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Uttio Roy Chowdhury, Cindy K. Bahler, Cheryl R. Hann, Bradley H. Holman, Michael P. Fautsch; The ATP-sensitive Potassium (KATP) Channel Opener Diazoxide Increases Outflow Facility by Activating the Erk1/2 Signaling Pathway. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3260.
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Studies from our laboratory have shown that the KATP channel opener diazoxide (DZ) increases outflow facility in an ex vivo human anterior segment culture model. DZ also activates Erk1/2 signaling in human trabecular meshwork primary cultures within 15 minutes of treatment. In this study, we evaluated whether DZ-induced outflow facility increase is mediated through the Erk1/2 pathway in ex vivo and in vivo models.
To assess the role of Erk1/2 in IOP modulation, cultured human anterior segments (n=6) were treated with DZ (20 µM) alone or in combination with U0126 (20 µM), an inhibitor of Erk1/2 phosphorylation. In vivo effects of DZ on intraocular pressure (IOP) were determined in wild type C57BL/6J mice (n=5) and in mice lacking the Kir6.2 subunit containing KATP channels (n=5). One eye of each animal received DZ (5 mM) while the contralateral eye received vehicle (DMSO), both administered topically, once daily for 14 consecutive days. In a separate experiment, C57BL/6J mice (n=5) were treated with DZ for 5 days followed by DZ plus U0126 (0.5 mM). In both in vivo experiments, IOP was measured three times daily and averaged to calculate the daily IOP. Histology of treated and control eyes was examined by light microscopy.
DZ treatment increased outflow facility in human anterior segments (0.13 ± 0.03 ul/min/mmHg to 0.29 ± 0.07 µl/min/mmHg, p<0.01) when compared to fellow paired vehicle controls (0.16 ± 0.07 to 0.16 ± 0.07 µl/min/mmHg, p>0.82). This action of DZ was abrogated by U0126 (0.13 ± 0.03 µl/min/mmHg to 0.15 ± 0.03 µl/min/mmHg, p>0.07). Topical application of DZ to wild-type mouse eyes showed a 20.7 ± 4.6% (p<0.05) reduction compared to vehicle alone. Cessation of DZ treatment or the addition of U0126 resulted in IOP returning to baseline. In contrast, Kir6.2(-/-) mice showed no change in IOP following DZ treatment. Histological examinations of treated and control eyes did not show any toxic side effects.
The KATP channel opener DZ lowers IOP and increases outflow facility in ex vivo human anterior segment culture and in vivo murine models by activation of Erk1/2. In vivo, DZ was found to lower IOP by acting through the KATP channels containing the Kir6.2 subunit. DZ shows potential as a future therapeutic modality for reducing elevated IOP.
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