Vascular Effect of Pravastatin in the Presence of Super Oxide Scavenger

Abstract

Purpose: Previously we have shown that pravastatin increases nitric oxide (NO) bioavailability in microvessels, thereby inhibiting constrictor responses. The objective of this study is to elucidate the mechanism responsible, by investigating the role of oxidative stress. Methods: Rat mesenteric arterial rings (250–50 m diameter, n= 8/treatment) were placed in a Mulvany wire myograph and endothelial integrity assessed with acetylcholine.Concentration–response curves to phenylepherine (PE) were determined before and after 60min preincubation with a therapeutically equivalent pravastatin concentration (112 nM). Constrictor responses were expressed as % of depolarizing potassium responses. These were repeated with endothelium-denuded vessels or in the presence of nitric oxide synthase inhibitor (L-NAME; 300 M). To explore the potential mechanism underlying pravastatin effect, experiments were repeated in the presence of polyethylene glycol superoxide dismutase (PEG-SOD; 150U/ml), super oxide scavenger. Data were expressed as mean ±S.E.M. and analyzed by ANOVA. Results: In endothelium-intact vessels, pre-treatment with pravastatin reduced the maximal constrictor responses to PE by 33± 6%, p< 0.001. The pravastatin effects were abolished by endothelial denudation or L-NAME pretreatment. Interestingly, Super oxide scavenging by PEG-SOD, enhanced an inhibitory effect of pravastatin in PE-induced constricted vessels to 53± 3%, p< 0.001; that is a potentiation in pravastatin response by 19± 4%, p< 0.05. Conclusions: Pravastatin increases NO bioavailability in microvessels, on the contrary, oxidative stress mechanism limits pravastatin effect on NO bioavailability in the absence of super oxide scavenger.