Cardioprotection by long-term ET(A) receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy.
OBJECTIVE
We investigated the effects of long-term endothelin A (ET(A)) receptor blockade and ACE inhibition, either alone or in combination, on the hemodynamics, neurohormonal activation and cardiac remodeling in rats with congestive heart failure (CHF) after extensive myocardial infarction (MI).


METHODS
Rats were treated with placebo, the ET(A) antagonist LU135252 (30 mg/kg/d), the ACE inhibitor trandolapril (0.3 mg/kg/d), or a combination of both for 11 weeks, starting 7 days after MI.


RESULTS
Despite comparable effects on left ventricular (LV) systolic pressure among all drug treatments, only combined ET(A) and ACE inhibition significantly reduced LV end-diastolic pressure (P<0.01), improved LV dP/dt(max) (P<0.01) and normalized sympathetic activation (P<0.05) in rats with CHF. The combination therapy was more effective in reducing type I and III collagen mRNA levels, MMP-2 zymographic activity and collagen accumulation in the surviving LV myocardium. Moreover, the increases in cardiac beta-myosin heavy chain and skeletal alpha-actin mRNAs, markers of hypertrophy or failure, were attenuated to a greater degree by the combination therapy than monotherapy, whereas right ventricular hypertrophy and ANF mRNA upregulation were significantly (P<0.01) prevented only by combined ET(A) and ACE inhibition.


CONCLUSIONS
Long-term combined ET(A) receptor and ACE inhibition improved cardiac failure after extensive MI more effectively than monotherapy. We show additive effects on LV fibrosis and fetal gene expression. ET(A) receptor antagonists could be a therapeutical option in CHF in addition to an ACE inhibitor.
Fraccarollo
Daniela
D
Medizinische Klinik, Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 2, Germany.
Bauersachs
Johann
J
Kellner
Markus
M
Galuppo
Paolo
P
Ertl
Georg
G
D000199:Actins / Q000235:genetics; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D003094:Collagen / Q000032:analysis / Q000235:genetics; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D015870:Gene Expression; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D023421:Models, Animal; D018995:Myosin Heavy Chains / Q000235:genetics; D009638:Norepinephrine / Q000097:blood; D010666:Phenylpropionates / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000097:blood; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics
D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007211:Indoles; D010666:Phenylpropionates; D011743:Pyrimidines; D016212:Transforming Growth Factor beta; D019716:Tissue Inhibitor of Metalloproteinase-2; C052035:trandolapril; C107831:darusentan; D009320:Atrial Natriuretic Factor; D003094:Collagen; D012083:Renin; D020778:Matrix Metalloproteinase 2; D018995:Myosin Heavy Chains; D009638:Norepinephrine