Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction.
OBJECTIVE
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 (tau) 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 beta-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.
Fraccarollo
Daniela
D
Medizinische Klinik der Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
Galuppo
Paolo
P
Hildemann
Steven
S
Christ
Michael
M
Ertl
Georg
G
Bauersachs
Johann
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D015153:Blotting, Western; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D000077545:Eplerenone; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy*; D020257:Ventricular Remodeling / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D000451:Mineralocorticoid Receptor Antagonists; C052035:trandolapril; D013148:Spironolactone; D000077545:Eplerenone; D019001:Nitric Oxide Synthase