title: Antivasospastic effects of hydroxyfasudil, a Rho-kinase inhibitor, after subarachnoid hemorrhage.
abstract: We investigated the anti-vasospastic potential of fasudil's active metabolite, hydroxyfasudil, a Rho-kinase inhibitor, after subarachnoid hemorrhage (SAH) and also its effect on hemorheological abnormalities following cerebral ischemia. Chronic cerebral vasospasm was produced using a two-hemorrhage canine model. On day 7, angiographic vasospasm was observed in all animals, and intravenous administration of hydroxyfasudil (3 mg·kg(-1)·30 min(-1)) significantly reversed the vasospasm (predose diameter of the basilar artery, 57.9% ± 2.0% of the baseline before the injection of blood; postdose diameter, 64.5% ± 1.9%). The viscosity of whole blood was significantly increased 24 h after 1 h middle cerebral artery occlusion in rats. Hydroxyfasudil (3 and 10 mg/kg, i.p.) significantly decreased blood viscosity. The specificity of hydroxyfasudil was examined against a panel of 17 protein kinases using ELISA analysis. Hydroxyfasudil inhibited Rho-kinase α and β at a concentration of 10 µM by 97.6% and 97.7%, respectively. No other protein kinase was inhibited with 10 µM hydroxyfasudil by over 40%. The present results indicate hydroxyfasudil is a selective inhibitor of Rho-kinase. The results also suggest that hydroxyfasudil contributes to the potency of fasudil to prevent cerebral vasospasm and hyperviscosity and suggest the potential utility of hydroxyfasudil as a therapeutic agent for patients with SAH.
authors.affiliation: Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Japan. sato.sn@om.asahi-kasei.co.jp
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Satoh
authors.forename: Masakazu
authors.initials: M
authors.lastname: Takayasu
authors.forename: Koh
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ikegaki
authors.forename: Asako
authors.initials: A
authors.lastname: Hitomi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yano
authors.forename: Masato
authors.initials: M
authors.lastname: Shibuya
authors.forename: Toshio
authors.initials: T
authors.lastname: Asano
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001809:Blood Viscosity / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006400:Hematocrit; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000503:physiopathology; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000503:physiopathology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; C431085:hydroxyfasudil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases