Antivasospastic Effects of Hydroxyfasudil, a Rho-Kinase Inhibitor, After Subarachnoid Hemorrhage

• Published in: Journal of Pharmacological Sciences Vol. 118; no. 1; pp. 92 - 98
• Main Authors: Satoh, Shin-ichi, Takayasu, Masakazu, Kawasaki, Koh, Ikegaki, Ichiro, Hitomi, Asako, Yano, Kazuo, Shibuya, Masato, Asano, Toshio
• Format: Journal Article
• Language: English; Japanese
• Published: Japan Elsevier B.V 2012; The Japanese Pharmacological Society; Elsevier
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - therapeutic use; Animals; Blood Viscosity - drug effects; Brain Ischemia - drug therapy; Brain Ischemia - enzymology; Brain Ischemia - physiopathology; Disease Models, Animal; Dogs; Female; Hematocrit; hemodynamic dysfunction; hydroxyfasudil; Male; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Rats; Rats, Wistar; rho-Associated Kinases - antagonists & inhibitors; Rho-kinase; subarachnoid hemorrhage; Subarachnoid Hemorrhage - drug therapy; Subarachnoid Hemorrhage - physiopathology; vasospasm; Vasospasm, Intracranial - drug therapy; Vasospasm, Intracranial - physiopathology; Rho-kinase; hemodynamic dysfunction; hydroxyfasudil; vasospasm; subarachnoid hemorrhage
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.11075FP

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.