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      Vasopeptidase Inhibition Normalizes Blood Pressure and Restores Endothelial Function in Renovascular Hypertension

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          Abstract

          Background/Aims: Vasopeptidase inhibitors by definition inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), therefore they may exceed the effect of ACE inhibitors in the treatment of hypertension. The present study investigated the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on systolic blood pressure (SBP) and endothelial function in renovascular hypertension. Methods: Wistar-Kyoto rats with renovascular hypertension (two-kidney one-clamp-model) were randomized 2 weeks after unilateral clamping of the right renal artery for 3 weeks’ oral treatment with either AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or placebo. SBP was measured by the tail-cuff method and endothelium-dependent and -independent vascular function was assessed in isolated preconstricted (norepinephrine 10<sup>–7</sup> mol/l) aortic rings as relaxation to acetylcholine (10<sup>–10</sup>–10<sup>–4</sup> mol/l) and sodium nitroprusside (10<sup>–10</sup>–10<sup>–4</sup> mol/l), respectively. Results: Two weeks after clamping, SBP was significantly elevated (196 ± 16 vs. 145 ± 8 mm Hg for sham-operated rats; p < 0.01) and further increased in placebo-treated animals to 208 ± 19 mm Hg. Treatment with AVE7688 and ramipril had a similar blood pressure-lowering effect (119 ± 8 and 124 ± 10 mm Hg, respectively; p < 0.01 vs. placebo). Maximum endothelium-dependent relaxation was reduced in hypertensive rats (72 ± 6 vs. 99 ± 7% in control rats; p < 0.05). Endothelium-dependent relaxation was restored by AVE7688 (101 ± 6%) and ramipril (94 ± 8%), respectively, whereas endothelium-independent relaxation was comparable in all groups. Conclusion: In renovascular hypertension the vasopeptidase inhibitor AVE7688 exhibited similar blood pressure-lowering and endothelial protective properties as compared to the ACE inhibitor ramipril. Therefore, in high renin models of hypertension, vasopeptidase inhibition may be considered an alternative treatment option to ACE inhibition.

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          Most cited references 34

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          Some statistical methods useful in circulation research.

          Some statistical techniques for analyzing the kinds of studies typically reported in Circulation Research are described. Particular emphasis is given to the comparison of means from more than two populations, the joint effect of several experimentally controlled variables, and the analysis of studies with repeated measurements on the same experimental units.
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            Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)

            Long-term administration of angiotensin-converting--enzyme (ACE) inhibitors has been shown to improve survival in patients with symptomatic left ventricular failure and to attenuate left ventricular dilatation in patients with myocardial infarction. We studied whether mortality could be reduced during the 6 months after an acute myocardial infarction with use of the ACE inhibitor enalapril. At 103 Scandinavian centers patients with acute myocardial infarctions and blood pressure above 100/60 mm Hg were randomly assigned to treatment with either enalapril or placebo, in addition to conventional therapy. Therapy was initiated with an intravenous infusion of enalapril (enalaprilat) within 24 hours after the onset of chest pain, followed by administration of oral enalapril. Of the 6090 patients enrolled, 3046 were assigned to placebo and 3044 to enalapril. The life-table mortality rates in the two groups at one and six months were not significantly different (6.3 and 10.2 percent in the placebo group vs. 7.2 and 11.0 percent in the enalapril group, P = 0.26). The relative risk of death in the enalapril group was 1.10 (95 percent confidence interval, 0.93 to 1.29). Death due to progressive heart failure occurred in 104 patients (3.4 percent) in the placebo group and 132 (4.3 percent) in the enalapril group (P = 0.06). Therapy had to be changed because of worsening heart failure in 30 percent of the placebo group and 27 percent of the enalapril group (P less than 0.006). Early hypotension (systolic pressure less than 90 mm Hg or diastolic pressure less than 50 mm Hg) occurred in 12 percent of the enalapril group and 3 percent of the placebo group (P less than 0.001). Enalapril therapy started within 24 hours of the onset of acute myocardial infarction does not improve survival during the 180 days after infarction.
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              Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure

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                Author and article information

                Journal
                KBR
                Kidney Blood Press Res
                10.1159/issn.1420-4096
                Kidney and Blood Pressure Research
                S. Karger AG
                1420-4096
                1423-0143
                2006
                January 2007
                16 January 2007
                : 29
                : 6
                : 351-359
                Affiliations
                aDepartment of Nephrology, University Hospital of Freiburg, Freiburg, bCenterfor Cardiovascular Research, Institute of Pharmacology, Berlin, cDepartment of Nephrology, University Hospital of Würzburg, Würzburg, and dUniversity Hospital of Heidelberg, Heidelberg, Germany
                Article
                97625 Kidney Blood Press Res 2006;29:351–359
                10.1159/000097625
                17139187
                © 2006 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: 8, References: 60, Pages: 9
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/97625
                Categories
                Original Paper

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