Thieme Hagen, Schimmat Christin, Münzer Galina, Boxberger Marianne, Fromm Michael, Pfeiffer Norbert, Rosenthal Rita
Augenklinik und Augenpoliklinik, Johannes Gutenberg-Universität Mainz, Mainz, Germany.
Invest Ophthalmol Vis Sci. 2006 Mar;47(3):938-45. doi: 10.1167/iovs.05-0527.
This study analyzes additional mechanisms behind the ocular hypotensive effect of prostaglandin F (PGF) receptor (FP receptor) agonists PGF2alpha and fluprostenol (fluprostenol-isopropyl ester [travoprost]), which reduce intraocular pressure (IOP) in patients with glaucoma probably by enhancing uveoscleral flow. The trabecular meshwork (TM) is actively involved in IOP regulation through contractile mechanisms. Contractility of TM is induced by endothelin (ET)-1, a possible pathogenic factor in glaucoma. The involvement of FP receptor agonists in the ET-1 effects on TM function was studied.
The effects of FP receptor agonists on contractility of bovine TM (BTM) were investigated using a force-length transducer. The effects of PGF2alpha on intracellular Ca2+ ([Ca2+]i) mobilization in cultured cells were measured using fura-2AM. The expression of the FP receptor protein was examined using Western blot analysis.
The ET-1-induced (10(-8) M) contraction in isolated BTM was inhibited by PGF2alpha (10(-6) M) and fluprostenol (10(-6) M). This effect was blocked by FP receptor antagonists. Carbachol-induced contraction or baseline tension was not affected by PGF2alpha or fluprostenol. In cultured TM cells, ET-1 caused a transient increase in [Ca2+]i that was reduced by PGF2alpha. No reduction occurred in the presence of the FP receptor antagonist Al-8810. Western blot analysis revealed the expression of the FP receptor in native and cultured TM.
FP receptor agonists operate by direct interaction with ET-1-induced contractility of TM. This effect is mediated by the FP receptor. Thus, FP receptor agonists may decrease IOP by enhancing aqueous humor outflow through the TM by inhibiting ET-1-dependent mechanisms.
本研究分析前列腺素F（PGF）受体（FP受体）激动剂前列腺素F2α（PGF2α）和氟前列醇（氟前列醇异丙酯[曲伏前列素]）降低眼压（IOP）的其他机制，这些药物可能通过增强葡萄膜巩膜外流来降低青光眼患者的眼压。小梁网（TM）通过收缩机制积极参与眼压调节。内皮素（ET）-1可诱导TM收缩，ET-1可能是青光眼的致病因素。本研究探讨了FP受体激动剂对ET-1作用于TM功能的影响。
使用力-长度传感器研究FP受体激动剂对牛TM（BTM）收缩性的影响。使用fura-2AM测量PGF2α对培养细胞内Ca2+（[Ca2+]i）动员的影响。使用蛋白质印迹分析检测FP受体蛋白的表达。
PGF2α（10-6 M）和氟前列醇（10-6 M）可抑制ET-1诱导的（10-8 M）离体BTM收缩。该作用被FP受体拮抗剂阻断。卡巴胆碱诱导的收缩或基础张力不受PGF2α或氟前列醇影响。在培养的TM细胞中，ET-1导致[Ca2+]i短暂升高，PGF2α可使其降低。在存在FP受体拮抗剂Al-8810的情况下，未出现降低。蛋白质印迹分析显示天然和培养的TM中均有FP受体表达。
FP受体激动剂通过与ET-1诱导的TM收缩直接相互作用发挥作用。该作用由FP受体介导。因此，FP受体激动剂可能通过抑制ET-1依赖性机制增强房水通过TM的流出，从而降低眼压。
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