HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (stati ns) significantly reduce cardiovascular mortality associated with hyperchol esterolemia. There is evidence that statins exert beneficial effects in par t through direct effects on vascular cells independent of lowering plasma c holesterol. We characterized the effect of a 30-day treatment with atorvast atin in normocholesterolemic, spontaneously hypertensive rats (SI-IR). Syst olic blood pressure was significantly decreased in atorvastatin-treated rat s (184 +/-5 versus 204 +/-6 mm Hg for control). Statin therapy improved end othelial dysfunction, as assessed by carbachol-induced vasorelaxation in ao rtic segments, and profoundly reduced angiotensin II-induced vasoconstricti on. Angiotensin type I (ATI) receptor, endothelial cell NO synthase (ecNOS) , and p22phox mRNA expression were determined with quantitative reverse tra nscription-polymerase chain reaction. Atorvastatin treatment downregulated aortic AT(1) receptor mRNA. expression to 44 +/- 12% of control and reduced mRNA expression of the essential NAD(P)H oxidase subunit p22phox to 63 +/- 7% of control. Aortic AT(1) receptor protein expression was consistently de creased. Vascular production of reactive oxygen species was reduced to 62 /- 12% of control in statin-treated SHR, as measured with lucigenin chemilu minescence assays. Accordingly, treatment of SHR with the AT(1) receptor an tagonist fonsartan improved endothelial dysfunction and reduced vascular fr ee-radical release. Moreover, atorvastatin caused an upregulation of ecNOS mRNA expression (138 +/-7% of control) and an enhanced ecNOS activity in th e vessel wall (209 +/- 46% of control). Treatment of SHR with atorvastatin causes a significant reduction of systolic blood pressure and a profound im provement of endothelial dysfunction mediated by a reduction of free radica l release in the vasculature. The underlying mechanism could in part be bas ed on the statin-induced downregulation of AT(1) receptor expression and de creased expression of the NAD(P)H oxidase subunit p22phox, because AT(1) re ceptor activation plays a pivotal role for the induction of this redox syst em in the vessel wall.