Inhibition of rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection

Endothelium-derived nitric oxide (NO) plays a pivotal role in vascular protection. The Rho kinase (ROCK) inhibitor, hydroxyfasudil, prevents the downregulation of endothelial NO synthase (eNOS) under hypoxic conditions. However, it is unknown whether inhibition of ROCK can attenuate ischemia-induced...

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Bibliographic Details
Published in:Stroke (1970) 2005-10, Vol.36 (10), p.2251-2257
Main Authors: RIKITAKE, Yoshiyuki, KIM, Hyung-Hwan, ZHIHONG HUANG, SETO, Minoru, YANO, Kazuo, ASANO, Toshio, MOSKOWITZ, Michael A, LIAO, James K
Format: Article
Language:English
Subjects:
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology
Amides - pharmacology
Analysis of Variance
Animals
Antihypertensive Agents - pharmacology
Aorta - cytology
Biological and medical sciences
Blotting, Northern
Blotting, Western
Brain Ischemia - pathology
Cattle
Cell Line
Cells, Cultured
Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges
Cerebrovascular Circulation
Dose-Response Relationship, Drug
Down-Regulation
Endothelium, Vascular - cytology
Endothelium, Vascular - pathology
Enzyme Inhibitors - pharmacology
Fundamental and applied biological sciences. Psychology
Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy
Humans
Hypoxia
Infarction, Middle Cerebral Artery
Intracellular Signaling Peptides and Proteins
Medical sciences
Mice
Mice, Inbred C57BL
Nervous system (semeiology, syndromes)
Neurology
Neuroprotective Agents - pharmacology
Nitric Oxide - metabolism
Nitric Oxide Synthase - metabolism
Nitric Oxide Synthase Type III - biosynthesis
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Pyridines - pharmacology
Regional Blood Flow
rho-Associated Kinases
RNA, Messenger - metabolism
Stroke - prevention & control
Time Factors
Umbilical Veins - cytology
Up-Regulation
Vascular diseases and vascular malformations of the nervous system
Vertebrates: nervous system and sense organs
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Summary:Endothelium-derived nitric oxide (NO) plays a pivotal role in vascular protection. The Rho kinase (ROCK) inhibitor, hydroxyfasudil, prevents the downregulation of endothelial NO synthase (eNOS) under hypoxic conditions. However, it is unknown whether inhibition of ROCK can attenuate ischemia-induced endothelial dysfunction and tissue damage in vivo. Human vascular endothelial cells were treated with increasing concentrations of hydroxyfasudil (0.1 to 100 micromol/L) and eNOS expression and activity were measured. To determine the physiological relevance of eNOS regulation by ROCK, we administered fasudil, which is metabolized to hydroxyfasudil in vivo, to mice for 2 days before subjecting them to middle cerebral artery occlusion. Cerebral blood flow, cerebral infarct size, and neurologic deficit were measured. In a concentration-dependent manner, hydroxyfasudil increased eNOS mRNA and protein expression, resulting in a 1.9- and 1.6-fold increase, respectively, at 10 micromol/L (P
ISSN:0039-2499
1524-4628
DOI:10.1161/01.STR.0000181077.84981.11