IOVS Journal of Biological Chemistry
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

(Investigative Ophthalmology and Visual Science. 2005;46:2006-2011.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.04-1527
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (13)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ota, T.
Right arrow Articles by Araie, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ota, T.
Right arrow Articles by Araie, M.

Prostaglandin Analogues and Mouse Intraocular Pressure: Effects of Tafluprost, Latanoprost, Travoprost, and Unoprostone, Considering 24-Hour Variation

Takashi Ota,1 Hiroshi Murata,1,2 Ei-ichiro Sugimoto,1,3 Makoto Aihara,1 and Makoto Araie1

1From the Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan; the 2Tokyo Metropolitan Geriatric Medical Center, Tokyo, Japan; and the 3Department of Ophthalmology, University of Hiroshima School of Medicine, Hiroshima, Japan.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To establish a mouse model for the pharmacological analysis of antiglaucoma drugs, considering the effect of variations in IOP during 24 hours on the drugs’ effects, and to evaluate the effect of a newly developed FP agonist, tafluprost, on mouse IOP, in comparison with three clinically available prostaglandin (PG) analogues.

METHODS. Inbred adult ddY mice were bred and acclimatized under a 12-hour light–dark cycle. With mice under general anesthesia, a microneedle method was used to measure IOP. A single drop of 3 µL of either drug or vehicle solution was topically applied once into one eye in each mouse, in a blinded manner, with the contralateral, untreated eye serving as the control. IOP reduction was evaluated by the difference in IOP between the treated and untreated eyes in the same mouse. First, to determine the period feasible for demonstrating a larger magnitude of ocular hypotensive effect, the 24-hour diurnal variation in mouse IOP was measured, and 0.005% latanoprost was applied at the peak or trough time of variation in 24-hour IOP. The time point of the most hypotensive effect was selected for further studies, to evaluate the effects of PG analogues. Second, mice received tafluprost (0.0003%, 0.0015%, 0.005%, or 0.015%), latanoprost (0.001%, 0.0025%, or 0.005%), travoprost (0.001%, 0.002%, or 0.004%), or isopropyl unoprostone (0.03%, 0.06%, or 0.12%), and each corresponding vehicle solution. IOP was then measured at 1, 2, 3, 6, 9, and 12 hours after drug administration. The ocular hypotensive effects of the other three PG analogues were compared with that of tafluprost. All experiments were conducted in a masked study design.

RESULTS. The IOP in the untreated mouse eye was higher at night than during the day. Latanoprost significantly lowered IOP at night (21.4%), compared with the IOP in the untreated contralateral eye 2 hours after administration. The maximum IOP reduction was 20.2% ± 2.0%, 18.7% ± 2.5%, and 11.2% ± 1.8% of that in the untreated eye 2 hours after administration of 0.005% tafluprost, 0.005% latanoprost, and 0.12% isopropyl unoprostone, respectively, whereas it was 20.8% ± 4.6% at 6 hours with 0.004% travoprost (n = 7~17). The order of ocular hypotensive effects of three clinically used PG analogues in mice was comparable to that in humans. Area under the curve (AUC) analysis revealed dose-dependent IOP reductions for each PG analogue. Tafluprost 0.005% decreased IOP more than 0.005% latanoprost at 3, 6, and 9 hours (P = 0.001–0.027) or 0.12% unoprostone at 2, 3, and 6 hours (P = 0.0004–0.01).

CONCLUSIONS. The 24-hour variation in mouse eyes should be taken into consideration when evaluating the reduction of IOP. The mouse model was found to be useful in evaluating the pharmacological response to PG analogues. A newly developed FP agonist, 0.005% tafluprost, lowered normal mouse IOP more effectively than did 0.005% latanoprost.

Prostaglandin (PG) analogues have been widely used for the treatment of glaucoma and ocular hypertension, because they are more effective in lowering intraocular pressure (IOP) and have considerably fewer systemic side effects than do ß-blockers. Currently, four different types of PG analogues—isopropyl unoprostone, latanoprost, travoprost, and bimatoprost—are used for the treatment of glaucoma. Recently, a new PG-analogue, tafluprost (AFP-168), has been developed.1 2 The intraocular metabolites of these PG analogues, with the exception of unoprostone, show a high affinity for the prostanoid FP receptor (FP).1 2 3 4 5 6 7 FP is expressed in human ocular tissues such as the ciliary body and the sclera.8 9 Latanoprost and travoprost, both selective FP agonists, have been thought to bind to FP, leading to IOP reduction by causing an increase in uveoscleral outflow.10 The molecular mechanisms of the ocular hypotensive effects of bimatoprost or unoprostone, however, have not been fully clarified.

