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首页> 外文期刊>Cellular Physiology and Biochemistry >Guanylate Cyclase Activators, Cell Volume Changes and IOP Reduction
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Guanylate Cyclase Activators, Cell Volume Changes and IOP Reduction

机译：鸟苷酸环化酶激活剂，细胞体积变化和眼压降低

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Glaucoma afflicts millions of people worldwide and is a major cause of blindness. The risk to develop glaucoma is enhanced by increases in IOP, which result from deranged flow of aqueous humor. Aqueous humor is a fluid located in the front of the eye that gives the eye its buoyancy and supplies nutrients to other eye tissues. Aqueous humor is secreted by a tissue called ciliary processes and exits the eye via two tissues; the trabecular meshwork (TM) and Schlemm’s canal. Because the spaces through which the fluid flows get smaller as the TM joins the area of the Schlemm’s canal, there is resistance to aqueous humor outflow and this resistance creates IOP. There is a correlation between changes in TM and Schlemm’s canal cell volume and rates of aqueous humor outflow; agents that decrease TM and Schlemm’s canal cell volume, increase the rate of aqueous humor outflow, thus decreasing IOP. IOP is regulated by guanylate cyclase activators as shown in humans, rabbits and monkeys. There are two distinct groups of guanylate cyclases, membrane guanylate cyclase and soluble guanylate cyclase (sGC); activation of both have been shown to decrease IOP. Members of the membrane guanylate cyclase family of receptors bind to peptide ligands, while the sGC responds to gases (such as NO and COsub2/sub) and compounds (such as YC1, [3-(5’-hydroxymethyl-2’furyl)-1-benzyl indazole), a benzyl indazole derivative, and BAY-58-2667); activation of either results in formation of cyclic GMP (cGMP) and activation of protein kinase G (PKG) and subsequent phosphorylation of target proteins, including the high conductance calcium activated potassium channel (BKca channel). While activators of both membrane guanylate cyclase and sGC have the ability to lower IOP, the IOP lowering effects of sGC are noteworthy because sGC activators can be topically applied to the eye to achieve an effect. We have demonstrated that activators of sGC increase the rate at which aqueous humor exits the eye in a time course that correlates with the time course for sGC-induced decreases in TM and Schlemm’s canal cell volume. Additionally, sGC-induced decrease in cell volume is accompanied by both Ksup+/sup and Clsup-/sup efflux induced by activation of Ksup+/sup and Clsup-/sup channels, including the BKca channel and/or Ksup+/supClsup-/sup symport. This suggests that parallel Ksup+/supClsup-/sup efflux, and resultant Hsub2/subO efflux result in decreases in cell volume. These observations suggest a functional role for sGC activators, and suggest that the sGC/cGMP/PKG systems are potential therapeutic targets in the treatment of glaucoma.
机译：青光眼困扰着全球数百万人，是失明的主要原因。房水流量紊乱导致眼压升高，会增加患青光眼的风险。房水是一种位于眼前的液体，可使眼球浮起并向其他眼部组织提供营养。房水由称为睫状突的组织分泌，并通过两个组织离开眼睛。小梁网（TM）和施勒姆运河。因为当TM连接到Schlemm的运河区域时，流体流动通过的空间变小，所以存在房水流出的阻力，并且这种阻力会产生IOP。 TM和Schlemm管细胞体积的变化与房水流出速率之间存在相关性。减少TM和Schlemm根管细胞体积的药物，增加房水流出的速率，从而降低IOP。如人，兔和猴所示，IOP受鸟苷酸环化酶激活剂调控。鸟苷酸环化酶有两个不同的组，膜鸟苷酸环化酶和可溶性鸟苷酸环化酶（sGC）。两者都被激活可以降低IOP。膜鸟苷酸环化酶受体家族的成员与肽配体结合，而sGC对气体（例如NO和CO 2 ）和化合物（例如YC1，[3-（5'-羟甲基） -2'呋喃基）-1-苄基吲唑），苄基吲唑衍生物和BAY-58-2667）;任一种激活都会导致形成环状GMP（cGMP）和激活蛋白激酶G（PKG），随后使目标蛋白磷酸化，包括高电导钙激活钾通道（BKca通道）。尽管膜鸟苷酸环化酶和sGC的激活剂均具有降低IOP的能力，但值得注意的是sGC的IOP降低效果很明显，因为sGC激活剂可局部应用于眼睛以达到一定效果。我们已经证明，sGC的激活剂可以在一定的时间范围内增加房水离开眼球的速度，该时间过程与sGC引起的TM和Schlemm根管细胞体积减少的时间过程相关。此外，sGC诱导的细胞体积减少伴随着K + 和Cl 和Cl -外排>-通道，包括BKca通道和/或K + Cl -共模端口。这表明平行的K + Cl -外排，以及所产生的H 2 O外排导致细胞体积减少。这些观察结果暗示了sGC激活剂的功能作用，并表明sGC / cGMP / PKG系统是治疗青光眼的潜在治疗靶标。

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