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Regression of ventricular and vascular hypertrophy: are there differences between structurally different angiotensin-converting enzyme inhibitors?

Raasch, Waltera; Bartels, Torstena; Schwartz, Christophera; Häuser, Waltera; Rütten, Hartmutb; Dominiak, Petera

Original papers: Heart

Objectives  It is well established that angiotensin-converting enzyme (ACE) inhibitors (ACEI) reduce blood pressure (BP) and hypertrophy of the left ventricle and vessels. The aim of our study was to compare chemically different ACEIs regarding their ability to modulate left ventricular and media hypertrophy, ACE activity and plasma endothelin-1 concentrations in spontaneously hypertensive rats (SHRs).

Design  After establishing equi-effective dose regimes, SHRs were treated (3 months) with captopril, enalapril, fosinopril or ramipril (2 × 25, 10, 20 or 1 mg/kg per day or corresponding 1% doses for studying blood pressure-independent effects).

Methods and results  Systolic blood pressure was reduced in SHRs receiving high doses of captopril, enalapril, fosinopril or ramipril (−61, −54, −35 and −47 mmHg), whereas low doses were ineffective. Left ventricular weight was decreased in animals treated with high doses (captopril/enalapril/fosinopril/ramipril: −17/−19/−17/−19%), but not low doses of agents. Media thickness of thoracal aorta was reduced by administering high doses (captopril/enalapril/fosinopril/ramipril: −31/−32/−27/−26%) and low doses (−16/−22/−22/−19%) of agents. ACE activity was reduced in heart, aorta and kidney of rats treated with high and low doses of all ACE inhibitors, whereby high doses showed more pronounced effects. Plasma endothelin-1 concentrations were not altered. A blood-pressure-ineffective treatment with an AT1-antagonist revealed similar effects on cardiovascular hypertrophy.

Conclusions  ACEIs reduce cardiovascular hypertrophy uniformly via an AT1-receptor- mediated mechanism, reinforcing the opinion that ACEI effects are indeed class effects. The significance of local renin–angiotensin systems was confirmed by antihypertrophic effects in the aorta that were apparent in the absence of any blood pressure reduction.

aInstitute of Experimental and Clinical Pharmacology and Toxicology, Medical University of Lübeck and bAventis Pharma Deutschland GmbH, Cardiovascular Disease Group, Frankfurt, Germany.

Sponsorship: The following companies supported this study by supplying a grant or test substances: AstraZeneca (Wedel, Germany), Aventis Pharma (Frankfurt, Germany), Bristol-Myers Squibb (München, Germany), and MSD Sharp & Dohme (Haar, Germany).

Correspondence and requests for reprints to Walter Raasch PhD, Institute of Experimental and Clinical Pharmacology and Toxicology, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Tel: + 49 451 5002698, fax: + 49 451 5003327, e-mail:raasch@medinf.mu-luebeck.de

Received 5 April 2002 Revised 8 July 2002 Accepted 21 August 2002

© 2002 Lippincott Williams & Wilkins, Inc.