H-1152 effects on intraocular pressure and trabecular meshwork morphology of rat eyes.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Yu
Man
M
Torsten Wiesel Research Institute, West China Eye Center & Ophthalmic Laboratories, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
Chen
Xiaoming
X
Wang
Ningli
N
Cai
Suping
S
Li
Ni
N
Qiu
Jinghua
J
Brandt
Curtis R
CR
Kaufman
Paul L
PL
Liu
Xuyang
X
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005123:Eye / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009798:Ocular Hypertension / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014129:Trabecular Meshwork / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology
C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine