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Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction.
J Am Coll Cardiol. 2003 Nov 05; 42(9):1666-73.JACC

Abstract

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 (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.

Authors+Show Affiliations

Medizinische Klinik der Julius-Maximilians-Universität Würzburg, Würzburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14607457

Citation

Fraccarollo, Daniela, et al. "Additive Improvement of Left Ventricular Remodeling and Neurohormonal Activation By Aldosterone Receptor Blockade With Eplerenone and ACE Inhibition in Rats With Myocardial Infarction." Journal of the American College of Cardiology, vol. 42, no. 9, 2003, pp. 1666-73.
Fraccarollo D, Galuppo P, Hildemann S, et al. Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. J Am Coll Cardiol. 2003;42(9):1666-73.
Fraccarollo, D., Galuppo, P., Hildemann, S., Christ, M., Ertl, G., & Bauersachs, J. (2003). Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. Journal of the American College of Cardiology, 42(9), 1666-73.
Fraccarollo D, et al. Additive Improvement of Left Ventricular Remodeling and Neurohormonal Activation By Aldosterone Receptor Blockade With Eplerenone and ACE Inhibition in Rats With Myocardial Infarction. J Am Coll Cardiol. 2003 Nov 5;42(9):1666-73. PubMed PMID: 14607457.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. AU - Fraccarollo,Daniela, AU - Galuppo,Paolo, AU - Hildemann,Steven, AU - Christ,Michael, AU - Ertl,Georg, AU - Bauersachs,Johann, PY - 2003/11/11/pubmed PY - 2003/12/5/medline PY - 2003/11/11/entrez SP - 1666 EP - 73 JF - Journal of the American College of Cardiology JO - J. Am. Coll. Cardiol. VL - 42 IS - 9 N2 - 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 (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. SN - 0735-1097 UR - https://www.unboundmedicine.com/medline/citation/14607457/Additive_improvement_of_left_ventricular_remodeling_and_neurohormonal_activation_by_aldosterone_receptor_blockade_with_eplerenone_and_ACE_inhibition_in_rats_with_myocardial_infarction_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0735109703010805 DB - PRIME DP - Unbound Medicine ER -