Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage

Matthew J. McGirt, John R. Lynch, Augusto Parra, Huaxin Sheng, Robert D. Pearlstein, Daniel T. Laskowitz, Dale A. Pelligrino, David S. Warner

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

Abstract

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 μm, SAH-vehicle=52±18 μm, P=0.03; sham-simvastatin= 102±8 μm, sham-vehicle=105±6 μm). Pretreatment reduced neurological deficits (SAH-simvastatin=25±2, SAH-vehicle=20±2, P=0.005; sham-simvastatin and shamvehicle=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 μm, SAH-vehicle=45±4 μm, P=0.03; sham-simvastatin=92±13 μm, sham-vehicle= 99±10 μm) 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.

Original languageEnglish (US)
Pages (from-to)2950-2956
Number of pages7
JournalStroke
Volume33
Issue number12
DOIs
StatePublished - Dec 1 2002

Keywords

  • HMG-CoA reductase inhibitors
  • Mice
  • Simvastatin
  • Subarachnoid hemorrhage
  • Vasospasm

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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