Published Online
on October 24, 2002

A more recent version of this article appeared on December 1, 2002

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Submitted on July 10, 2002
Accepted on July 11, 2002

Simvastatin Increases Endothelial Nitric Oxide Synthase and Ameliorates Cerebral Vasospasm Resulting From Subarachnoid Hemorrhage

Matthew J. McGirt BS; John R. Lynch MD; Augusto Parra MD, MPH; Huaxin Sheng MD; Robert D. Pearlstein PhD; Daniel T. Laskowitz MD; Dale A. Pelligrino PhD; and David S. Warner MD^*

From the Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center (M.J.M., J.R.L., A.P., H.S., R.D.P., D.T.L., D.A.P., D.S.W.), Duke University School of Medicine (M.J.M.), and Departments of Medicine (J.R.L., A.P., D.T.L.), Anesthesiology (H.S., D.S.W.), and Surgery (R.D.P., D.S.W.), Duke University Medical Center, Durham, NC; and Department of Anesthesiology, University of Illinois at Chicago (D.A.P.).

^* To whom correspondence should be addressed. E-mail: warne002{at}mc.duke.edu.

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 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 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.

Key words: HMG-CoA reductase inhibitors • simvastatin • subarachnoid hemorrhage • vasospasm • mice

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