The Rho kinase inhibitor azaindole-1 has long-acting vasodilator activity in the pulmonary vascular bed of the intact chest rat

Canadian Journal of Physiology and Pharmacology

Volumn 90, Issue 7, 2012, Pages 825-835

  Kadowitz, Philip J ^a   PankeyRyuk, Edward A ^a   Byun, Ryuk J ^a   Smith II, William B ^a   Bhartiya, Manish ^a   Bueno, Franklin R ^a   Badejo, Adeleke M ^a   Stasch, Johannes Peter ^b   Murthy, Subramanyam N ^a   Nossaman, Bobby D ^a,c  

^a TULANE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b BAYER AG   (Germany)

^c OCHSNER MEDICAL CENTER   (United States)

Author keywords

Azaindole 1; Fasudil; Hypoxia; L NAME; Monocrotaline; Pulmonary and systemic circulation; ROCK; U46619; Vasodilator responses

Indexed keywords

15 HYDROXY 11ALPHA,9ALPHA EPOXYMETHANOPROSTA 5,13 DIENOIC ACID; AZAINDOLE 1 [6 CHLORO N 4 [3,5 DIFLUORO 4 [(3 METHYL 1H PYRROL(2,3 B)PYRIDIN 4 YL) OXY]PHENYL]YRIMIDINE 2,4 DIAMINE]; FASUDIL; MONOCROTALINE; N(G) NITROARGININE METHYL ESTER; RHO KINASE; UNCLASSIFIED DRUG; VASODILATOR AGENT;

ANIMAL EXPERIMENT; ARTERIAL PRESSURE; ARTICLE; CONTROLLED STUDY; CORONARY BLOOD VESSEL; ENZYME INHIBITION; HEART OUTPUT; HYPOXIA; LUNG ARTERY PRESSURE; MALE; NONHUMAN; PRIORITY JOURNAL; PULMONARY HYPERTENSION; RAT; STIMULUS RESPONSE; VASOCONSTRICTION; VASODILATATION;

15-HYDROXY-11 ALPHA,9 ALPHA-(EPOXYMETHANO)PROSTA-5,13-DIENOIC ACID; ANIMALS; ANOXIA; BLOOD PRESSURE; CARDIAC OUTPUT; CARDIOVASCULAR SYSTEM; HYPERTENSION, PULMONARY; MALE; MONOCROTALINE; NG-NITROARGININE METHYL ESTER; NITRIC OXIDE SYNTHASE; PROTEIN KINASE INHIBITORS; PULMONARY ARTERY; PULMONARY CIRCULATION; RATS; RATS, SPRAGUE-DAWLEY; RHO-ASSOCIATED KINASES; VASODILATOR AGENTS;

EID: 84863698886     PISSN: 00084212     EISSN: 12057541     Source Type: Journal    
DOI: 10.1139/Y2012-061     Document Type: Article

References (45)

