Yalong Dang1, Chao Wang1,2, Priyal Shah1,3, Susannah Waxman1, Ralitsa T Loewen1, Nils A Loewen4. 1. Department of Ophthalmology, University of Pittsburgh School of Medicine, 203 Lothrop St, Suite 819, Pittsburgh, PA, 15213, USA. 2. Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. 3. Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, NJ, USA. 4. Department of Ophthalmology, University of Pittsburgh School of Medicine, 203 Lothrop St, Suite 819, Pittsburgh, PA, 15213, USA. loewen.nils@gmail.com.
Abstract
PURPOSE: This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor, in a porcine ex vivo pigmentary glaucoma model. METHODS: Twenty-eight porcine anterior chambers were perfused with medium supplemented with 1.67 × 107 pigment particles/ml for 48 h before treatment with RKI-1447 (n = 16) or vehicle control (n = 12). Intraocular pressure (IOP) was recorded and outflow facility was calculated. Primary trabecular meshwork cells were exposed to RKI-1447 or vehicle control; effects on the cytoskeleton, motility, and phagocytosis were evaluated. RESULT: Compared to baseline, the perfusion of pigment caused a significant increase in IOP in the RKI-1447 group (P = 0.003) at 48 h. Subsequent treatment with RKI-1447 significantly reduced IOP from 20.14 ± 2.59 to 13.38 ± 0.91 mmHg (P = 0.02). Pigment perfusion reduced the outflow facility from 0.27 ± 0.03 at baseline to 0.18 ± 0.02 at 48 h (P < 0.001). This was partially reversed with RKI-1447. RKI-1447 caused no apparent histological changes in the micro- or macroscopic TM appearance. RKI-1447-treated primary TM cells showed significant disruption of the actin cytoskeleton both in the presence and absence of pigment (P < 0.001) but no effect on TM migration was observed. Pigment-treated TM cells exhibited a reduction in TM phagocytosis, which RKI-1447 reversed. CONCLUSION: RKI-1447 significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it useful for the treatment of secondary glaucomas with an increased phagocytic load.
PURPOSE: This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor, in a porcine ex vivo pigmentary glaucoma model. METHODS: Twenty-eight porcine anterior chambers were perfused with medium supplemented with 1.67 × 107 pigment particles/ml for 48 h before treatment with RKI-1447 (n = 16) or vehicle control (n = 12). Intraocular pressure (IOP) was recorded and outflow facility was calculated. Primary trabecular meshwork cells were exposed to RKI-1447 or vehicle control; effects on the cytoskeleton, motility, and phagocytosis were evaluated. RESULT: Compared to baseline, the perfusion of pigment caused a significant increase in IOP in the RKI-1447 group (P = 0.003) at 48 h. Subsequent treatment with RKI-1447 significantly reduced IOP from 20.14 ± 2.59 to 13.38 ± 0.91 mmHg (P = 0.02). Pigment perfusion reduced the outflow facility from 0.27 ± 0.03 at baseline to 0.18 ± 0.02 at 48 h (P < 0.001). This was partially reversed with RKI-1447. RKI-1447 caused no apparent histological changes in the micro- or macroscopic TM appearance. RKI-1447-treated primary TM cells showed significant disruption of the actin cytoskeleton both in the presence and absence of pigment (P < 0.001) but no effect on TM migration was observed. Pigment-treated TM cells exhibited a reduction in TM phagocytosis, which RKI-1447 reversed. CONCLUSION: RKI-1447 significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it useful for the treatment of secondary glaucomas with an increased phagocytic load.
Authors: M Honjo; H Tanihara; M Inatani; N Kido; T Sawamura; B Y Yue; S Narumiya; Y Honda Journal: Invest Ophthalmol Vis Sci Date: 2001-01 Impact factor: 4.799
Authors: Yasmin Siddiqui; Richard D Ten Hulzen; J Douglas Cameron; David O Hodge; Douglas H Johnson Journal: Am J Ophthalmol Date: 2003-06 Impact factor: 5.258