RKI-1447, a Rho kinase inhibitor, causes ocular hypotension, actin stress fiber disruption, and increased phagocytosis.

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.

• Authors: Yalong Dang, Chao Wang, Priyal Shah, Susannah Waxman, Ralitsa T Loewen, Nils A Loewen
• Journal: Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie (Graefes Arch Clin Exp Ophthalmol) Vol. 257 Issue 1 Pg. 101-109 (Jan 2019) ISSN: 1435-702X [Electronic] Germany
• PMID: 30456419 (Publication Type: Journal Article)

Chemical References

• RKI-1447
• Thiazoles
• Urea
• rho-Associated Kinases

Topics

• Animals
• Cells, Cultured
• Disease Models, Animal
• Glaucoma, Open-Angle (drug therapy, physiopathology)
• Intraocular Pressure (drug effects)
• Ocular Hypotension (drug therapy, metabolism, physiopathology)
• Phagocytosis
• Stress Fibers (drug effects, metabolism)
• Swine
• Thiazoles (pharmacology)
• Trabecular Meshwork (drug effects, metabolism, pathology)
• Urea (analogs & derivatives, pharmacology)
• rho-Associated Kinases (antagonists & inhibitors)