(Hypertension. 2001;37:1450.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
HMG-CoA Reductase Inhibitors Improve Endothelial Dysfunction in Normocholesterolemic Hypertension via Reduced Production of Reactive Oxygen Species
From the Medizinische Klinik und Poliklinik, Innere Medizin III, Universitätsklinken des Saarlandes (S.W., K.M., K.A., M.B., G.N.), Hamburg/Saar, Germany; Klinik III für Innere Medizin (A.T.B.) and Institut für Pharmakologie (R.R.), Universität zu Köln, Germany; and Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases (W.L., G.I.), Frankfurt/Main, Germany.
Correspondence to Dr Georg Nickenig, Medizinische Klinik und Poliklinik, Innere Medizin III, Universitätskliniken des Saarlandes, 66421 Homburg/Saar, Germany. E-mail Nickenig{at}med-in.uni-sb.de
Abstract—3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) significantly reduce cardiovascular mortality associated with hypercholesterolemia. There is evidence that statins exert beneficial effects in part through direct effects on vascular cells independent of lowering plasma cholesterol. We characterized the effect of a 30-day treatment with atorvastatin in normocholesterolemic, spontaneously hypertensive rats (SHR). Systolic blood pressure was significantly decreased in atorvastatin-treated rats (184±5 versus 204±6 mm Hg for control). Statin therapy improved endothelial dysfunction, as assessed by carbachol-induced vasorelaxation in aortic segments, and profoundly reduced angiotensin II–induced vasoconstriction. Angiotensin type 1 (AT1) receptor, endothelial cell NO synthase (ecNOS), and p22phox mRNA expression were determined with quantitative reverse transcription–polymerase chain reaction. Atorvastatin treatment downregulated aortic AT1 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 AT1 receptor protein expression was consistently decreased. Vascular production of reactive oxygen species was reduced to 62±12% of control in statin-treated SHR, as measured with lucigenin chemiluminescence assays. Accordingly, treatment of SHR with the AT1 receptor antagonist fonsartan improved endothelial dysfunction and reduced vascular free-radical release. Moreover, atorvastatin caused an upregulation of ecNOS mRNA expression (138±7% of control) and an enhanced ecNOS activity in the vessel wall (209±46% of control). Treatment of SHR with atorvastatin causes a significant reduction of systolic blood pressure and a profound improvement of endothelial dysfunction mediated by a reduction of free radical release in the vasculature. The underlying mechanism could in part be based on the statin-induced downregulation of AT1 receptor expression and decreased expression of the NAD(P)H oxidase subunit p22phox, because AT1 receptor activation plays a pivotal role for the induction of this redox system in the vessel wall.
Key Words: statins • angiotensin • reactive oxygen species • endothelial dysfunction • rats, spontaneously hypertensive
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