Endothelin antagonism: Effects of FP receptor agonists prostaglandin F 2α and fluprostenol on trabecular meshwork contractility

Abstract

PURPOSE. This study analyzes additional mechanisms behind the ocular hypotensive effect of prostaglandin F (PGF) receptor (FP receptor) agonists PGF2α and fluprostenol (fluprostenolisopropyl 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 Ca 2α ([Ca2α]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 PGF 2α (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 [Ca 2+]i that was reduced by PGF2α. 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. Copyright © Association for Research in Vision and Ophthalmology.