The IOP-lowering effects and mechanism of action of tafluprost in prostanoid receptor-deficient mice
- Takashi Ota,
- Makoto Aihara (aihara-tky{at}umin.ac.jp),
- Tadashiro Saeki,
- Shuh Narumiya,
- Makoto Araie
- Department of Ophthalmology, University of Tokyo, Japan
- Department of Ophthalmology, University of Tokyo, Japan
- Department of Ophthalmology, University of Tokyo, Japan
- Department of Pharmacology, Kyoto University, Japan
- Department of Ophthalmology, University of Tokyo, Japan
- Published Online First 23 November 2006
Abstract
Aims: To clarify the intraocular pressure (IOP)- lowering profile of tafluprost, a newly synthesized prostaglandin F2αanalog, in mice.
Methods: C57BL/6J, and EP1, EP2, EP3 and FP receptor-deficient (WT, EP1KO, EP2KO, EP3KO, and FPKO, respectively) mice were bred and acclimatized under a 12-hour light (06:00 to 18:00)-dark cycle. To evaluate effects of tafluprost (0.0015%) on IOP at night, a single 3μL drop of tafluprost solution was applied topically at 18:00 once into one eye in each mouse. IOP was measured 3 hours after the application with a microneedle method. To clarify whether endogenous prostaglandin is concerned with the tafluprost-induced IOP reduction, we applied 0.5% diclofenac Na, a cyclooxygenase inhibitor, or PBS 30 minutes before the application of tafluprost in WT and EP3KO mice and measured IOP 3 hours after the tafluprost application. We also determined whether animals responded predictably to 0.1% bunazosin HCl, a drug known to increase uveoscleral outflow.
Results: Three hours after the application of 0.0015% tafluprost, IOP reductions were 25.8 ±2.1%, 26.3 ± 0.8%, 24.2 ±1.4%, 16.5 ±1.7% and -0.9 ±1.5% in WT, EP1KO, EP2KO, EP3KO, and FPKO mice, respectively. IOP reductions in EP3KO and FPKO mice were significantly smaller than in WT mice. Pretreatment with diclofenac Na significantly attenuated the IOP lowering effect of tafluprost in WT mice but not in EP3KO mice. Bunazosin HCl lowered IOP significantly in all genotypes by the same amount.
Conclusion: We conclude that tafluprost lowers IOP through the prostanoid FP receptor. A part of ocular hypotensive effect of tafluprost is attributed to FP receptor-mediated prostaglandin production acting through the prostanoid EP3 receptor.
