IOVS Archives of Disease in Childhood
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(Investigative Ophthalmology and Visual Science. 2006;47:938-945.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-0527

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Endothelin Antagonism: Effects of FP Receptor Agonists Prostaglandin F2{alpha} and Fluprostenol on Trabecular Meshwork Contractility

Hagen Thieme,1,2 Christin Schimmat,3 Galina Münzer,3 Marianne Boxberger,3 Michael Fromm,3 Norbert Pfeiffer,1 and Rita Rosenthal2,3

1From the Augenklinik und Augenpoliklinik, Johannes Gutenberg-Universität Mainz, Mainz, Germany; and 2Augenklinik und Hochschulambulanz and 3Institut für Klinische Physiologie, Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.

PURPOSE. This study analyzes additional mechanisms behind the ocular hypotensive effect of prostaglandin F (PGF) receptor (FP receptor) agonists PGF2{alpha} 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 PGF2{alpha} 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 PGF2{alpha} (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 PGF2{alpha} or fluprostenol. In cultured TM cells, ET-1 caused a transient increase in [Ca2+]i that was reduced by PGF2{alpha}. 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.





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