The availability of various transgenic mice allows us to investigate the role of a molecule in vivo. To clarify physiological mechanisms in finely structured tissues such as those involved in IOP reduction, in vivo assessment using an animal model is indispensable. The ocular hypotensive effects of latanoprost and aqueous dynamics in mice have recently been demonstrated.11 12 Latanoprost decreases IOP in a dose-dependent manner,11 a finding that is supported by the fact that aqueous outflow in mice mainly depends on the uveoscleral outflow pathway.12 These results suggest the possibility of using prostanoid-receptor knockout mice to investigate the relationship between prostanoid receptors and the reduction of IOP. In fact, Crowston et al.13 recently found that the latanoprost-induced ocular hypotensive effect is mainly dependent on the FP receptor, since its effect diminishes in FP receptor knockout mice. However, the ocular hypotensive effects of PG analogues other than latanoprost have not been fully investigated in mouse eyes, and the influence of the 24-hour variation in IOP on ocular hypotensive effects has not yet been considered.

Thus, the present investigation was undertaken to establish a ddY mouse model for the pharmacological analysis of antiglaucoma drugs, taking the 24-hour IOP variation into consideration, and to evaluate the ocular hypotensive effect of a newly developed FP agonist, tafluprost, in comparison with three other clinically used PG analogues.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Animals
All experiments were performed in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Male ddY inbred mice, the most widely used strain in Japan, were obtained at 6 or 7 weeks after birth from Saitama Jikken (Saitama, Japan). All mice were housed in clear cages covered with air filters and containing white chips for bedding. The environment was kept at 21°C with a 12-hour light–dark cycle (on at 0600; off at 1800). All mice were fed ad libitum. The animals were acclimatized to the environment for at least 2 weeks before experiments.

Preparation and Application of Ophthalmic Solution
Latanoprost was purchased from Cayman Chemical Co. (Ann Arbor, MI) and dissolved in its vehicle solution, as reported previously.14 Travoprost, isopropyl unoprostone, tafluprost, and their vehicle solutions were provided by Alcon Inc. (Fort Worth, TX), R-Tech Ueno Ltd. (Hyogo, Japan), and Santen Pharmaceutical Co., Ltd. (Osaka, Japan), respectively. The solutions were originally prepared in their clinically used concentrations, and then serial dilutions were prepared with their corresponding vehicle solutions. With a micropipette, 3 µL of PG solution or vehicle was topically applied to one randomly selected eye in a masked manner. The untreated contralateral eye served as the control.

IOP Measurement
IOP was measured by a microneedle method in mice anesthetized by ketamine and xylazine, as described previously.11 Briefly, a microneedle made of borosilicate glass (100-µm tip diameter) was connected to a pressure transducer (Model BLPR; World Precision Instruments, Sarasota, FL). The system pressure detected by the transducer was recorded by a data-acquisition and analysis system (PowerLab; ADInstruments, Colorado Springs, CO). In mice under general anesthesia, the microneedle was placed in the anterior chamber, and the conducted pressure was sequentially recorded in both eyes during a 4- to 7-minute time window. The effect of each drug and vehicle was calculated as the difference in IOP ({Delta}IOP = IOP in the treated eye – IOP in the untreated contralateral eye). The percentage of IOP reduction was defined as 100 x {Delta}IOP/IOP in the untreated contralateral eye (%) in each mouse. In addition, the data thus obtained underwent area-under-the-curve (AUC; percent per hour) analysis, according to the trapezoidal rule.

Assessment of 24-Hour Variation and Difference in IOP between the Eyes of the ddY Mouse
The 24-hour IOP pattern was assessed by collecting IOP measurements at 3-hour intervals, starting from 0600, as reported previously (n = 6).15 One of two eyes in each mouse was selected randomly. During the IOP measurement, room lighting similar to that in the vivaria was maintained. During the dark phase, all procedures were performed under red-light illumination to eliminate the effect of lighting on IOP. For each mouse, data points were collected at 1-week intervals to eliminate any effects of the previous IOP measurement. The measurements at 0600 were obtained after turning the light on and those at 1800 were obtained before turning the light off.

Because ocular hypotensive effects were evaluated by comparison of IOP between treated and untreated contralateral eyes, the similarity of IOP in both eyes was validated in ddY mice. In mice under general anesthesia,11 the IOP in both eyes was sequentially measured in the time window just described, and the bilateral difference was compared.

