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
AI Summary
IWP-953, an sGC stimulator, increased aqueous outflow facility in mouse eyes by modulating the cGMP pathway. This suggests its potential as a new glaucoma drug to lower eye pressure.
Abstract
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.
MeSH Terms
Shields Classification
Key Concepts5
The soluble guanylate cyclase (sGC) stimulator IWP-953 markedly stimulated cGMP production in HEK-293 cells with half maximal effective concentrations of 17 nM (in the presence of DETA-NO) and 9.5 μM (in the absence of DETA-NO).
The sGC stimulator IWP-953 stimulated cGMP production in myofibroblast-like primary human trabecular meshwork (HTM) cells (HTM120 and HTM123), an effect that was greatly amplified by the presence of DETA-NO.
The sGC stimulator IWP-953 stimulation of cGMP production in endothelial-like primary human trabecular meshwork (HTM) cells (HTM130 and HTM141) was observed, but was markedly less prominent than in myofibroblast-like HTM120 and HTM123 cells.
Intracameral injection of the soluble guanylate cyclase (sGC) stimulator IWP-953 at 10, 30, 60, and 100 μM concentration-dependently increased conventional outflow facility in paired enucleated mouse eyes ex vivo.
The maximal increase in conventional outflow facility by the soluble guanylate cyclase (sGC) stimulator IWP-953 was 89.5% at 100 μM (P = 0.002) in paired enucleated mouse eyes ex vivo, which was comparable in magnitude to DETA-NO at 100 μM (97.5% increase, P = 0.030).
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