Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator.[1] Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage,[2] as well as to improve the cognitive decline seen in stroke patients. It has been found to be effective for the treatment of pulmonary hypertension.[3] It was demonstrated in February 2009 that fasudil could improve memory in normal mice, identifying the drug as a possible treatment for age-related or neurodegenerative memory loss.[4]

Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
Pharmacokinetic data
Elimination half-life0.76 hours. Active metabolite (hydroxyfasudil) 4.66 hours.
CAS Number
PubChem CID
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.250.347
Chemical and physical data
Molar mass291.36 g/mol g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

It is approved for use in Japan and China, but has not been approved by the United States Food and Drug Administration or by the European Medicines Agency.

Molecular mechanism

Fasudil (HA-1077) is a selective RhoA/Rho kinase (ROCK) inhibitor.[5] ROCK is an enzyme that plays an important role in mediating vasoconstriction and vascular remodeling in the pathogenesis of pulmonary hypertension. ROCK induces vasoconstriction by phosphorylating the myosin-binding subunit of myosin light chain (MLC) phosphatase, thus decreasing MLC phosphatase activity and enhancing vascular smooth muscle contraction.[5]

ACE expression

Angiotensin-converting enzyme (ACE) is an enzyme that catalyzes the conversion of angiotensin-I (Ang-I) to angiotensin-II (Ang-II). Ang-II is a peptide hormone which increases blood pressure by initiating vasoconstriction and aldosterone secretion. ROCK increases ACE expression and activity in pulmonary hypertension. By inhibiting ROCK with fasudil, circulating ACE and Ang-II are reduced, leading to a decrease in pulmonary vascular pressure.[6]

eNOS expression

Endothelial nitric oxide synthase (eNOS) mediates the production of the vasodilator nitric oxide (NO). Pulmonary arterial cell cultures treated with fasudil showed a significant increase in eNOS mRNA levels in a dose dependent manner, and the half-life of eNOS mRNA increased 2-folds. These findings suggested that ROCK inhibition with fasudil increases eNOS expression by stabilizing eNOS mRNA, which contributed to an increase of NO level to enhance vasodilation.[7]

ERK activation

The proliferative effects of ROCK on vascular endothelial cells is due to the activation of extracellular signal-regulated kinase (ERK).[8] ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate of p27Kip1.[9] p27Kip1 is a cyclin-dependent kinase (CDK) inhibitor which down-regulates cell cycle by binding cyclin-CDK complex.[10] Human pulmonary arterial smooth muscle cells treated with fasudil showed a decrease in cell proliferation in a dose-dependent manner. Fasudil also decreases ERK activities, as well as increases level of p27Kip1. This suggested that the anti-proliferative effects of fasudil is due to the decrease of ERK activities via the inhibition of ROCK.[8]

See also

  • Ripasudil, a fasudil derivative used to treat glaucoma and ocular hypertension


  1. "Drug Found That Could Reduce Risk Of Alzheimer's". Science Daily.
  2. Shibuya M, Suzuki Y (Sep 1993). "[Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877]". Nō to Shinkei - Brain and Nerve (in Japanese). 45 (9): 819–24. PMID 8217408.
  3. Doggrell SA (Sep 2005). "Rho-kinase inhibitors show promise in pulmonary hypertension". Expert Opinion on Investigational Drugs. 14 (9): 1157–9. doi:10.1517/13543784.14.9.1157. PMID 16144499.
  4. Huentelman MJ, Stephan DA, Talboom J, Corneveaux JJ, Reiman DM, Gerber JD, Barnes CA, Alexander GE, Reiman EM, Bimonte-Nelson HA (Feb 2009). "Peripheral delivery of a ROCK inhibitor improves learning and working memory". Behavioral Neuroscience. 123 (1): 218–23. doi:10.1037/a0014260. PMC 2701389. PMID 19170447.
  5. Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M, Takuwa Y (Jan 2000). "Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells". American Journal of Physiology. Cell Physiology. 278 (1): C57–65. doi:10.1152/ajpcell.2000.278.1.c57. PMID 10644512.
  6. Ocaranza MP, Rivera P, Novoa U, Pinto M, González L, Chiong M, Lavandero S, Jalil JE (Apr 2011). "Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension". Journal of Hypertension. 29 (4): 706–15. doi:10.1097/HJH.0b013e3283440665. PMID 21330937.
  7. Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK (Jul 2002). "Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase". Circulation. 106 (1): 57–62. doi:10.1161/01.cir.0000020682.73694.ab. PMID 12093770.
  8. Liu AJ, Ling F, Wang D, Wang Q, Lü XD, Liu YL (Oct 2011). "Fasudil inhibits platelet-derived growth factor-induced human pulmonary artery smooth muscle cell proliferation by up-regulation of p27kip¹ via the ERK signal pathway". Chinese Medical Journal. 124 (19): 3098–104. PMID 22040563.
  9. Delmas C, Manenti S, Boudjelal A, Peyssonnaux C, Eychène A, Darbon JM (Sep 2001). "The p42/p44 mitogen-activated protein kinase activation triggers p27Kip1 degradation independently of CDK2/cyclin E in NIH 3T3 cells". The Journal of Biological Chemistry. 276 (37): 34958–65. doi:10.1074/jbc.m101714200. PMID 11418594.
  10. Fouty BW, Rodman DM (Mar 2003). "Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27Kip1-independent pathway". Circulation Research. 92 (5): 501–9. doi:10.1161/01.RES.0000061180.03813.0F. PMID 12600884.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.