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The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes

PURPOSE: 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...

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Autores principales: Ge, Pei, Navarro, Iris D., Kessler, Marco M., Bernier, Sylvie G., Perl, Nicholas R., Sarno, Renee, Masferrer, Jaime, Hannig, Gerhard, Stamer, W. Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811179/
https://www.ncbi.nlm.nih.gov/pubmed/26998718
http://dx.doi.org/10.1167/iovs.15-18958
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author Ge, Pei
Navarro, Iris D.
Kessler, Marco M.
Bernier, Sylvie G.
Perl, Nicholas R.
Sarno, Renee
Masferrer, Jaime
Hannig, Gerhard
Stamer, W. Daniel
author_facet Ge, Pei
Navarro, Iris D.
Kessler, Marco M.
Bernier, Sylvie G.
Perl, Nicholas R.
Sarno, Renee
Masferrer, Jaime
Hannig, Gerhard
Stamer, W. Daniel
author_sort Ge, Pei
collection PubMed
description PURPOSE: 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.
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spelling pubmed-48111792016-09-01 The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes Ge, Pei Navarro, Iris D. Kessler, Marco M. Bernier, Sylvie G. Perl, Nicholas R. Sarno, Renee Masferrer, Jaime Hannig, Gerhard Stamer, W. Daniel Invest Ophthalmol Vis Sci Physiology and Pharmacology PURPOSE: 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. The Association for Research in Vision and Ophthalmology 2016-03-21 2016-03 /pmc/articles/PMC4811179/ /pubmed/26998718 http://dx.doi.org/10.1167/iovs.15-18958 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Physiology and Pharmacology
Ge, Pei
Navarro, Iris D.
Kessler, Marco M.
Bernier, Sylvie G.
Perl, Nicholas R.
Sarno, Renee
Masferrer, Jaime
Hannig, Gerhard
Stamer, W. Daniel
The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes
title The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes
title_full The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes
title_fullStr The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes
title_full_unstemmed The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes
title_short The Soluble Guanylate Cyclase Stimulator IWP-953 Increases Conventional Outflow Facility in Mouse Eyes
title_sort soluble guanylate cyclase stimulator iwp-953 increases conventional outflow facility in mouse eyes
topic Physiology and Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811179/
https://www.ncbi.nlm.nih.gov/pubmed/26998718
http://dx.doi.org/10.1167/iovs.15-18958
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