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Cardiovascular Research 2002 54(1):85-94; doi:10.1016/S0008-6363(01)00553-3
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Cardioprotection by long-term ETA receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy

Daniela Fraccarollo1, Johann Bauersachs1, Markus Kellner, Paolo Galuppo and Georg Ertl*

Medizinische Klinik, Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany

g.ertl{at}medizin.uni-wuerzburg.de

* Corresponding author. Tel.: +49-931-201-5301; fax: +49-931-201-5302

Objectives: We investigated the effects of long-term endothelin A (ETA) receptor blockade and ACE inhibition, either alone or in combination, on the hemodynamics, neurohormonal activation and cardiac remodeling in rats with congestive heart failure (CHF) after extensive myocardial infarction (MI). Methods: Rats were treated with placebo, the ETA antagonist LU135252 (30 mg/kg/d), the ACE inhibitor trandolapril (0.3 mg/kg/d), or a combination of both for 11 weeks, starting 7 days after MI. Results: Despite comparable effects on left ventricular (LV) systolic pressure among all drug treatments, only combined ETA and ACE inhibition significantly reduced LV end-diastolic pressure (P<0.01), improved LV dP/dtmax (P<0.01) and normalized sympathetic activation (P<0.05) in rats with CHF. The combination therapy was more effective in reducing type I and III collagen mRNA levels, MMP-2 zymographic activity and collagen accumulation in the surviving LV myocardium. Moreover, the increases in cardiac β-myosin heavy chain and skeletal {alpha}-actin mRNAs, markers of hypertrophy or failure, were attenuated to a greater degree by the combination therapy than monotherapy, whereas right ventricular hypertrophy and ANF mRNA upregulation were significantly (P<0.01) prevented only by combined ETA and ACE inhibition. Conclusion: Long-term combined ETA receptor and ACE inhibition improved cardiac failure after extensive MI more effectively than monotherapy. We show additive effects on LV fibrosis and fetal gene expression. ETA receptor antagonists could be a therapeutical option in CHF in addition to an ACE inhibitor.

KEYWORDS Infarction; Heart failure; Endothelins; Angiotensin; Fibrosis

1 Both authors contributed equally to this work.


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A. Schafer, D. Fraccarollo, P. Tas, I. Schmidt, G. Ertl, and J. Bauersachs
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