title: Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production.
abstract: Insulin-resistance induces cerebrovascular dysfunction and increases the risk for stroke. We investigated whether rosuvastatin (RSV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, can reverse reduced cerebrovascular responsiveness in insulin-resistant rats. Dilator responses of the basilar artery (BA) were examined after 1-day or 4-wk RSV (2 mg.kg(-1).day(-1)) treatment in anesthetized 12-wk-old insulin-resistant Zucker obese (ZO) and lean (ZL) rats by using a cranial window preparation. Vehicle-treated ZO rats had significantly higher fasting insulin, total cholesterol (TC), and triglyceride (TG) levels compared with ZL rats. In addition, in the ZO rats, dilator responses of the BA to acetylcholine, iloprost, cromakalim, and potassium chloride were significantly reduced when compared with ZL rats. One-day RSV treatment improved dilator responses of the ZO BAs without altering lipid levels. Four-week RSV treatment lowered both TC and TG by 30% and also improved dilator responses of the ZO BAs, although without additional effects compared with the 1-day RSV treatment. NAD(P)H oxidase-dependent superoxide production was significantly higher in the cerebral arteries of vehicle-treated ZO rats compared with ZL rats, but both 1-day and 4-wk RSV treatments normalized elevated superoxide levels in the ZO arteries. These findings demonstrate that RSV improves cerebrovascular function in insulin-resistance independently from its lipid-lowering effect by the inhibition of NAD(P)H oxidase.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Blvd., Winston-Salem, North Carolina 27157-1083, USA.
authors.forename: Benedek
authors.initials: B
authors.lastname: Erdös
authors.forename: James A
authors.initials: JA
authors.lastname: Snipes
authors.forename: Christina D
authors.initials: CD
authors.lastname: Tulbert
authors.forename: Prasad
authors.initials: P
authors.lastname: Katakam
authors.forename: Allison W
authors.initials: AW
authors.lastname: Miller
authors.forename: David W
authors.initials: DW
authors.lastname: Busija
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects* / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D005464:Fluorobenzenes / Q000008:administration & dosage; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D007333:Insulin Resistance; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage; D051381:Rats; D011924:Rats, Zucker; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage; D013481:Superoxides / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013481:Superoxides; D000068718:Rosuvastatin Calcium; D019255:NADPH Oxidases