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(Hypertension. 2004;44:186.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Atorvastatin Prevents End-Organ Injury in Salt-Sensitive Hypertension

Role of eNOS and Oxidant Stress

Ming-Sheng Zhou; Edgar A. Jaimes; Leopoldo Raij

From the Nephrology and Hypertension Section, Veterans Affairs Medical Center, Renal Division and Vascular Biology Institute, University of Miami School of Medicine, Fla.

Correspondence to Leopoldo Raij, MD, Chief, Nephrology-Hypertension Section, Veterans Affairs Medical Center, 1201 NW 16 St (Room A-1009), Miami, FL 33125. E-mail LRaij{at}med.miami.edu

Statins, inhibitors of cholesterol biosynthesis, are endowed with pleiotropic effects that may contribute to their favorable clinical results. Hypertensive Dahl salt-sensitive (DS) rats have endothelial dysfunction and cardiorenal injury associated with decreased NO bioavailability and increased superoxide (O₂^–) production linked to a functional upregulation of angiotensin II. We investigated whether atorvastatin (30 mg/kg per day; by gavage) would prevent endothelial nitric oxide (eNOS) downregulation and the increase in O₂^– in DS rats, thereby reducing end-organ injury. DS rats given a high-salt diet (4% NaCl) for 10 weeks developed hypertension (systolic blood pressure [SBP] 200±8 versus 150±2 mm Hg in DS rats fed 0.5% NaCl diet [NS]; P<0.05), impaired endothelium-dependent relaxation, functional upregulation of endothelin-1, left ventricular hypertrophy (LVH; 30%), and proteinuria (167%), accompanied by downregulation of aortic eNOS activity (0.7±0.2 versus 1.8±0.3 nmol/min per gram protein in NS; P<0.05) and increased aortic O₂^–(2632±316 versus 1176±112 counts/min per milligram in NS; P<0.05) and plasma 8-F₂ isoprostanes. Atorvastatin prevented the decrease in eNOS activity (1.5±0.3 nmol/min per gram protein) as well as the increase in O₂^–(1192±243 counts/min per milligram) and plasma 8-F₂ isoprostanes, reduced LVH and proteinuria, and normalized endothelial function and vascular response to endothelin-1, although reduction in SBP was modest (174±8 mm Hg). Atorvastatin combined with removal of high salt normalized aortic eNOS activity, SBP, LVH, and proteinuria. These findings strongly suggest that concomitant prevention of vascular eNOS downregulation and inhibition of oxidative stress may contribute to the protection against end-organ injury afforded by this statin in salt-sensitive hypertension.

Key Words: nitric oxide synthase • oxidative stress • hypertension, sodium dependent • statins

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