1. Aaronson, P.I., Robertson, T.P., Knock, G.A., Becker, S., Lewis, T. H., Snetkov, V., and Ward, J.P. 2006. Hypoxic pulmonary vasoconstriction: mechanisms and controversies. J. Physiol. 570 (1): 53-58. doi:10.1113/jphysiol.2005.098855. PMID:16254010.
2. Amano, M., Ito, M., Kimura, K., Fukata, Y., Chihara, K., Nakano, T., et al. 1996. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J. Biol. Chem. 271(34): 20246-20249. doi:10.1074/jbc.271.34.20246. PMID:8702756.
3. Badejo, A.M., Jr, Dhaliwal, J.S., Casey, D.B., Gallen, T.B., Greco, A. J., and Kadowitz, P.J. 2008. Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat. Am. J. Physiol. Lung Cell. Mol. Physiol. 295(5): L828-L836. doi:10.1152/ajplung.00042.2008. PMID:18689606.
4. 2+-independent contractions induced by phorbol-12,13-dibutyrate. Clin. Exp. Pharmacol. Physiol. 36(3): 256-261. doi:10.1111/j.1440-1681.2008.05045.x. PMID:18986333.
5. Bain, J., Plater, L., Elliott, M., Shpiro, N., Hastie, C.J., McLauchlan, H., et al. 2007. The selectivity of protein kinase inhibitors: a further update. Biochem. J. 408(3): 297-315. doi:10.1042/ BJ20070797. PMID:17850214.
6. Budzyn, K., Marley, P.D., and Sobey, C.G. 2006. Targeting Rho and Rho-kinase in the treatment of cardiovascular disease. Trends Pharmacol. Sci. 27(2): 97-104. doi:10.1016/j.tips.2005.12.002. PMID:16376997.
7. Casey, D.B., Badejo, A.M., Dhaliwal, J.S., Sikora, J.L., Fokin, A., Golwala, N.H., et al. 2010. Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat. Am. J. Physiol. Heart Circ. Physiol. 299(1): H184- H192. doi:10.1152/ajpheart.00181.2009. PMID:20435851.
8. Dahal, B.K., Kosanovic, D., Pamarthi, P.K., Sydykov, A., Lai, Y.J., Kast, R., et al. 2010. Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension. Eur. Respir. J. 36(4): 808-818. doi:10.1183/09031936.00140309. PMID:20530035.
9. Davies, S.P., Reddy, H., Caivano, M., and Cohen, P. 2000. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351(1): 95-105. doi:10.1042/0264-6021:3510095. PMID:10998351.
10. 2+ entry mediate increased pulmonary and systemic vascular resistance in L-NAME-treated rats. Am. J. Physiol. Lung Cell. Mol. Physiol. 293(5): L1306-L1313. doi:10.1152/ajplung.00189.2007. PMID:17766587.
11. Dhaliwal, J.S., Badejo, A.M., Jr, Casey, D.B., Murthy, S.N., and Kadowitz, P.J. 2009. Analysis of pulmonary vasodilator responses to SB-772077-B [4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine], a novel aminofurazan-based Rho kinase inhibitor. J. Pharmacol. Exp. Ther. 330(1): 334-341. doi:10.1124/jpet.109.151449. PMID:19369577.
12. Dong, M., Yan, B.P., Liao, J.K., Lam, Y.Y., Yip, G.W., and Yu, C.M. 2010. Rho-kinase inhibition: a novel therapeutic target for the treatment of cardiovascular diseases. Drug Discov. Today, 15(15-16): 622-629. doi:10.1016/j.drudis.2010.06.011. PMID:20601092.
13. Etienne-Manneville, S., and Hall, A. 2002. Rho GTPases in cell biology. Nature, 420(6916): 629-635. doi:10.1038/nature01148. PMID:12478284.
14. Fujita, H., Fukumoto, Y., Saji, K., Sugimura, K., Demachi, J., Nawata, J., and Shimokawa, H. 2010. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels, 25(2): 144-149. doi:10.1007/s00380-009-1176-8. PMID:20339976.
15. Gao, Y., Portugal, A.D., Negash, S., Zhou, W., Longo, L.D., and Usha Raj, J. 2007. Role of Rho kinases in PKG-mediated relaxation of pulmonary arteries of fetal lambs exposed to chronic high altitude hypoxia. Am. J. Physiol. Lung Cell. Mol. Physiol. 292(3): L678- L684. doi:10.1152/ajplung.00178.2006. PMID:17085525.