Effect of Latanoprost on Daytime and Nighttime IOP
First, to determine the period feasible for demonstrating a greater degree of ocular hypotensive effect in consideration of the 24-hour IOP variation,15 we applied 0.005% latanoprost at 0700 or 1900, and measured IOP as described, 2 hours after administration.

Effects of PG Analogues on Mouse IOP
Tafluprost (0.0003%, 0.0015%, 0.005%, or 0.015%), latanoprost (0.001%, 0.0025%, or 0.005%), travoprost (0.001%, 0.002%, or 0.004%), isopropyl unoprostone (0.03%, 0.06%, or 0.12%), or each vehicle solution was administrated topically to one randomly chosen eye. Three investigators instilled eye drops, each without knowing what the other two were doing, and the fourth investigator, masked to the treatments, measured IOP at 1, 2, 3, 6, 9, or 12 hours after the drugs were administered, as described earlier. Thus, all measurements were performed under masked conditions. The ocular hypotensive effect of each drug was calculated, and its dose-dependency was evaluated by AUC analysis. Finally, IOP reduction by 0.005% tafluprost was compared with that produced by clinically used concentrations of the other drugs—0.005% latanoprost, 0.004% travoprost, and 0.12% unoprostone at each time point—and also by AUC analysis. Because of this invasive measurement, IOP at each time point was measured in different animals. In some mice, the measurements were repeated at 2-week intervals.

Statistical Analysis
All IOP data are shown as the mean ± SEM. The Kruskal-Wallis test was used for comparison of the 24-hour IOP variation. The Mann-Whitney test was used for comparison of the mean IOP difference and the ratio of IOP reduction between day and night. The Wilcoxon signed-ranks test was used for comparison of mean IOP between treated and contralateral eyes. The Steel test was used for multiple comparisons. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
IOP of ddY Mouse
Twenty-four-hour IOP Variation in ddY Mouse.
The mean IOP of mice bred in the 12-hour light–dark cycle showed a 24-hour variation (Kruskal-Wallis test, P < 0.001), in which IOP was lower in the day and higher at night (Fig. 1) . The peak IOP measurement was 21.0 ± 0.8 mm Hg observed at 2100 and the trough IOP measurement was 15.0 ± 0.5 mm Hg at 0900 (n = 6). There was a significant difference between the peak and trough IOPs (P < 0.001).



View larger version (11K):
[in this window]
[in a new window]
  		FIGURE 1. The 24-hour IOP pattern in ddY mice. The difference between the peak and trough IOP was significant (P < 0.001). The data are the mean mm Hg ± SEM (n = 6).

 
Difference between Bilateral IOP in ddY Mice.
The IOPs of ddY mouse eyes were measured at 0900 and 2100, as shown in Table 1 . The mean IOP in the right eyes was 14.4 ± 0.4 mm Hg and in the left eye was 14.2 ± 0.4 mm Hg at 0900 (n = 13). At 2100 (n = 12), the pressures were 21.0 ± 0.7 and 21.1 ± 0.5 mm Hg in the right and left eye mean, respectively. There was no significant difference in IOP between the two eyes.


View this table:
[in this window]
[in a new window]
  		TABLE 1. IOP of the Right and Left Eyes in ddY Mice

 
Data are reported as the mean ± SEM. There was no significant difference between the right and left eyes.

Effect of Latanoprost on Diurnal IOP
To evaluate the effect of latanoprost on the IOP during the day and night, we measured the IOP in normal ddY mice treated with 0.005% latanoprost at 0900 or 2100, based on the 24-hour pattern of mouse IOP (Fig. 1) . During the day, the IOP of the untreated contralateral and treated eyes 2 hours after drug administration was 13.3 ± 0.7 and 12.3 ± 0.7 mm Hg, respectively, whereas at night, the IOP in the untreated contralateral and treated eyes 2 hours after administration was 22.0 ± 1.8 and 17.1 ± 0.8 mm Hg, respectively. IOP reduction by 0.005% latanoprost was 1.0 mm Hg (7.1%) during the day and 4.9 mm Hg (21.4%) at night, and the latter was statistically significant (P = 0.002). Further, the change ({Delta}) and the percent IOP reduction at night were significantly greater than those during the day (P = 0.017 and 0.028, respectively, Table 2 ). These results indicate that the effect of latanoprost on IOP is more pronounced at night when baseline IOP is higher. Hence, in the following experiments, we examined IOP reduction by PG analogues at night.


