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

Dang, Yalong; Wang, Chao; Shah, Priyal; Waxman, Susannah; Loewen, Ralitsa T.; Loewen, Nils A.

doi:10.1007/s00417-018-4175-6

Cited by 22 publications

(10 citation statements)

References 45 publications

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“…These functions are mediated by its downstream Rho effectors, such as Rho‐associated protein kinase (ROCK; Fukata et al, 2001 ; Honjo et al, 2001 ). ROCK‐mediated changes in TM cell contractility (Rao et al, 2005 ), focal adhesions (Rao et al, 2001 ), disruption of actin fibers (Dang et al, 2019 ), and alterations of associated giant vacuoles and tight junctions in Schlemm's canal (SC) cells (Kameda et al, 2012 ) are associated with increased conventional outflow facility and IOP lowering (Kaneko et al, 2016 ; Rao et al, 2001 ). Y27632 is the first ROCK inhibitor shown to lower IOP in rabbit eyes (Honjo et al, 2001 ), suggesting that inhibition of the ROCK pathway may be a viable therapeutic strategy for glaucoma.…”

Section: Introductionmentioning

confidence: 99%

Thrombospondin‐1 mediates Rho‐kinase inhibitor‐induced increase in outflow‐facility

Shan

Wai

Lam

et al. 2021

Journal Cellular Physiology

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Rho-kinase (ROCK) inhibitors, a novel class of anti-glaucoma agents, act by increasing the aqueous humor outflow through the conventional trabecular meshwork pathway. However, the downstream signaling consequences of the ROCK inhibitor are not completely understood. Our data show that Y39983, a selective ROCK inhibitor, could induce filamentous actin remodeling, reduced cell motility (as measured by cell migration), and transepithelial resistance in primary human TM (hTM) cells. After 2 days Y39983 treatment of hTM cells, a proteomic study identified 20 proteins whose expression was significantly altered. Pathway analysis of those proteins revealed the involvement of the p53 pathway, integrin signaling pathway, and cytoskeletal pathway regulation by Rho GTPase. Thrombospondin-1 (TSP1), a matricellular protein that is increased in glaucoma patients, was downregulated fivefold following Y39983 treatment. More importantly, both TSP1 antagonist leucine-serine-lysine-leucine (LSKL) and small interfering RNA (siRNA) reduced TSP1 gene and protein expressions as well as hTM cell migration. In the presence of Y39983, no further inhibition of cell migration resulted after LSKL and TSP1 siRNA knockdown. Likewise, LSKL triggered a dose-dependent increase in outflow facility in ex vivo mouse eyes, to a similar extent as Y39983 (83.8% increase by Y39983 vs. 71.2% increase by LSKL at 50 µM). There were no additive effects with simultaneous treatment with LSKL and Y39983, supporting the notion that the effects of ROCK inhibition were mediated by TSP1.

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Section: Introductionmentioning

confidence: 99%

Thrombospondin‐1 mediates Rho‐kinase inhibitor‐induced increase in outflow‐facility

Shan

Wai

Lam

et al. 2021

Journal Cellular Physiology

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“…Netarsudil lowers IOP through a combination of three mechanisms, reduction of aqueous humor, increased trabecular facility and decreased episcleral venous pressure [28] . Aqueous humor production is reduced primarily through its action on the norepinephrine transporter, while the inhibition of Rho-kinase reduces stiffness [26] and stress fibers in the TM as seen with other Rho-kinase inhibitors [30] . The impact on vessel diameters is variable, but in clinical use, conjunctival hyperemia is a common observation [31] and probably caused by rendering vascular smooth muscle cells less sensitive to intracellular Ca 2+ [32] .…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent effects of netarsudil, a Rho-kinase inhibitor, on the distal outflow tract

