The IOP-lowering effects and mechanism of action of tafluprost in prostanoid receptor-deficient mice.
OBJECTIVE
To clarify the intraocular pressure (IOP)-lowering profile of tafluprost, a newly synthesised prostaglandin F(2alpha) analogue, in mice.


METHODS
C57BL/6J, and EP1, EP2, EP3 and postaglandin F (FP) receptor-deficient wild-type (WT), EP1KO, EP2KO, EP3KO and FPKO, respectively mice were bred and acclimatised under a 12-h (6:00-18:00) light-dark cycle. To evaluate effects of tafluprost (0.002%) on IOP at night, a single 3 microl drop of tafluprost solution was applied topically at 18:00 once into one eye in each mouse. IOP was measured 3 h after the application with a microneedle method. To clarify whether endogenous prostaglandin is concerned with the tafluprost-induced IOP reduction, we applied 0.1% diclofenac Na, a cyclo-oxygenase inhibitor or PBS 30 min before the application of tafluprost in WT and EP3KO mice and measured IOP 3 h after the tafluprost application. We also determined whether animals responded predictably to 0.1% bunazosin HCl, a drug known to increase uveoscleral outflow.


RESULTS
3 h after the application of 0.0015% tafluprost, mean (SEM) 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.


CONCLUSIONS
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.
Ota
Takashi
T
Department of Ophthalmology, University of Tokyo School of Medicine, 7-3-1 Hongo Bunkyo-ku Tokyo 113-8655, Japan.
Aihara
Makoto
M
Saeki
Tadashiro
T
Narumiya
Shuh
S
Araie
Makoto
M
D000287:Administration, Topical; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D007429:Intraocular Pressure / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009883:Ophthalmic Solutions; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D011460:Prostaglandins F / Q000008:administration & dosage / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000172:deficiency*
D000959:Antihypertensive Agents; D009883:Ophthalmic Solutions; D011355:Prodrugs; D011460:Prostaglandins F; D011982:Receptors, Prostaglandin; D004008:Diclofenac; C485333:tafluprost