View this table:
[in this window]
[in a new window]
  		TABLE 2. Effect of Latanoprost (0.005%) on IOP during the Day and at Night

 
Dose–Response and Time Course of IOP Reduction by Four PG Analogues
Tafluprost.
The maximum IOP reductions in the tafluprost (0.0003%, 0.0015%, 0.005%, and 0.015%)-treated groups were observed at 2 (–3.5 ± 0.7 mm Hg, 15.7% ± 2.6%), 3 (–4.0 ± 0.5 mm Hg, 17.6% ± 1.7%), 2 (–4.8 ± 0.7 mm Hg, 20.2% ± 2.0%), and 3 (–5.5 ± 1.0 mm Hg, 24.3% ± 3.3%) hours after drug administration, respectively (Fig. 2A) . At 1, 2, 3, 6, and 9 hours, 0.0015%, 0.005%, and 0.015% tafluprost significantly reduced IOP compared with its effect in the vehicle-treated eye. AUC analysis of tafluprost showed a dose-dependent effect on IOP reduction, which saturated at 0.005% (Fig. 2B) .



View larger version (17K):
[in this window]
[in a new window]
  		FIGURE 2. Dose-dependent IOP reduction by tafluprost in ddY mice. (A) Effect of tafluprost (0.0003%, 0.0015%, 0.005%, or 0.015%) on mouse IOP. Eye drops were instilled at 1800. The data indicate the percentage reduction in IOP due to treatment and are expressed as the mean ± SEM (n = 7–10 per time point). *P < 0.05 for the drug-treated versus vehicle-treated eyes, by the Steel test. (B) The ocular hypotensive effect of tafluprost, shown as the AUC (percent per hour).

 
Latanoprost.
The maximum IOP reductions in the latanoprost (0.001%, 0.0025%, and 0.005%)-treated groups were observed at 1 (–1.8 ± 0.3 mm Hg, 8.3% ± 1.4%), 2 (–3.1 ± 0.7 mm Hg, 15.9% ± 3.1%), and 2 (–3.9 ± 0.6 mm Hg, 18.7% ± 2.5%) hours, respectively, after drug administration (Fig. 3A) . At 1, 2, and 3 hours after administration, 0.005% and 0.0025% of latanoprost significantly reduced IOP compared with that in the vehicle-treated eye. AUC analysis of the latanoprost-treated groups showed a dose-dependent effect on IOP reduction, which saturated at 0.0025% (Fig. 3B) .



View larger version (15K):
[in this window]
[in a new window]
  		FIGURE 3. Dose-dependent IOP reduction by latanoprost in ddY mice. (A) Effect of latanoprost (0.001%, 0.0025%, and 0.005%) on mouse IOP. Eye drops were instilled at 1800. The data indicate the percent reduction in IOP due to treatment and are expressed as the mean ± SEM (n = 7–9 per time point). *P < 0.05 for the drug-treated versus vehicle-treated eyes, by the Steel test. (B) The ocular hypotensive effect of latanoprost, shown as the AUC (percent per hour).

 
Travoprost.
The maximum IOP reductions in the travoprost (0.001%, 0.002%, and 0.004%)-treated groups were observed at 3 (–2.9 ± 1.1 mm Hg, 12.0% ± 4.7%), 2 (–2.3 ± 0.5 mm Hg, 9.8% ± 2.2%), and 6 (–3.8 ± 0.8 mm Hg, 20.8% ± 4.6%) hours after drug administration (Fig. 4A) . At 2, 3, and 6 hours, 0.004% travoprost significantly reduced IOP, when compared with its effect in the vehicle-treated eye. AUC analysis of travoprost treated groups showed a dose-dependent reduction of IOP (Fig. 4B) .



View larger version (15K):
[in this window]
[in a new window]
  		FIGURE 4. Dose-dependent IOP reduction by travoprost in ddY mice. (A) Effect of travoprost (0.001%, 0.002%, or 0.004%) on mouse IOP. Eye drops were instilled at 1800. The data indicate the percent reduction in IOP due to treatment and are expressed as the mean ± SEM (n = 6–9 per time point). *P < 0.05 for the drug-treated versus vehicle-treated eye, by the Steel test. (B) The ocular hypotensive effect of travoprost, shown as the AUC (percent per hour).

 
Isopropyl Unoprostone.
Isopropyl unoprostone had the weakest effect on IOP among the four PG analogues (Fig. 5A) . The maximum IOP reduction (–2.0 ± 0.3 mm Hg, 11.2% ± 1.8%) was observed at 2 hours after the administration of 0.12% isopropyl unoprostone (Fig. 5B) . At 2 hours, 0.12% unoprostone significantly reduced IOP compared with its effect in the vehicle-treated eye. AUC analysis of the unoprostone-treated groups showed a dose-dependent IOP reduction, which saturated at 0.06% (Fig. 5B) .



View larger version (15K):
[in this window]
[in a new window]
  		FIGURE 5. Dose-dependent IOP reduction by isopropyl unoprostone in ddY mice. (A) Effect of isopropyl unoprostone (0.03%, 0.06%, or 0.12%) on mouse IOP. Eye drops were instilled at 1800. The data indicate the percent reduction in IOP due to treatment and are expressed as the mean ± SEM (n = 9–17 per time point). *P < 0.05 for the drug-treated versus vehicle-treated eyes, by the Steel test. (B) The ocular hypotensive effect of unoprostone, shown as the AUC (percent per hour).

 
Comparison of the IOP Reduction Induced by Three PG Analogues with That Induced by Tafluprost
The baseline IOP (at 1800) in the untreated contralateral eyes in the tafluprost-, latanoprost-, travoprost-, and isopropyl unoprostone–treated groups showed no significant difference among the groups. Tafluprost 0.005% decreased IOP more than 0.005% latanoprost at 3, 6, and 9 hours (P = 0.001–0.027) or 0.12% unoprostone at 2, 3, and 6 hours (P = 0.0004–0.01). There was no significant difference between 0.005% tafluprost and 0.004% travoprost.

Among the four PGs, tafluprost showed the largest AUC and isopropyl unoprostone, the smallest (Fig. 6B) .



View larger version (26K):
[in this window]
[in a new window]
  		FIGURE 6. Effects of treatment with prostaglandin analogues on ddY mouse IOP. (A) Long-term effects of tafluprost (0.005%), latanoprost (0.005%), travoprost (0.004%), and isopropyl unoprostone (0.12%). Eye drops were instilled at 1800. The data indicate the percent reduction in IOP due to treatment and are expressed as the mean ± SEM (n = 6–15 per time point). *P < 0.0167 versus the tafluprost-treated group, by the Steel test. (B) The comparative ocular hypotensive effects of the four drugs are indicated by the AUC (percent per hour).

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
A new FP agonist, tafluprost, and the clinically used PG analogues (except for bimatoprost)—latanoprost, travoprost, and unoprostone—significantly reduced IOP in a dose-dependent manner in ddY mouse eyes. These findings suggest mouse eyes are well suited for the pharmacological evaluation of PG analogues. Moreover, IOP reduction by these four PG analogues in mouse eyes was almost comparable to that in human eyes, as was their affinity for the FP receptor.3 16 17

The 24-hour variation in mouse eyes should be taken into consideration when evaluating the pressure. The IOP during the day and night varies among the many mouse strains.18 In this study, the ddY strain showed a 24-hour pattern of IOP variation similar to that of NIH Swiss white, as previously reported.15 These data, as well as the data from our study, demonstrate that mouse IOP is higher at night and lower in the day. Thus, to determine whether drug-induced ocular hypotension was affected by the diurnal variation of IOP, latanoprost was administered at 0700 or 1900. The results revealed a more pronounced reduction in IOP at night (21.4%) than during the day (7.1%). This finding may be compatible with those of a previous study using NIH Swiss white mice, which also showed a lesser reduction (14%) in IOP during the day than that at night (21.4%).11 13 It is not clear whether this greater IOP reduction by latanoprost at night is simply due to circadian differences in baseline IOP or to the parameters of aqueous dynamics. In other mammals, including humans, a diurnal difference in the conventional outflow facility or aqueous production has been reported,19 20 whereas the diurnal variation of uveoscleral outflow has not. In humans, higher baseline IOP is associated with greater IOP reduction by latanoprost,21 which may also apply to latanoprost’s effect on mouse IOP.

The PG-analogue–induced IOP reductions demonstrated in the current mouse study deserve discussion. The PG analogues currently examined, excluding unoprostone, are mainly thought to enhance uveoscleral outflow via interaction with the FP receptor.3 10 IOP reduction by FP agonists in mouse eyes is compatible with the fact that the mouse outflow pathway is mainly dependent on uveoscleral outflow, as shown in young monkey eyes in aqueous outflow studies.12 22 PGF2{alpha} analogues have very little effect on ocular hypotension in rabbits and cats.23 24 Our data indicate that mouse eyes are more comparable to human eyes for the pharmacological study of drugs that enhance the uveoscleral outflow pathway.

In this study, the clinically used concentration of each drug was also tested (Fig. 6) . Because the main purpose was to evaluate the usefulness of ddY mouse eyes for the pharmacological evaluation of PG analogues and a new PG analogue, tafluprost, direct comparison among all four drugs at their clinical concentrations was not a primary measure. However, the more potent FP agonist tended to reduce IOP more, almost paralleling the results obtained in humans.17 Tafluprost is a recently developed PG derivative that has a 10-fold higher affinity for the FP receptor than does latanoprost acid.1 2 By AUC analysis, tafluprost was more effective in reducing mouse IOP, and its ocular hypotensive effect lasted longer than that of latanoprost (Fig. 2) . In monkey eyes, treatment with 0.0025% or 0.005% tafluprost once daily lowered IOP more effectively than latanoprost, by increasing uveoscleral outflow.2 Moreover, tafluprost lowered the trough IOP more than latanoprost after continuous use.1 2 These results may indicate the potential of tafluprost as a new ocular hypotensive agent in the future.

Travoprost (0.004%) showed similar ocular hypotensive potency to tafluprost in mouse eyes. Travoprost acid also has a high affinity for the FP receptor.3 This property of travoprost may result in a longer duration of reduction of IOP than that achieved with latanoprost. In addition, the current results are consistent with the fact that IOP reduction by travoprost was greater than that by latanoprost after 2 weeks of treatment in humans.25

The maximum IOP reduction by isopropyl unoprostone (0.12%) in mouse eyes was approximately 50% of that with latanoprost (0.005%). This observation is consistent with previous reports in humans that unoprostone has less effect on ocular hypotension than does latanoprost.26 27 The receptor-related mechanism of action of unoprostone has not been clarified, since this drug shows a low affinity for all prostanoid receptors.3 7 However, there are several hypotheses to explain unoprostone-induced IOP reduction. Unoprostone free acid and further metabolites have been reported to stimulate the release of PGE2, which may play a role in IOP reduction by unoprostone.28 29 Unoprostone free acid activates maxi-K channels to inhibit trabecular meshwork contraction, which can lead to increases in aqueous outflow.30 Unoprostone can induce cellular responses similar to other FP agonists in cultured ciliary muscle and trabecular meshwork cells, probably by acting as a weak FP agonist.3 16 31 32 Thus, the use of various prostanoid receptor knockout mice and the mouse IOP model established in the present study should be very useful in further studying the mechanism of IOP reduction by unoprostone.

In conclusion, our study examined the effects of four different PG analogues on IOP in the mouse eye at night, taking 24-hour IOP variation into consideration, and clearly demonstrated the presence of dose-dependent responses in ocular hypotension to the four PG analogues. The ocular hypotensive effects of the four PG analogues in mouse eyes are comparable to those reported in humans,17 correlating with their affinity for the FP receptor. IOP measurements using knockout mice lacking various prostanoid receptors or other receptors related to control of ocular hypotension, should be useful in investigating the mechanism of the ocular hypotensive effect of various antiglaucoma drugs. The mouse IOP model is thought to be a potential tool for basic research in the field of glaucoma.


   Footnotes
 
Supported by Grant-in-Aid for Science Research (A)14207049 from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MAr).

Submitted for publication December 28, 2004; revised February 12, 2005; accepted February 14, 2005.

Disclosure: T. Ota, None; H. Murata, None; E. Sugimoto, None; M. Aihara, None; M. Araie, 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: Makoto Aihara, Department of Ophthalmology, University of Tokyo School of Medicine, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan; aihara-tky{at}umin.ac.jp.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

  1. Nakajima T, Matsugi T, Goto W, et al. New fluoroprostaglandin F(2alpha) derivatives with prostanoid FP-receptor agonistic activity as potent ocular-hypotensive agents. Biol Pharm Bull. 2003;26:1691–1695.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  2. Takagi Y, Nakajima T, Shimazaki A, et al. Pharmacological characteristics of AFP-168 (tafluprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug. Exp Eye Res. 2004;78:767–776.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  3. Sharif NA, Kelly CR, Crider JY, Williams GW, Xu SX. Ocular hypotensive FP prostaglandin (PG) analogs: PG receptor subtype binding affinities and selectivities, and agonist potencies at FP and other PG receptors in cultured cells. J Ocul Pharmacol Ther. 2003;19:501–515.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  4. Sharif NA, Williams GW, Kelly CR. Bimatoprost and its free acid are prostaglandin FP receptor agonists. Eur J Pharmacol. 2001;432:211–213.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  5. Sharif NA, Davis TL, Williams GW. [3H]AL-5848 ([3H]9beta-(+)-Fluprostenol): carboxylic acid of travoprost (AL-6221), a novel FP prostaglandin to study the pharmacology and autoradiographic localization of the FP receptor. J Pharm Pharmacol. 1999;51:685–694.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  6. Maxey KM, Johnson JL, LaBrecque J. The hydrolysis of bimatoprost in corneal tissue generates a potent prostanoid FP receptor agonist. Surv Ophthalmol. 2002;47:S34–S40.
  7. Goh Y, Kishino J. Pharmacological characterization of prostaglandin-related hypotensive agents. Jpn J Ophthalmol. 1994;38:236–245.
  8. Anthony TL, Pierce KL, Stamer WD, Regan JW. Prostaglandin F2 alpha receptors in the human trabecular meshwork. Invest Ophthalmol Vis Sci. 1998;39:315–321.[Abstract/Free Full Text]
  9. Anthony TL, Lindsey JD, Aihara M, Weinreb RN. Detection of prostaglandin EP(1), EP(2), and FP receptor subtypes in human sclera. Invest Ophthalmol Vis Sci. 2001;42:3182–3186.[Abstract/Free Full Text]
  10. Lindsey JD, Weinreb RN. Mechanism of prostaglandin action on uveoscleral outflow. Weinreb RN Kitazawa Y Krieglstein GK eds. Glaucoma in the 21st Century. 2000;195–200. Mosby International London.
  11. Aihara M, Lindsey JD, Weinreb RN. Reduction of intraocular pressure in mouse eyes treated by latanoprost. Invest Ophthalmol Vis Sci. 2002;43:146–150.[Abstract/Free Full Text]
  12. Aihara M, Lindsey JD, Weinreb RN. Aqueous humor dynamics in mice. Invest Ophthalmol Vis Sci. 2003;44:5168–5173.[Abstract/Free Full Text]
  13. Crowston JG, Lindsey JD, Aihara M, Weinreb RN. Effect of Latanoprost on intraocular pressure in mice lacking the prostaglandin FP receptor. Invest Ophthalmol Vis Sci. 2004;45:3555–3559.[Abstract/Free Full Text]
  14. Camras CB. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month masked, multicenter trial in the United States. The United States Latanoprost Study Group. Ophthalmology. 1996;103:138–147.[Web of Science][Medline][Order article via Infotrieve]
  15. Aihara M, Lindsey JD, Weinreb RN. Twenty-four-hour pattern of mouse intraocular pressure. Exp Eye Res. 2003;77:681–686.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  16. Sharif NA, Kelly CR, Crider JY. Agonist activity of bimatoprost, travoprost, latanoprost, unoprostone isopropyl ester and other prostaglandin analogs at the cloned human ciliary body FP prostaglandin receptor. J Ocul Pharmacol Ther. 2002;18:313–324.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  17. Alexander CL, Miller SJ, Abel SR. Prostaglandin analog treatment of glaucoma and ocular hypertension. Ann Pharmacother. 2002;36:504–511.[Abstract]
  18. Savinova OV, Sugiyama F, Martin JE, et al. Intraocular pressure in genetically distinct mice: an update and strain survey. BMC Genet. 2001;2:12.[CrossRef][Medline][Order article via Infotrieve]
  19. Boyd TA, McLeod LE. Circadian rhythms of plasma corticoid levels, intraocular pressure and aqueous outflow facility in normal and glaucomatous eyes. Ann NY Acad Sci. 1964;117:597–613.
  20. Reiss GR, Lee DA, Topper JE, Brubaker RF. Aqueous humor flow during sleep. Invest Ophthalmol Vis Sci. 1984;25:776–778.[Abstract/Free Full Text]
  21. Ziai N, Dolan JW, Kacere RD, Brubaker RF. The effects on aqueous dynamics of PhXA41, a new prostaglandin F2 alpha analogue, after topical application in normal and ocular hypertensive human eyes. Arch Ophthalmol. 1993;111:1351–1358.[Abstract/Free Full Text]
  22. Gabelt BT, Gottanka J, Lütjen-Drecoll E, Kaufman PL. Aqueous humor dynamics and trabecular meshwork and anterior ciliary muscle morphologic changes with age in rhesus monkeys. Invest Ophthalmol Vis Sci. 2003;44:2118–2125.[Abstract/Free Full Text]
  23. Resul B, Stjernschantz J, Selen G, Bito L. Structure-activity relationships and receptor profiles of some ocular hypotensive prostanoids. Surv Ophthalmol. 1997;41:S47–S52.
  24. Stjernschantz JW. From PGF2{alpha}-isopropyl ester to latanoprost: a review of the development of Xalatan. The Proctor Lecture. Invest Ophthalmol Vis Sci. 2001;42:1134–1145.[Free Full Text]
  25. Dubiner HB, Sircy MD, Landry T, et al. Comparison of the diurnal ocular hypotensive efficacy of travoprost and latanoprost over a 44-hour period in patients with elevated intraocular pressure. Clin Ther. 2004;26:84–91.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  26. Sponsel WE, Paris G, Trigo Y, Pena M. Comparative effects of latanoprost (Xalatan) and unoprostone (Rescula) in patients with open-angle glaucoma and suspected glaucoma. Am J Ophthalmol. 2002;134:552–559.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  27. Jampel HD, Bacharach J, Sheu WP, Wohl LG, Solish AM, Christie W. Randomized clinical trial of latanoprost and unoprostone in patients with elevated intraocular pressure. Am J Ophthalmol. 2002;134:863–871.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  28. Kashiwagi K, Kanai N, Tsuchida T, et al. Comparison between isopropyl unoprostone and latanoprost by prostaglandin E(2)induction, affinity to prostaglandin transporter, and intraocular metabolism. Exp Eye Res. 2002;74:41–49.[CrossRef][Web of Science][Medline][Order article via Infotrieve]
  29. Kashiwagi K, Iizuka Y, Tsukahara S. Metabolites of isopropyl unoprostone as potential ophthalmic solutions to reduce intraocular pressure in pigmented rabbits. Jpn J Pharmacol. 1999;81:56–62.[CrossRef][Medline][Order article via Infotrieve]
  30. Thieme H, Stumpff F, Ottlecz A, Percicot CL, Lambrou GN, Wiederholt M. Mechanisms of action of unoprostone on trabecular meshwork contractility. Invest Ophthalmol Vis Sci. 2001;42:3193–3201.[Abstract/Free Full Text]
  31. Sharif NA, Kelly CR, Crider JY. Human trabecular meshwork cell responses induced by bimatoprost, travoprost, unoprostone, and other FP prostaglandin receptor agonist analogues. Invest Ophthalmol Vis Sci. 2003;44:715–721.[Abstract/Free Full Text]
  32. Sharif NA, Crider JY, Husain S, Kaddour-Djebbar I, Ansari HR, Abdel-Latif AA. Human ciliary muscle cell responses to FP-class prostaglandin analogs: phosphoinositide hydrolysis, intracellular Ca2+ mobilization and MAP kinase activation. J Ocul Pharmacol Ther. 2003;19:437–455.[CrossRef][Web of Science][Medline][Order article via Infotrieve]



