Reduction of intraocular pressure by topical administration of an inhibitor of the Rho-associated protein kinase.
OBJECTIVE
Rho-associated coiled coil-forming protein kinase (ROCK) is a downstream target of a small GTPase, Rho. The kinase has been reported to regulate actomyosin-based contractility of smooth muscles by modulation of myosin phosphatase activity. Contractility of ciliary muscle could be implicated in regulation of intraocular pressure while that of ocular vessels could affect blood flow to retina. The present study has been performed to investigate the effect of a ROCK inhibitor on intraocular pressure in rabbits.


METHODS
An inhibitor of ROCK, Y-27632, was dissolved in an ophthalmic solution and topically administered to the eye of a Japanese white rabbit. Intraocular pressure was measured by pneumatonography (n = 12, 24 eyes). Constriction of ciliary muscle was measured by the Magnus method using 12 eyes.


RESULTS
Topical application of 0.1 and 0.03% Y-27632 significantly decreased the intraocular pressure, with maximum decreases of 5.3 and 4.3 mm Hg after 90 minutes compared with the control eye. Y-27632 inhibited the carbachol-induced constriction of rabbit ciliary muscle.


CONCLUSIONS
The ROCK inhibitor reduced intraocular pressure in rabbits by topical instillation. The inhibitor relaxed the excised ciliary muscle which was previously constricted by carbachol suggesting that the inhibitor acts to increase the uveoscleral outflow. Our results suggest that the ROCK inhibitor is a promising treatment for glaucoma therapy in the next generation.
Waki
M
M
Research Laboratory, Senju Pharmaceutical Co., Ltd., Kobe 651-2241, Japan. mitsunori-waki@senju.co.jp
Yoshida
Y
Y
Oka
T
T
Azuma
M
M
D000287:Administration, Topical; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002924:Ciliary Body / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009883:Ophthalmic Solutions; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D014065:Tonometry, Ocular; D054460:rho-Associated Kinases
D000577:Amides; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009883:Ophthalmic Solutions; D011725:Pyridines; C108830:Y 27632; D002217:Carbachol; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases