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Rosuvastatin reduces superoxide anion production and improves cerebrovascular function in Zucker obese rats Insulin-resistance (IR) induces cerebrovascular dysfunction (Erdös et al., 2004a/b) and increases the risk for stroke. In the present study we investigated the effect of rosuvastatin (RSV; Crestor®, a gift from AstraZeneca Ltd.), an HMG-CoA reductase inhibitor, on the cerebrovascular function of IR Zucker obese (ZO) and lean (ZL) rats. In addition, we examined the role of NAD(P)H oxidase-dependent production of superoxide anion in dysfunction of cerebral arteries. Dilator responses of the basilar artery (BA) were examined after acute (1-day) or chronic (4-week) RSV (2 mg/kg/day) treatments in anesthetized 12-wk-old ZL and ZO rats using a cranial window preparation. ZO rats were heavier than ZL rats (510±5 g versus 328±9 g) (mean±sem) and had significantly higher fasting insulin levels (16±1 versus 1±0.1 ng/dL). Additionally, total cholesterol (TC) and triglyceride (TG) levels were higher in ZO compared to ZL rats. Resting diameter of the BA was similar in all experimental groups: saline-treated ZL and ZO rats [267±4 µm (n=9) and 264±5 µm (n=9), respectively], 1-day RSV treated ZL and ZO rats [257±5 µm (n=6) and 256±2 µm (n=7), respectively], and 4-week RSV treated ZL and ZO rats [260±6 µm (n=8) and 258±5 µm (n=8), respectively]. Dilator responses of the ZO BAs elicited by acetylcholine, iloprost, cromakalim, and potassium chloride were significantly reduced compared to ZLs. 1-day RSV had no effect on TC and TG levels, but improved dilator responses of the ZO BAs, such that differences diminished between the ZL and ZO groups. 4-wk RSV lowered both TC and TG by 30%, and also improved dilator responses of the ZO BAs, although without additional effects compared to 1-day RSV. Baseline and NAD(P)H-induced superoxide anion production measured in isolated cerebral arteries using the lucigenin-enhanced chemiluminescence assay was 2.6x and 1.9x higher in the vehicle treated ZO group compared to ZL, respectively. However, both 1-day and 4-wk RSV normalized elevated superoxide levels in the ZO arteries. Also, acute addition of the NAD(P)H oxidase inhibitor apocynin (3 X 10-4 mol/L) in the absence of RSV restored superoxide anion production to normal levels in ZO arteries. Experiments utilizing RT-PCR showed that the RSV effect was not mediated by down regulation of NAD(P)H-oxidase subunits. These findings demonstrate that RSV improves cerebrovascular function independently from its lipid lowering effect likely by the inhibition of NAD(P)H-oxidase-dependent superoxide anion production. In addition, beneficial effects take place both at the endothelial and vascular smooth muscle levels. Furthermore, we suggest that acute treatment of patients with statins may have rapid beneficial influences on resistance arteries which are independent of lipid lowering effects. Erdös et al. (2004a) Stroke 35 , 964-9. This work was supported by grants from NIH and AstraZeneca Ltd. |
