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

  • Laboratory Investigation
  • Published:
Japanese Journal of Ophthalmology Aims and scope Submit manuscript

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.

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References

  1. 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.

    Article  PubMed  Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Dong Y, Ishikawa H, Wu Y, Yoshitomi T. Vasodilatory mechanism of levobunolol on vascular smooth muscle cells. Exp Eye Res. 2007;84:1039–46.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mulvany MJ, Halpern W. Mechanical properties of vascular smooth muscle cells in situ. Nature. 1976;260:617–9.

    Article  CAS  PubMed  Google Scholar 

  26. Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977;41:19–26.

    Article  CAS  PubMed  Google Scholar 

  27. Keef KD, Bowen SM. Effect of Ach on electrical and mechanical activity in guinea pig coronary arteries. Am J Physiol. 1989;257:H1096–103.

    CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    CAS  PubMed  Google Scholar 

  31. 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.

    CAS  PubMed  Google Scholar 

  32. Laporte R, Laher I. Sarcoplasmic reticulum-sarcolemma interactions and vascular smooth muscle tone. J Vasc Res. 1997;34:325–43.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Senju Pharmaceutical for providing Y-27632 and Y-39983 for these experiments, and Ms. Sanae Takaseki for her excellent technical assistance. This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (nos. 18591908 and 20592070).

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Authors and Affiliations

  1. Department of Ophthalmology, Akita University School of Medicine, 1-1-1 Hondo, Akita, Japan

    Hiroshi Watabe, Sanae Abe & Takeshi Yoshitomi

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  1. Hiroshi Watabe
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  2. Sanae Abe
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  3. Takeshi Yoshitomi
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Correspondence to Hiroshi Watabe.

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Watabe, H., Abe, S. & Yoshitomi, T. Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries. Jpn J Ophthalmol 55, 411–417 (2011). https://doi.org/10.1007/s10384-011-0048-9

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  • DOI: https://doi.org/10.1007/s10384-011-0048-9

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