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Published in: Graefe's Archive for Clinical and Experimental Ophthalmology 2/2019

01-02-2019 | Basic Science

Effects of ripasudil, a rho kinase inhibitor, on blood flow in the optic nerve head of normal rats

Authors: Yasushi Wada, Tomomi Higashide, Atsushi Nagata, Kazuhisa Sugiyama

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 2/2019

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Abstract

Purpose

To evaluate the effect of topically administrated ripasudil, a rho kinase inhibitor, on blood flow in the optic nerve head (ONH) of normal rats.

Methods

Ripasudil (0.4%) or placebo was administered in the right eye of normal Brown Norway rats in a double-blind manner. Laser speckle flowgraphy was measured in the ONH of the right eye 20 or 40 min after a single instillation and before and after 7 or 14 days of twice daily instillation. Mean blur rate was evaluated in the total area (MA), the vessel region (MV), and the tissue region (MT). Intraocular pressure (IOP), blood pressure, ocular perfusion pressure (OPP), and heart rate were also recorded at each time point.

Results

After a single instillation, MV was significantly larger at 40 min than 20 min in the ripasudil group (P = 0.044) and was significantly lower in the placebo group (P = 0.023). MA and MV 40 min after instillation were significantly larger in the ripasudil group than in the placebo group (P = 0.022 and P = 0.006, respectively). After continuous instillation, MA and MV in the ripasudil group significantly increased from baseline after 7 and 14 days of treatment (both P < 0.05) and MA, MV, and MT were significantly higher than in the placebo group (MA: 7 and 14 days, P < 0.01; MV: 7 days, P = 0.003, and 14 days, P = 0.012; MT: 7 days, P = 0.046). There were no significant changes in IOP, blood pressure, or OPP after single or continuous instillation.

Conclusions

Topical instillation of ripasudil increased blood flow around the ONH in the eyes of normal rats.
Literature
2.
go back to reference Flammer J, Orgül S, Costa VP et al (2002) The impact of ocular blood flow in glaucoma. Prog Retina Eye Res 21:359–393CrossRef Flammer J, Orgül S, Costa VP et al (2002) The impact of ocular blood flow in glaucoma. Prog Retina Eye Res 21:359–393CrossRef
3.
go back to reference Hwang JC, Konduru R, Zhang X et al (2012) Relationship among visual field, blood flow, and neural structure measurements in glaucoma. Invest Ophthalmol Vis Sci 53:3020–3026CrossRefPubMedPubMedCentral Hwang JC, Konduru R, Zhang X et al (2012) Relationship among visual field, blood flow, and neural structure measurements in glaucoma. Invest Ophthalmol Vis Sci 53:3020–3026CrossRefPubMedPubMedCentral
4.
go back to reference Sugiyama T, Kojima S, Ishida O, Ikeda T (2009) Changes in optic nerve head blood flow induced by the combined therapy of latanoprost and beta blockers. Acta Ophthalmol 87:797–800CrossRefPubMed Sugiyama T, Kojima S, Ishida O, Ikeda T (2009) Changes in optic nerve head blood flow induced by the combined therapy of latanoprost and beta blockers. Acta Ophthalmol 87:797–800CrossRefPubMed
5.
go back to reference Tsuda S, Yokoyama Y, Chiba N et al (2013) Effect of topical tafluprost on optic nerve head blood flow in patients with myopic disc type. J Glaucoma 22:398–403CrossRefPubMed Tsuda S, Yokoyama Y, Chiba N et al (2013) Effect of topical tafluprost on optic nerve head blood flow in patients with myopic disc type. J Glaucoma 22:398–403CrossRefPubMed
6.
go back to reference Sugiyama T, Nakamura H, Shimizu H et al (2015) Clinical usefulness of the measurement of optic nerve head blood flow in myopic normal-tension glaucoma. Int J Ophthalmic Res 1:11–18CrossRef Sugiyama T, Nakamura H, Shimizu H et al (2015) Clinical usefulness of the measurement of optic nerve head blood flow in myopic normal-tension glaucoma. Int J Ophthalmic Res 1:11–18CrossRef
7.
go back to reference Witkowska KJ, Bata AM, Calzetti G et al (2017) Optic nerve head and retinal blood flow regulation during isometric exercise as assessed with laser speckle flowgraphy. PLoS One 12(9):e0184772CrossRefPubMedPubMedCentral Witkowska KJ, Bata AM, Calzetti G et al (2017) Optic nerve head and retinal blood flow regulation during isometric exercise as assessed with laser speckle flowgraphy. PLoS One 12(9):e0184772CrossRefPubMedPubMedCentral
8.
go back to reference Wang L, Cull GA, Piper C, Burgoyne CF, Fortune B (2012) Anterior and posterior optic nerve head blood flow in nonhuman primate experimental glaucoma model measured by laser speckle imaging technique and microsphere method. Invest Ophthalmol Vis Sci 53:8303–8309CrossRefPubMedPubMedCentral Wang L, Cull GA, Piper C, Burgoyne CF, Fortune B (2012) Anterior and posterior optic nerve head blood flow in nonhuman primate experimental glaucoma model measured by laser speckle imaging technique and microsphere method. Invest Ophthalmol Vis Sci 53:8303–8309CrossRefPubMedPubMedCentral
9.
go back to reference Sugiyama T, Shibata M, Kajiura S et al (2011) Effects of fasudil, a rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. Invest Ophthalmol Vis Sci 52:64–69CrossRefPubMed Sugiyama T, Shibata M, Kajiura S et al (2011) Effects of fasudil, a rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. Invest Ophthalmol Vis Sci 52:64–69CrossRefPubMed
10.
go back to reference Ohta Y, Takaseki S, Yoshitomi T (2017) Effects of ripasudil hydrochloride hydrate (K-115), a rho-kinase inhibitor, on ocular blood flow and ciliary artery smooth muscle contraction in rabbits. Jpn J Ophthalmol 61:423–432CrossRefPubMed Ohta Y, Takaseki S, Yoshitomi T (2017) Effects of ripasudil hydrochloride hydrate (K-115), a rho-kinase inhibitor, on ocular blood flow and ciliary artery smooth muscle contraction in rabbits. Jpn J Ophthalmol 61:423–432CrossRefPubMed
11.
go back to reference Wada Y, Higashide T, Nagata A, Sugiyama K (2016) Longitudinal changes in optic nerve head blood flow in normal rats evaluated by laser speckle flowgraphy. Invest Ophthalmol Vis Sci 57:5568–5575CrossRefPubMed Wada Y, Higashide T, Nagata A, Sugiyama K (2016) Longitudinal changes in optic nerve head blood flow in normal rats evaluated by laser speckle flowgraphy. Invest Ophthalmol Vis Sci 57:5568–5575CrossRefPubMed
12.
go back to reference Kaneko Y, Ohta M, Inoue T, Mizuno K, Isobe T, Tanabe S, Tanihara H (2016) Effects of K-115 (ripasudil), a novel ROCK inhibitor, on trabecular meshwork and Schlemm’s canal endothelial cells. Sci Rep 6:19640CrossRefPubMedPubMedCentral Kaneko Y, Ohta M, Inoue T, Mizuno K, Isobe T, Tanabe S, Tanihara H (2016) Effects of K-115 (ripasudil), a novel ROCK inhibitor, on trabecular meshwork and Schlemm’s canal endothelial cells. Sci Rep 6:19640CrossRefPubMedPubMedCentral
13.
go back to reference Tanihara H, Inoue T, Yamamoto T et al (2015) Additive intraocular pressure-lowering effects of the rho kinase inhibitor ripasudil (K-115) combined with timolol or latanoprost: a report of 2 randomized clinical trials. JAMA Ophthalmol 133:755–761CrossRefPubMed Tanihara H, Inoue T, Yamamoto T et al (2015) Additive intraocular pressure-lowering effects of the rho kinase inhibitor ripasudil (K-115) combined with timolol or latanoprost: a report of 2 randomized clinical trials. JAMA Ophthalmol 133:755–761CrossRefPubMed
14.
go back to reference Tanihara H, Inoue T, Yamamoto T et al (2013) Phase 2 randomized clinical study of a rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 156:731–736CrossRefPubMed Tanihara H, Inoue T, Yamamoto T et al (2013) Phase 2 randomized clinical study of a rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 156:731–736CrossRefPubMed
15.
go back to reference Hidaka T, Chuman H, Nao-i N (2017) Evaluation of optic nerve head blood flow in normal rats and a rodent model of non-arteritic ischemic optic neuropathy using laser speckle flowgraphy. Graefes Arch Clin Exp Ophthalmol 255:1973–1980CrossRef Hidaka T, Chuman H, Nao-i N (2017) Evaluation of optic nerve head blood flow in normal rats and a rodent model of non-arteritic ischemic optic neuropathy using laser speckle flowgraphy. Graefes Arch Clin Exp Ophthalmol 255:1973–1980CrossRef
16.
go back to reference Matsumoto T, Saito Y, Itokawa T et al (2017) Retinal VEGF levels correlate with ocular circulation measured by a laser speckle-micro system in an oxygen-induced retinopathy rat model. Graefes Arch Clin Exp Ophthalmol 255:1981–1990CrossRefPubMed Matsumoto T, Saito Y, Itokawa T et al (2017) Retinal VEGF levels correlate with ocular circulation measured by a laser speckle-micro system in an oxygen-induced retinopathy rat model. Graefes Arch Clin Exp Ophthalmol 255:1981–1990CrossRefPubMed
17.
go back to reference Ishii K, Tomidokoro A, Nagahara M, Tamaki Y, Kanno M, Fukaya Y, Araie M (2001) Effects of topical latanoprost on optic nerve head circulation in rabbits, monkeys, and humans. Invest Ophthalmol Vis Sci 42:2957–2963PubMed Ishii K, Tomidokoro A, Nagahara M, Tamaki Y, Kanno M, Fukaya Y, Araie M (2001) Effects of topical latanoprost on optic nerve head circulation in rabbits, monkeys, and humans. Invest Ophthalmol Vis Sci 42:2957–2963PubMed
18.
go back to reference Van der Zypen E (1977) Experimental morphological study on structure and function of the filtration angel of the rat eye. Ophthalmologica 174:285–298CrossRefPubMed Van der Zypen E (1977) Experimental morphological study on structure and function of the filtration angel of the rat eye. Ophthalmologica 174:285–298CrossRefPubMed
19.
go back to reference Zhi Z, Cepurna W, Johnson E, Shen T, Morrison J, Wang RK (2011) Volumetric and quantitative imaging of retinal blood flow in rats with optical microangiography. Biomed Opt Express 2:579–591CrossRefPubMedPubMedCentral Zhi Z, Cepurna W, Johnson E, Shen T, Morrison J, Wang RK (2011) Volumetric and quantitative imaging of retinal blood flow in rats with optical microangiography. Biomed Opt Express 2:579–591CrossRefPubMedPubMedCentral
20.
go back to reference Srinivasan VJ, Radhakrishnan H (2013) Total average blood flow and angiography in the rat retina. J Biomed Opt 18:076025–076021–5 Srinivasan VJ, Radhakrishnan H (2013) Total average blood flow and angiography in the rat retina. J Biomed Opt 18:076025–076021–5
21.
go back to reference Choi W, Baumann B, Liu JJ et al (2012) Measurement of pulsatile total blood flow in the human and rat retina with ultrahigh speed spectral/Fourier domain OCT. Biomed Opt Express 3:1047–1061CrossRefPubMedPubMedCentral Choi W, Baumann B, Liu JJ et al (2012) Measurement of pulsatile total blood flow in the human and rat retina with ultrahigh speed spectral/Fourier domain OCT. Biomed Opt Express 3:1047–1061CrossRefPubMedPubMedCentral
22.
go back to reference Shi J, Wei L (2007) Rho kinase in the regulation of cell death and survival. Arch Immunol Ther Exp 55:61–75CrossRef Shi J, Wei L (2007) Rho kinase in the regulation of cell death and survival. Arch Immunol Ther Exp 55:61–75CrossRef
23.
go back to reference Rao PV, Deng P, Sasaki Y, Epstein DL (2005) Regulation of myosin light chain phosphorylation in the trabecular meshwork: role in aqueous humour outflow facility. Exp Eye Res 80:197–206CrossRefPubMed Rao PV, Deng P, Sasaki Y, Epstein DL (2005) Regulation of myosin light chain phosphorylation in the trabecular meshwork: role in aqueous humour outflow facility. Exp Eye Res 80:197–206CrossRefPubMed
24.
go back to reference Tanihara H, Inoue T, Yamamoto T et al (2016) One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertension. Acta Ophthalmol 94:e26–e34CrossRefPubMed Tanihara H, Inoue T, Yamamoto T et al (2016) One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertension. Acta Ophthalmol 94:e26–e34CrossRefPubMed
25.
go back to reference Rao VP, Epstein DL (2007) Rho GTPase/rho kinase inhibition as a novel target for the treatment of glaucoma. BioDrugs 21:167–177CrossRefPubMed Rao VP, Epstein DL (2007) Rho GTPase/rho kinase inhibition as a novel target for the treatment of glaucoma. BioDrugs 21:167–177CrossRefPubMed
26.
go back to reference Tokushige H, Waki M, Takayama Y, Tanihara H (2011) Effects of Y-39983, a selective rho-associated protein kinase inhibitor, on blood flow in optic nerve head in rabbits and axonal regeneration of retinal ganglion cells in rats. Curr Eye Res 36:964–970CrossRefPubMed Tokushige H, Waki M, Takayama Y, Tanihara H (2011) Effects of Y-39983, a selective rho-associated protein kinase inhibitor, on blood flow in optic nerve head in rabbits and axonal regeneration of retinal ganglion cells in rats. Curr Eye Res 36:964–970CrossRefPubMed
27.
go back to reference Nakabayashi S, Kawai M, Yoshioka T et al (2015) Effect of intravitreal rho kinase inhibitor ripasudil (K-115) on feline retinal microcirculation. Exp Eye Res 139:132–135CrossRefPubMed Nakabayashi S, Kawai M, Yoshioka T et al (2015) Effect of intravitreal rho kinase inhibitor ripasudil (K-115) on feline retinal microcirculation. Exp Eye Res 139:132–135CrossRefPubMed
28.
go back to reference Yamamoto K, Maruyama K, Himori N et al (2014) The novel rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest Ophthalmol Vis Sci 55:7126–7136CrossRefPubMed Yamamoto K, Maruyama K, Himori N et al (2014) The novel rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest Ophthalmol Vis Sci 55:7126–7136CrossRefPubMed
29.
go back to reference Song H, Gao D (2011) Fasudil, a rho-associated protein kinase inhibitor, attenuates retinal ischemia and reperfusion injury in rats. Int J Mol Med 28:193–198PubMed Song H, Gao D (2011) Fasudil, a rho-associated protein kinase inhibitor, attenuates retinal ischemia and reperfusion injury in rats. Int J Mol Med 28:193–198PubMed
30.
go back to reference Kitaoka Y, Sase K, Tsukahara C et al (2017) Axonal protection by ripasudil, a rho kinase inhibitor, via modulating autophagy in TNF-induced optic nerve degeneration. Invest Ophthalmol Vis Sci 58:5056–5064CrossRefPubMed Kitaoka Y, Sase K, Tsukahara C et al (2017) Axonal protection by ripasudil, a rho kinase inhibitor, via modulating autophagy in TNF-induced optic nerve degeneration. Invest Ophthalmol Vis Sci 58:5056–5064CrossRefPubMed
31.
go back to reference Akaiwa K, Namekata K, Azuchi Y et al (2018) Topical ripasudil suppresses retinal ganglion cell death in a mouse model of normal tension glaucoma. Invest Ophthalmol Vis Sci 59:2080–2089CrossRefPubMed Akaiwa K, Namekata K, Azuchi Y et al (2018) Topical ripasudil suppresses retinal ganglion cell death in a mouse model of normal tension glaucoma. Invest Ophthalmol Vis Sci 59:2080–2089CrossRefPubMed
32.
