Additive effects of statin and dipyridamole on cerebral blood flow and stroke protection - PubMed (original) (raw)

Additive effects of statin and dipyridamole on cerebral blood flow and stroke protection

Hyung-Hwan Kim et al. J Cereb Blood Flow Metab. 2008 Jul.

Abstract

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.

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Figures

Figure 1

Figure 1

Concentration-dependent effects of (A) dipyridamole (DP; 10 to 60 mg/kg, q12 h, 3 days, gavage) or (B) simvastatin (S; 0.1 to 20 mg/kg per day, 14 days, intraperitoneally) on cerebral infarct size (stroke volume). *P<0.05 versus vehicle.

Figure 2

Figure 2

Effects of subtherapeutic doses of simvastatin (statin, 1 mg/kg per day, 14 days) and dipyridamole (DP; 30 mg/kg, q12 h, 3 days), alone or in combination, on (A) absolute cerebral blood flow (percentage of baseline) in ischemic territory, (B) cerebral infarct size (stroke volume, mm3), and (C) frequency of NDS in WT mice. Mann–Whitney analysis and χ2 test were used to determine statistical differences in NDS. *P<0.05 versus vehicle.

Figure 3

Figure 3

Effects of simvastatin (statin, 1 mg/kg per day, 14 days), dipyridamole (DP, 60 mg/kg, q12 h, 3 days), alone or in combination, on (A) tension of phenylephrine (PE) preconstricted aortic strips in response to acetylcholine (ACh)-induced vasodilation, (B) aortic eNOS activity, and (C) aortic cGMP levels in WT mice. *significant difference versus control; **significant difference versus statin treatment.

Figure 4

Figure 4

Effects of simvastatin (statin, 1 mg/kg per day, 14 days), dipyridamole (DP, 30 mg/kg, q12 h, 3 days), alone or in combination, on (A) absolute cerebral blood flow (percentage of baseline) in ischemic territory, (B) cerebral infarct size (stroke volume, mm3), and (C) frequency of NDS in eNOS−/− mice. Mann–Whitney analysis and χ2 test were used to determine statistical differences in NDS.

Figure 5

Figure 5

Effects of simvastatin (statin, 1 mg/kg per day, 14 days), dipyridamole (DP, 30 mg/kg, q12 h, 3 days), alone or in combination, on aortic (A) eNOS activity and (B) cGMP levels in eNOS−/− mice. *P<0.01 versus vehicle-WT.

Figure 6

Figure 6

Effects of aspirin (ASA, 10 mg/kg per day, 3 days), dipyridamole (DP, 30 and 60 mg/kg, q12 h, 3 days), statin (simvastatin, 1 mg/kg per day, 14 days), alone or in combination, on (A) cerebral infarct size (stroke volume, mm3) and (B) frequency of NDS in WT mice. Mann–Whitney analysis and χ2 test were used to determine statistical differences in NDS. *significant difference versus vehicle; **significant difference versus ASA/DP60 treatment.

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