Effect of Endothelin Blockade on Early Cardiovascular Remodeling in the One-Clip-Two-Kidney Hypertension of the Rat

Abstract

Background: In models of hypertension and of renal failure, pharmacological blockade of the ET_A receptor has been shown to cause some inconsistent lowering of blood pressure (BP) and lesser left ventricular hypertrophy (LVH). The effects of ET_A receptor blockade (ET_A-RB) on vascular remodeling and their potential relation to BP lowering, have not been clarified. Design: The experimental study in male Sprague-Dawley rats was designed to compare four experimental groups: (1) sham-operated controls (sham); (2) untreated rats with one-clip-two-kidney (1C-2K) renovascular hypertension; (3) 1C-2K rats treated with the ACE inhibitor (ACE-i) trandolapril (0.3 mg/kg b.w./day), and (4) 1C-2K rats treated with the ET_A-RB LU-135252 (50 mg/kg b.w./day). BP was measured weekly by tail plethysmography. After 3 weeks, animals were sacrificed and cardiac, aortic and mesenteric artery morphology was evaluated using morphometric and stereological techniques. Results: Systolic BP was significantly higher in 1C-2K rats compared to sham. BP was not significantly affected by ET_A-RB, but was significantly lowered by the ACE-i. Despite no significant change in BP, ET_A-RB treatment led to a significantly less volume density of the cardiac interstitium (sham 1.40 ± 0.18, 1C-2K 2.66 ± 0.56, 1C-2K + ACE-i 1.88 ± 0.38, 1C-2K + ET_A-RB 2.15 ± 0.37%). In contrast, ET_A-RB had no significant effect on left ventricular/body weight ratio (sham 2.85 ± 0.26, 1C-2K 2.96 ± 0.33, 1C-2K + ACE-i 2.54 ± 0.22 and 1C-2K + ET_A-RB 3.15 ± 0.44 mg/g) or on wall thickness of intramyocardial arteries. Conclusions: The ET_A-RB LU-135252 ameliorated the development of myocardial fibrosis in a short-term hyperreninemic normal salt model of experimental hypertension nearly as effectively as an ACE-i. This effect of LU-135252 is independent of systemic BP. In contrast to findings in other models, ET_A receptor blockade had no significant effect on LVH or vascular remodeling. Only the ACE-i but not the ET_A-RB prevented structural changes of small intramyocardial arteries and of the aorta.

Journal

Journal ID (publisher-id): KBR

Journal ID (nlm-ta): Kidney Blood Press Res

Journal ID (doi): 10.1159/issn.1420-4096

Title: Kidney and Blood Pressure Research

Publisher: S. Karger AG

ISSN (Print): 1420-4096

ISSN (Electronic): 1423-0143

Publication date Subscription-year: 2003

Publication date (Print): 2003

Publication date (Electronic): 19 November 2003

Volume: 26

Issue: 5-6

Pages: 325-332

Affiliations

^aDepartment of Nephrology, University of Heidelberg, ^bDepartment of Physiology, University of Hamburg, and Departments of ^cInternal Medicine and ^dPathology, University of Erlangen-Nürnberg, Germany

Article

Publisher ID: 73938 Other ID: Kidney Blood Press Res 2003;26:325–332

DOI: 10.1159/000073938

PubMed ID: 14610336

Copyright statement: © 2003 S. Karger AG, Basel

License:

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: 3, Tables: 3, References: 26, Pages: 8

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Categories

Subject: Original Paper