Ota Takashi, Aihara Makoto, Saeki Tadashiro, Narumiya Shuh, Araie Makoto
Department of Ophthalmology, University of Tokyo School of Medicine, 7-3-1 Hongo Bunkyo-ku Tokyo 113-8655, Japan.
Br J Ophthalmol. 2007 May;91(5):673-6. doi: 10.1136/bjo.2006.105585. Epub 2006 Nov 23.
To clarify the intraocular pressure (IOP)-lowering profile of tafluprost, a newly synthesised prostaglandin F(2alpha) analogue, in mice.
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.
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.
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.
阐明新合成的前列腺素F(2α)类似物他氟前列素在小鼠体内降低眼压（IOP）的情况。
分别培育C57BL/6J小鼠以及EP1、EP2、EP3和前列腺素F（FP）受体缺陷的野生型（WT）、EP1基因敲除（KO）、EP2KO、EP3KO和FPKO小鼠，并使其在12小时（6:00 - 18:00）明暗循环条件下适应环境。为评估他氟前列素（0.002%）在夜间对眼压的影响，于18:00给每只小鼠的一只眼局部滴入一滴3微升的他氟前列素溶液。用药后3小时用微针法测量眼压。为明确内源性前列腺素是否与他氟前列素引起的眼压降低有关，在WT和EP3KO小鼠应用他氟前列素前30分钟，分别给予0.1%双氯芬酸钠（一种环氧化酶抑制剂）或磷酸盐缓冲液（PBS），并在应用他氟前列素后3小时测量眼压。我们还确定了动物对0.1%盐酸布那唑嗪（一种已知可增加葡萄膜巩膜流出的药物）是否有可预测的反应。
应用0.0015%他氟前列素3小时后，WT、EP1KO、EP2KO、EP3KO和FPKO小鼠的平均（标准误）眼压降低分别为25.8（2.1）%、26.3（0.8）%、24.2（1.4）%、16.5（1.7）%和 -0.9（1.5）%。EP3KO和FPKO小鼠的眼压降低明显小于WT小鼠。双氯芬酸钠预处理显著减弱了他氟前列素在WT小鼠中的眼压降低作用，但在EP3KO小鼠中未减弱。盐酸布那唑嗪在所有基因型中均显著降低眼压，且降低幅度相同。
我们得出结论，他氟前列素通过前列腺素FP受体降低眼压。他氟前列素的部分降眼压作用归因于通过前列腺素EP3受体起作用的FP受体介导的前列腺素生成。
