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Ken Mizuno, Tomoyuki Isobe, Takashi Koide, Masanao Watanabe, Yoshio Kaneko, Yuta Inokuchi, Jiro Matsumoto, Sohei Tanabe; Ocular Hypotensive Mechanism Of K-115, A Rho-kinase Inhibitor, And Rho-kinase Expression In The Eye. Invest. Ophthalmol. Vis. Sci. 2011;52(14):237.
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© ARVO (1962-2015); The Authors (2016-present)
Previously, we presented the ocular hypotensive effect of K-115 ophthalmic solution in rabbits and monkeys (ARVO2007), and the effects of K-115 on aqueous humor outflow in rabbits (ARVO2008). In this study, the effect of K-115 on intraocular pressure (IOP), its combination effect with latanoprost, and on aqueous humor production were investigated. Additionally, the ocular distribution of topically instilled K-115, and the Rho-kinase expression in the eye was evaluated.
This study was conducted in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Either 0.4% K-115, 0.005% latanoprost, or 0.4% K-115 with 0.005% latanoprost were instilled topically into the same eye, and IOP was measured for 6 hours in male cynomolgus monkeys. To evaluate the aqueous humor production, 0.4% K-115 was instilled topically into randomly selected one eye, and aqueous flow rate was measured with Fluorophotometry in Male Japanese White rabbits. The ocular distribution of K-115 was performed by the whole head autoradiography with [14C]K-115 in rabbits. Frozen sequential sections (8 µm) were made and the expression of ROCK-1 and ROCK-2 were evaluated with immunohistochemistry in rabbits and monkeys.
Of 0.1, 0.2, and 0.4% K-115 revealed significant IOP reduction (p<0.01) in a dose-dependent manner by 11.7 ± 1.2%, 16.6 ± 1.4%, and 22.0 ± 1.4%, respectively. IOP reduction in K-115/latanoprost treatment (28.9 ± 1.5%) was significantly higher than that in latanoprost treatment (16.1 ± 0.9%, p<0.01). K-115 had no effect on aqueous flow rate (1.88 ± 0.35 µL/min) compared to the pre-treatment (1.97 ± 0.23 µL/min). Topical instillation of K-115 penetrated into the anterior part of the eye including the trabecular meshwork. Immunohistochemical analysis revealed that ROCK-1 and -2 were co-expressed in the trabecular meshwork.
K-115 reduced IOP in a dose dependent manner and showed a significant additive effect with latanoprost on IOP reduction. In addition, results suggest that the effect of K-115 on IOP is presumably due to the increment of aqueous humor outflow via trabecular meshwork route by inhibition of ROCKs.
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