This article has been cited by other articles:


Home page
 IOVSHome page
T. Saeki, T. Ota, M. Aihara, and M. Araie
Effects of Prostanoid EP Agonists on Mouse Intraocular Pressure
Invest. Ophthalmol. Vis. Sci., May 1, 2009; 50(5): 2201 - 2208.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
H Liang, C Baudouin, A Pauly, and F Brignole-Baudouin
Conjunctival and corneal reactions in rabbits following short- and repeated exposure to preservative-free tafluprost, commercially available latanoprost and 0.02% benzalkonium chloride
Br. J. Ophthalmol., September 1, 2008; 92(9): 1275 - 1282.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
T. Ota, M. Aihara, T. Saeki, S. Narumiya, and M. Araie
The IOP-lowering effects and mechanism of action of tafluprost in prostanoid receptor-deficient mice
Br. J. Ophthalmol., May 1, 2007; 91(5): 673 - 676.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
T. Ota, M. Aihara, T. Saeki, S. Narumiya, and M. Araie
The Effects of Prostaglandin Analogues on Prostanoid EP1, EP2, and EP3 Receptor-Deficient Mice.
Invest. Ophthalmol. Vis. Sci., August 1, 2006; 47(8): 3395 - 3399.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
T. Ota, M. Aihara, S. Narumiya, and M. Araie
The Effects of Prostaglandin Analogues on IOP in Prostanoid FP-Receptor-Deficient Mice
Invest. Ophthalmol. Vis. Sci., November 1, 2005; 46(11): 4159 - 4163.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (13)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ota, T.
Right arrow Articles by Araie, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ota, T.
Right arrow Articles by Araie, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS