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New Orleans, LA, United States

Susic D.,Hypertension Research Laboratory | Frohlich E.D.,Hypertension Research Laboratory | Kobori H.,Tulane University | Shao W.,Tulane University | And 2 more authors.
Journal of Hypertension | Year: 2011

Objective: This study aimed to examine the effects of salt loading, with or without simultaneous angiotensin receptor blocker (ARB) treatment, on the systemic and tissue renin-angiotensin system (RAS) in spontaneously hypertensive rats (SHRs). METHOD: Evaluation was performed early (4 weeks) in the course of salt loading in order to examine initial mediating events of cardiovascular and renal damage produced by salt excess. Four groups of rats were studied. Group 1 received regular rat chow (normal-salt diet); group 2 received normal-salt diet and an ARB (losartan, 30 mg/kg per day); group 3 received high-salt (8%) chow; and group 4 received high-salt diet and losartan. Results: High-salt diet increased systolic pressure to 193 ± 1 mmHg compared to 180 ± 2 in normal-salt diet group. Losartan reduced SBP in SHRs fed normal-salt diet but did not reduce SBP in the SHRs fed high-salt diet (192 ± 2 mmHg). High-salt diet markedly increased urinary protein excretion from 27 ± 4 to 64 ± 13 mg/day and this increase was ameliorated by losartan (40 ± 9 mg/day). In SHRs on high-salt diet, plasma angiotensin II concentration increased three to four-fold, whereas urinary angiotensinogen excretion increased 10-fold; and these changes were significantly reduced by losartan. High-salt diet accelerated glomerular injury and interstitial fibrosis in SHRs which were reduced by losartan. Conclusion: These results demonstrate that the activity of RAS was either not suppressed or, even augmented, after 4 weeks of salt loading despite high salt intake and increased SBP. The data suggest that an augmented intrarenal RAS during high-salt diet may contribute to the development of renal injury in this experimental model. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Susic D.,Hypertension Research Laboratory | Varagic J.,Hypertension Research Laboratory | Frohlich E.D.,Hypertension Research Laboratory
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2010

This study examined the role of the renin-angiotensin-aldosterone system (RAAS) in mediating cardiovascular and renal damage in spontaneously hypertensive rats (SHR) given salt excess. Since the circulating RAAS is inhibited in this model, it permits examination of the role of local tissue RAASs in mediating this injury. To this end, male 8-wk SHR were divided into 7 groups. The control group (C) received normal NaCl (0.6%) diet. All other groups were given 8% NaCl chow. In addition, group 2 was given placebo, group 3 the mineralocorticoid receptor blocker eplerenone (100 mg·kg -1·day-1), group 4 the angiotensin converting enzyme inhibitor quinapril (3 mg·kg-1·day -1), group 5 the angiotensin II type 1 receptor blocker candesartan (10 mg·kg-1·day-1), and groups 6 and 7 eplerenone and either quinapril or candesartan. The treatments lasted 8 wk. Compared with controls, mean arterial pressure (MAP), renal blood flow, coronary flow reserve, minimal coronary vascular resistance, diastolic time constant, and maximal rate of ventricular pressure fall were all adversely affected by salt loading. Left ventricular mass and fibrosis as well as proteinuria were also markedly increased by salt overload. Eplerenone induced only slight changes, whereas quinapril and candesartan normalized all indexes except MAP. Combination therapy also normalized all indexes, including MAP. These data suggest that 1) cardiovascular and renal damage induced by salt excess in the SHR were not pressure dependent; 2) mineralocorticoids were only marginally involved in this model; and 3) local tissue generation of angiotensin II may be, at least in part, responsible for the other adverse effects. Copyright © 2010 the American Physiological Society.

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