Skip to main content
Erschienen in: Japanese Journal of Ophthalmology 4/2011

01.07.2011 | Laboratory Investigation

Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries

verfasst von: Hiroshi Watabe, Sanae Abe, Takeshi Yoshitomi

Erschienen in: Japanese Journal of Ophthalmology | Ausgabe 4/2011

Einloggen, um Zugang zu erhalten

Abstract

Purpose

In normotensive eyes, reduced ocular blood flow can lead to glaucoma pathogenesis. Drugs that reduce intraocular pressure (IOP) often cause vasodilation of the ciliary arteries and improve blood flow to the eye. A novel class of drugs called Rho-associated coiled coil-forming protein kinase (ROCK) inhibitors can lower IOP. Therefore, we tested the ability of two ROCK inhibitors, Y-27632 and Y39983, to relax rabbit ciliary arteries.

Methods

We measured in vitro ciliary artery smooth muscle contractions by isometric tension recordings and changes of intracellular free calcium concentration ([Ca2+]i) by fluorescence photometry.

Results

Both Y-27632 and Y-39983 induced a concentration-dependent relaxation in rabbit ciliary arteries precontracted with a high-potassium (high-K) solution. The amplitude of relaxation induced by Y-27632 and Y-39983 was not affected by either 100 μM N G-nitro-l-arginine methyl ester (l-NAME) or 10 μM indomethacin. In Ca2+-free solution, Y-27632 and Y-39983 significantly inhibited the transient contraction of ciliary arteries induced by 10 μM histamine. However, neither Y-27632 nor Y-39983 affected the elevation of [Ca2+]i induced by high-K solution and histamine.

