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Abstract #13527 Published in IGR 8-1
Endothelin Antagonism: Effects of FP Receptor Agonists Prostaglandin F2α and Fluprostenol on Trabecular Meshwork Contractility
Thieme H; Schimmat C; Munzer G; Boxberger M; Fromm M; Pfeiffer N; Rosenthal RInvestigative Ophthalmology and Visual Science 2006; 47: 938-945
See also comment(s) by Paul Kaufman •
PURPOSE: This study analyzes additional mechanisms behind the ocular hypotensive effect of prostaglandin F (PGF) receptor (FP receptor) agonists PGF2α 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. METHODS: The effects of FP receptor agonists on contractility of bovine TM (BTM) were investigated using a force-length transducer. The effects of PGF2α 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. RESULTS: The ET-1-induced (10-8 M) contraction in isolated BTM was inhibited by PGF2α (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 PGF2α or fluprostenol. In cultured TM cells, ET-1 caused a transient increase in [Ca2+ ]i that was reduced by PGF(2α). 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. CONCLUSIONS: 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.
Dr. H. Thieme, Augenklinik und Augenpoliklinik, Johannes Gutenberg-Universität Mainz, Mainz, Germany
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
