Recent progress in the treatment of pulmonary arterial hypertension: Expectation for Rho-Kinase inhibitors

Tohoku Journal of Experimental Medicine

Volumn 211, Issue 4, 2007, Pages 309-320

  Fukumoto, Yoshihiro ^a   Tawara, Shunsuke ^a   Shimokawa, Hiroaki ^a,b  

^a TOHOKU UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

Author keywords

Pulmonary arterial hyperconstriction; Pulmonary arterial hypertension; Pulmonary arteriosclerosis; Rho kinase

Indexed keywords

ACTIN; ANTICOAGULANT AGENT; BERAPROST; BOSENTAN; CALCIUM CHANNEL BLOCKING AGENT; FASUDIL; MONOCROTALINE; MYOSIN; NITRIC OXIDE; OXYGEN; PHOSPHATASE; PROSTACYCLIN; RHO KINASE; RHO KINASE INHIBITOR; SILDENAFIL; VASODILATOR AGENT; WARFARIN;

ABSENCE OF SIDE EFFECTS; ANTICOAGULANT THERAPY; ARTERIOSCLEROSIS; ARTERY CONSTRICTION; ARTERY DILATATION; CELL ADHESION; CELL MOTILITY; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; CONTINUOUS INFUSION; CYTOKINESIS; CYTOSKELETON; DIARRHEA; DISEASE SEVERITY; DRUG ERUPTION; DRUG INDUCED HEADACHE; DRUG POTENTIATION; DRUG TARGETING; DYSPEPSIA; EPISTAXIS; FATALITY; FLUSHING; GENE EXPRESSION; HUMAN; HYPOTENSION; HYPOXIA; JAW DISEASE; LIFESTYLE MODIFICATION; LIVER DYSFUNCTION; LOW DRUG DOSE; LUNG ARTERY PRESSURE; LUNG TRANSPLANTATION; MONOTHERAPY; MUSCULOSKELETAL PAIN; NAUSEA; NONHUMAN; PATHOGENESIS; PROGNOSIS; PULMONARY ARTERY; PULMONARY HYPERTENSION; REVIEW; SIDE EFFECT; VASCULAR RESISTANCE; VASCULAR SMOOTH MUSCLE;

1-(5-ISOQUINOLINESULFONYL)-2-METHYLPIPERAZINE; ANIMALS; HUMANS; HYPERTENSION, PULMONARY; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MUTATION; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; VASODILATOR AGENTS;

EID: 34247168120     PISSN: 00408727     EISSN: 13493329     Source Type: Journal    
DOI: 10.1620/tjem.211.309     Document Type: Review

References (68)

