| Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. | |
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MedLine Citation:
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PMID: 12468796 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Endothelial nitric oxide synthase (eNOS) activity is decreased after subarachnoid hemorrhage (SAH). Simvastatin increases eNOS activity. We hypothesized that simvastatin would increase eNOS protein and ameliorate SAH-induced cerebral vasospasm. METHODS: Mice were treated with subcutaneous simvastatin or vehicle for 14 days and then subjected to endovascular perforation of the right anterior cerebral artery or sham surgery. Three days later, neurological deficits were scored (5 to 27; 27=normal), and middle cerebral artery diameter and eNOS protein were measured. The study was repeated, but simvastatin treatment was started after SAH or sham surgery. RESULTS: In SAH mice, simvastatin pretreatment increased middle cerebral artery diameter (SAH-simvastatin=74+/-22 micro m, SAH-vehicle=52+/-18 micro m, P=0.03; sham-simvastatin=102+/-8 micro m, sham-vehicle=105+/-6 micro m). Pretreatment reduced neurological deficits (SAH-simvastatin=25+/-2, SAH-vehicle=20+/-2, P=0.005; sham-simvastatin and sham-vehicle=27+/-0). Simvastatin pretreatment also increased eNOS protein. Simvastatin posttreatment caused a modest increase in middle cerebral artery diameter in SAH mice (SAH-simvastatin=56+/-12 micro m, SAH-vehicle=45+/-4 micro m, P=0.03; sham-simvastatin=92+/-13 micro m, sham-vehicle=99+/-10 micro m) and reduced neurological deficits (SAH-simvastatin=21+/-1, SAH-vehicle=19+/-2, P=0.009). Simvastatin posttreatment did not significantly increase eNOS protein. CONCLUSIONS: Simvastatin treatment before or after SAH attenuated cerebral vasospasm and neurological deficits in mice. The mechanism may be attributable in part to eNOS upregulation. |
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Authors:
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Matthew J McGirt; John R Lynch; Augusto Parra; Huaxin Sheng; Robert D Pearlstein; Daniel T Laskowitz; Dale A Pelligrino; David S Warner |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Stroke; a journal of cerebral circulation Volume: 33 ISSN: 1524-4628 ISO Abbreviation: Stroke Publication Date: 2002 Dec |
Date Detail:
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Created Date: 2002-12-06 Completed Date: 2003-01-09 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0235266 Medline TA: Stroke Country: United States |
Other Details:
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Languages: eng Pagination: 2950-6 Citation Subset: IM |
Affiliation:
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Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Duke University School of Medicine Duke University Medical Center, Durham, NC, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Brain / blood supply, enzymology Disease Models, Animal Endothelium, Vascular / drug effects*, enzymology Enzyme Activation / drug effects Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology, therapeutic use Injections, Subcutaneous Male Mice Mice, Inbred C57BL Middle Cerebral Artery / drug effects, physiopathology Nitric Oxide Synthase / metabolism* Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Simvastatin / pharmacology*, therapeutic use Subarachnoid Hemorrhage / complications, drug therapy*, physiopathology Time Factors Up-Regulation / drug effects Vascular Patency / drug effects Vasospasm, Intracranial / drug therapy*, etiology, physiopathology |
| Grant Support | |
ID/Acronym/Agency:
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5P01 HL4244-12/HL/NHLBI NIH HHS; R01 NS38944-02/NS/NINDS NIH HHS; T35-GM08679/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 79902-63-9/Simvastatin; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, mouse |
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