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Pei Ge, Iris Navarro, Marco Kessler, Sylvie Bernier, Nicholas Perl, Renee Sarno, Jaime Masferrer, Gerhard Hannig, W Daniel Stamer; The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3010.
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© ARVO (1962-2015); The Authors (2016-present)
The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine-3’,5’-monophosphate (cGMP) pathway regulates aqueous humor outflow and therefore, intraocular pressure. We investigated the pharmacologic effects of the sGC stimulator, IWP-953, on primary human trabecular meshwork (HTM) cells and conventional outflow facility in mouse eyes.
Cyclic GMP levels were determined in vitro in Human Embryonic Kidney 293 (HEK-293) cells and four different HTM strains (HTM120/HTM123: predominantly myofibroblast-like phenotype, and HTM130/HTM141: predominantly endothelial cell-like phenotype), and in HTM culture supernatants. Conventional outflow facility was measured using a computerized pressure-controlled perfusion system following intracameral injection of IWP-953 or diethylenetriamine nitric oxide (DETA-NO) into enucleated mouse eyes ex vivo.
IWP-953 markedly stimulated cGMP production in HEK-293 cells in the presence and absence of DETA-NO (EC50: 17 nM and 9.5 µM, respectively). 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 cell-like HTM130 and HTM141 cells was observed, but markedly less prominent in the presence or absence of DETA-NO. Notably, cGMP was found in all HTM culture supernatants, following IW-953/DETA-NO stimulation. In paired enucleated mouse eyes, IWP-953 at 10, 30, 60, 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).
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.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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