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BASIC SCIENCE

Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction

Daniela Fraccarollo, PhD^*, Paolo Galuppo, PhD^*, Steven Hildemann, MD, Michael Christ, MD, Georg Ertl, MD^* and Johann Bauersachs, MD^*,*

^* Medizinische Klinik der Julius-Maximilians-Universität Würzburg, Würzburg, Germany
Pharmacia Corp., Peapack, New Jersey, USA
Klinik für Innere Medizin-Kardiologie Phillips-Universität Marburg, Marburg, Germany

^* Reprint requests and correspondence: Dr. Johann Bauersachs, Medizinische Universitätsklinik, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany.
bauersachs_j{at}medizin.uni-wuerzburg.de

OBJECTIVES: We investigated the effects of the aldosterone blocker eplerenone alone and in combination with angiotensin-converting enzyme (ACE) inhibition on ventricular remodeling in rats with left ventricular (LV) dysfunction after extensive myocardial infarction (MI).

BACKGROUND: Adding an aldosterone antagonist to ACE inhibition reduces mortality and morbidity in heart failure.

METHODS: Starting 10 days after MI, rats were treated with placebo, eplerenone (100 mg/kg/day), the ACE inhibitor trandolapril (0.3 mg/kg/day), or a combination of both for nine weeks.

RESULTS: Both monotherapies attenuated the rise in LV end-diastolic pressure (LVEDP) and LV end-diastolic volume (LVEDV) compared with placebo, whereas combined treatment further attenuated LVEDP and LVEDV, significantly improved LV function and reduced plasma norepinephrine levels. The time constant of LV pressure isovolumic decay () was prolonged in placebo MI rats, significantly shortened by eplerenone, and normalized by eplerenone/trandolapril. Increased collagen type I gene expression and collagen content in the noninfarcted LV myocardium from MI placebo rats was attenuated by trandolapril, but almost completely prevented by eplerenone and eplerenone/trandolapril. The addition of eplerenone to ACE inhibition prevented sarcoplasmic-reticulum calcium ATPase downregulation and the increases in LV gene expression of ß-MHC and atrial natriuretic factor more effectively than either monotherapy. Furthermore, combination treatment attenuated the increase in myocardial angiotensin II type 1 receptor expression and increased phosphorylated endothelial nitric oxide synthase protein levels.

CONCLUSIONS: The aldosterone blocker eplerenone improved LV remodeling in rats with LV dysfunction after extensive MI. Combination therapy with an ACE inhibitor substantially potentiates this effect by a complementary prevention of LV fibrosis, cardiac hypertrophy, and molecular alterations.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   ANF = atrial natriuretic factor   ANOVA = analysis of variance   AT1 = angiotensin II type 1   CHF = congestive heart failure   dP/dtmax = maximal rate of pressure rise   dP/dtmin = maximal rate of pressure decline   eNOS = endothelial nitric oxide synthase   GAPDH = glyceraldehyde-3-phosphate-dehydrogenase   LV = left ventricle/ventricular   LVEDP = left ventricular end-diastolic pressure   LVEDV = left ventricular end-diastolic volume   MHC = myosin heavy chain   MI = myocardial infarction   MMP = matrix metalloproteinase   mRNA = messenger ribonucleic acid   NT-proANP = N-terminal pro-atrial natriuretic peptide   PCR = polymerase chain reaction   RALES = Randomized Aldactone Evaluation Study   RV = right ventricle/ventricular   SERCA2 = sarcoplasmic-reticulum calcium

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