Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

European Respiratory Journal

Volumn 36, Issue 4, 2010, Pages 808-818

  Dahal, B K ^a   Kosanovic, D ^a   Pamarthi, P K ^a   Sydykov, A ^a   Lai, Y J ^a   Kast, R ^b   Schirok, H ^b   Stasch, J P ^b   Ghofrani, H A ^a   Weissmann, N ^a   Grimminger, F ^a   Seeger, W ^a,c   Schermuly, R T ^a,c  

^a JUSTUS LIEBIG UNIVERSITY GIESSEN   (Germany)

^b BAYER PHARMA AG   (Germany)

^c MAX PLANCK INSTITUTE FOR HEART AND LUNG RESEARCH   (Germany)

Author keywords

Azaindole 1; Hypoxia; Monocrotaline; Pulmonary hypertension; Rho kinase

Indexed keywords

4 (1 AMINOETHYL) N (4 PYRIDYL)CYCLOHEXANECARBOXAMIDE; AZAINDOLE 1; CYCLINE; FASUDIL; MONOCROTALINE; MYOSIN; MYOSIN PHOSPHATASE TARGET SUBUNIT 1; PHOSPHATASE; RHO KINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTERY MUSCLE; ARTICLE; CELL PROLIFERATION; CONTROLLED STUDY; DRUG EFFECT; DRUG EFFICACY; ENZYME ACTIVITY; HEART RIGHT VENTRICLE HYPERTROPHY; IMMUNOREACTIVITY; LUNG HEMODYNAMICS; MALE; NONHUMAN; PRIORITY JOURNAL; PULMONARY HYPERTENSION; RAT; VASOCONSTRICTION;

ANIMALS; AZABICYCLO COMPOUNDS; CELL PROLIFERATION; DISEASE MODELS, ANIMAL; ENZYME INHIBITORS; HEMODYNAMICS; HYPERTENSION, PULMONARY; INDOLES; LUNG; MALE; MICE; RATS; RATS, SPRAGUE-DAWLEY; RHO-ASSOCIATED KINASES; TELEMETRY; TETRAZOLIUM SALTS; THIAZOLES; THYMIDINE; TREATMENT OUTCOME;

EID: 77957828780     PISSN: 09031936     EISSN: 13993003     Source Type: Journal    
DOI: 10.1183/09031936.00140309     Document Type: Article

References (49)

1. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: Suppl. S, 13S-24S.
2. Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54: Suppl., S20-S31.
3. Ghofrani HA, Barst RJ, Benza RL, et al. Future perspectives for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54: Suppl., S108-S117.
4. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature 2002; 420: 629-635.
5. Leung T, Manser E, Tan L, et al. 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.
6. Matsui T, Amano M, Yamamoto T, et al. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J 1996; 15: 2208-2216.
7. Nakagawa O, Fujisawa K, Ishizaki T, et al. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 1996; 392: 189-193.
8. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006; 98: 322-334.
9. Oka M, Fagan KA, Jones PL, et al. Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension. Br J Pharmacol 2008; 155: 444-454.
10. Abe K, Shimokawa H, Morikawa K, et al. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res 2004; 94: 385-393.
11. Abe K, Tawara S, Oi K, et al. Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol 2006; 48: 280-285.
12. Hemnes AR, Zaiman A, Champion HC. PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation. Am J Physiol Lung Cell Mol Physiol 2008; 294: L24-L33.
13. Homma N, Nagaoka T, Karoor V, et al. Involvement of RhoA/ Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone. Am J Physiol Lung Cell Mol Physiol 2008; 295: L71-L78.
14. McNamara PJ, Murthy P, Kantores C, et al. Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide. Am J Physiol Lung Cell Mol Physiol 2008; 294: L205-L213.
15. Nagaoka T, Gebb SA, Karoor V, et al. Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat. J Appl Physiol 2006; 100: 996-1002.
16. Oka M, Homma N, Taraseviciene-Stewart L, et al. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 2007; 100: 923-929.
17. Do EZ, Fukumoto Y, Takaki A, et al. Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circ J 2009; 73: 1731-1739.
18. Fukumoto Y, Matoba T, Ito A, et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 2005; 91: 391-392.
19. Guilluy C, Eddahibi S, Agard C, et al. RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med 2009; 179: 1151-1158.
20. Ishikura K, Yamada N, Ito M, et al. Beneficial acute effects of Rho-kinase inhibitor in patients with pulmonary arterial hypertension. Circ J 2006; 70: 174-178.
21. Laumanns IP, Fink L, Wilhelm J, et al. The noncanonical WNT pathway is operative in idiopathic pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2009; 40: 683-691.
22. Li F, Xia W, Yuan S, et al. Acute inhibition of Rho-kinase attenuates pulmonary hypertension in patients with congenital heart disease. Pediatr Cardiol 2009; 30: 363-366.
23. Liu Y, Ren W, Warburton R, et al. Serotonin induces Rho/ROCK-dependent activation of Smads 1/5/8 in pulmonary artery smooth muscle cells. FASEB J 2009; 23: 2299-2306.
24. Ono-Saito N, Niki I, Hidaka H. H-Series protein kinase inhibitors and potential clinical applications. Pharmacol Ther 1999; 82: 123-131.
25. Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 1997; 389: 990-994.
26. Asano T, Ikegaki I, Satoh S, et al. A protein kinase inhibitor, Fasudil (AT-877): a novel approach to signal transdcution therapy. Cardiovasc Drug Rev 1998; 16: 76-87.
27. Nagumo H, Seto M, Sakurada K, et al. HA1077, a protein kinase inhibitor, inhibits calponin phosphorylation on Ser175 in porcine coronary artery. Eur J Pharmacol 1998; 360: 257-264.
28. Kast R, Schirok H, Figueroa-Perez S, et al. Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase. Br J Pharmacol 2007; 152: 1070-1080.
29. Schirok H, Kast R, Figueroa-Perez S, et al. Design and synthesis of potent and selective azaindole-based Rho kinase (ROCK) inhibitors. Chem Med Chem 2008; 3: 1893-1904.
30. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005; 115: 2811-2821.
31. Schermuly RT, Kreisselmeier KP, Ghofrani HA, et al. Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 2004; 169: 39-45.
32. Schermuly RT, Pullamsetti SS, Kwapiszewska G, et al. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy. Circulation 2007; 115: 2331-2339.
33. Dahal BK, Cornitescu T, Tretyn A, et al. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med 2010; 181: 158-167.
34. Weissmann N, Hackemack S, Dahal BK, et al. The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol 2009; 297: L658-L665.
35. Chin KM, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol 2008; 51: 1527-1538.
36. Boutet K, Montani D, Jais X, et al. Review: therapeutic advances in pulmonary arterial hypertension. Ther Adv Respir Dis 2008; 2: 249-265.
37. Tamura M, Nakao H, Yoshizaki H, et al. Development of specific Rho-kinase inhibitors and their clinical application. Biochim Biophys Acta 2005; 1754: 245-252.
38. Wang Y, Zheng XR, Riddick N, et al. ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res 2009; 104: 531-540.
39. Nagaoka T, Fagan KA, Gebb SA, et al. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 2005; 171: 494-499.
40. Jiang BH, Tawara S, Abe K, et al. Acute vasodilator effect of fasudil, a Rho-kinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2007; 49: 85-89.
41. Hyvelin JM, Howell K, Nichol A, et al. Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation. Circ Res 2005; 97: 185-191.
42. Fagan KA, Oka M, Bauer NR, et al. Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol 2004; 287: L656-L664.
43. Li F, Xia W, Li A, et al. Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats. Pharmacol Res 2007; 55: 64-71. (Pubitemid 46108589)
44. Tawara S, Fukumoto Y, Shimokawa H. Effects of combined therapy with a Rho-kinase inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2007; 50: 195-200. (Pubitemid 47267745)
45. Mukai Y, Shimokawa H, Matoba T, et al. Involvement of Rho-kinase in hypertensive vascular disease - a novel therapeutic target in hypertension. FASEB J 2001; 15: 1062-1064.
46. Chapados R, Abe K, Ihida-Stansbury K, et al. ROCK controls matrix synthesis in vascular smooth muscle cells: coupling vasoconstriction to vascular remodeling. Circ Res 2006; 99: 837-844.
47. Girgis RE, Mozammel S, Champion HC, et al. Regression of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Lung Cell Mol Physiol 2007; 292: L1105-L1110.
48. Guilluy C, Sauzeau V, Rolli-Derkinderen M, et al. Inhibition of RhoA/Rho kinase pathway is involved in the beneficial effect of sildenafil on pulmonary hypertension. Br J Pharmacol 2005; 146: 1010-1018.
49. Homma N, Nagaoka T, Morio Y, et al. Endothelin-1 and serotonin are involved in activation of RhoA/Rho kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation. J Cardiovasc Pharmacol 2007; 50: 697-702.