title: Rosuvastatin treatment protects against nitrate-induced oxidative stress.
abstract: Nitrate tolerance is associated with an enhanced superoxide anion production and can be attenuated by statins, which interact with the 2 main [eNOS and NAD(P)H oxidase] pathways involved in producing this oxidative stress. Three groups of normocholesterolemic rats were treated: group 1 received rosuvastatin (10 mg/kg/d PO) for 5 weeks and in the last 3 days cotreatment with nitroglycerin (NTG 50 mg/kg/d, subcutaneous injections BID); group 2 received only NTG (50 mg/kg/d BID for the last 3 days); and group 3 served as control. Rings of thoracic aortas from these groups were studied in organ baths. Relaxations to NTG (0.1 nM to 0.1 mM) were determined on phenylephrine-preconstricted rings and O2 production (RLU/10 s/mg dry weight) was assessed by lucigenin and the luminol analogue (L-012) chemiluminescence technique. In group 2 (NTG), the concentration-response curves to NTG were significantly shifted to the right: the pD2 (-log NTG concentration evoking a half-maximal relaxation) was 6.75+/-0.06 (n=7) versus 7.75+/-0.07 (n=7) in group 3 (not exposed to NTG, P<0.05); O2 production was enhanced (10,060+/-1,205, n=7 versus 5,235+/-1,052, n=7; P<0.05). In contrast, in group 1, the rightward shift was attenuated: pD2 value was 7.20+/-0.10 (n=8), P<0.05 versus group 2; O2 production was decreased (5911+/-663; n=9, P<0.05 versus group 2). In addition, before NTG exposure, rosuvastatin treatment decreased p22phox [the essential NAD(P)H oxidase subunit] abundance in the aortic wall and decreased NAD(P)H oxidase activity. In contrast, this treatment did not alter either eNOS abundance or the basal release of endothelium-derived NO. Interestingly, in vivo treatment with apocynin, an NAD(P)H oxidase inhibitor, produced a protection similar to that with rosuvastatin. Long-term rosuvastatin treatment protects against nitrate tolerance in the rat aorta by counteracting NTG-induced increase in O2 production. This protection seems to involve a direct interaction with the NAD(P)H oxidase pathway rather than an up-regulation of the eNOS pathway.
authors.affiliation: Fundamental Physiology and Pharmacology Department, Université Libre de Bruxelles, Brussels, Belgium. anne.otto@ulb.ac.be
authors.forename: Anne
authors.initials: A
authors.lastname: Otto
authors.forename: David
authors.initials: D
authors.lastname: Fontaine
authors.forename: Jeanine
authors.initials: J
authors.lastname: Fontaine
authors.forename: Guy
authors.initials: G
authors.lastname: Berkenboom
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010656:Phenylephrine / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D010656:Phenylephrine; D000068718:Rosuvastatin Calcium; D005996:Nitroglycerin; D006152:Cyclic GMP; D000109:Acetylcholine