Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)2022-10-142022-10-142022-02-01Roy Chowdhury, U., Millar, J. C., Holman, B. H., Anderson, K. J., Dosa, P. I., Roddy, G. W., & Fautsch, M. P. (2022). Effect of ATP-sensitive Potassium Channel Openers on Intraocular Pressure in Ocular Hypertensive Animal Models. Investigative ophthalmology & visual science, 63(2), 15. https://doi.org/10.1167/iovs.63.2.151552-5783https://hdl.handle.net/20.500.12503/31851Purpose: To evaluate the effect of ATP-sensitive potassium channel openers cromakalim prodrug 1 (CKLP1) and diazoxide on IOP in three independent mouse models of ocular hypertension. Methods: Baseline IOP was measured in TGFbeta2 overexpression, steroid-induced, and iris dispersion (DBA/2J) ocular hypertension mouse models, followed by once daily eyedrop administration with CKLP1 (5 mM) or diazoxide (5 mM). The IOP was measured in conscious animals with a handheld rebound tonometer. Aqueous humor dynamics were assessed by a constant perfusion method. Effect of treatment on ocular tissues was evaluated by transmission electron microscopy. Results: CKLP1 decreased the IOP by 20% in TGFbeta2 overexpressing mice (n = 6; P < 0.0001), 24% in steroid-induced ocular hypertensive mice (n = 8; P < 0.0001), and 43% in DBA/2J mice (n = 15; P < 0.0001). Diazoxide decreased the IOP by 32% in mice with steroid-induced ocular hypertension (n = 13; P < 0.0001) and by 41% in DBA/2J mice (n = 4; P = 0.005). An analysis of the aqueous humor dynamics revealed that CKLP1 decreased the episcleral venous pressure by 29% in TGFbeta2 overexpressing mice (n = 13; P < 0.0001) and by 72% in DBA/2J mice (n = 4 control, 3 treated; P = 0.0002). Diazoxide lowered episcleral venous pressure by 35% in steroid-induced ocular hypertensive mice (n = 3; P = 0.03). Tissue histology and cell morphology appeared normal when compared with controls. Accumulation of extracellular matrix was reduced in CKLP1- and diazoxide-treated eyes in the steroid-induced ocular hypertension model. Conclusions: ATP-sensitive potassium channel openers CKLP1 and diazoxide effectively decreased the IOP in ocular hypertensive animal models by decreasing the episcleral venous pressure, supporting a potential therapeutic application of these agents in ocular hypertension and glaucoma.http://creativecommons.org/licenses/by-nc-nd/4.0/AnimalsAntihypertensive Agents / administration & dosageCromakalim / administration & dosageDiazoxide / administration & dosageDisease Models, AnimalEye / ultrastructureIntraocular Pressure / drug effectsKATP Channels / drug effectsKATP Channels / metabolismMiceMice, Inbred DBAMicroscopy, Electron, TransmissionOcular Hypertension / drug therapyOcular Hypertension / metabolismOcular Hypertension / physiopathologyOphthalmic SolutionsArticleCopyright 2022 The Authors632