Conclusions

We concluded that Y-27632 and Y-39983 relaxed isolated rabbit ciliary artery segments in vitro. The mechanism of relaxation was not dependent on endothelial-derived factors such as nitric oxide (NO) or prostacyclin, nor was it dependent on changes in intracellular Ca2+ concentration.
Literatur
1.
Zurück zum Zitat Flammer J, Orgul S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res. 2002;21:359–93.CrossRefPubMed Flammer J, Orgul S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res. 2002;21:359–93.CrossRefPubMed
2.
Zurück zum Zitat Sato EA, Ohtake Y, Shinoda K, Mashima Y, Kimura I. Decreased blood flow at neuroretinal rim of optic nerve head corresponds with visual field deficit in eyes with normal tension glaucoma. Graefes Arch Clin Exp Ophthalmol. 2006;244:795–801.CrossRefPubMed Sato EA, Ohtake Y, Shinoda K, Mashima Y, Kimura I. Decreased blood flow at neuroretinal rim of optic nerve head corresponds with visual field deficit in eyes with normal tension glaucoma. Graefes Arch Clin Exp Ophthalmol. 2006;244:795–801.CrossRefPubMed
3.
Zurück zum Zitat Altan-Yaycioglu R, Türker G, Akdöl S, Acunaş G, Izgi B. The effects of beta-blockers on ocular blood flow in patients with primary open angle glaucoma: a color Doppler imaging study. Eur J Ophthalmol. 2001;11:37–46.CrossRefPubMed Altan-Yaycioglu R, Türker G, Akdöl S, Acunaş G, Izgi B. The effects of beta-blockers on ocular blood flow in patients with primary open angle glaucoma: a color Doppler imaging study. Eur J Ophthalmol. 2001;11:37–46.CrossRefPubMed
4.
Zurück zum Zitat Mizuno K, Koide T, Saito N, Fujii M, Nagahara M, Tomidokoro A, et al. Topical nipradilol: effects on optic nerve head circulation in humans and periocular distribution in monkeys. Invest Ophthalmol Vis Sci. 2002;43:3243–50.PubMed Mizuno K, Koide T, Saito N, Fujii M, Nagahara M, Tomidokoro A, et al. Topical nipradilol: effects on optic nerve head circulation in humans and periocular distribution in monkeys. Invest Ophthalmol Vis Sci. 2002;43:3243–50.PubMed
5.
Zurück zum Zitat Kurashima H, Watabe H, Sato N, Abe S, Ishida N, Yoshitomi T. Effects of prostaglandin F(2α) analogues on endothelin-1-induced impairment of rabbit ocular blood flow: comparison among tafluprost, travoprost, and latanoprost. Exp Eye Res. 2010;91:853–9.CrossRefPubMed Kurashima H, Watabe H, Sato N, Abe S, Ishida N, Yoshitomi T. Effects of prostaglandin F(2α) analogues on endothelin-1-induced impairment of rabbit ocular blood flow: comparison among tafluprost, travoprost, and latanoprost. Exp Eye Res. 2010;91:853–9.CrossRefPubMed
6.
Zurück zum Zitat Hayashi-Morimoto R, Yoshitomi T, Ishikawa H, Hayashi E, Sato Y. Effects of beta antagonists on mechanical properties in rabbit ciliary artery. Graefes Arch Clin Exp Ophthalmol. 1999;237:661–7.CrossRefPubMed Hayashi-Morimoto R, Yoshitomi T, Ishikawa H, Hayashi E, Sato Y. Effects of beta antagonists on mechanical properties in rabbit ciliary artery. Graefes Arch Clin Exp Ophthalmol. 1999;237:661–7.CrossRefPubMed
7.
Zurück zum Zitat Dong Y, Ishikawa H, Wu Y, Shimizu K, Goseki T, Yoshitomi T. Effect and mechanisms of betaxolol and timolol on vascular relaxation in isolated rabbit ciliary artery. Jpn J Ophthalmol. 2006;50:504–8.CrossRefPubMed Dong Y, Ishikawa H, Wu Y, Shimizu K, Goseki T, Yoshitomi T. Effect and mechanisms of betaxolol and timolol on vascular relaxation in isolated rabbit ciliary artery. Jpn J Ophthalmol. 2006;50:504–8.CrossRefPubMed
8.
Zurück zum Zitat Dong Y, Ishikawa H, Wu Y, Yoshitomi T. Vasodilatory mechanism of levobunolol on vascular smooth muscle cells. Exp Eye Res. 2007;84:1039–46.CrossRefPubMed Dong Y, Ishikawa H, Wu Y, Yoshitomi T. Vasodilatory mechanism of levobunolol on vascular smooth muscle cells. Exp Eye Res. 2007;84:1039–46.CrossRefPubMed
9.
Zurück zum Zitat Yoshitomi T, Yamaji K, Ishikawa H, Ohnishi Y. Vasodilatory effects of nipradilol, an alpha- and beta-adrenergic blocker with nitric oxide releasing action, in rabbit ciliary artery. Exp Eye Res. 2002;75:669–76.CrossRefPubMed Yoshitomi T, Yamaji K, Ishikawa H, Ohnishi Y. Vasodilatory effects of nipradilol, an alpha- and beta-adrenergic blocker with nitric oxide releasing action, in rabbit ciliary artery. Exp Eye Res. 2002;75:669–76.CrossRefPubMed
10.
Zurück zum Zitat Yoshitomi T, Yamaji K, Ishikawa H, Ohnishi Y. Vasodilatory mechanism of unoprostone isopropyl on isolated rabbit ciliary artery. Curr Eye Res. 2004;28:167–74.CrossRefPubMed Yoshitomi T, Yamaji K, Ishikawa H, Ohnishi Y. Vasodilatory mechanism of unoprostone isopropyl on isolated rabbit ciliary artery. Curr Eye Res. 2004;28:167–74.CrossRefPubMed
11.
Zurück zum Zitat Ishikawa H, Yoshitomi T, Mashimo K, Nakanishi M, Shimizu K. Pharmacological effects of latanoprost, prostaglandin E2 and F2α on isolated rabbit ciliary artery. Graefes Arch Clin Exp Ophthalmol. 2002;240:120–5.CrossRefPubMed Ishikawa H, Yoshitomi T, Mashimo K, Nakanishi M, Shimizu K. Pharmacological effects of latanoprost, prostaglandin E2 and F on isolated rabbit ciliary artery. Graefes Arch Clin Exp Ophthalmol. 2002;240:120–5.CrossRefPubMed
12.
Zurück zum Zitat Dong Y, Watabe H, Su G, Ishikawa H, Sato N, Yoshitomi T. Relaxing effect and mechanism of tafluprost on isolated rabbit ciliary arteries. Exp Eye Res. 2008;87:251–6.CrossRefPubMed Dong Y, Watabe H, Su G, Ishikawa H, Sato N, Yoshitomi T. Relaxing effect and mechanism of tafluprost on isolated rabbit ciliary arteries. Exp Eye Res. 2008;87:251–6.CrossRefPubMed
13.
Zurück zum Zitat Honjo M, Tanihara H, Inatani M, Kido N, Yue BY, Narumiya S, et al. Effect of Rho-associated protein kinase inhibitor, Y-27632, on intraocular pressure and outflow facility. Invest Ophthalmol Vis Sci. 2001;42:137–44.PubMed Honjo M, Tanihara H, Inatani M, Kido N, Yue BY, Narumiya S, et al. Effect of Rho-associated protein kinase inhibitor, Y-27632, on intraocular pressure and outflow facility. Invest Ophthalmol Vis Sci. 2001;42:137–44.PubMed
14.
Zurück zum Zitat Waki M, Yoshida Y, Oka T, Azuma M. Reduction of intraocular pressure by topical administration of an inhibitor of the Rho-associated protein kinase. Curr Eye Res. 2001;22:470–4.CrossRefPubMed Waki M, Yoshida Y, Oka T, Azuma M. Reduction of intraocular pressure by topical administration of an inhibitor of the Rho-associated protein kinase. Curr Eye Res. 2001;22:470–4.CrossRefPubMed
15.
Zurück zum Zitat Tokushige H, Inatani M, Nemoto S, Sakaki H, Katayama K, Uehata M, et al. Effects of topical administration of Y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest Ophthalmol Vis Sci. 2007;48:3216–22.CrossRefPubMed Tokushige H, Inatani M, Nemoto S, Sakaki H, Katayama K, Uehata M, et al. Effects of topical administration of Y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest Ophthalmol Vis Sci. 2007;48:3216–22.CrossRefPubMed
16.
Zurück zum Zitat Nishio M, Fukunaga T, Sugimoto M, Ikesugi K, Sumi K, Hidaka H, et al. The effect of the H-1152P, a potent Rho-associated coiled coil-formed protein kinase inhibitor, in rabbit normal and ocular hypertensive eyes. Curr Eye Res. 2009;34:282–6.CrossRefPubMed Nishio M, Fukunaga T, Sugimoto M, Ikesugi K, Sumi K, Hidaka H, et al. The effect of the H-1152P, a potent Rho-associated coiled coil-formed protein kinase inhibitor, in rabbit normal and ocular hypertensive eyes. Curr Eye Res. 2009;34:282–6.CrossRefPubMed
17.
Zurück zum Zitat Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Kawano Y, Fukata Y, et al. Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation. 2000;101:1319–23.CrossRefPubMed Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Kawano Y, Fukata Y, et al. Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation. 2000;101:1319–23.CrossRefPubMed
