The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice. Invest Ophthalmol Vis Sci

PURPOSE. This study was designed to clarify the involvement of the prostanoid FP receptor in the intraocular pressure (IOP)-lowering effects of latanoprost, travoprost, bimatoprost, and unoprostone with the use of FP-receptor-deficient (FPKO) mice. METHODS. FPKO and wild-type (WT) mice were bred and acclimatized under a 12-hour light-dark cycle. IOP was measured under general anesthesia by a microneedle method. To evaluate the effects of each drug, a single drop (3 L) of each drug solution was topically applied in a masked manner to a randomly selected eye. IOP reduction was evaluated by the difference in IOP between the treated eye and the untreated contralateral eye in the same mouse. First, the diurnal variation and baseline IOP in WT and FPKO mice were measured. Then, to determine the window feasible for demonstrating the most marked ocular hypotensive effect, 0.005% latanoprost was applied to WT mice during the day or at night. The time when the ocular hypotensive effect was larger was selected for further studies to evaluate the effects of latanoprost (0.005%), travoprost (0.004%), bimatoprost (0.03%), and unoprostone (0.12%). In addition, bunazosin (0.1%) was also applied to demonstrate functional uveoscleral outflow in FPKO mice. All experiments were conducted under a masked study design. RESULTS. The baseline IOP (mean Ϯ SEM) in WT and FPKO mice was 15.0 Ϯ 0.2 and 15.0 Ϯ 0.3 mm Hg, respectively, during the day, and 18.9 Ϯ 0.4 and 19.2 Ϯ 0.4 mm Hg, respectively, at night. In WT mice, latanoprost significantly lowered IOP both during the day and at night, at 2 to 6 hours and 1 to 6 hours after application, respectively. Maximal IOP reduction was observed at 3 hours after drug instillation both during the day (10.9 Ϯ 1.8%) and at night (23.2 Ϯ 1.1%). At 3 hours after instillation, latanoprost (10.9 Ϯ 1.8% and 23.2 Ϯ 1.1%, daytime and nighttime, respectively), travoprost (15.9 Ϯ 1.4% and 26.1 Ϯ 1.2%) and bimatoprost (8.8 Ϯ 2.0 and 19.8 Ϯ 1.5%) significantly lowered IOP in WT mice both during the day and at night; isopropyl unoprostone significantly lowered IOP at night (13.7 Ϯ 1.9%) but not during the day (5.3 Ϯ 3.2%). In FPKO mice, latanoprost, travoprost, bimatoprost, and unoprostone showed no significant IOP-lowering effect. Bunazosin significantly lowered IOP in both WT (22.1 Ϯ 1.6%) and FPKO mice (22.2 Ϯ 2.1%). CONCLUSIONS. A single application of latanoprost, travoprost, bimatoprost, or unoprostone had no effect on IOP in FPKO mice with presumed functional uveoscleral outflow pathways. The prostanoid FP receptor plays a crucial role in the mechanism of early IOP lowering of all commercially available prostaglandin analogues. (Invest Ophthalmol Vis Sci. 2005;46: 4159 -4163) DOI:10.1167/iovs.05-0494 P rostaglandin (PG) analogues have been widely used as ocular hypotensive drugs for the treatment of glaucoma and ocular hypertension, because of both a greater effect in lowering intraocular pressure (IOP) and fewer systemic side effects than ␤-blockers. Currently, four different types of PG analogues, latanoprost, travoprost, bimatoprost, and isopropyl unoprostone (unoprostone), are used for the treatment of glaucoma. Latanoprost and travoprost are thought to lower IOP mainly via the FP receptor because of their high degree of specificity to this receptor. 1 This is supported by a recent report that latanoprost showed no IOP-lowering effect in FPreceptor-deficient (FPKO) mice. 2 On the other hand, the IOPlowering mechanisms of bimatoprost and unoprostone are not fully understood. Bimatoprost, which has the structure of a prostamide, was originally reported not to act as a PG analogue because of not binding to all prostanoid receptors. 3 So far, no specific receptor for bimatoprost has been determined. However, its metabolite, bimatoprost free acid, binds to the FP receptor with a potency similar to that of latanoprost. 1,4 -11 Recently, bimatoprost has been shown to be readily hydrolyzed to the free acid in human eyes 12 (Dahlin DC. IOVS 2004;45:ARVO E-Abstract 2096). In addition, bimatoprost itself has a weak affinity to FP, leading to increased intracellular calcium concentration