Chen

Waxman

Wang

et al. 2020

Preprint

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AbstractPurposeTo characterize the effects of netarsudil on the aqueous humor outflow tract distal to the trabecular meshwork (TM). We hypothesized that netarsudil increases outflow facility in eyes with and without circumferential ab interno trabeculectomy (AIT) that removes the TM.Methods64 porcine anterior segment cultures were randomly assigned to groups with (n=32) and without circumferential AIT (n=32). Cultures were exposed to 0.1, 1, and 10 μM netarsudil (N= 8 eyes per concentration). For each concentration, IOP and vessel diameters were compared to their respective pretreatment baselines. Outflow tract vessel diameters were assessed by spectral-domain optical coherence tomography (SDOCT) and rendered in 4D (XYZ time-series).ResultsNetarsudil at 1 μM reduced IOP in both eyes with TM (−0.60±0.24 mmHg, p = 0.01) and in eyes without TM (−1.79±0.42 mmHg, p<0.01). At this concentration, vessels of the distal outflow tract dilated by 72%. However, at 0.1 μM netarsudil elevated IOP in eyes with TM (1.59±0.36 mmHg, p<0.001) as well as in eyes without TM (0.23±0.32 mmHg, p<0.001). Vessels of the distal outflow tract constricted by 31%. Similarly, netarsudil at a concentration of 10 μM elevated IOP both in eyes with TM (1.91±0.193, p<0.001) and in eyes without TM (3.65±0.86 mmHg, p<0.001). At this concentration, outflow tract vessels constricted by 27%.ConclusionIn the porcine anterior segment culture, the dose-dependent IOP changes caused by netarsudil matched the diameter changes of distal outflow tract vessels. Hyper- and hypotensive properties of netarsudil persisted after TM removal.

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“…Netarsudil lowers IOP through a combination of three mechanisms, reduction of aqueous humor, increased trabecular facility, and decreased episcleral venous pressure [35]. Aqueous humor production is reduced primarily through its action on the norepinephrine transporter, while the inhibition of Rho-kinase reduces stiffness [33] and stress fibers in the TM as seen with other RKIs [21]. The impact on vessel diameters is variable, but in clinical use, conjunctival hyperemia is a common observation [37] and caused by rendering vascular smooth muscle cells less sensitive to intracellular Ca 2+ [38].…”

Section: Discussionmentioning

confidence: 99%

“…Ocular perfusion and outflow measurements were done with a system established for the anterior chamber perfusion model [8, [18][19][20][21]. Before each use, the system was calibrated with a water column calibration kit.…”

Section: Ocular Perfusion and Outflow Measurementmentioning

confidence: 99%

Dose-dependent effects of netarsudil, a Rho-kinase inhibitor, on the distal outflow tract

Chen

Waxman

Wang

et al. 2020

Graefes Arch Clin Exp Ophthalmol

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Purpose To characterize the effects of netarsudil on the aqueous humor outflow tract distal to the trabecular meshwork (TM). We hypothesized that netarsudil increases outflow facility in eyes with and without circumferential ab interno trabeculectomy (AIT) that removes the TM. Methods Sixty-four porcine anterior segment cultures were randomly assigned to groups with (n = 32) and without circumferential AIT (n = 32). Cultures were exposed to 0.1, 1, and 10 μM netarsudil (N = 8 eyes per concentration). For each concentration, IOP and vessel diameters were compared with their respective pretreatment baselines. Outflow tract vessel diameters were assessed by spectral-domain optical coherence tomography (SDOCT) and rendered in 4D (XYZ time series). Results Netarsudil at 1 μM reduced IOP both in eyes with TM (− 0.60 ± 0.24 mmHg, p = 0.01) and in eyes without TM (− 1.79 ± 0.42 mmHg, p < 0.01). At this concentration, vessels of the distal outflow tract dilated by 72%. However, at 0.1 μM netarsudil elevated IOP in eyes with TM (1.59 ± 0.36 mmHg, p < 0.001) as well as in eyes without TM (0.23 ± 0.32 mmHg, p < 0.001). Vessels of the distal outflow tract constricted by 31%. Similarly, netarsudil at a concentration of 10 μM elevated IOP both in eyes with TM (1.91 ± 0.193, p < 0.001) and in eyes without TM (3.65 ± 0.86 mmHg, p < 0.001). At this concentration, outflow tract vessels constricted by 27%. Conclusion In the porcine anterior segment culture, the dose-dependent IOP changes caused by netarsudil matched the diameter changes of distal outflow tract vessels. Hyper-and hypotensive properties of netarsudil persisted after TM removal.

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

Cited by 22 publications

References 45 publications

Thrombospondin‐1 mediates Rho‐kinase inhibitor‐induced increase in outflow‐facility

Thrombospondin‐1 mediates Rho‐kinase inhibitor‐induced increase in outflow‐facility

Dose-dependent effects of netarsudil, a Rho-kinase inhibitor, on the distal outflow tract

Dose-dependent effects of netarsudil, a Rho-kinase inhibitor, on the distal outflow tract

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