Ota Takashi, Aihara Makoto, Narumiya Shuh, Araie Makoto
Department of Ophthalmology, University of Tokyo School of Medicine, Japan.
Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4159-63. doi: 10.1167/iovs.05-0494.
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.
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
To evaluate the effects of each drug, a single drop (3 muL) 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.
The baseline IOP (mean +/- SEM) in WT and FPKO mice was 15.0 +/- 0.2 and 15.0 +/- 0.3 mm Hg, respectively, during the day, and 18.9 +/- 0.4 and 19.2 +/- 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 +/- 1.8%) and at night (23.2 +/- 1.1%). At 3 hours after instillation, latanoprost (10.9 +/- 1.8% and 23.2 +/- 1.1%, daytime and nighttime, respectively), travoprost (15.9 +/- 1.4% and 26.1 +/- 1.2%) and bimatoprost (8.8 +/- 2.0 and 19.8 +/- 1.5%) significantly lowered IOP in WT mice both during the day and at night; isopropyl unoprostone significantly lowered IOP at night (13.7 +/- 1.9%) but not during the day (5.3 +/- 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 +/- 1.6%) and FPKO mice (22.2 +/- 2.1%).
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.
本研究旨在通过使用前列腺素FP受体缺陷（FPKO）小鼠，阐明前列腺素FP受体在拉坦前列素、曲伏前列素、比马前列素和乌诺前列酮降低眼压（IOP）作用中的参与情况。
将FPKO和野生型（WT）小鼠在12小时明暗循环条件下饲养并适应环境。在全身麻醉下用微针测量眼压。
为评估每种药物的效果，将每种药物溶液的一滴（3μL）以遮蔽方式局部应用于随机选择的一只眼睛。通过同一只小鼠中治疗眼与未治疗的对侧眼之间的眼压差异来评估眼压降低情况。首先，测量WT和FPKO小鼠的昼夜眼压变化和基线眼压。然后，为确定显示最显著降眼压效果的可行时间段，在白天或晚上将0.005%拉坦前列素应用于WT小鼠。选择眼压降低效果较大的时间进行进一步研究，以评估拉坦前列素（0.005%）、曲伏前列素（0.004%）、比马前列素（0.03%）和乌诺前列酮（0.12%）的效果。此外，还应用布那唑嗪（0.1%）以证明FPKO小鼠中的功能性葡萄膜巩膜流出。所有实验均在遮蔽研究设计下进行。
白天WT和FPKO小鼠的基线眼压（平均值±标准误）分别为15.0±0.2和15.0±0.3mmHg，晚上分别为18.9±0.4和19.2±0.4mmHg。在WT小鼠中，拉坦前列素在白天和晚上均显著降低眼压，分别在用药后2至6小时和1至6小时。在白天（10.9±1.8%）和晚上（23.2±1.1%）用药后3小时观察到最大眼压降低。在用药后3小时，拉坦前列素（白天和晚上分别为10.9±1.8%和23.2±1.1%）、曲伏前列素（15.9±1.4%和26.1±1.2%）和比马前列素（8.8±2.0和19.8±1.5%）在WT小鼠的白天和晚上均显著降低眼压；异丙基乌诺前列酮在晚上显著降低眼压（13.7±1.9%），但在白天无显著降低（5.3±3.2%）。在FPKO小鼠中，拉坦前列素、曲伏前列素、比马前列素和乌诺前列酮均未显示出显著的降眼压效果。布那唑嗪在WT小鼠（22.1±1.6%）和FPKO小鼠（22.2±2.1%）中均显著降低眼压。
单次应用拉坦前列素、曲伏前列素、比马前列素或乌诺前列酮对推测具有功能性葡萄膜巩膜流出途径的FPKO小鼠的眼压无影响。前列腺素FP受体在所有市售前列腺素类似物早期降低眼压的机制中起关键作用。