1. Abe, K., Shimokawa, H., Morikawa, K., Uwatoku, T., Oi, K., Matsumoto, Y., Hattori, T., Nakashima, Y., Kaibuchi, K., Sueishi, K. & Takeshit, A. (2004) Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ. Res., 94, 385-393.
2. Abe, K., Morikawa, K., Hizume, T., Uwatoku, T., Oi, K., Seto, M., Ikegaki, I., Asano, T., Kaibuchi, K. & Shimokawa, H. (2005) Prostacyclin does not inhibit rho-kinase: an implication for the treatment of pulmonary hypertension. J. Cardiovasc. Pharmacol., 45, 120-124.
3. Abe, K., Tawara, S., Oi, K., Hizume, T., Uwatoku, T., Fukumoto, Y., Kaibuchi, K. & Shimokawa, H. (2006) Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J. Cardiovasc. Pharmacol., 48, 280-285.
4. Barst, R.J., Rubin, L.J., Long, W.A., McGoon, M.D., Rich, S., Badesch, D.B., Groves, B.M., Tapson, V.F., Bourge, R.C., Brundage, B.H., Koerner, S.K., Langleben, D., Keller, C.A., Murali, S., Uretsky, B.F., Clayton, L.M., Jobsis, M.M., Blackburn, S.D., Shortino, D. & Crow, J.W. (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N. Engl. J. Med., 334, 296-302.
5. Barst, R.J., McGoon, M., Torbicki, A., Sitbon, O., Krowka, M.J., Olschewski, H. & Gaine, S. (2004) Diagnosis and differential assessment of pulmonary arterial hypertension. J. Am. Coll. Cardiol., 43, 40S-47S.
6. Belardinelli, R., Paolini, I., Cianci, G., Piva, R., Georgiou, D. & Purcaro, A. (2001) Exercise training intervention after coronary angioplasty: the ETICA trial. J. Am. Coll. Cardiol., 37, 1891-1900.
7. Channick, R.N., Simonneau, G., Sitbon, O., Robbins, I.M., Frost, A., Tapson, V.F., Badesch, D.B., Roux, S., Rainisio, M., Bodin, F. & Rubin, L.J. (2001) Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet, 358, 1119-1123.
8. Chapelier, A., Vouhe, P., Macchiarini, P., Lenot, B., Cerrina, J., Le Roy Ladurie, F., Parquin, F., Herve, P., Brenot, F. & Lafont, D. (1993) Comparative outcome of heart-lung and lung transplantation for pulmonary hypertension. J. Thorac. Cardiovasc. Surg., 106, 299-307.
9. Christman, B.W., McPherson, C.D., Newman, J.H., King, G.A., Bernard, G.R., Groves, B.M. & Loyd, J.E. (1992) An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N. Engl. J. Med., 327, 70-75.
10. de Vroomen, M., Takahashi, Y., Gournay, V., Roman, C., Rudolph, A.M. & Heymann, M.A. (1997) Adrenomedullin increases pulmonary blood flow in fetal sheep. Pediatr. Res., 41, 493-497.
11. Dorfmuller, P., Perros, F., Balabanian, K. & Humbert, M. (2003) Inflammation in pulmonary arterial hypertension. Eur. Respir. J., 22, 358-363.
12. Eddahibi, S., Raffestin, B., Hamon, M. & Adnot, S. (2002) Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension? J. Lab. Clin. Med., 139, 194-201.
13. Fukata Y., Amano, M. & Kaibuchi, K. (2001) Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol. Sci., 22, 32-39.
14. Fukumoto, Y., Shimokawa, H., Kozai, T., Kadokami, T., Kuwata, K., Owada, M.K., Shiraishi, T., Kuga, T., Egashira, K. & Takeshita, A. (1996) Tyrosine kinase inhibitor suppresses the (re) stenotic changes of the coronary artery after balloon injury in pigs. Cardiovasc. Res., 32, 1131-1140.
15. Fukumoto, Y., Shimokawa, H., Kozai, T., Kadokami, T., Kuwata, K., Yonemitsu, Y., Kuga, T., Egashira, K., Sueishi, K. & Takeshita, A. (1997) Vasculoprotective role of inducible nitric oxide synthase at inflammatory coronary lesions induced by chronic treatment with interleukin-1beta in pigs in vivo. Circulation, 96, 3104-3111.
16. Fukumoto, Y., Matoba, T., Ito, A., Tanaka, H., Kishi, T., Hayashidani, S., Abe, K., Takeshita, A. & Shimokawa, H. (2005) Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart, 91, 391-392.
17. Fuster, V., Steele, P.M., Edwards, W.D., Gersh, B.J., McGoon, M.D. & Frye, R.L. (1984) Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation, 70, 580-587.
18. Galie, N., Hinderliter, A.L., Torbicki, A., Fourme, T., Simonneau, G., Pulido, T., Espinola-Zavaleta, N., Rocchi, G., Manes, A., Frantz, R., Kurzyna, M., Nagueh, S.F., Barst, R., Channick, R., Dujardin, K., Kronenberg, A., Leconte, I., Rainisio, M. & Rubin, L. (2003) Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension. J. Am. Coll. Cardiol., 41, 1380-1386.
19. Galie, N., Ghofrani, H.A., Torbicki, A., Barst, R.J., Rubin, L.J., Badesch, D., Fleming, T., Parpia, T., Burgess, G., Branzi, A., Grimminger, F., Kurzyna, M. & Simonneau, G. (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med., 353, 2148-2157.
20. Giaid, A., Yanagisawa, M., Langleben, D., Michel, R.P., Levy, R., Shennib, H., Kimura, S., Masaki, T., Duguid, W.P. & Stewart, D.J. (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N. Engl. J. Med., 328, 1732-1739.
