Rho-kinase is an important therapeutic target in cardiovascular medicine

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 25, Issue 9, 2005, Pages 1767-1775

  Shimokawa, Hiroaki ^a,b,c   Takeshita, Akira ^a  

^a KYUSHU UNIVERSITY   (Japan)

^b JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

^c TOHOKU UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

Cardiovascular disease; Rho; Rho kinase; Signal transduction; Small G proteins

Indexed keywords

4 (1 AMINOETHYL) N (4 PYRIDYL)CYCLOHEXANECARBOXAMIDE; ACTIN; ANGIOTENSIN; BONE MORPHOGENETIC PROTEIN 2; DNA; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ESTROGEN; FASUDIL; GAMMA INTERFERON; GUANINE NUCLEOTIDE BINDING PROTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1BETA; INTERLEUKIN 6; MACROPHAGE MIGRATION INHIBITION FACTOR; MESSENGER RNA; MONOCYTE CHEMOTACTIC PROTEIN 1; OSTEOCALCIN; PLASMINOGEN ACTIVATOR INHIBITOR 1; PROTEIN BCL 2; PROTEIN KINASE C; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; RHO FACTOR; RHO KINASE; RHO KINASE INHIBITOR; SEROTONIN 2A RECEPTOR; THROMBIN; THROMBOCYTE ACTIVATING FACTOR; THROMBOPLASTIN; TRANSFORMING GROWTH FACTOR BETA1; UNINDEXED DRUG;

ANGINA PECTORIS; ARTERIOSCLEROSIS; BRAIN VASOSPASM; CARDIOVASCULAR DISEASE; CELL ADHESION; CELL MIGRATION; CELL MOTILITY; CELL PROLIFERATION; CORONARY ARTERY SPASM; CYTOKINESIS; CYTOSKELETON; DRUG SAFETY; DRUG TARGETING; GENE EXPRESSION; HEART FAILURE; HUMAN; HYPERTENSION; INFLAMMATION; ISCHEMIA; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PULMONARY HYPERTENSION; REPERFUSION INJURY; SHORT SURVEY; SIGNAL TRANSDUCTION; STROKE; SYMPATHETIC TONE; THROMBOGENESIS; VASCULAR SMOOTH MUSCLE;

ANIMALS; CARDIOVASCULAR DISEASES; ENZYME INHIBITORS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; PROTEIN-SERINE-THREONINE KINASES;

EID: 24144498411     PISSN: 10795642     EISSN: None     Source Type: Journal    
DOI: 10.1161/01.ATV.0000176193.83629.c8     Document Type: Short Survey

References (104)

1. Fukata Y, Amano M, Kaibuchi K. Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol Sci. 2001;22:32-39.
2. Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev. 2001;81:153-208.
3. Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Rho-associated kinase, a novel serine threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J. 1996;15:2208-2216.
4. Leung T, Manser E, Tan L, Lim L. A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem. 1995;270:29051-29054.
5. Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S. The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J. 1996;15:1885-1893.
6. Hall A. Rho GTPase and the actin cytoskeleton. Science. 1998;279: 509-514.
7. Kaibuchi K, Kuroda S, Amano M. Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Ann Rev Biochem. 1999;68:459-486.
8. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996;273:245-248.
9. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem. 1996;271:20246-20249.
10. Shimokawa H. Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases. J Cardiovasc Pharmacol. 2002;39:319-327.
11. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001; 21:1712-1719.
12. Asano T, Ikegaki I, Satoh S, Suzuki Y, Shibuya M, Takayasu M, Hidaka H. Mechanism of action of a novel antivasospasm drug, HA1077. J Pharmacol Exp Ther. 1987;24:1033-1040.
13. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389:990-994.
14. Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000;351:95-105.
15. Shimokawa H, Seto M, Katsumata N, Amano M, Kozai T, Yamawaki T, Kuwata K, Egashira K, Ikegaki I, Asano T, Kaibuchi K, Takeshita A. Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm. Cardiovasc Res. 1999;43:1029-1039.
16. Higashi M, Shimokawa H, Hattori T, Hiroki J, Mukai Y, Morikawa K, Ichiki T, Takahashi S, Takeshita A. Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo. Effects on endothelial NAD(P)H oxidase system. Circ Res. 2003; 93:767-775.
17. Radeff JM, Nagy Z, Stern PH. Rho and Rho kinase are involved in parathyroid hormone-stimulated protein kinase C alpha translocation and IL-6 promotor activity in osteoblast cells. J Bone Mineral Res. 2004;19:1882-1891.
18. Funakoshi Y, Ichiki T, Shimokawa H, Egashira K, Kaibuchi K, Takeya M, Yoshimura T, Takeshita A. Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. Hypertension. 2001;38:100-104.
19. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Kaibuchi K, Takeshita A. Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice. Circ Res. 2004;94: 46-52.
20. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Tsutsui H, Kaibuchi K, Takeshita A. Long-term inhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation. 2004;109:2234-2239.
21. Takeda K, Ichiki T, Tokunou T, Iino N, Fujii S, Kitabatake A, Shimokawa H, Takeshita A. Critical role of Rho-kinase and MEK/ERK pathways for angiotension II-induced plasminogen activator inhibitor-1 gene expression. Arterioscler Thromb Vasc Biol. 2001;21:868-873.
22. Matsumoto Y, Uwatoku T, Abe K, Oi K, Hattori T, Morishige K, Eto Y, Fukumoto Y, Nakamura K, Shibata Y, Matsuda T, Takeshita A, Shimokawa H. Long-term inhibition of Rho-kinase suppresses neointimal formation after stent implantation in porcine coronary arteries. Involvement of multiple mechanisms. Arterioscler Thromb Vasc Biol. 2004;24:181-186.
23. Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation. 2002;106:57-62.
24. Ohnaka K, Shimoda S, Nawata H, Shimokawa H, Kaibuchi K, Iwamoto Y, Takayanagi R. Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts. Biophys Biochem Res Comm. 2001;287:337-342.
25. Hiroki J, Shimokawa H, Higashi M, Morikawa K, Kandabashi T, Kawamura N, Kubota T, Ichiki T, Amano M, Kaibuchi K, Takeshita A. Inflammatory stimuli upregulate Rho-kinase in human vascular smooth muscle. J Mol Cell Cardiol. 2004;37:537-546.
26. Hiroki J, Shimokawa H, Mukai Y, Ichiki T, Takeshita A. Divergent effects of estrogen and nicotine on Rho-kinase expression in human coronary vascular smooth muscle cells. Biophys Biochem Res Commun. 2005;326:154-159.
27. Oi K, Shimokawa H, Hiroki J, Uwatoku T, Abe K, Matsumoto Y, Nakajima Y, Nakajima K, Takeichi S, Takeshita A. Remnant lipoproteins from patients with sudden cardiac death enhance coronary vasospastic activity through upregulation of Rho-kinase. Arterioscler Thromb Vasc Biol. 2004;24:918-922.
28. Shimokawa H. Cellular and molecular mechanisms of coronary artery spasm. Lessons from animal models. Jpn Circ J. 2000;64:1-12.
29. Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Kawano Y, Fukata Y, Higo T, Egashira K, Takahashi S, Kaibuchi K, Takeshita A. Inhibition of myosin phosphatase by upregulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1β. Circulation. 2000;101:1319-1323.
30. Kandabashi T, Shimokawa H, Mukai Y, Matoba T, Kunihiro I, Morikawa K, Ito M, Takahashi S, Kaibuchi K, Takeshita A. Involvement of Rho-kinase in agonists-induced contractions of arteriosclerotic human arteries. Arterioscler Throm Vasc Biol. 2002;22:243-248.
31. Hiroki J, Shimokawa H. Inflammatory stimuli upregulate Rho-kinase expression in human coronary vascular smooth muscle cells. Circ J. 2005;69(Suppl 1):606 (Abstract).
32. Kamiunten H, Koike J, Mashiba J, Shimokawa H, Takeshita A. A comprehensive analysis of a novel missense mutation in Rho-kinase that causes coronary vasospasm in the Japanese. Circ J. 2004;68 (Suppl I):211 (Abstract).
33. Yamakawa T, Tanaka S, Numaguchi K, Yamakawa Y, Motley ED, Ichihara S, Inagami T. Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells. Hypertension. 2000;35:313-318.
34. van Nieuw Amerongen GP, van Delft S, Vermeer MA, Collard JG, van Hinsbergh VW. Activation of RhoA by thrombin in endothelial hyperpermeability: role of Rho kinase and protein tyrosine kinases. Circ Res. 2000;87:335-340.
35. Seasholtz TM, Majumdar M, Kaplan DD, Brown JH. Rho and Rho kinase mediate thrombin-stimulated vascular smooth muscle cell DNA synthesis and migration. Circ Res. 1999;84:1186-1193.
36. Yamamoto Y, Ikegaki I, Sasaki Y, Uchida T. The protein kinase inhibitor fasudil protects against ischemic myocardial injury induced by endothelin-1 in the rabbit. J Cardiovasc Pharmacol. 2000;35:203-211.
37. Tangkijvanich P, Tam SP, Yee HF Jr. Wound-induced migration of rat hepatic stellate cells is modulated by endothelin-1 through Rho-kinase-mediated alterations in the actomyosin cytoskeleton. Hepatology. 2001; 33:74-80.
38. 2+ handling of human small arteries. Am J Physiol. 2000;279:H1228-H1238.
39. Kishi H, Bao J, Kohama K. Inhibitory effects of ML-9, wortmannin, and Y-27632 on the chemotaxis of vascular smooth muscle cells in response to platelet-derived growth factor-BB. J Biochem. 2000;128:719-722.
40. 6 receptors are coupled to Rho and Rho kinase activation in vascular myocytes. Am J Physiol. 2000;278:H1751-H1761.
41. Sauzeau V, Le Mellionnec E, Bertoglio J, Scalbert E, Pacaud P, Loirand G. Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase. Circ Res. 2001;88:1102-1104.
42. Amano M, Chihara K, Kimura K, Fukata Y, Nakamura N, Matsuura Y, Kaibuchi K. Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science. 1997;275:1308-1311.
43. van Nieuw Amerongen GP, van Hinsbergh VWM. Cytoskeletal effects of Rho-like small guanine nucleotide-binding proteins in the vascular system. Arterioscler Thromb Vasc Biol. 2001;21:300-311.
44. Horwitz AR, Parsons JT. Cell migration: movein' on. Science. 1999; 286:1102-1103.
45. Narumiya S. The small GTPase Rho: cellular functions and signal transduction. J Biochem (Tokyo). 1996;120:215-228.
46. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Mede. 1999;340:115-126.
47. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868-874.
48. Wolfram S, Dendorfer A, Rikitake Y, Stalker TJ, Gong Y, Scalia R, Dominiak P, Liao JK. Inhibition of Rho-kinase leads to rapid activation of phosphatidyl inositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol. 2004;24:1842-1847.
49. Bolz SS, Vogel L, Sollinger D, Derwand R, de Wit C, Loirand G, Pohl U. Nitric oxide-induced decrease in calcium sensitivity of resistsance arteries is attributable to activation of the myosin light chain phosphatase and antagonized by the RhoA/Rho kinase pathway. Circulation. 2003;107:3081-3087.
50. van Nieuw Amerongen GP, Vermeer MA, van Hinsbergh VW. Role of RhoA and Rho kinase in lysophosphatidic acid-induced endothelial barrier dysfunction. Arterioscler Throm Vasc Biol. 2000;20:E127-E133.
51. Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Eto Y, Morishige K, Matsumoto Y, Obara K, Nakayama K, Takahashi S, Takeshita A. Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arterioslcer Thromb Vasc Biol. 2003;23:2209-2214.
52. Shibata R, Kai H, Seki Y, Kusaba K, Takemiya K, Koga M, Jalalidin A, Tokuda K, Tahara N, Niiyama H, Nagata T, Kuwahara F, Imaizumi T. Rho-kinase inhibition reduces neointima formation after vascular injury by enhancing Bax expression and apoptosis. J Cardiovasc Pharmacol. 2003;42(Suppl 1):S43-S47.
53. Miyata K, Shimokawa H, Kandabashi T, Higo T, Morishige K, Eto Y, Egashira K, Kaibuchi K, Takeshita A. Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo. Arterioscler Thromb Vasc Biol. 2000;20:2351-2358.
54. Katsumata N, Shimokawa H, Seto M, Kozai T, Yamawaki T, Kuwata K, Egashira K, Ikegaki I, Asano T, Sasaki Y, Takeshita A. Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1β. Circulation. 1997;96:4357-4363.
55. Shimokawa H, Ito A, Fukumoto Y, Kadokami T, Nakaike R, Sakata M, Takayanagi T, Egashira K, Takeshita A. Chronic treatment with interleukin-1β induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor. J Clin Invest. 1996;97:769-776.
56. Sato S, Ikegaki I, Asano T, Shimokawa H. Antiischemic properties of fasudil in experimental models of vasospastic angina. Jpn J Pharmacol. 2001;87:34-40.
57. Utsunomiya T, Satoh S, Ikegaki I, Toshima Y, Asano T, Shimokawa H. Antianginal effect of hydroxyfasudil, a Rho-kinase inhibitor, in a canine model of effort angina. Br J Pharmacol. 2001;134:1724-1730.
58. Satoh S, Ikegaki I, Toshima Y, Watanabe A, Asano T, Shimokawa H. A new model of chronic angina in rats and anti-anginal and anti-fibrotic properties of Rho-kinase inhibitor. Life Sci. 2002;72:103-112.
59. Hizume T, Morikawa K, Uwatoku T, Oi K, Abe K, Shimokawa H. Sustained elevation of serum level of cortisol induces hyperconstriction of porcine coronary arteries-Possible involvement of Rho-kinase. Circulation. 2004;110 (Suppl III):III-153.
60. 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.
61. Lan C, Das D, Wloskowicz A, Vollrath B. Endothelin-1 modulates hemoglobin-mediated signaling in cerebrovascular smooth muscle via RhoA/Rho kinase and protein kinase C. Am J Physiol. 2004;286: H165-H173.
62. Eto Y, Shimokawa H, Hiroki J, Morishige K, Kandabashi T, Matsumoto Y, Amano M, Hoshijima M, Kaibuchi K, Takeshita A. Gene transfer of dominant negative Rho-kinase suppresses neointimal formation after balloon injury in pigs. Am J Physiol. 2000;278:H1744-H1750.
63. Sawada N, Itoh H, Ueyama K, Yamashita J, Doi K, Chun T-H, Inoue M, Masatsugu K, Saito T, Fukunaga Y, Sakaguchi S, Arai H, Ohno N, Komeda M, Nakao K. Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries. Circulation. 2000;101:2030-2033.
64. Shibata R, Kai H, Seki Y, Kalo S, Morimatsu M, Kaibuchi K, Imaizumi T. Role of Rho-associated kinase in neointima formation after vascular injury. Circulation. 2001;103:284-289.
65. Anderson HR, Maeng M, Thrwest M, Falk E. Remodeling rather than neointimal formation explains luminal narrowing after deep vessel wall injury: insights from a porcine coronary (re)stenosis model. Circulation. 1996;93:1716-1724.
66. Shimokawa H, Morishige K, Miyata K, Kandabashi T, Eto Y, Ikegaki I, Asano T, Kaibuchi K, Takeshita A. Long-term inhibition of Rho-kinase induces a marked regression of arteriosclerotic coronary lesions in a porcine model in vivo. Cardiovasc Res. 2001;51:169-177,
