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Uttio Roy Chowdhury, Cindy K Bahler, Bradley H Holman, Michael P Fautsch; Ocular hypotensive effects of the KATP channel opener cromakalim in murine and human experimental model systems. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3547.
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© ARVO (1962-2015); The Authors (2016-present)
Studies from our laboratory have shown that the KATP channel opener diazoxide lowers intraocular pressure (IOP) by activating the SUR2B/Kir6.2 subunit containing channels. In this study, we evaluated the IOP lowering ability of the broad spectrum KATP channel opener cromakalim (CKL) which activates both SUR2B/Kir6.2 and SUR2A/Kir6.2 subunit containing channels. Efficacy of combination therapy with CKL and latanoprost free acid (LFA) was also evaluated.
Human anterior segment pairs (n=10, mean age 72.5±15.1, range 52 to 88 years) were placed in perfusion organ culture and treated with CKL (0.02 µM, 0.2 µM, and 2 µM) or vehicle (DMSO). In vivo IOP-lowering effects of topically administered CKL (5 mM in 10% cremophor EL), either alone or in combination with LFA (0.005% in PBS, n=10), was evaluated in wild type C57BL/6 mice using a handheld rebound tonometer. Subunit specificity of CKL was studied in Kir6.2(-/-) mice (n=10). Tissue morphology of all eyes treated with CKL, LFA and respective vehicles was imaged by transmission electron microscopy and evaluated by at least two independent masked observers.
Cromakalim (2 µM) increased outflow facility in human anterior segments compared to baseline (0.13±0.02 to 0.20±0.04 µl/min/mmHg, n=10, P<0.001). Outflow facility was unchanged in the vehicle treated segments (0.18±0.06 to 0.17±0.05 µl/min/mmHg, n=10, P=0.9). No change in outflow facility was observed with cromakalim added at 0.02 or 0.2 µM. In vivo, mouse eyes treated with CKL alone showed a 20.3% reduction in IOP compared to control (13.63±0.16 to 17.1±0.35 mmHg, n=5, P<0.001). When CKL was combined with LFA, IOP decreased by an additional 71% compared to mice eyes treated with CKL alone (n=10, P<0.001). Treatment of Kir6.2(-/-) mice with CKL did not show any reduction in IOP (16.09±0.26 mmHg to 16.09±0.29 mmHg, n=10, P>0.05). Histologic analysis of treated and control eyes showed no major disruptions of the inner and outer wall of Schlemm's canal, comparable cell numbers, and extracellular matrix integrity throughout the trabecular meshwork.
The KATP channel opener CKL is a potent ocular hypotensive agent that specifically acts through the Kir6.2 subunit containing KATP channels. The mechanism of action of CKL is distinct to that of LFA. The KATP channel opener CKL has potential as an ocular hypotensive agent either alone or in combination with LFA.
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