title: Effects of spironolactone and eprosartan on cardiac remodeling and angiotensin-converting enzyme isoforms in rats with experimental heart failure.
abstract: Angiotensin-converting enzyme (ACE)-2 is a newly described enzyme with antagonistic effects to those of the classical ACE (ACE-1). Both ANG II and aldosterone play an important role in the pathophysiology of congestive heart failure (CHF) and in the adverse cardiac remodeling during its development. In this study, we examined the effects of experimental CHF induced by an aortocaval fistula (ACF) and of its treatment with ANG II and aldosterone inhibitors on the relative levels of ACE-1 and ACE-2. We also compared the effects of spironolactone, an aldosterone antagonist, and eprosartan, an ANG II receptor antagonist, on heart hypertrophy and fibrosis in rats with ACF. Spironolactone (15 mg x kg(-1) x day(-1) ip, via minipump) or eprosartan (5 mg x kg(-1) x day(-1) ip, via minipump) was administered into rats with ACF for 14 and 28 days. Specific antibodies were used to determine the protein levels of myocardial ACE-1 and ACE-2. ACF increased the cardiac levels of ACE-1 and decreased those of ACE-2. Heart-to-body weight ratio significantly increased from 0.30 +/- 0.004% in sham-operated controls to 0.50 +/- 0.018% and 0.56 +/- 0.044% (P < 0.001) in rats with ACF, 2 and 4 wk after surgery, respectively, in association with increased plasma levels of aldosterone. The area occupied by collagen increased from 2.33 +/- 0.27% to 6.85 +/- 0.65% and 8.03 +/- 0.93% (P < 0.01), 2 and 4 wk after ACF, respectively. Both spironolactone and eprosartan decreased cardiac mass and collagen content and reversed the shift in ACE isoforms. ACF alters the ratio between ACE isoforms in a manner that increases local ANG II and aldosterone levels. Early treatment with both ANG II and aldosterone antagonists is effective in reducing this effect. Thus ACE isoform shift may represent an important component of the development of cardiac remodeling in response to hemodynamic overload, and its correction may contribute to the beneficial therapeutic effects of renin-angiotensin-aldosterone system inhibitors.
authors.affiliation: Department of Vascular Surgery and Transplantation, Rambam Medical Ctr., Haifa, PO Box 9649, Haifa 31096, Israel. t_karram@rambam.health.gov.il
authors.forename: Tony
authors.initials: T
authors.lastname: Karram
authors.forename: Anan
authors.initials: A
authors.lastname: Abbasi
authors.forename: Shlomo
authors.initials: S
authors.lastname: Keidar
authors.forename: Eliahu
authors.initials: E
authors.lastname: Golomb
authors.forename: Irit
authors.initials: I
authors.lastname: Hochberg
authors.forename: Joseph
authors.initials: J
authors.lastname: Winaver
authors.forename: Aaron
authors.initials: A
authors.lastname: Hoffman
authors.forename: Zaid
authors.initials: Z
authors.lastname: Abassi
mesh_terms: D000179:Acrylates / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001164:Arteriovenous Fistula; D002268:Carboxypeptidases / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000179:Acrylates; D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D000451:Mineralocorticoid Receptor Antagonists; D013876:Thiophenes; D013148:Spironolactone; C068373:eprosartan; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2