18.
Zurück zum Zitat Sato M, Tani E, Fujikawa H, Kaibuchi K. Involvement of Rho-kinase-mediated phosphorylation of myosin light chain in enhancement of cerebral vasospasm. Circ Res. 2000;87:195–200.CrossRefPubMed Sato M, Tani E, Fujikawa H, Kaibuchi K. Involvement of Rho-kinase-mediated phosphorylation of myosin light chain in enhancement of cerebral vasospasm. Circ Res. 2000;87:195–200.CrossRefPubMed
19.
Zurück zum Zitat Iizuka K, Shimizu Y, Tsukagoshi H, Yoshii A, Harada T, Dobashi K, et al. Evaluation of Y-27632, a rho-kinase inhibitor, as a bronchodilator in guinea pigs. Eur J Pharmacol. 2000;406:273–9.CrossRefPubMed Iizuka K, Shimizu Y, Tsukagoshi H, Yoshii A, Harada T, Dobashi K, et al. Evaluation of Y-27632, a rho-kinase inhibitor, as a bronchodilator in guinea pigs. Eur J Pharmacol. 2000;406:273–9.CrossRefPubMed
20.
Zurück zum Zitat Takahashi R, Nishimura J, Hirano K, Seki N, Naito S, Kanaide H. Ca2+ sensitization in contraction of human bladder smooth muscle. J Urol. 2004;172:748–52.CrossRefPubMed Takahashi R, Nishimura J, Hirano K, Seki N, Naito S, Kanaide H. Ca2+ sensitization in contraction of human bladder smooth muscle. J Urol. 2004;172:748–52.CrossRefPubMed
21.
Zurück zum Zitat Chitaley K, Wingard CJ, Clinton Webb R, Branam H, Stopper VS, Lewis RW, et al. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat Med. 2001;7:119–22.CrossRefPubMed Chitaley K, Wingard CJ, Clinton Webb R, Branam H, Stopper VS, Lewis RW, et al. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat Med. 2001;7:119–22.CrossRefPubMed
22.
Zurück zum Zitat Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, et al. Calcium sensitization of smooth muscle mediated by Rho-associated protein kinase in hypertension. Nature. 1997;389:990–4.CrossRefPubMed Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, et al. Calcium sensitization of smooth muscle mediated by Rho-associated protein kinase in hypertension. Nature. 1997;389:990–4.CrossRefPubMed
23.
Zurück zum Zitat Nakajima E, Nakajima T, Minagawa Y, Shearer TR, Azuma M. Contribution of ROCK in contraction of trabecular meshwork: proposed mechanism for regulating aqueous outflow in monkey and human eyes. J Pharm Sci. 2005;94:701–8.CrossRefPubMed Nakajima E, Nakajima T, Minagawa Y, Shearer TR, Azuma M. Contribution of ROCK in contraction of trabecular meshwork: proposed mechanism for regulating aqueous outflow in monkey and human eyes. J Pharm Sci. 2005;94:701–8.CrossRefPubMed
24.
Zurück zum Zitat Halpern W, Mulvany MJ, Warshaw DM. Mechanical properties of smooth muscle cells in the wall of arterial resistance vessels. J Physiol. 1978;275:85–101.CrossRefPubMedPubMedCentral Halpern W, Mulvany MJ, Warshaw DM. Mechanical properties of smooth muscle cells in the wall of arterial resistance vessels. J Physiol. 1978;275:85–101.CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Mulvany MJ, Halpern W. Mechanical properties of vascular smooth muscle cells in situ. Nature. 1976;260:617–9.CrossRefPubMed Mulvany MJ, Halpern W. Mechanical properties of vascular smooth muscle cells in situ. Nature. 1976;260:617–9.CrossRefPubMed
26.
Zurück zum Zitat Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977;41:19–26.CrossRefPubMed Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977;41:19–26.CrossRefPubMed
27.
Zurück zum Zitat Keef KD, Bowen SM. Effect of Ach on electrical and mechanical activity in guinea pig coronary arteries. Am J Physiol. 1989;257:H1096–103.PubMed Keef KD, Bowen SM. Effect of Ach on electrical and mechanical activity in guinea pig coronary arteries. Am J Physiol. 1989;257:H1096–103.PubMed
28.
Zurück zum Zitat Ushio-Fukai M, Abe S, Kobayashi S, Nishimura J, Kanaide H. Effects of isoprenaline on cytosolic calcium concentrations and on tension in the porcine coronary artery. J Physiol. 1993;462:679–96.CrossRefPubMedPubMedCentral Ushio-Fukai M, Abe S, Kobayashi S, Nishimura J, Kanaide H. Effects of isoprenaline on cytosolic calcium concentrations and on tension in the porcine coronary artery. J Physiol. 1993;462:679–96.CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Sugiyama T, Shibata M, Kajiura S, Okuno T, Tonari M, Oku H, et al. Effects of Fasudil, a Rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. Invest Ophthalmol Vis Sci. 2011;52:64-9.CrossRefPubMed Sugiyama T, Shibata M, Kajiura S, Okuno T, Tonari M, Oku H, et al. Effects of Fasudil, a Rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. Invest Ophthalmol Vis Sci. 2011;52:64-9.CrossRefPubMed
30.
Zurück zum Zitat Ishii K, Tomidokoro A, Nagahara M, Tamaki Y, Kanno M, Fukaya Y, et al. Effects of topical latanoprost on optic nerve head circulation in rabbits, monkeys, and humans. Invest Ophthalmol Vis Sci. 2001;42:2957–63.PubMed Ishii K, Tomidokoro A, Nagahara M, Tamaki Y, Kanno M, Fukaya Y, et al. Effects of topical latanoprost on optic nerve head circulation in rabbits, monkeys, and humans. Invest Ophthalmol Vis Sci. 2001;42:2957–63.PubMed
31.
Zurück zum Zitat Gustafsson H. Vasomotion and underlying mechanisms in small arteries. An in vitro study of rat blood vessels. Acta Physiol Scand Suppl. 1993;614:1–644.PubMed Gustafsson H. Vasomotion and underlying mechanisms in small arteries. An in vitro study of rat blood vessels. Acta Physiol Scand Suppl. 1993;614:1–644.PubMed
32.
Zurück zum Zitat Laporte R, Laher I. Sarcoplasmic reticulum-sarcolemma interactions and vascular smooth muscle tone. J Vasc Res. 1997;34:325–43.CrossRefPubMed Laporte R, Laher I. Sarcoplasmic reticulum-sarcolemma interactions and vascular smooth muscle tone. J Vasc Res. 1997;34:325–43.CrossRefPubMed
33.
Zurück zum Zitat Schubert R, Kalentchuk VU, Krien U. Rho kinase inhibition partly weakens myogenic reactivity in rat small arteries by changing calcium sensitivity. Am J Physiol Heart Circ Physiol. 2002;283:H2288–95.CrossRefPubMed Schubert R, Kalentchuk VU, Krien U. Rho kinase inhibition partly weakens myogenic reactivity in rat small arteries by changing calcium sensitivity. Am J Physiol Heart Circ Physiol. 2002;283:H2288–95.CrossRefPubMed
34.
Zurück zum Zitat Hashiba Y, Tosaka M, Saito N, Imai H, Shimizu T, Sasaki T. Vasorelaxing effect of the Rho-kinase inhibitor, Y-27632, in isolated canine basilar arteries. Neurol Res. 2007;29:485–9.CrossRefPubMed Hashiba Y, Tosaka M, Saito N, Imai H, Shimizu T, Sasaki T. Vasorelaxing effect of the Rho-kinase inhibitor, Y-27632, in isolated canine basilar arteries. Neurol Res. 2007;29:485–9.CrossRefPubMed
35.
Zurück zum Zitat Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem. 1996;271:20246–9.CrossRefPubMed Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem. 1996;271:20246–9.CrossRefPubMed
36.
Zurück zum Zitat Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996;273:245–8.CrossRefPubMed Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996;273:245–8.CrossRefPubMed
Metadaten
Titel
Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries
verfasst von
Hiroshi Watabe
Sanae Abe
Takeshi Yoshitomi
Publikationsdatum
01.07.2011
Verlag
Springer Japan
Erschienen in
Japanese Journal of Ophthalmology / Ausgabe 4/2011
Print ISSN: 0021-5155
Elektronische ISSN: 1613-2246
DOI
https://doi.org/10.1007/s10384-011-0048-9

Weitere Artikel der Ausgabe 4/2011

Japanese Journal of Ophthalmology 4/2011 Zur Ausgabe

Neu im Fachgebiet Augenheilkunde

Update Augenheilkunde

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.