Abstract
Ripasudil hydrochloride hydrate (K-115), a specific Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor, was the first ophthalmic solution developed for the treatment of glaucoma and ocular hypertension in Japan. Topical administration of K-115 decreased intraocular pressure (IOP) and increased outflow facility in rabbits. This study evaluated the effect of K-115 on monkey trabecular meshwork (TM) cells and Schlemm’s canal endothelial (SCE) cells. K-115 induced retraction and rounding of cell bodies as well as disruption of actin bundles in TM cells. In SCE-cell monolayer permeability studies, K-115 significantly decreased transendothelial electrical resistance (TEER) and increased the transendothelial flux of FITC-dextran. Further, K-115 disrupted cellular localization of ZO-1 expression in SCE-cell monolayers. These results indicate that K-115 decreases IOP by increasing outflow facility in association with the modulation of TM cell behavior and SCE cell permeability in association with disruption of tight junction.
Highlights
Rho-kinase (Rho-associated coiled-coil containing protein kinase; ROCK), a member of the serine-threonine protein kinases, is an effector protein of low molecular weight protein, Rho[1]
We examined the effects of K-115 on trabecular meshwork and Schlemm’s canal endothelial cell morphology in vitro
These results indicate that ROCK inhibitors reduce transendothelial electrical resistance (TEER) and increase fluorescein isothiocyanate (FITC)-dextran permeability in a dose-dependent manner
Summary
IOP-Lowering Effect of K-115 in Rabbits and Monkeys. In rabbits, 0.4% K-115 ophthalmic solution demonstrated a significant IOP-lowering effect. In TM cells, treatment with 1 and 10 μ mol/L of K-115, 10 μ mol/L of Y-27632, or 10 μ mol/L of fasudil for 30 and 60 min reduced actin bundles (Fig. 3). Induced cytoskeletal changes, including retraction and cell rounding and reduced actin bundles, recovered 2 h after the removal of ROCK inhibitors. These data suggest that ROCK inhibition may initiate cytoskeletal rearrangement in TM cells. Treatment of SCE cell monolayers with 5 μ mol/L of K-115, 25 μ mol/L of Y-27632, or 25 μ mol/L of fasudil resulted in significant reduction in TEER as 30 min. Similar effects were observed with 25 μ mol/L of Y-27632 and fasudil These results indicate that ROCK inhibitors reduce TEER and increase FITC-dextran permeability in a dose-dependent manner. The changes in adherence junctions in response to ROCK inhibitors were less prominent, if present at all, compared to changes in tight junctions
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