67. Morishige K, Shimokawa H, Eto Y, Kandabashi T, Miyata K, Matsumoto Y, Kaibuchi K, Takeshita A. Adenovirus-mediated transfer of dominant-negative Rho-kinase induces a regression of coronary arteriosclerosis in a porcine model in vivo. Arterioscler Thromb Vasc Biol. 2001;21:548-554.
68. Yada T, Shimokawa H, Hiramatsu O, Kajiya T, Shigeto F, Tanaka E, Shinozaki Y, Mod H, Kiyooka T, Katsura M, Ohkuma S, Goto M, Ogasawara Y, Kajiya F. Beneficial effects of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia-reperfusion injury in canine coronary microcirculation in vivo. J Am Coll Cardiol. 2005;45:599-607.
69. Sanada S, Asanuma H, Tsukamoto O, Minamino T, Node K, Takashima S, Fukushima T, Ogai A, Shinozaki Y, Fujita M, Hirata A, Okuda H, Shimokawa H, Tomoike H, Hori M, Kitakaze M. Protein kinase A as another mediator of ischemic preconditioning independent of protein kinase C. Circulation. 2004;110:51-57.
70. Shiotani S, Shimada M, Suehiro T, Soejima Y, Shimokawa H, Maehara Y. Involvement of Rho-kinase in cold ischemia-reperfusion injury after liver transplantation in rats. Transplantation. 2004;78:375-382.
71. Mukai Y, Shimokawa H, Matoba T, Kandabashi T, Satoh S, Kaibuchi K, Takeshita A. Involvement of Rho-kinase in hypertensive vascular disease. A novel therapeutic target in hypertension. FASEB J. 2001;15: 1062-1064.
72. FASEB J (online). 2001;10:1096/fj. 00-0735fje.
73. Ito K, Hirooka Y, Sakai K, Kishi T, Kaibuchi K, Shimokawa H, Takeshita A. Rho/Rho-kinase pathway in brain stem contributes to blood pressure regulation via sympathetic nervous system: possible involvement of neural mechanisms of hypertension. Circ Res. 2003;92: 1337-1343.
74. Ito K, Hirooka Y, Sagara Y, Kimura Y, Kaibuchi K, Shimokawa H, Takeshita A, Sunagawa K. Inhibition of Rho-kinase in the brainstem augments baroreflex control of heart rate in rats. Hypertension. 2004; 44:478-483.
75. Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y, Hattori T, Nakashima Y, Kaibuchi K, Sueishi K, Takeshita A. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res. 2004;94:385-393.
76. Abe K, Uwatoku T, Oi K, Hizume T, Shimokawa H. Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice: partial dependence of endothelial NO synthase. Circulation. 2004;110:111-132 (Abstract).
77. Nagaoka T, Pagan KA, Gebb SA, Morris KG, Suzuki T, Shimokawa H, McMurtry IF, Oka M. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med. 2005;171:494-499.
78. Abe K, Morikawa K, Hizume T, Uwatoku T, Oi K, Seto M, Ikegaki I, Asano T, Kaibuchi K, Shimokawa H. Prostacyclin does not inhibit Rho-kinase: An implication for the treatment of pulmonary hypertension. J Cardiovasc Pharmacol. 2005;45:120-124.
79. Toshima Y, Satoh S, Ikegaki I, Asano T. A new model of cerebral microthrombosis in rats and the neuroprotective effect of a Rho-kinase inhibitor. Stroke. 2000;31:2245-2250.
80. Satoh S, Utsunomiya T, Tsurui K, Kobayashi T, Ikegaki I, Sasaki Y, Asano T. Pharamacological profile of hydroxy fasudil as a selective rho kinase inhibitor on ischemic brain damage. Life Sci. 2001;69: 1441-1453.
81. Hisaoka T, Yano M, Ohkusa T, Suetsugu M, Ono K, Kohno M, Yamada J, Kobayashi S, Kohno M, Matsuzaki M. Enhancement of Rho/Rho-kinase system in regulation of vascular smooth muscle contraction in tachycardia-induced heat failure. Cardiovasc Res. 2001;49:319-329.
82. Satoh S, Yamaguchi T, Hitomi A, Sato N, Shiraiwa K, Ikegaki I, Asano T, Shimokawa H. Fasudil attenuates interstitial fibrosis in rat kidneys with unilateral obstruction. Eur J Pharmacol. 2002;455:169-174.
83. Nishikimi T, Akimoto K, Wang X, Mori Y, Tadokoro K, Ishikawa Y, Shimokawa H, Ono H, Matsuoka H. Fasudil, a new Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats. J Hypert. 2004;22:1787-1796.
84. Iizuka K, Shimizu Y, Tsukagoshi H, Yoshii A, Harada T, Dobashi K, Murozono T, Nakazawa T, Mori M. Evaluation of Y-27632, a Rho-kinase inhibitor, as a bronchodilator in guinea pigs. Eur J Pharmacol. 2000;406:273-279.
