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

Abstract

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) 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.

Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs

“…The intravenous dose of fasudil used in the in vivo studies (2.5 mg/kg) was based on studies in rats (2), pigs (60), dogs (58), and humans (28,59). Given the nearly 20-h combined elimination half-life of fasudil and its active metabolite hydroxyfasudil, and its volume of distribution, we estimate the plasma concentration was greater than 10 M throughout the experiment.…”

The effects of Y-27632 on pial microvessels during global brain ischemia and reperfusion in rabbits

“…In contrast, continuous application of Y-27632 before and during ischemia-reperfusion produced pial arteriolar dilation before and after ischemia-reperfusion. Consistent with this observation, Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia [20] and fasudil is antivasospastic in the context of subarachnoid hemorrhage [10]. …”

“…Rho-kinase is activated in endothelial cells during cerebral ischemia and apparently contributes to consequent microcirculatory disturbances [9]. Fasudil, a Rho-kinase inhibiter, prevents cerebral vasospasm and reduces blood viscosity, and has been used therapeutically in patients with subarachnoid hemorrhage [10]. In addition, vasodilation after brain ischemia may provide sufficient oxygen and glucose and may remove acidic metabolites from the ischemic brain tissue for preservation of normal neuronal function [11].…”

Drug treatment of cerebral vasospasm after subarachnoid hemorrhage following aneurysms

“…Shin-ichi Satoh et al [27] used canine and rat model to verify validation effect of fasudil in the treatment of vasospasm and proved the effectiveness. It was suggested that hydroxyfasudil was contributed to the potency of fasudil to prevent CVS and hyperviscosity, and the potential utility of hydroxyfasudil as a therapeutic agent for patients with SAH was also suggested.…”