Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction.

Abstract

OBJECTIVES:

The mechanisms underlying the clinical benefits of mineralocorticoid receptor antagonism in patients with left ventricular (LV) dysfunction and heart failure (CHF) after myocardial infarction (MI) are poorly understood.

METHODS:

We investigated whether long-term (9 weeks) aldosterone antagonism with eplerenone (100 mg/kg/day) provides additional benefit to angiotensin II type 1 (AT1) receptor inhibition with irbesartan (50 mg/kg/day) on cardiac remodeling after MI in rats.

RESULTS:

Eplerenone monotherapy, like AT1 receptor blockade, significantly reduced LV end-diastolic pressure (LVEDP), end-systolic volume (LVESV) and end-diastolic volume (LVEDV) compared to placebo. Improvement of LV dilation by aldosterone antagonism was associated with a significant reduction of increased AT1 receptor, angiotensin-converting enzyme (ACE) and endothelin-1 gene expression in the noninfarcted LV myocardium. Combination therapy with irbesartan led to a substantial further leftward shift of the LV pressure-volume curve and decrease in LVEDP, LVESV and LVEDV. Moreover, combination therapy significantly improved LV systolic and diastolic function and reversed LV alterations of alpha- and beta-myosin heavy-chain isoforms, ANF and SERCA2 ATPase expression more effectively than monotherapies. LV collagen type I and type III expression as well as interstitial fibrosis were substantially increased in placebo CHF rats, similarly decreased by eplerenone and irbesartan, and further reduced by eplerenone/irbesartan. However, no additive effects of eplerenone/irbesartan on myocardial AT1 receptor, ACE and endothelin-1 mRNAs were observed.

CONCLUSIONS:

Aldosterone receptor antagonism provides additional benefit to AT1 receptor blockade on LV function and remodeling associated with improvement of molecular alterations responsible for progressive contractile dysfunction post-MI.

• Authors: Daniela Fraccarollo, Paolo Galuppo, Isabel Schmidt, Georg Ertl, Johann Bauersachs
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 67 Issue 1 Pg. 97-105 (Jul 01 2005) ISSN: 0008-6363 [Print] England
• PMID: 15949473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Biphenyl Compounds
• Collagen Type I
• Mineralocorticoid Receptor Antagonists
• Tetrazoles
• Spironolactone
• Eplerenone
• Irbesartan

Topics

• Angiotensin II Type 1 Receptor Blockers (therapeutic use)
• Animals
• Biphenyl Compounds (therapeutic use)
• Blotting, Western (methods)
• Collagen Type I (analysis)
• Eplerenone
• Heart Failure (prevention & control)
• Hemodynamics
• Irbesartan
• Male
• Mineralocorticoid Receptor Antagonists (therapeutic use)
• Myocardial Infarction (drug therapy, metabolism)
• Myocardium (metabolism)
• Rats
• Rats, Wistar
• Spironolactone (analogs & derivatives, therapeutic use)
• Tetrazoles (therapeutic use)
• Ventricular Remodeling (drug effects)