Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment

Nitric oxide, a product of nitric oxide synthase activity, relaxes vascular smooth muscle and elevates brain blood flow. We evaluated the importance o f eNOS to cerebral blood flow augmentation after L-arginine infusion and in creases in flow after eNOS upregulation in SV-129 mice. Blood flow was meas ured by laser-Doppler flowmetry before and after L-arginine infusion (450 m g/kg during a 15-minute period) or measured by C-14-iodoamphetamine indicat or fractionation or C-14-iodoantipyrine tissue equilibration techniques. rC BF increased by 26% (laser Doppler flowmetry) after L-arginine infusion but did not change in mutant mice deficient in eNOS expression. After eNOS upr egulation by chronic simvastatin treatment (2 mg/kg subcutaneously, daily f or 14 days), L-arginine amplified and sustained the hyperemia (38%) and inc reased absolute brain blood flow from 86 +/- 7 to 119 +/- 10 mL/100 g per m inute. Furthermore, pretreatment with simvastatin enhanced blood flow withi n ischemic brain tissue after middle cerebral artery occlusion. Together, t hese findings suggest that eNOS activity is critical for blood flow augment ation during acute L-arginine infusion, and chronic eNOS upregulation combi ned with L-arginine administration provides a novel strategy to elevate cer ebral blood flow in the normal and ischemic brain.