関: fasudil hydrochloride、fasudil hydrochloride hydrate

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/01/24 21:51:39」(JST)

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Fasudil Hydrochloride (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 victims. It has been found to be effective for the treatment of pulmonary hypertension.^[3] It was demonstrated in February 2009 that fasudil could also be used to enhance memory and improve the prognosis of Alzheimers patients.^[4]

Pulmonary Hypertension[edit]

Pulmonary Hypertension (PH) is a cardiovascular disease characterized by a resting mean pulmonary arterial pressure exceeding 25 mmHg, or more than 30 mmHg during exercise.^[5] It arises from the pulmonary vascular remodeling accompanied by endothelial dysfunction, fibroblast activation, and endothelial cellular proliferation. Symptoms of PH include shortness of breath, chronic fatigue, dizziness, peripheral edema, cyanosis, and chest pain. If untreated, PH could lead to heart failure and death.^[6] PH is divided into 5 classifications: arterial, venous, hypoxemia, thromboembolic, and miscellaneous.^[7]

Molecular Mechanism[edit]

Fasudil (HA-1077) is a selective RhoA/Rho kinase(ROCK) inhibitor.^[8] ROCK is an enzyme that plays an important role in mediating vasoconstriction and vascular remodeling in the pathogenesis of PH. 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.^[8]

Angiotensin-converting Enzyme (ACE) expression and Angiotensin-II (Ang-II) levels[edit]

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 PH. By inhibiting ROCK with fasudil, circulating ACE and Ang-II are reduced, leading to a decrease in pulmonary vascular pressure.^[9]

Endothelial Nitric Oxide Synthase (eNOS) expression[edit]

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.^[10]

Extracellular signal-regulated kinase(ERK) activity and p27Kip1 levels[edit]

The proliferative effects of ROCK on vascular endothelial cells is due to the activation of extracellular signal-regulated kinase (ERK).^[11] ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate of p27Kip1.^[12] p27Kip1 is a cyclin-dependent kinase (CDK) inhibitor which down-regulates cell cycle by binding cyclin-CDK complex.^[13] 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.^[11]

References[edit]

^ . Science Daily http://www.sciencedaily.com/releases/2009/02/090202102932.htm Missing or empty |title= (help)
^ Shibuya M, Suzuki Y (September 1993). "[Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877]". No to Shinkei (in Japanese) 45 (9): 819–24. PMID 8217408.
^ Doggrell SA (2005). "Rho-kinase inhibitors show promise in pulmonary hypertension.". Expert Opin Investig Drugs 14 (9): 1157–1159. doi:10.1517/13543784.14.9.1157. PMID 16144499.
^ Huentelman, Matthew J.; Stephan, DA; Talboom, J; Corneveaux, JJ; Reiman, DM; Gerber, JD; Barnes, CA; Alexander, GE et al. (2009). "Peripheral delivery of a ROCK inhibitor improves learning and working memory". Behavioral Neuroscience 123 (1): 218. doi:10.1037/a0014260. PMC 2701389. PMID 19170447 |displayauthors= suggested (help)
^ Badesch, D.B., Champion, H.C., Sanchez, M.A.G., Hoeper, M.M., Hoyd, J.E., Manes, A., McGoon, M., Naeije, R., Olschewski, H., Oudiz, R.J., and Torbicki, A. (2009). Diagnosis and Assessment of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology. 54:55-66.
^ Zeller, J.L., Burke, A.E., and Glass, R.M. (2008). Pulmonary Hypertension. The Journal of the American Medical Association. 299:3.
^ Simonneau, G., Galie, M., Rubin, L.J., Langleben, D., Seeger, W., Domenighetti, G., Gibbs, S., Lebrec, D., Speich, R., Beghetti, M., Rich, S., and Fishman, A. (2004). Clinical Classification of Pulmonary Hypertension. Journal of the American College of Cardiology. 43:5-12.
^ ^a ^b Nagumo, H., Sasaki, Y., Ono, Y., Okamato, H., Seto, M., and Takuwa, Y. (2000). Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells. American Journal of Physiology. 278: C57-C65.
^ Ocaranze M.P., Prvera, P., Novoa, U., Pinto, M., Gonzalez, L., Chiong, M., Lavandero, S., and Jalil, J.E. (2011). Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension. Journal of Hypertension. 29:706-715.
^ Takemoto, M., Sun, J., Hiroko, J., Shimokawa, H., and Liao, J.K. (2002). Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase. Journal of the American Heart Association. 106:57-62.
^ ^a ^b Liu, A., Ling, F., Wang, D., Wang, Q., Lu, X., and Liu, Y. (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. 124:3098-3104.
^ Delmas, C., Manenti, S., Boudjelal, A., Peyssonnaux, C., Eychene, A., and Darbon, J.R. (2001). The p42/p44 Mitoen-activated protein kinase activation triggers p27kip1 degradation independently of CDK2/Cyclin E in NIH 3T3 cells.The Journal of Biological Chemistry. 276:34958-34965.
^ Rodman D.M., and Fouty, B.W. (2003). Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth muscle cells through a p27kip1-independent pathway. Journal of the American Heart Associations. 92:501-509.