85. Amrani Y, Tliba O, Deshpande DA, Walseth TF, Kannan MS, Panettieri RA Jr. Bronchial hyperresponsiveness: insights into new signaling molecules. Curr Opin Pharmacol. 2004;4:230-234.
86. Rao PV, Deng PF, Kumar J, Epstein DL. Modulation of aquous humor outflow facility by the Rho-kinase-specific inhibitor Y-27632. Invest Ophthalmol Visual Sci. 2001;42:1029-1037.
87. Khurana RN, Maddala RL, Shimokawa H, Zigler JS, Epstein DL, Rao PV. Inhibition of Rho-kinase induces αB-crystallin expression in lens epithelial cells. Biochem Biophys Res Comm. 2002;294:981-987.
88. Hirayama K, Hata Y, Noda Y, Miura M, Yamanaka I, Shimokawa H, Ishibashi T. The involvement of the Rho-kinase pathway and its regulation in cytokine-induced collagen gel contraction by hyalocytes. Invest Ophthalmol Visual Sci. 2004;45:3896-3903.
89. Rao PV, Deng P, Maddala R, Epstein DL, Li C-Y, Shimokawa H. Expression of dominant negative Rho-binding domain of Rho-kinase in organ cultured human eye anterior segments increases aqueous humor outflow. Mol Vision. 2005;11:288-297.
90. Chitaley K, Wingard CJ, Clinton Webb R, Branam H, Stopper VS, Lewis RW, Mills TM. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nature Med. 2001;7:119-122.
91. Gonzalez-Cadavid NF, Rajfer J. Therapy of erectile dysfunction: potential future treatment. Endocrine. 2004;23:167-176.
92. Ito K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S. An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat Med. 1999;5:221-225.
93. Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, Takakura K, Okamoto S, Kikuchi H, Takemae T, Hidaka H. Dose escalation trial of a novel calcium antagonist, AT877, in patients with aneurysmal subarachnoid haemorrhage. Acta Neurochir. 1990;107:11-15.
94. Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, Takakura K, Nagata I, Kikuchi H, Takemae T, Hidaka H. Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial. J Neurosurg. 1992;76:571-577.
95. Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida H, Osada H, Katagiri T, Yamauchi K, Yui Y, Minamino T, Nakashima M, Kato K. Antianginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. J Cardiovasc Pharmacol. 2002;39:319-327.
96. Vicari RM, Smith WB, Chaitman B, Chrysant SG, Tonkon MJ, Bitter N, Weiss RJ, Thadani U. A randomized, double-blind, placebo-controlled, Phase 2 study: the efficacy of fasudil in patients with stable angina. Eur Heart J. 2004;25:138 (Abstract).
97. Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A. Suppression of coronary artery spasm by a Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation. 2002;105:1545-1547.
98. Mohri M, Shimokawa H, Hirakawa Y, Masumoto A, Takeshita A. Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with angina and normal coronary angiograms. J Am Coll Cardiol. 2003;41:15-19.
99. Fukumoto Y, Mohri M, Shimokawa H, Hirakawa Y, Ito A, Takeshita A. Inhibition of Rho-kinase with fasudil ameliorates pacing-induced myocardial ischemia in patients with effort angina Circ J. 2003;67:142 (Abstract).
100. Inokuchi K, Ito A, Fukumoto Y, Matoba T, Shiose A, Nishida T, Masuda M, Morita S, Shimokawa H. Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery. J Cardiovasc Pharamacol. 2004;44:275-277.
101. Masumoto A, Hirooka Y, Shimokawa H, Hironaga K, Setoguchi S, Takeshita A. Possible involvement of Rho-kinase in the pathogensis of hypertension in humans. Hypertension. 2001;38:1307-1310.
102. Fukumoto Y, Matoba T, Ito A, Tanaka H, Kishi T, Hayashidani S, Abe K, Takeshita A, Shimokawa H. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart. 2005;91:391-392.
103. Shibuya M, Hirai S, Seto M, Satoh S, Ohtomo E. Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial. J Neurol Sci. in press.
104. Kishi T, Hirooka Y, Masumoto A, Ito K, Kimura Y, Inokuchi K, Tagawa T, Shimokawa H, Takeshita A, Sunagawa K. Rho-kinase inhibitor improves increased vascular resistance and impaired vasodilation of the forearm in patients with heart failure. Circulation. 2005;111: 2741-2747.