Effect of ATP-sensitive Potassium Channel Openers on Intraocular Pressure in Ocular Hypertensive Animal Models

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dc.creatorRoy Chowdhury, Uttio
dc.creatorMillar, J. Cameron
dc.creatorHolman, Bradley H.
dc.creatorAnderson, Kjerston J.
dc.creatorDosa, Peter I.
dc.creatorRoddy, Gavin W.
dc.creatorFautsch, Michael P.
dc.date.accessioned2022-10-14T14:32:30Z
dc.date.available2022-10-14T14:32:30Z
dc.date.issued2022-02-01
dc.description.abstractPurpose: 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.
dc.description.sponsorshipSupported by NIH grant EY21727 (to M.P.F.), EY031758 (to G.W.R.); Mayo Clinic Department of Ophthalmology grant (to U.R.C.), and Mayo Foundation (to M.P.F., and G.W.R.).
dc.identifier.citationRoy 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.63.2.15
dc.identifier.issn1552-5783
dc.identifier.issue2
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31851
dc.identifier.volume63
dc.publisherARVO Journals
dc.relation.urihttps://doi.org/10.1167/iovs.63.2.15
dc.rights.holderCopyright 2022 The Authors
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceInvestigative Ophthalmology & Visual Science
dc.subject.meshAnimals
dc.subject.meshAntihypertensive Agents / administration & dosage
dc.subject.meshCromakalim / administration & dosage
dc.subject.meshDiazoxide / administration & dosage
dc.subject.meshDisease Models, Animal
dc.subject.meshEye / ultrastructure
dc.subject.meshIntraocular Pressure / drug effects
dc.subject.meshKATP Channels / drug effects
dc.subject.meshKATP Channels / metabolism
dc.subject.meshMice
dc.subject.meshMice, Inbred DBA
dc.subject.meshMicroscopy, Electron, Transmission
dc.subject.meshOcular Hypertension / drug therapy
dc.subject.meshOcular Hypertension / metabolism
dc.subject.meshOcular Hypertension / physiopathology
dc.subject.meshOphthalmic Solutions
dc.titleEffect of ATP-sensitive Potassium Channel Openers on Intraocular Pressure in Ocular Hypertensive Animal Models
dc.typeArticle
dc.type.materialtext

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