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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Association for Research in Vision and Ophthalmology
2016
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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. |
format | Online Article Text |
id | pubmed-4811179 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Association for Research in Vision and Ophthalmology |
record_format | MEDLINE/PubMed |
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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