21. Giaid, A. & Saleh, D. (1995) Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N. Engl. J. Med., 333, 214-221.
22. Hambrecht, R., Wolf, A., Gielen, S., Linke, A., Hofer, J., Erbs, S. Schoene, N. & Schuler, G. (2000) Effect of exercise on coronary endothelial function in patients with coronary artery disease. N. Engl. J. Med., 342, 454-460.
23. Herve, P., Launay, J.M., Scrobohaci, M.L., Brenot, F., Simonneau, G., Petitpretz, P., Poubeau, P., Cerrina, J., Duroux, P., & Drouet, L. (1995) Increased plasma serotonin in primary pulmonary hypertension. Am. J. Med., 99, 249-254.
24. Higashi, M., Shimokawa, H., Hattori, T., Hiroki, J., Mukai, Y., Morikawa, K., Ichiki, T., Takahashi, S. & Takeshita, A. (2003) Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system. Circ. Res., 93, 767-775.
25. Higenbottam, T.W. & Laude, E.A. (1998) Endothelial dysfunction providing the basis for the treatment of pulmonary hypertension: Giles F. Filley lecture. Chest, 114, 72S-79S.
26. Hizume, T., Morikawa, K., Takaki, A., Abe, K., Sunagawa, K., Amano, M., Kaibuchi, K., Kubo, C. & Shimokawa, H. (2006) Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm. Circ. Res., 99, 767-775.
27. Ishizaki, T., Maekawa, M., Fujisawa, K., Okawa, K., Iwamatsu, A., Fujita, A., Watanabe, N., Saito, Y., Kakizuka, A., Morii, N. & Narumiya, S. (1996) The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J., 15, 1885-1893.
28. Jiang, B.H., Tawara, S., Abe, K., Takaki, A., Fukumoto, Y. & Shimokawa, H. (2007) Acute vasodilator effect of fasudil, a Rho-kinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats. J. Cardiovasc. Pharmacol., 49, 85-89.
29. Kakishita, M., Nishikimi, T., Okano, Y., Satoh, T., Kyotani, S., Nagaya, N., Fukushima, K., Nakanishi, N., Takishita, S., Miyata, A., Kangawa, K., Matsuo, H. & Kunieda, T. (1999) Increased plasma levels of adrenomedullin in patients with pulmonary hypertension. Clin. Sci. (Lond.), 96, 33-39.
30. Mandegar, M., Fung, Y.C., Huang, W., Remillard, C.V., Rubin, L.J. & Yuan, J.X. (2004) Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvasc. Res., 68, 75-103.
31. Masumoto, A., Hirooka, Y., Shimokawa, H., Hironaga, K., Setoguchi, S. & Takeshita, A. (2001) Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension, 38, 1307-1310.
32. Masumoto, A., Mohri, M., Shimokawa, H., Urakami, L., Usui, M. & Takeshita, A. (2002) Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation, 105, 1545-1547.
33. McLaughlin, V.V., Sitbon, O., Badesch, D.B., Barst, R.J., Black, C., Galie, N., Rainisio, M., Simonneau, G. & Rubin, L.J. (2005) Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur. Respir. J., 25, 244-249.
34. McLaughlin, V.V. & McGoon, M.D. (2006) Pulmonary Arterial Hypertension. Circulation, 114, 1417-1431.
35. Mereles, D., Ehlken, N., Kreuscher, S., Ghofrani, S., Hoeper, M.M., Halank, M., Meyer, F.J., Karger, G., Buss, J., Juenger, J., Holzapfel, N., Opitz, C., Winkler, J., Herth, F.F., Wilkens, H., Katus, H.A., Olschewski, H. & Grunig, E. (2006) Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation, 114, 1482-1489.
36. Michelakis, E., Tymchak, W., Lien, D., Webster, L., Hashimoto, K. & Archer, S. (2002) Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation, 105, 2398-2403.
37. Moncada, S. & Higgs, E.A. (2006) Nitric oxide and the vascular endothelium. Handb. Exp. Pharmacol., 213-254.
38. Morecroft, I., Heeley, R.P., Prentice, H.M., Kirk, A. & MacLean, M.R. (1999) 5-hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5-HT1B receptor. Br. J. Pharmacol., 128, 730-734.
39. Morishige, K., Shimokawa, H., Eto, Y., Kandabashi, T., Miyata, K., Matsumoto, Y., Hoshijima, M., Kaibuchi, K. & Takeshita, A. (2001) Adenovirus-mediated transfer of dominant-negative rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo. Arterioscler. Thromb. Vasc. Biol., 21, 548-554.
40. Morse, J.H., Deng, Z. & Knowles, J.A. (2001) Genetic aspects of pulmonary arterial hypertension. Ann. Med., 33, 596-603.
41. Nagaoka, T., Fagan, K.A., Gebb, S.A., Morris, K.G., Suzuki, T., Shimokawa, H., McMurtry, I.F. & Oka, M. (2005) Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am. J. Respir. Crit. Care Med., 171, 494-499.
42. Nagaya, N., Uematsu, M., Satoh, T., Kyotani, S., Sakamaki, F., Nakanishi, N., Yamagishi, M., Kunieda, T. & Miyatake, K. (1999) Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am. J. Respir. Crit. Care Med., 160, 487-492.
43. Nagaya, N., Nishikimi, T., Uematsu, M., Satoh, T., Kyotani, S., Sakamaki, F., Kakishita, M., Fukushima, K., Okano, Y., Nakanishi, N., Miyatake, K. & Kangawa, K. (2000) Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation, 102, 865-870.
44. Newman, J.H., Trembath, R.C., Morse, J.A., Grunig, E., Loyd, J.E., Adnot, S., Coccolo, F., Ventura, C., Phillips, J.A., 3rd, Knowles, J.A., Janssen, B., Eickelberg, O., Eddahibi, S., Herve, P., Nichols, W.C. & Elliott, G. (2004) Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J. Am. Coll. Cardiol., 43, 33S-39S.
45. Palevsky, H.I., Schloo, B.L., Pietra, G.G., Weber, K.T., Janicki, J.S., Rubin, E. & Fishman, A.P. (1989) Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation, 80, 1207-1221.
46. Rich, S., Kaufmann, E. & Levy, P.S. (1992) The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N. Engl. J. Med., 327, 76-81.
47. Rich, S. & McLaughlin, V.V. (2005) Braunwald's Heart Disease, 7th ed., Chap.67, Elsevier Inc., Pennsylvania, pp. 1807-1842.
48. Roman, A., Gispert, P., Monforte, V., Bravo, C., Domingo, E. & Morell, F. (2006) Long-term Outcomes of Treatment With Bosentan in Pulmonary Hypertension. Arch. Bronconeumol., 42, 616-620.
49. Rubens, C., Ewert, R., Halank, M., Wensel, R., Orzechowski, H.D., Schultheiss, H.P. & Hoeffken, G. (2001) Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest, 120, 1562-1569.
50. Shimokawa, H., Tomoike, H., Nabeyama, S., Yamamoto, H., Araki, H., Nakamura, M., Ishii, Y. & Tanaka, K. (1983) Coronary artery spasm induced in atherosclerotic miniature swine. Science, 221, 560-562.
51. Shimokawa, H., Seto, M., Katsumata, N., Amano, M., Kozai, T., Yamawaki, T., Kuwata, K., Kandabashi, T., Egashira, K., Ikegaki, I., Asano, T., Kaibuchi, K. & Takeshita, A. (1999) Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm. Cardiovasc. Res., 43, 1029-1039.
52. Shimokawa, H. (2000) Cellular and molecular mechanisms of coronary artery spasm: lessons from animal models. Jpn. Circ. J., 64, 1-12.
53. Shimokawa, H. (2002) Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases. J. Cardiovasc. Pharmacol., 39, 319-327.
54. Shimokawa, H. & Takeshita, A. (2005) Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler. Thromb. Vasc. Biol., 25, 1767-1775.
55. Shimokawa, H. & Rashid, M. (2007) Rho-kinase inhibitors for cardiovascular medicine. Its rationale and current status. Trends Pharmacol Sci., (in press)
56. Simonneau, G., Galie, N., Rubin, L.J., Langleben, D., Seeger, W., Domenighetti, G., Gibbs, S., Lebrec, D., Speich, R., Beghetti, M., Rich, S. & Fishman, A. (2004) Clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol., 43, Suppl. 12, 5S-12S.
57. Singer, S.T., Kuypers, F.A., Styles, L., Vichinsky, E.P., Foote, D. & Rosenfeld, H. (2006) Pulmonary hypertension in thalassemia: association with platelet activation and hypercoagulable state. Am. J. Hematol., 81, 670-675.
58. Sitbon, O., Humbert, M., Nunes, H., Parent, F., Garcia, G., Herve, P., Rainisio, M. & Simonneau, G. (2002) Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J. Am. Coll. Cardiol., 40, 780-788.
59. Sitbon, O., Humbert, M., Jais, X., Ioos, V., Hamid, A.M., Provencher, S., Garcia, G., Parent, F., Herve, P. & Simonneau, G. (2005) Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation, 111, 3105-3111.
60. Somlyo, A.P. & Somlyo, A.V. (2000) Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J. Physiol., 522, 177-185.
61. Stewart, D.J., Levy, R.D., Cernacek, P. & Langleben, D. (1991) Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann. Intern. Med., 114, 464-469.
62. Takai, Y., Sasaki, T. & Matozaki, T. (2001) Small GTP-binding proteins. Physiol. Rev., 81, 153-208.
63. Takemoto, M. & Liao, J.K. (2001) Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler. Thromb. Vasc. Biol., 21, 1712-1719.
64. Tawara, S., Abe, K., Morikawa, K., Fukumoto, Y. & Shimokawa, H. (2007) Prostacyclin lacks inhibitory effects on Rho-kinase -Possible benefits of combined therapy with prostacyclin and a Rho-kinase inhibitor in pulmonary hypertension. Circ. J., 71, Suppl. I, 232.
65. Tuder, R.M., Groves, B., Badesch, D.B. & Voelkel, N.F. (1994) Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am. J. Pathol., 144, 275-285.
66. Uehata, M., Ishizaki, T., Satoh, H., Ono, T., Kawahara, T., Morishita, T., Tamakawa, H., Yamagami, K., Inui, J., Maekawa, M. & Narumiya, S. (1997) Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature, 389, 990-994.
67. Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., Yazaki, Y., Goto, K. & Masaki, T. (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature, 332, 411-415.
68. Yuan, J.X., Aldinger, A.M., Juhaszova, M., Wang, J., Conte, J.V., Jr., Gaine, S.P., Orens, J.B. & Rubin, L.J. (1998) Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation, 98, 1400-1406.