H-1152 Effects on Intraocular Pressure and Trabecular Meshwork Morphology of Rat Eyes

Abstract

The aim of this study was to elucidate the effects of the Rho-kinase inhibitor, H-1152, on cultured human trabecular meshwork (HTM) cells, TM morphology, and intraocular pressure (IOP) in rats. Cultured HTM cells were treated with H-1152. Changes in cell morphology and the organization of the actin cytoskeleton and focal adhesions were evaluated by microscopy and immunofluorescence. H-1152 was administered topically to the eyes of conscious rats, and IOP was measured with a commercially available tonometer before and after treatment. The eyes were enucleated 1 h after treatment, fixed, and processed for morphologic analysis by light and electron microscopy. Exposure of the cultured HTM cells to 20 microM of H-1152 induced elongation and separation of cells, deterioration, and loss of actin stress fibers and focal adhesions within 2 h. Topical administration of H-1152 resulted in a significant decrease in IOP from 0.5 to 6 h, with the maximum IOP reduction of 28.1% at 1 h post-treatment (P < 0.001; n = 10). H-1152 caused an expansion of the intercellular spaces and loss of extracellular material in the juxtacanalicular region of the TM in rat eyes. The IOP-lowering effect of H-1152 in rat eyes is likely due to changes in TM-cell morphology, the actin cytoskeleton, and cellular adhesions in the conventional outflow pathway. H-1152 has potential as a new antiglaucoma medication.