+1 Recommend
1 collections
      • Record: found
      • Abstract: found
      • Article: found

      Aldosterone Antagonism Ameliorates Proteinuria and Nephrosclerosis Independent of Glomerular Dynamics in L-NAME/SHR Model

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Background: The renin-angiotensin-aldosterone system participates importantly in the progression of hypertensive renal disease. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists have been demonstrated to afford renoprotection in L-NAME-exacerbated nephrosclerosis in SHR rats. This study was designed to examine the effects of the aldosterone antagonist eplerenone on systemic and renal hemodynamics, glomerular dynamics, renal function and histopathology in L-NAME/SHR, and determine whether aldosterone antagonism would enhance the effectiveness of ACE inhibition. Methods: Six groups of 20-week-old SHR were studied using renal micropuncture and histopathological techniques after 3 weeks of treatment: SHR control (tapwater, n = 10); SHR + eplerenone (101 ± 8.3 mg/kg/day, n = 10); SHR + L-NAME (5.0 ± 0.12 mg/kg/day, n = 9); SHR + L-NAME + eplerenone (n = 8); SHR + L-NAME + lisinopril (3 mg/kg/day, n = 9), and SHR + L-NAME + eplerenone + lisinopril (n = 9). Results: L-NAME-treated SHR developed massive proteinuria, severe hypertensive nephrosclerosis, and tubulointerstitial damage. Eplerenone significantly reduced proteinuria (127.4 ± 26.5 vs. 51.9 ± 16.7 mg/24 h, p < 0.01), improved glomerular and arteriolar injuries (65 ± 9 vs. 29 ± 9 score/100 glomeruli, p < 0.01; 116 ± 18 vs. 41 ± 13 score/100 arterioles, p < 0.01, respectively), and decreased tubulointerstitial damage index (1.43 ± 0.07 vs. 0.39 ± 0.07, p < 0.01) without altering mean arterial pressure or glomerular dynamics. Combined therapy of eplerenone with lisinopril produced no further benefits than lisinopril alone. Conclusion: The aldosterone antagonist eplerenone significantly ameliorated proteinuria and nephrosclerosis in the L-NAME/SHR model, independent of hemodynamic effects.

          Related collections

          Most cited references 6

          • Record: found
          • Abstract: found
          • Article: not found

          Effects of the selective aldosterone blocker eplerenone versus the calcium antagonist amlodipine in systolic hypertension.

          Eplerenone is a highly selective aldosterone blocker, which is under development for the treatment of hypertension and heart failure. To assess its usefulness in older patients with systolic hypertension and widened pulse pressure, we compared the effects of eplerenone with amlodipine, on clinic blood pressure (BP) and pulse pressure and in a subset of the patients, ambulatory BP, vascular compliance, and urinary albumin excretion. The study involved 269 patients > or =50 years of age who were randomly assigned to either eplerenone (50 to 200 mg daily) or amlodipine (2.5 to 10 mg daily) in a double-blind titration to effect design. After 24 weeks of therapy, reductions in clinic systolic BP were similar for both treatments (eplerenone, -20.5+/-1.1 mm Hg; amlodipine, -20.1+/-1.1 mm Hg). Reductions in clinic diastolic BP were modestly larger on amlodipine (-6.9+/-0.7 mm Hg) compared with eplerenone (-4.5+/-0.7 mm Hg) (P=0.014). Pulse pressure was also reduced similarly from baseline by the 2 treatment groups (eplerenone, -15.9 mm Hg versus amlodipine, -13.4 mm Hg, P=0.07). Changes from baseline in pulse wave velocity after 24 weeks of therapy were statistically similar for eplerenone and amlodipine. In patients with microalbuminuria at baseline (>30 mg albumin/g creatinine), eplerenone reduced the urinary albumin/creatinine ratio by 52% compared with a reduction of 10% by amlodipine (P=0.04). Thus, eplerenone was as effective as amlodipine in lowering systolic BP and pulse pressure as well as pulse wave velocity in older patients with widened pulse pressure hypertension. Furthermore, eplerenone reduced microalbuminuria to a greater extent than amlodipine in this older patient group.
            • Record: found
            • Abstract: not found
            • Article: not found

            Effectiveness of Aldosterone Blockade in Patients With Diabetic Nephropathy

              • Record: found
              • Abstract: found
              • Article: not found

              Regulation of aldosterone secretion.

              Regulation of aldosterone secretion is complex both in terms of the number of secretagogues that can influence its biosynthesis and the number of second messengers utilized by these secretagogues (Table 1, Figure 1). ACTH primarily acts via the adenylate cyclase system through a stimulatory G protein; however, there is evidence that at low concentration it may also activate calcium influx and phospholipase C in some species. The primary effect of AII is activation of phospholipase C, which increases both calcium release from intracellular stores and calcium flux across the cell membrane and activates protein kinase C. Potassium depolarizes the membrane, thereby activating calcium flow through voltage-dependent calcium channels. It also directly or indirectly causes release of calcium from intracellular binding sites. A small change in cAMP levels may also be involved in the sustained secretory response to potassium. Species variation in the regulation of aldosterone secretion probably exists; the control mechanisms in the human appear to be closer to those in the rat than to those in cow and sheep. How changes in dietary sodium and potassium modify aldosterone secretion and the adrenal's responsiveness to secretagogues remains unclear. Yet these effects may be of considerable importance, both in terms of understanding the overall regulation of aldosterone secretion and in resolving the discrepancies in the results obtained under different experimental conditions.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                April 2004
                08 April 2004
                : 24
                : 2
                : 242-249
                Hypertension Research Laboratories, Ochsner Clinic Foundation, New Orleans, La., USA
                77396 Am J Nephrol 2004;24:242–249
                © 2004 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 2, References: 36, Pages: 8
                Self URI (application/pdf):
                Original Report: Laboratory Investigation


                Comment on this article