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English Journal

Rho-associated kinase inhibitors promote the cardiac differentiation of embryonic and induced pluripotent stem cells.

Cheng YT1, Yeih DF2, Liang SM1, Chien CY1, Yu YL1, Ko BS3, Jan YJ4, Kuo CC1, Sung LY5, Shyue SK6, Chen MF3, Yet SF1, Wu KK7, Liou JY8.
International journal of cardiology.Int J Cardiol.2015 Dec 15;201:441-8. doi: 10.1016/j.ijcard.2015.08.118. Epub 2015 Aug 15.
BACKGROUND: Rho-associated kinase (ROCK) plays an important role in maintaining embryonic stem (ES) cell pluripotency. To determine whether ROCK is involved in ES cell differentiation into cardiac and hematopoietic lineages, we evaluated the effect of ROCK inhibitors, Y-27632 and fasudil on murine E
PMID 26313863

Ontogenetic changes in contribution of calcium sensitization and calcium entry to blood pressure maintenance of Wistar-Kyoto and spontaneously hypertensive rats.

Behuliak M1, Vavřínová A, Bencze M, Polgárová K, Ergang P, Kuneš J, Vaněčková I, Zicha J.
Journal of hypertension.J Hypertens.2015 Dec;33(12):2443-54. doi: 10.1097/HJH.0000000000000746.
BACKGROUND: Altered calcium sensitization (mediated by RhoA/Rho-kinase pathway) and enhanced calcium entry through L-type voltage-dependent calcium channels (L-VDCCs) participate in blood pressure (BP) maintenance of adult spontaneously hypertensive rats (SHRs). This study aimed to evaluate ontogene
PMID 26418671

Inhibition of Rho-kinase by Fasudil protects dopamine neurons and attenuates inflammatory response in intranasal LPS-mediated Parkinson's model.

He Q1,2, Li YH3, Guo SS2, Wang Y2, Lin W2, Zhang Q2, Wang J2, Ma CG3,4, Xiao BG2.
The European journal of neuroscience.Eur J Neurosci.2015 Nov 13. doi: 10.1111/ejn.13132. [Epub ahead of print]
Microglia activation and inflammatory factors in brain microenvironment are associated with degeneration of neurons in the SN of PD patients and various PD models. There is increasing evidence that the Rho/ROCK (Rho kinase) signaling pathway may play a critical role in the inflammatory response and
PMID 26565388

Japanese Journal

Fasudil is a superior vasodilator for the internal thoracic artery in coronary surgery

Watanabe Go,Noda Yukihiro,Takagi Takeshi,Tomita Shigeyuki,Yamaguchi Shojiro,Kiuchi Ryuta
Annals of Thoracic Surgery 96(2), 543-547, 2013-08
… With the purpose to dilate the ITA graft and increase graft free flow (GFF) intraoperatively, we evaluated the usefulness of intraluminal injection of fasudil, a Rho-kinase inhibitor, in comparison to the conventional graft dilating agent, papaverine. … The patients were randomly assigned to 2 groups: the fasudil group (n = 15) in which fasudil solution 0.9 mg/dL was injected into the ITA, and the papaverine group (n = 15) in which papaverine solution (0.4 mg/mL) mixed with heparinized blood was used. …
NAID 120005327253

CASE REPORT : A case report of very late stent thrombosis with peri-stent coronary artery aneurysm and stent-related coronary vasospasm

Takeda Morihiko,Shiba Nobuyuki,Takahashi Jun [他]
Cardiovascular intervention and therapeutics 28(3), 272-278, 2013-07
NAID 40019716799

Fasudil Inhibits Epithelial-Myofibroblast Transdifferentiation of Human Renal Tubular Epithelial HK-2 Cells Induced by High Glucose

Gu Lingjia,Gao Qian,Ni Liansong [他]
Chemical and pharmaceutical bulletin 61(7), 688-694, 2013-07
NAID 40019678428

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★リンクテーブル★

リンク元	「ファスジル」
拡張検索	「fasudil hydrochloride hydrate」「fasudil hydrochloride」

「ファスジル」

Fasudil
Systematic (IUPAC) name
	5-(1,4-diazepane-1-sulfonyl)isoquinoline
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	?
Pharmacokinetic data
Bioavailability	well absorbed
Metabolism	metabolized quickly to hydroxyfasudil
Half-life	0.76 hours. Active metabolite (hydroxyfasudil) 4.66 hours.
Identifiers
CAS number	103745-39-7
ATC code	C04AX32
PubChem	CID 3547
UNII	Q0CH43PGXS
KEGG	D07941
ChEMBL	CHEMBL38380
Chemical data
Formula	C14H17N3O2S
Mol. mass	291.36 g/mol
	SMILES C1CNCCN(C1)S(=O)(=O)C2=CC=CC3=C2C=CN=C3;
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