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Iris Navarro, Marco Kessler, Una L Kelly, Megan Parker, Gerhard Hannig, Pei Ge, W Daniel Stamer; sGC Stimulators and Trabecular Meshwork Biology. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1649. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Nitric oxide (NO) relaxes the trabecular meshwork, increases outflow facility and lowers intraocular pressure. As opposed to direct treatment using NO-donating compounds, priming sensitivity of soluble guanylate cyclase (sGC) to NO may provide more efficacious therapeutic benefits as sGC stimulators work synergistically with endogenous NO to amplify cGMP production. The goal of the present study was to investigate the synergistic relationship between the sGC stimulator, IWP-953 and NO in trabecular meshwork (TM) cell models.
Methods: To determine IWP-953 and NO synergy on sGC activity in 3 different confluent strains of human TM cells, we measured intracellular cGMP to generate a concentration-response curve for low fixed concentration of IWP-953 (1 or 10 µM) with escalating DETA-NO concentrations (10 pM-1mM). Synergistic effects of IWP-953/NO on TM cellular contraction was measured using two methods, a gel contraction assay and phosphorylation status of myosin light chain (pMLC) by Western blot.
Results: Using a fixed dose of IWP-953 in the cGMP assay, the average EC50 in the 3 cell strains for DETA-NO was 98.1 μM in the presence of 1 μM IWP-953 and 20.9 µM in the presence of 10 μM IWP-953. Similarly, the combination of 10 μM IWP-953 and 1 μM DETA-NO was equally efficacious as 100μM DETA-NO alone in relaxing TM cells and decreasing proportion of MLC that was phosphorylated.
Conclusions: These data indicate that IWP-953 synergistically works with NO to modulate the sGC-cGMP pathway and relax human TM cells. By restoring physiological levels of cellular contraction/relaxation to the TM, sGC stimulators may stop or reverse the cell contraction-induced fibrosis in glaucomatous tissues that is thought to contribute to outflow dysfunction.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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