go back to reference Isobe T, Mizuno K, Kaneko Y et al (2014) Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits. Curr Eye Res 39:813–822CrossRefPubMed Isobe T, Mizuno K, Kaneko Y et al (2014) Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits. Curr Eye Res 39:813–822CrossRefPubMed
33.
go back to reference Isobe T, Kasai T, Kawai H (2016) Ocular penetration and pharmacokinetics of ripasudil following topical administration to rabbits. J Ocul Pharmacol Ther 32:405–415CrossRefPubMed Isobe T, Kasai T, Kawai H (2016) Ocular penetration and pharmacokinetics of ripasudil following topical administration to rabbits. J Ocul Pharmacol Ther 32:405–415CrossRefPubMed
34.
go back to reference Shaw PX, Sang A, Wang Y et al (2016) Topical administration of a Rock/Net inhibitor promotes retinal ganglion cell survival and axon regeneration after optic nerve injury. Exp Eye Res 18:30181–30186 Shaw PX, Sang A, Wang Y et al (2016) Topical administration of a Rock/Net inhibitor promotes retinal ganglion cell survival and axon regeneration after optic nerve injury. Exp Eye Res 18:30181–30186
35.
go back to reference Leblanc B, Jezequel S, Davies T, Hanton G, Taradach C (1998) Binding of drugs to eye melanin is not predictive of ocular toxicity. Regul Toxicol Pharmacol 28:124–132CrossRefPubMed Leblanc B, Jezequel S, Davies T, Hanton G, Taradach C (1998) Binding of drugs to eye melanin is not predictive of ocular toxicity. Regul Toxicol Pharmacol 28:124–132CrossRefPubMed
36.
go back to reference Rimpelä A, Reinisalo M, Hellinen L et al (2017) Implications of melanin binding in ocular drug delivery. Adv Drug Deliv Rev 13226:1–21 Rimpelä A, Reinisalo M, Hellinen L et al (2017) Implications of melanin binding in ocular drug delivery. Adv Drug Deliv Rev 13226:1–21
37.
go back to reference Morrison JC, Jia L, Cepurna W, Guo Y, Johnson E (2009) Reliability and sensitivity of the TonoLab rebound tonometer in awake Brown Norway rats. Invest Ophthalmol Vis Sci 50:2802–2808CrossRefPubMed Morrison JC, Jia L, Cepurna W, Guo Y, Johnson E (2009) Reliability and sensitivity of the TonoLab rebound tonometer in awake Brown Norway rats. Invest Ophthalmol Vis Sci 50:2802–2808CrossRefPubMed
38.
go back to reference Jia L, Cepurna WO, Johnson EC, Morrison JC (2000) Effect of general anesthetics on IOP in rats with experimental aqueous outflow obstruction. Invest Ophthalmol Vis Sci 41:3415–3419PubMed Jia L, Cepurna WO, Johnson EC, Morrison JC (2000) Effect of general anesthetics on IOP in rats with experimental aqueous outflow obstruction. Invest Ophthalmol Vis Sci 41:3415–3419PubMed
39.
go back to reference Man Y, Chen X, Wang N et al (2008) H-1152 effects on intraocular pressure and trabecular meshwork morphology of rat eyes. J Ocul Pharmacol Ther 24:373–379CrossRef Man Y, Chen X, Wang N et al (2008) H-1152 effects on intraocular pressure and trabecular meshwork morphology of rat eyes. J Ocul Pharmacol Ther 24:373–379CrossRef
40.
go back to reference Uehata M, Ishizaki T, Satoh H et al (1997) Calcium sensitization of smooth muscle mediated by a rho-associated protein kinase in hypertension. Nature 389:990–994CrossRefPubMed Uehata M, Ishizaki T, Satoh H et al (1997) Calcium sensitization of smooth muscle mediated by a rho-associated protein kinase in hypertension. Nature 389:990–994CrossRefPubMed
41.
go back to reference Okamura N, Saito M, Mori A et al (2007) Vasodilator effects of fasudil, a rho-kinase inhibitor, on retinal arterioles in stroke-prone spontaneously hypertensive rats. J Ocul Pharmacol Ther 23:207–212CrossRefPubMed Okamura N, Saito M, Mori A et al (2007) Vasodilator effects of fasudil, a rho-kinase inhibitor, on retinal arterioles in stroke-prone spontaneously hypertensive rats. J Ocul Pharmacol Ther 23:207–212CrossRefPubMed
42.
Metadata
Title
Effects of ripasudil, a rho kinase inhibitor, on blood flow in the optic nerve head of normal rats
Authors
Yasushi Wada
Tomomi Higashide
Atsushi Nagata
Kazuhisa Sugiyama
Publication date
01-02-2019
Publisher
Springer Berlin Heidelberg
Published in
Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 2/2019
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-018-4191-6

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