Additive improvement of left ventricular remodeling by aldosterone receptor blockade with eplerenone and angiotensin II type 1 receptor antagonist in rats with myocardial infarction.
We investigated the effects of the aldosterone blocker eplerenone alone and in combination with angiotensin II type 1 receptor antagonist on ventricular remodeling in rats with left ventricular (LV) dysfunction after extensive myocardial infarction (MI). Adding an aldosterone antagonist to an ACE inhibitor reduces mortality and morbidity in heart failure. Starting 1 day after MI, rats were treated with placebo, eplerenone (100 mg/kg/day), the angiotensin type 1 receptor antagonist candesartan (1 mg/kg/day), or a combination of both for nine weeks. Both monotherapies attenuated the rise in LV end-diastolic dimension (LVDd) and LV end-diastolic volume (LVEDV) compared with placebo, whereas combined treatment further attenuated LVDd and LVEDV and significantly improved LV function. Increased collagen type I and III gene expressions in the noninfarcted LV myocardium from MI placebo rats was attenuated by candesartan, but almost completely prevented by eplerenone and eplerenone/candesartan. The addition of eplerenone to candesartan prevented the increases in LV gene expression of ANP and BNP more effectively than either monotherapy. The aldosterone blocker eplerenone improved LV remodeling in rats with LV dysfunction after extensive MI. Combination therapy with an candesartan substantially potentiates this effect by a complementary prevention of LV fibrosis, cardiac hypertrophy, and molecular alterations.
Department of Internal Medicine and Cardiology, Osaka City University Medical School, Graduate School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. yoshiyama@med.osaka-cu.ac.jp
Minoru
M
Yoshiyama
Takashi
T
Omura
Jyunichi
J
Yoshikawa
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage; D001713:Biphenyl Compounds; D000077545:Eplerenone; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D009203:Myocardial Infarction / Q000503:physiopathology; D051381:Rats; D013148:Spironolactone / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D013777:Tetrazoles / Q000008:administration & dosage; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D000451:Mineralocorticoid Receptor Antagonists; D013777:Tetrazoles; D013148:Spironolactone; D000077545:Eplerenone; C081643:candesartan