title: Endothelin antagonism: effects of FP receptor agonists prostaglandin F2alpha and fluprostenol on trabecular meshwork contractility.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Augenklinik und Augenpoliklinik, Johannes Gutenberg-Universität Mainz, Mainz, Germany.
authors.forename: Hagen
authors.initials: H
authors.lastname: Thieme
authors.forename: Christin
authors.initials: C
authors.lastname: Schimmat
authors.forename: Galina
authors.initials: G
authors.lastname: Münzer
authors.forename: Marianne
authors.initials: M
authors.lastname: Boxberger
authors.forename: Michael
authors.initials: M
authors.lastname: Fromm
authors.forename: Norbert
authors.initials: N
authors.lastname: Pfeiffer
authors.forename: Rita
authors.initials: R
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003008:Cloprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology*; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016257:Fura-2 / Q000031:analogs & derivatives / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000502:physiology*; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000037:antagonists & inhibitors; D014129:Trabecular Meshwork / Q000502:physiology*; D000069557:Travoprost
chemical_list: D019332:Endothelin-1; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; C049925:fura-2-am; C121227:AL 8810; D003008:Cloprostenol; D015237:Dinoprost; D002118:Calcium; D016257:Fura-2; D000069557:Travoprost