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W. M. Dismuke, D. Z. Ellis; Direct Activation of BKca Channels by NS1619 Increases Outflow Facility and Decreases TM Cell Volume. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2035.
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The large-conductance calcium-activated potassium (BKca) channels mediate the nitric oxide (NO)-induced increase in outflow facility and decrease in trabecular meshwork (TM) cell volume. This NO-induced reduction in TM cell volume is mediated through a signal transduction pathway involving soluble guanylate cyclase (sGC), cGMP generation and protein kinase G (PKG). In this study we investigate the ability of a direct activator of the BKca channel, NS1619, to increase outflow facility and decrease TM cell volume.
Outflow facility was measured using an anterior segment organ perfusion system. Low passage TM cells were loaded with Calcein AM and visualized using a confocal microscope. Images were taken of TM cells that were treated with or without: DETA-NO, NS1619, hypotonic medium (30% water). Cell volumes were quantified from confocal image stacks using NIH ImageJ software.
Following a steady basal outflow facility (0.4199+0.0071 ul/min/mmHg) (mean+SEM) a bolus administration of NS1619 (30uM) resulted in a significant increase in outflow facility (0.7816+0.0528 ul/min/mmHg). Outflow facility remained elevated for 3 hours post drug administration before returning to baseline values. Additionally, NS1619 dose-dependently decreased TM cell volume and prevented a hypotonic-induced TM cell volume increase. Finally, exposure to either the NO donor DETA-NO or NS1619 resulted in decreases in TM cell volume, but when administered in combination, produced no additional cell volume decrease.
These data demonstrate the ability of NS1619, a direct activator of the BKca channel, to increase outflow facility and decrease TM cell volume in a dose-dependent manner. Additionally, NS1619 when administered with a hypotonic shock, attenuated the hypotonic-induced increases in TM cell volume, further implicating the BKca channel in TM cell regulatory volume decrease. The inability of DETA-NO and NS1619 to cause greater decreases in TM cell volume when compared with NS1619 or with DETA-NO alone, suggest that their combined effects are not additive. Taken together, our data suggest that activators of the BKca channel, like NS1619, may have ocular hypotensive properties.
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