A myosin light chain kinase inhibitor, ML-9, lowers the intraocular pressure in rabbit eyes.
The role of myosin light chain kinase (MLCK) in regulating the intraocular pressure (IOP) and outflow facility in rabbit eyes were studied. The IOP and pupil diameter were determined before and after intracameral and intravitreal administration of ML-9, a specific MLCK inhibitor. Total outflow facility and uveoscleral outflow facility was determined 3hr after intracameral administration of ML-9. Immunoblotting was performed to identify MLCK and the 20-kDa light chain of myosin (MLC) isoforms in human trabecular meshwork (TM) cells. The phosphorylation status of MLC was examined following ML-9 treatment. The effects of ML-9 on the morphology and actin and vinculin distribution in cultured TM cells were also studied. In rabbit eyes, administration of ML-9 resulted in a dose-dependent decrease in IOP. An increase of the outflow facility was also observed. Immunoblot analysis revealed the presence of MLCK in human TM cells. Exposure to ML-9 dose-dependently inhibited MLC phosphorylation/activation. The inhibitor caused retraction and dissociation of cells, disruption of actin bundles and impairment of focal adhesion formation in TM cells. ML-9 induces a reduction in IOP and an increase in the outflow facility in rabbit eyes. The IOP-lowering effects may be related to alterations in TM cell shapes. Inhibitors of MLCK may potentially be developed into novel medications for glaucoma.
Honjo
Megumi
M
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. Megumi@kuhp.kyoto-u.ac.jp
Inatani
Masaru
M
Kido
Noriaki
N
Sawamura
Tatsuya
T
Yue
Beatrice Y J T
BY
Honda
Yoshihito
Y
Tanihara
Hidenobu
H
D000199:Actins / Q000378:metabolism; D000818:Animals; D001381:Azepines / Q000378:metabolism / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005123:Eye / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D015151:Immunoblotting; D007429:Intraocular Pressure / Q000187:drug effects*; D008858:Microscopy, Phase-Contrast; D010766:Phosphorylation; D011680:Pupil / Q000187:drug effects; D011817:Rabbits; D014129:Trabecular Meshwork / Q000187:drug effects
D000199:Actins; D001381:Azepines; D004791:Enzyme Inhibitors; C056218:ML 9