomatous human eyes.


   Acknowledgements
 
The authors thank Dean Darcey and Judi Granger for technical assistance.


   Footnotes
 
Supported by the National Health and Medical Research Council of Australia and by Ciba Vision.

Submitted for publication September 13, 2000; revised December 11, 2000; accepted January 24, 2001.

Commercial relationships policy: C (D-YY, E-NS, SJC); E (CS, CPP, GNL).

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: Dao-Yi Yu, Lions Eye Institute, 2 Verdun Street, Nedlands, Perth, Western Australia 6009. dyyu{at}cyllene.uwa.edu.au


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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