16. Jacobs, M., Hayakawa, K., Swenson, L., Bellon, S., Fleming, M., Taslimi, P., and Doran, J. 2006. The structure of dimeric ROCK I reveals the mechanism for ligand selectivity. J. Biol. Chem. 281 (1): 260-268. doi:10.1074/jbc.M508847200. PMID:16249185.
17. Jiang, B.H., Tawara, S., Abe, K., Takaki, A., Fukumoto, Y., and Shimokawa, H. 2007. Acute vasodilator effect of fasudil, a Rho-kinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats. J. Cardiovasc. Pharmacol. 49(2): 85-89. doi:10.1097/ FJC.0b013e31802df112. PMID:17312448.
18. Kandabashi, T., Shimokawa, H., Miyata, K., Kunihiro, I., Eto, Y., Morishige, K., et al. 2003. Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arterioscler. Thromb. Vasc. Biol. 23(12): 2209-2214. doi:10.1161/01.ATV.0000104010.87348.26. PMID:14592852.
19. Kast, R., Schirok, H., Figueroa-Perez, S., Mittendorf, J., Gnoth, M.J., Apeler, H., et al. 2007. Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase. Br. J. Pharmacol. 152(7): 1070-1080. doi:10.1038/sj.bjp.0707484. PMID:17934515.
20. Kumar, R., Singh, V.P., and Baker, K.M. 2007. Kinase inhibitors for cardiovascular disease. J. Mol. Cell. Cardiol. 42(1): 1-11. doi:10. 1016/j.yjmcc.2006.09.005. PMID:17059822.
21. Leung, T., Manser, E., Tan, L., and Lim, L. 1995. A novel serine/ threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J. Biol. Chem. 270 (49): 29051-29054. doi:10.1074/jbc.270.49.29051. PMID:7493923.
22. Li, F., Xia, W., Li, A., Zhao, C., and Sun, R. 2007. Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats. Pharmacol. Res. 55(1): 64-71. doi:10.1016/j.phrs.2006.10.009. PMID:17127075.
23. Li, F., Xia, W., Yuan, S., and Sun, R. 2009. Acute inhibition of Rho-kinase attenuates pulmonary hypertension in patients with congenital heart disease. Pediatr. Cardiol. 30(3): 363-366. doi:10.1007/s00246-008-9315-z. PMID:18953591.
24. Loirand, G., Guerin, P., and Pacaud, P. 2006. Rho kinases in cardiovascular physiology and pathophysiology. Circ. Res. 98(3): 322-334. doi:10.1161/01.RES.0000201960.04223.3c. PMID: 16484628.
25. Matsui, T., Amano, M., Yamamoto, T., Chihara, K., Nakafuku, M., Ito, M., et al. 1996. Rho-associated kinase, a novel serine/ threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J. 15(9): 2208-2216. PMID:8641286.
26. McMurtry, I.F., Abe, K., Ota, H., Fagan, K.A., and Oka, M. 2010. Rho kinase-mediated vasoconstriction in pulmonary hypertension. Adv. Exp. Med. Biol. 661: 299-308. doi:10.1007/978-1-60761-500-2_19. PMID:20204738.
27. McNamara, P.J., Murthy, P., Kantores, C., Teixeira, L., Engelberts, D., van Vliet, T., et al. 2008. Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide. Am. J. Physiol. Lung Cell. Mol. Physiol. 294(2): L205-L213. doi:10.1152/ajplung.00234.2007. PMID:18032699.
28. Mohri, M., Shimokawa, H., Hirakawa, Y., Masumoto, A., and Takeshita, A. 2003. Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. J. Am. Coll. Cardiol. 41(1): 15-19. doi:10. 1016/S0735-1097(02)02632-3. PMID:12570938.
29. Murthy, S.N., Nossaman, B.D., and Kadowitz, P.J. 2010. New approaches to the treatment of pulmonary hypertension: from bench to bedside. Cardiol. Rev. 18(2): 76-84. doi:10.1097/CRD. 0b013e3181cbcbf3. PMID:20160533.
30. Nagaoka, T., Fagan, K.A., Gebb, S.A., Morris, K.G., Suzuki, T., Shimokawa, H., et al. 2005. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am. J. Respir. Crit. Care Med. 171(5): 494-499. doi:10.1164/ rccm.200405-637OC. PMID:15563635.
