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

Area of Science:

• Pharmacology
• Neuroscience
• Cardiovascular Research

Background:

• Subarachnoid hemorrhage (SAH) can lead to cerebral vasospasm and hemorheological abnormalities.
• Fasudil's active metabolite, hydroxyfasudil, is a known Rho-kinase inhibitor.
• The therapeutic potential of hydroxyfasudil in SAH and cerebral ischemia requires further investigation.

Purpose of the Study:

• To investigate the anti-vasospastic effects of hydroxyfasudil after subarachnoid hemorrhage.
• To evaluate hydroxyfasudil's impact on hemorheological abnormalities following cerebral ischemia.
• To determine the selectivity of hydroxyfasudil as a Rho-kinase inhibitor.

Main Methods:

• A two-hemorrhage canine model was used to induce chronic cerebral vasospasm.
• Hydroxyfasudil was administered intravenously to canines, and basilar artery diameter was measured.
• Middle cerebral artery occlusion in rats was used to induce cerebral ischemia, followed by hydroxyfasudil administration and blood viscosity measurement.
• Enzyme-linked immunosorbent assay (ELISA) was employed to assess hydroxyfasudil's inhibitory activity against a panel of protein kinases.

Main Results:

• Intravenous hydroxyfasudil significantly reversed angiographic vasospasm in canines.
• Hydroxyfasudil administration significantly decreased blood viscosity in rats with cerebral ischemia.
• Hydroxyfasudil demonstrated high selectivity, potently inhibiting Rho-kinase α and β (97.6% and 97.7% inhibition at 10 μM) with minimal effect on other kinases.

Conclusions:

• Hydroxyfasudil is a selective inhibitor of Rho-kinase.
• Hydroxyfasudil effectively mitigates cerebral vasospasm and hemorheological abnormalities.
• Hydroxyfasudil shows potential as a therapeutic agent for patients suffering from subarachnoid hemorrhage.