Abstract-The role of oxidative stress in the long-term regulation of arterial pressure, renal hemodynamics, and renal damage was studied in Dahl salt-sensitive rats. Twenty-eight Dahl S/Rapp strain rats, equipped with indwelling arterial and venous catheters, were subjected to a 3-week intravenous infusion of either low Na (0.9 mmol/d) or high Na (20.6 mmol/d) or the superoxide dismutase mimetic, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), at 125 mol · kg Ϫ1 · h Ϫ1 plus low Na or high Na. After 21 days, mean arterial pressure was 140Ϯ3 mm Hg in the high-Na group, 118Ϯ1 mm Hg (PϽ0.05) in the high-Na/Tempol group, and unchanged in the low-Na/Tempol and low-Na groups. Tempol did not change renal blood flow, glomerular filtration rate, or glomerular cross-sectional area in rats subjected to the high-Na intake but did decrease urinary protein excretion, the percentage of sclerotic glomeruli, and the kidney weight to body weight ratio. In 15 additional Dahl S rats subjected to high or low Na intake for 3 weeks, renal cortical and medullary O 2 · Ϫ release increased significantly in the high-Na group when compared with the low-Na group. Tempol decreased both renal cortical and medullary O 2 · Ϫ release in the high-and low-Na rats, but the decrease in O 2 · Ϫ release was greater in high-Na rats. The data suggest that oxidative stress contributes to Dahl salt-sensitive hypertension and the accompanying renal damage. Key Words: arterial pressure Ⅲ renal disease Ⅲ urine Ⅲ glomerulosclerosis Ⅲ oxidative stress R eactive oxygen species, including superoxide anions (O 2 ·Ϫ ), hydroxyl radicals, and hydrogen peroxide (H 2 O 2 ), have been found in pathological conditions such as atherosclerosis, diabetes, renal disease, and hypertension. O 2 ·Ϫ and H 2 O 2 production by polymorphonuclear leukocytes and the plasma level of lipid peroxides were higher in uncontrolled hypertensive patients than in controls. 1 After blood pressure was reduced in these patients, free-radical generation and lipid peroxide levels returned to normal values. 1 Hypertensive subjects have been shown to have lower levels of the endogenous antioxidants serum ascorbic acid and serum thiols, which might reflect greater consumption of antioxidants. 2 Oxidative stress has also been shown to be involved in hypertensive animal models. The spontaneous hypertensive rat (SHR) is characterized by increased oxidative stress, as demonstrated by the increased O 2 ·Ϫ production in mesenteric arterioles of the SHR. 3,4 In the stroke-prone SHR, O 2 ·Ϫ generation in abdominal aortic tissue was increased compared with their Wistar-Kyoto counterparts. 5 Swei et al 6,7 found enhanced production of superoxide radicals in the microvessels of the mesentery, and plasma H 2 O 2 concentration was increased in hypertensive Dahl salt-sensitive (S) rats compared with Dahl salt-resistant (R) rats. Yet whether increased O 2 ·Ϫ generation contributes to the salt-induced hypertension in the Dahl S rat is not known.Hypertension induces important functional and structural alte...

• The use of systems analysis as an experimental tool for solving complex physiological problems is not new. Actually, systems analysis is merely the logical analysis of how systems perform. However, modern usage of the term implies a more formalized type of logic, especially a type of logic that includes quantification at each step in the analysis. Several of the figures in this paper illustrate systems analysis flow diagrams that show interrelationships between the different parts of simple or complex mechanisms for the control of arterial blood pressure. One can readily see that each part of each systems analysis diagram is only a symbolic way in which a composite of individual physiological phenomena fit together in a complete system.The principal advantage of the formalized systems analysis approach to understanding any physiological mechanism is that it often allows greater depth of thought than our minds can perform using simple logical procedures. The mind has the capability of holding and analyzing perhaps five to ten different sequential phenomena, each occurring at different rates and each interrelated with the other phenomena by various cross-linkages. However, beyond this size of system it is almost impossible to think through all the complex relationships simultaneously. On the other hand, the modern computer can handle literally thousands of such crosslinking interrelationships at the same time and can develop answers that the mind alone cannot achieve. Now setting aside this philosophizing about systems analysis per se, we will attempt to show how the systems analysis approach has been useful in the study of long-range arterial blood pressure control and the understanding of hypertensive

