The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice
The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice
复制标题
DOI：
10.1167/iovs.05-0494
复制
发表时间：
2005-11-01
影响因子：
4.4
通讯作者：
Araie, M
中科院分区：
文献类型：
--
作者：
Ota, T;Aihara, M;Araie, M
目的.本研究旨在阐明前列腺素类FP受体参与拉坦前列素、曲伏前列素、比马前列素和乌诺前列酮对FP受体缺陷（FPKO）小鼠的降眼压作用。FPKO和野生型（WT）小鼠在12小时光-暗循环下饲养和驯化。在全身麻醉下通过微针法测量IOP。为了评价每种药物的作用，将每种药物溶液的单滴（3 μ L）以掩蔽的方式局部应用于随机选择的眼睛。通过同一只小鼠中治疗眼和未治疗对侧眼之间的IOP差异评价IOP降低。首先，测量WT和FPKO小鼠的昼夜变化和基线IOP。然后，为了确定证明最显著眼部肿胀效应的可行窗口，在白天或晚上向WT小鼠施用0.005%拉坦前列素。选择眼部肿胀效应较大的时间进行进一步研究，以评价拉坦前列素（0.005%）、曲伏前列素（0.004%）、比马前列素（0.03%）和乌诺前列酮（0.12%）的作用。此外，还应用布那唑嗪（0.1%）证明FPKO小鼠的功能性葡萄膜巩膜流出。所有实验均在设盲研究设计下进行。WT和FPKO小鼠的基线IOP（平均值+/- SEM）在白天分别为15.0 +/- 0.2和15.0 +/- 0.3 mm Hg，在夜间分别为18.9 +/- 0.4和19.2 +/- 0.4 mm Hg。在WT小鼠中，拉坦前列素在白天和夜间分别在给药后2 - 6小时和1 - 6小时显著降低IOP。白天（10.9 +/- 1.8%）和夜间（23.2 +/- 1.1%）在药物滴注后3小时观察到最大的IOP降低。滴注后3小时，拉坦前列素（白天和夜间分别为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%）在白天和夜间均显著降低WT小鼠的IOP;异丙基乌诺前列酮在夜间显著降低IOP（13.7 ± 1.9%），但在白天不显著降低IOP（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未显示出显著的降IOP作用。布那唑嗪显著降低WT（22.1 +/- 1.6%）和FPKO小鼠（22.2 +/- 2.1%）的IOP。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具有假定功能性葡萄膜巩膜流出途径的FPKO小鼠的IOP没有影响。前列腺素类FP受体在所有市售前列腺素类似物的早期IOP降低机制中起关键作用。
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 mu 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 +/- 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%).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.