| Abstract | OBJECTIVES: Increased calcium sensitization mediated by Rho/Rho-kinase may be important in the pathogenesis of cerebral vasospasm. The effects of a highly selective Rho-kinase inhibitor, Y-27632, were investigated on spasmogen-induced contractions of canine basilar artery. METHODS: Typical spasmogenic substances present after subarachnoid hemorrhage (SAH), including prostaglandin F2a (PGF2a), 12-deoxyphorbol 13-isobutyrate (DPB), sphingosylpho-sphorylcholine (SPC) and high K+, were used in the study. Isometric tension was recorded in canine basilar artery rings in vitro. Intracellular calcium concentration ([Ca2+]i) and contraction force were measured simultaneously in fura-2-loaded canine basilar artery strips. The myosin light chain (MLC) phosphorylation levels were measured by glycerol gel electrophoresis followed by Western blotting. RESULTS: Isometric tension recording revealed that the Rho-kinase inhibitor, Y-27632, dose-dependently inhibited vasocontraction induced by PGF2a and SPC, but not that induced by DPB. Simultaneous recordings of [Ca2+]i and tension revealed that the vasorelaxing effect of Y-27632 was not associated with changes in [Ca2+]i, suggesting that Y-27632 may inhibit calcium sensitization. Vasocontraction induced by DPB was not inhibited by Y-27632, but was inhibited by staurosporine. Phosphorylation of MLC was increased by PGF2a and SPC, and significantly inhibited by Y-27632, whereas such phosphorylation was increased by DPB, but not significantly inhibited by Y-27632. DISCUSSION: Several spasmogenic mediators released after SAH may cause vasospasm through Rho-kinase-mediated increase in calcium sensitization. Rho-kinase inhibitors, including Y-27632, may be effective for the prevention of cerebral vasospasm after SAH. |
| Authors | Yasuhiro Hashiba, Masahiko Tosaka, Nobuhito Saito, Hideaki Imai, Tatsuya Shimizu, Tomio Sasaki
(Affiliation: Department of Neurosurgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. nshashi at showa.gunma-u.ac.jp)
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| Journal | Neurological research
(Neurol Res)
Vol. 29
Issue 5
Pg. 485-9
(Jul 2007)
ISSN: 0161-6412 England |
| PMID | 17806208
(Publication Type: In Vitro, Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Amides
- Enzyme Inhibitors
- Myosin Light Chains
- Pyridines
- sphingosine phosphorylcholine
- Phosphorylcholine
- Sphingosine
- Y 27632
- Dinoprost
- Calcium
|
| Topics |
- Amides
(pharmacology)
- Animals
- Basilar Artery
(drug effects)
- Calcium
(metabolism)
- Dinoprost
(pharmacology)
- Dogs
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(pharmacology)
- Myosin Light Chains
(metabolism)
- Phosphorylation
(drug effects)
- Phosphorylcholine
(analogs & derivatives, pharmacology)
- Pyridines
(pharmacology)
- Sphingosine
(analogs & derivatives, pharmacology)
- Vasodilation
(drug effects)
|