The roles of oxidative stress and renal superoxide dismutase (SOD) levels and their association with renal damage were studied in Dahl salt-sensitive (S) and salt-resistant (R)/Rapp strain rats during changes in Na intake. After 3 wk of a high (8%)-Na diet in S rats, renal medullary Cu/Zn SOD was 56% lower and Mn SOD was 81% lower than in R high Na-fed rats. After 1, 2, and 3 wk of high Na, urinary excretion of F(2)-isoprostanes, an index of oxidative stress, was significantly greater in S rats compared with R rats. Plasma F(2)-isoprostane concentration increased in the 2-wk S high Na-fed group. After 3 wk, renal cortical and medullary superoxide production was significantly increased in Dahl S rats on high Na intake, and urinary protein excretion, an index of renal damage, was 273 +/- 32 mg/d in S high Na-fed rats and 35 +/- 4 mg/d in R high Na-fed rats (P < 0.05). In conclusion, salt-sensitive hypertension in the S rat is accompanied by marked decreases in renal medullary SOD and greater renal oxidative stress and renal damage than in R rats.

Abstract-The goal of this study was to test the hypothesis that oxidative stress in Dahl salt-sensitive (SS) rats on a high-sodium intake contributes to the progression of renal damage, the decreases in renal hemodynamics, and the development of hypertension. We specifically studied whether antioxidant therapy, using vitamins C and E, could help prevent renal damage and glomerular filtration rate (GFR) and renal plasma flow reductions and attenuate the increases in arterial pressure. Thirty-three 7-to 8-week old Dahl SS/Rapp strain rats were placed on either a high-sodium (8%) or a low-sodium (0.3%) diet with or without vitamin E (111 IU/d) in the food and 98 mg/d vitamin C in the drinking water for 5 weeks. Rats were equipped with indwelling arterial and venous catheters at day 21. By day 35 in the rats with high-sodium diet, vitamin C and E treatment significantly decreased renal cortical and medullary O 2 ⅐Ϫ release, mean arterial pressure, urinary protein excretion, glomerular necrosis, and renal tubulointerstitial damage. At this time, GFR significantly decreased in the high-sodium diet group (1.6Ϯ0.2 mL/min) when compared with either the high-sodium plus vitamins C and E (2.9Ϯ0.2 mL/min) or the low-sodium diet group (2.9Ϯ0.3 mL/min). In SS rats on high-sodium diet, renal plasma flow decreased 40%, and this reduced flow was restored by vitamin treatment. In Dahl salt-sensitive hypertension, increased oxidative stress plays an important role in the renal damage, decreases in renal hemodynamics, and increases in arterial pressure that occur. Antioxidant treatment with vitamins C and E improves renal dysfunction, lessens renal injury, and decreases arterial pressure in Dahl salt-sensitive hypertension. Key Words: antioxidants Ⅲ hemodynamics Ⅲ hypertension Ⅲ renal disease H ypertension continues to be a major cardiovascular risk factor and a major contributor to end-stage renal disease (ESRD). In particular, patients with salt-sensitive hypertension are much more likely to experience ESRD compared with salt-insensitive hypertensive patients. 1 Recent studies in humans and in animal models of salt-sensitive hypertension indicate that an increase in oxidative stress is associated with a progressive elevation in arterial pressure and a reduction in renal function. However, the mechanisms underlying the progression of hypertension and ESRD in salt-sensitive hypertension are not clear.A model that closely mimics human salt-sensitive essential hypertension is the Dahl S rat. Common traits shared by salt-sensitive humans and the S rat include progressive increases in arterial pressure and renal damage, 2,3 increased O 2 ⅐Ϫ release, 4 and endothelial dysfunction. 5 Recently, we have shown that the oxidative stress that occurs in Dahl S rats on high-sodium intake for 3 weeks contributes to the increase in arterial pressure, but renal hemodynamics were unchanged in high-sodium diet rats and renal damage was minor. 6 In contrast, renal damage is much more severe in S rats on high-sodium diet for 5 weeks, with progressive ...