31. Nakagawa, O., Fujisawa, K., Ishizaki, T., Saito, Y., Nakao, K., and Narumiya, S. 1996. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett. 392(2): 189-193. doi:10.1016/0014-5793(96) 00811-3. PMID:8772201.
32. Nossaman, B.D., Nossaman, V.E., Murthy, S.N., and Kadowitz, P.J. 2010. Role of the RhoA/Rho-kinase pathway in the regulation of pulmonary vasoconstrictor function. Can. J. Physiol. Pharmacol. 88(1): 1-8. doi:10.1139/Y09-092. PMID:20130732.
33. Nunes, K.P., Rigsby, C.S., and Webb, R.C. 2010. RhoA/Rho-kinase and vascular diseases: what is the link? Cell. Mol. Life Sci. 67(22): 3823-3836. doi:10.1007/s00018-010-0460-1. PMID:20668910.
34. Oka, M., Fagan, K.A., Jones, P.L., and McMurtry, I.F. 2008. Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension. Br. J. Pharmacol. 155(4): 444-454. doi:10.1038/bjp. 2008.239. PMID:18536743.
35. Pankey, E.A., Bhartiya, M., Badejo, A.M., Jr, Haider, U., Stasch, J.P., Murthy, S.N., et al. 2011. Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase activator, BAY 60-2770, are not dependent on endogenous nitric oxide or reduced heme. Am. J. Physiol. Heart Circ. Physiol. 300(3): H792-H802. doi:10. 1152/ajpheart.00953.2010. PMID:21217076.
36. Schirok, H., Kast, R., Figueroa-Perez, S., Bennabi, S., Gnoth, M.J., Feurer, A., et al. 2008. Design and synthesis of potent and selective azaindole-based Rho kinase (ROCK) inhibitors. ChemMedChem, 3 (12): 1893-1904. doi:10.1002/cmdc.200800211. PMID:18973168.
37. Shimokawa, H., and Rashid, M. 2007. Development of Rho-kinase inhibitors for cardiovascular medicine. Trends Pharmacol. Sci. 28(6): 296-302. doi:10.1016/j.tips.2007.04.006. PMID:17482681.
38. Shimokawa, H., and Yasuda, S. 2008. Myocardial ischemia: current concepts and future perspectives. J. Cardiol. 52(2): 67-78. doi:10. 1016/j.jjcc.2008.07.016. PMID:18922380.
39. Shimokawa, H., Hiramori, K., Iinuma, H., Hosoda, S., Kishida, H., Osada, H., et al. 2002. Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. J. Cardiovasc. Pharmacol. 40(5): 751-761. doi:10.1097/ 00005344-200211000-00013. PMID:12409984.
40. Suzuki, Y., Shibuya, M., Satoh, S., Sugimoto, Y., and Takakura, K. 2007. A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surg. Neurol., 68(2): 126-131, discussion 131-132. doi:10.1016/j.surneu.2006.10.037. PMID:17586012.
41. Tachibana, E., Harada, T., Shibuya, M., Saito, K., Takayasu, M., Suzuki, Y., and Yoshida, J. 1999. Intra-arterial infusion of fasudil hydrochloride for treating vasospasm following subarachnoid haemorrhage. Acta Neurochir. (Wien), 141(1): 13-19. doi:10. 1007/s007010050260. PMID:10071681.
42. Takai, Y., Kaibuchi, K., Sasaki, T., Tanaka, K., Shirataki, H., and Nakanishi, H. 1994. Rho small G protein and cytoskeletal control. Princess Takamatsu Symp. 24: 338-350. PMID:8983086.
43. Takaishi, K., Sasaki, T., Kato, M., Yamochi, W., Kuroda, S., Nakamura, T., et al. 1994. Involvement of Rho p21 small GTP-binding protein and its regulator in the HGF-induced cell motility. Oncogene, 9(1): 273-279. PMID:8302589.
44. 2+ signaling in hypoxic pulmonary vasoconstriction: effects of myosin light chain and Rho kinase antagonists. Am. J. Physiol. Lung Cell. Mol. Physiol. 293(3): L674-L685. doi:10. 1152/ajplung.00141.2007. PMID:17575009.
45. Ward, J.P., and McMurtry, I.F. 2009. Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem. Curr. Opin. Pharmacol. 9(3): 287-296. doi:10.1016/j.coph.2009.02.006. PMID:19297247.