© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Activation of the cardiac endothelin system in left ventricular hypertrophy before onset of heart failure in TG(mREN2)27 rats
aInstitut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054 Erlangen, Germany
bMedizinische Universitätsklinik und Poliklinik der Universität des Saarlandes, Innere Medizin — Kardiologie und Angiologie, 66421 Homburg, Germany
* Corresponding author. Tel.: +49-131-852-2783 zolk{at}pharmakologie.uni-erlangen.de
Objective: To characterize the cardiac angiotensin and endothelin (ET) system in compensated left ventricular hypertrophy due to long standing arterial hypertension and to assess the role of angiotensin and ET converting enzymes in mediating the observed changes of angiotensin and ET levels, respectively. Methods: We studied the left ventricular renin–angiotensin system (RAS) and ET system in 20-week-old male transgenic hypertensive TG(mREN2)27 rats, a model of the monogenic renin-dependent form of severe hypertension. Age-matched Sprague–Dawley rats served as controls. Results: TG(mREN2)27 rats exhibited left ventricular hypertrophy without signs of congestion. Transgene overexpression led to an activation of the tissue RAS with increased angiotensin II levels in spite of unchanged angiotensin converting enzyme (ACE) activity and ACE mRNA levels. ET-1 production was markedly increased in TG(mREN2)27 rats indicating that the ET-system was activated. Cardiac ET-1 in TG(mREN2)27 originated most likely from increased preproET-1 production because preproET-1 mRNA levels were increased but ET converting enzyme gene expression and activity were unchanged. Furthermore, ET-1 binding sites were significantly increased in TG(mREN2)27 rats without changes in KD values and ETA/ETB receptor ratios. ETA receptor gene expression was not altered whereas ETB receptor mRNA levels were up-regulated twofold in TG(mREN2)27 rats suggesting that ETA and ETB receptor expression may be regulated differentially. Conclusions: Cardiac ET and angiotensin systems are co-activated in compensated cardiac hypertrophy before onset of heart failure, and thus may be involved in the mechanism by which cardiac remodelling and progression of left ventricular dysfunction occur in TG(mREN2)27 rats.
KEYWORDS Endothelins; Hypertension; Hypertrophy; Renin angiotensin system
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