Effects of protein kinase inhibitor, HA1077, on intraocular pressure and outflow facility in rabbit eyes.
OBJECTIVE
To elucidate the roles of protein kinase in regulating the intraocular pressure (IOP) and outflow facility in rabbit eyes.


METHODS
A protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-homopiperazine (HA1077), was used. The IOP and the outflow facility were measured before and after topical, intracameral, or intravitreal administration of HA1077 in rabbits. Western blot analysis was performed to detect the 20-kd light chain of myosin in human trabecular meshwork (TM) cells and bovine ciliary muscle (CM) tissues. The cell morphologic condition and distribution of actin filaments and vinculin in TM cells were studied using cell biology techniques. Carbachol-induced contraction of isolated bovine CM strips following administration of HA1077 was examined in a perfusion chamber.


RESULTS
In rabbit eyes, the administration of HA1077 resulted in a significant decrease in IOP in a dose-dependent manner. An increased outflow facility was also observed. Western blot analysis revealed the presence of 20-kd light chain of myosin in human TM cells and bovine CM tissues. In cultured human TM cells, exposure to HA1077 disrupted actin bundles and impaired focal adhesion formation. In addition HA1077 showed relaxation of bovine CM strips.


CONCLUSIONS
Use of HA1077 caused a reduction in IOP and an increase in the outflow facility. The results of in vitro experiments suggest that the IOP-lowering effects of HA1077 may be related to the altered cellular behavior of TM cells and relaxation of CM contraction. The results of these studies suggested that protein kinase inhibitors have the potential to be developed into a treatment modality for glaucoma.
Honjo
M
M
Department of Ophthalmology and Visual Sciences, Kyoto University School of Medicine, Kyoto, Japan.
Inatani
M
M
Kido
N
N
Sawamura
T
T
Yue
B Y
BY
Honda
Y
Y
Tanihara
H
H
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000199:Actins / Q000378:metabolism; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D015153:Blotting, Western; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019084:Fluorescent Antibody Technique, Indirect; D007429:Intraocular Pressure / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D009883:Ophthalmic Solutions / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011817:Rabbits; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism
D000199:Actins; D004791:Enzyme Inhibitors; D009883:Ophthalmic Solutions; D047428:Protein Kinase Inhibitors; D016596:Vinculin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002217:Carbachol; D009218:Myosins; C049347:fasudil