Tian Baohe, Kaufman Paul L
Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Medical School, Madison, F4/328 CSC, 600 Highland Avenue Madison, WI 53792, USA.
Exp Eye Res. 2005 Feb;80(2):215-25. doi: 10.1016/j.exer.2004.09.002.
Previous studies have shown that the inhibition of Rho kinase is involved in the regulation of outflow facility in the live rabbit eye and the enucleated porcine eye. However, it is unknown whether the Rho kinase inhibition will do the same in non-human primates. To determine if the Rho kinase inhibitor Y-27632 will reduce outflow resistance in the live monkey eye, if Y-27632 and the phosphatase inhibitor calyculin A (Caly-A which antagonises Y-27632-induced MLC dephosphorylation) will affect outflow facility differently, and if the latter will inhibit effect of the former on facility, we studied effects of Y-27632 and Caly-A on outflow facility in living monkeys separately and concurrently. Total outflow facility was measured by 2-level constant pressure perfusion of the anterior chamber (AC) before and after exchange with different doses of Y-27632 (1, 10 and 100 microM) or Caly-A (10, 50 and 100 nM), or vehicles, followed by continuous AC infusion of corresponding drug/vehicle solution, in opposite eyes of cynomolgus or rhesus monkeys. The effect of 100 microM Y-27632 or 100 nM Caly-A vs vehicle and the effect of 100 microM Y-27632+100 nM Caly-A vs 100 microM Y-27632 alone on outflow facility were also determined in monkeys pre-treated topically with 10 microl of 1% atropine in both eyes 1 hr before perfusion. Both Y-27632 and Caly-A dose-dependently increased outflow facility by up to 2-3 fold in monkeys, adjusted for baseline and contralateral control eye washout. Pre-treatment with 1% topical atropine partially inhibited the effect of 100 nM Caly-A, but not 100 microM Y-27632, on outflow facility. 100 nM Caly-A gradually and partially inhibited the Y-27632-induced facility increase. In conclusion, Y-27632 increases outflow facility in monkeys presumably by inhibiting cellular contractility in the TM. Caly-A increases outflow facility by complicated mechanisms perhaps including drug-induced ciliary muscle contraction and cytoskeletal reorganisation in TM cells. The partial inhibitory effect of Caly-A on the Y-27632-induced increase in outflow facility may reflect the former partially inhibiting the latter's relaxation of cells in the TM.
先前的研究表明，抑制Rho激酶参与活体兔眼和摘除眼球的猪眼中房水流出易度的调节。然而，Rho激酶抑制在非人灵长类动物中是否有同样的作用尚不清楚。为了确定Rho激酶抑制剂Y-27632是否会降低活体猴眼的流出阻力，Y-27632和磷酸酶抑制剂花萼海绵诱癌素A（Caly-A，可拮抗Y-27632诱导的肌球蛋白轻链去磷酸化）是否会对房水流出易度产生不同影响，以及后者是否会抑制前者对房水流出易度的作用，我们分别并同时研究了Y-27632和Caly-A对活体猴眼房水流出易度的影响。在用不同剂量的Y-27632（1、10和100微摩尔）或Caly-A（10、50和100纳摩尔）或赋形剂进行前房（AC）置换前后，通过对AC进行两级恒压灌注来测量总房水流出易度，随后在食蟹猴或恒河猴的对侧眼中持续输注相应的药物/赋形剂溶液。在灌注前1小时双眼局部用10微升1%阿托品预处理的猴子中，还测定了100微摩尔Y-27632或100纳摩尔Caly-A与赋形剂相比的效果，以及100微摩尔Y-27632 + 100纳摩尔Caly-A与单独使用100微摩尔Y-27632相比对房水流出易度的影响。校正基线和对侧对照眼洗脱后，Y-27632和Caly-A均剂量依赖性地使猴的房水流出易度增加高达2至3倍。1%局部阿托品预处理部分抑制了100纳摩尔Caly-A对房水流出易度的作用，但不影响100微摩尔Y-27632的作用。100纳摩尔Caly-A逐渐并部分抑制Y-27632诱导的房水流出易度增加。总之，Y-27632可能通过抑制小梁网中的细胞收缩性来增加猴的房水流出易度。Caly-A通过复杂的机制增加房水流出易度，可能包括药物诱导的睫状肌收缩和小梁网细胞中的细胞骨架重组。Caly-A对Y-27632诱导的房水流出易度增加的部分抑制作用可能反映前者部分抑制了后者对小梁网中细胞的舒张作用。
