Recent studies suggest that
dipyridamole (DP) may exert
stroke protective effects beyond platelet inhibition. The purpose of this study is to determine whether
statin and DP could enhance
stroke protection through
nitric oxide (NO)-dependent vascular effects. Mice were pretreated with DP (10 to 60 mg/kg, q 12 h, 3 days) alone or in combination with a
statin (
simvastatin; 0.1 to 20 mg/kg per day, 14 days) before transient intraluminal
middle cerebral artery occlusion. Although
simvastatin (1 mg/kg per day, 14 days) increased endothelial
NO synthase (eNOS) activity by 25% and DP (30 mg/kg, q12 h, 3 days) increased aortic cGMP levels by 55%, neither
statin nor DP alone, at these subtherapeutic doses, increased absolute cerebral blood flow (CBF) or conferred
stroke protection. However, the combination of subtherapeutic doses of
simvastatin and DP increased CBF by 50%, decreased stroke volume by 54%, and improved neurologic motor deficits, all of which were absent in eNOS-deficient mice. In contrast, treatment with
aspirin (10 mg/kg per day, 3 days) did not augment the
neuroprotective effects of DP and/or
simvastatin. These findings indicate that
statin and DP exert additive NO-dependent vascular effects and suggest that the combination of
statin and DP has greater benefits in
stroke protection than
statin alone through vascular protection.