title: The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes.
abstract: OBJECTIVE
  The nitric oxide (NO)-cyclic guanosine-3',5'-monophosphate (cGMP) pathway regulates aqueous humor outflow and therefore, intraocular pressure. We investigated the pharmacologic effects of the soluble guanylate cyclase (sGC) stimulator IWP-953 on primary human trabecular meshwork (HTM) cells and conventional outflow facility in mouse eyes.
  
  
  METHODS
  Cyclic GMP levels were determined in vitro in HEK-293 cells and four HTM cell strains (HTM120/HTM123: predominantly myofibroblast-like phenotype, HTM130/HTM141: predominantly endothelial-like phenotype), and in HTM cell culture supernatants. Conventional outflow facility was measured following intracameral injection of IWP-953 or DETA-NO using a computerized pressure-controlled perfusion system in enucleated mouse eyes ex vivo.
  
  
  RESULTS
  IWP-953 markedly stimulated cGMP production in HEK-293 cells in the presence and absence of DETA-NO (half maximal effective concentrations: 17 nM, 9.5 μM). Similarly, IWP-953 stimulated cGMP production in myofibroblast-like HTM120 and HTM123 cells, an effect that was greatly amplified by the presence of DETA-NO. In contrast, IWP-953 stimulation of cGMP production in endothelial-like HTM130 and HTM141 cells was observed, but was markedly less prominent than in HTM120 and HTM123 cells. Notably, cGMP was found in all HTM culture supernatants, following IWP-953/DETA-NO stimulation. In paired enucleated mouse eyes, IWP-953 at 10, 30, 60, and 100 μM concentration-dependently increased outflow facility. This effect (89.5%) was maximal at 100 μM (P = 0.002) and in magnitude comparable to DETA-NO at 100 μM (97.5% increase, P = 0.030).
  
  
  CONCLUSIONS
  These data indicate that IWP-953, via modulation of the sGC-cGMP pathway, increases aqueous outflow facility in mouse eyes, suggesting therapeutic potential for sGC stimulators as novel ocular hypotensive drugs.
authors.affiliation: Ironwood Pharmaceuticals Cambridge, Massachusetts, United States.
authors.forename: Pei
authors.initials: P
authors.lastname: Ge
authors.affiliation: Ophthalmology Department, Duke University, Durham, North Carolina, United States.
authors.forename: Iris D
authors.initials: ID
authors.lastname: Navarro
authors.affiliation: Ironwood Pharmaceuticals Cambridge, Massachusetts, United States.
authors.forename: Marco M
authors.initials: MM
authors.lastname: Kessler
authors.affiliation: Ironwood Pharmaceuticals Cambridge, Massachusetts, United States.
authors.forename: Sylvie G
authors.initials: SG
authors.lastname: Bernier
authors.affiliation: formerly of Ironwood Pharmaceuticals, Cambridge, Massachusetts, United States.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Perl
authors.affiliation: Ironwood Pharmaceuticals Cambridge, Massachusetts, United States.
authors.forename: Renee
authors.initials: R
authors.lastname: Sarno
authors.affiliation: Ironwood Pharmaceuticals Cambridge, Massachusetts, United States.
authors.forename: Jaime
authors.initials: J
authors.lastname: Masferrer
authors.affiliation: Ironwood Pharmaceuticals Cambridge, Massachusetts, United States.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hannig
authors.affiliation: Ophthalmology Department, Duke University, Durham, North Carolina, United States.
authors.forename: W Daniel
authors.initials: WD
authors.lastname: Stamer
mesh_terms: D000328:Adult; D000818:Animals; D001082:Aqueous Humor / Q000737:chemistry*; D002478:Cells, Cultured; D002675:Child, Preschool; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005902:Glaucoma, Open-Angle / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007429:Intraocular Pressure / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D014129:Trabecular Meshwork / Q000378:metabolism* / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D006162:Guanylate Cyclase; D006152:Cyclic GMP