Document Detail


Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage.
MedLine Citation:
PMID:  12468796     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Stroke; a journal of cerebral circulation     Volume:  33     ISSN:  1524-4628     ISO Abbreviation:  Stroke     Publication Date:  2002 Dec 
Date Detail:
Created Date:  2002-12-06     Completed Date:  2003-01-09     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0235266     Medline TA:  Stroke     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2950-6     Citation Subset:  IM    
Affiliation:
Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Duke University School of Medicine Duke University Medical Center, Durham, NC, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
5P01 HL4244-12/HL/NHLBI NIH HHS; R01 NS38944-02/NS/NINDS NIH HHS; T35-GM08679/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
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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