Effect of ATP-sensitive Potassium Channel Openers on Intraocular Pressure in Ocular Hypertensive Animal Models.
Effect of ATP-sensitive Potassium Channel Openers on Intraocular Pressure in Ocular Hypertensive Animal Models.
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DOI：
10.1167/iovs.63.2.15
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发表时间：
2022-02-01
影响因子：
4.4
通讯作者：
Fautsch MP
中科院分区：
文献类型：
--
作者：
Roy Chowdhury U;Millar JC;Holman BH;Anderson KJ;Dosa PI;Roddy GW;Fautsch MP
目的观察atp敏感的钾通道打开剂cromakalim前药1 （CKLP1）和二氮氧化物对高眼压小鼠眼压的影响。在tgf - β2过表达、类固醇诱导和虹膜离散度（DBA/2J）高眼压小鼠模型中测量基线IOP，然后每天滴一次CKLP1 （5 mM）或二氮氧化合物（5 mM）。用手持式回弹眼压计测量清醒动物的眼压。采用恒灌注法评价房水动力学。通过透射电镜观察治疗对眼部组织的影响。CKLP1使tgf - β2过表达小鼠的IOP降低20% (n = 6, P < 0.0001)，使激素性高眼压小鼠的IOP降低24% (n = 8, P < 0.0001)，使DBA/2J小鼠的IOP降低43% （n = 15, P < 0.0001）。二氮氧化物使类固醇性高眼压小鼠IOP降低32% (n = 13, P < 0.0001)，使DBA/2J小鼠IOP降低41% （n = 4, P = 0.005）。一项房水动力学分析显示，CKLP1使tgf - β2过表达小鼠的锁膜外静脉压降低29% (n = 13, P < 0.0001)，使DBA/2J小鼠的锁膜外静脉压降低72% （n = 4对照组，3治疗组，P = 0.0002）。二氮氧化物使激素性高眼压小鼠锁膜外静脉压降低35% （n = 3; P = 0.03）。与对照组相比，组织组织学和细胞形态正常。在激素性高眼压模型中，CKLP1和二氮氧化物处理的眼睛细胞外基质的积累减少。atp敏感的钾通道开放剂CKLP1和二氮氧化合物通过降低锁膜外静脉压有效降低眼高压动物模型的IOP，支持这些药物在眼高压和青光眼中的潜在治疗应用。
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. Baseline IOP was measured in TGFβ2 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. CKLP1 decreased the IOP by 20% in TGFβ2 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 TGFβ2 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. 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.
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