Long-term survival and hemodynamics after endothelin-a receptor antagonism and angiotensin-converting enzyme inhibition in rats with chronic heart failure: monotherapy versus combination therapy.
BACKGROUND
In patients with congestive heart failure (CHF) receiving ACE inhibitors, acute administration of selective endothelin (ET) antagonists additionally improves systemic and cardiac hemodynamics. We investigated, in a rat model of CHF, whether such acute synergistic effects are sustained and accompanied, in the long term, by an additional limitation of left ventricular remodeling or an increase in survival.


RESULTS
Rats were subjected to coronary artery ligation and treated for 3 or 9 months with vehicle or with the ACE inhibitor trandolapril (Tr) (0.3 mg/kg(-1) per day(-1)), the ET(A) antagonist LU 135252 (LU, 30 mg/kg(-1) per day(-1)), or their combination starting 7 days after ligation. After 3 months, the combination decreased LV systolic- and end-diastolic pressures (-32% and -80%, respectively) more markedly than Tr (-21% and -61%, respectively) or LU alone (-14% and -48%, respectively). Echocardiographic studies revealed that all treatments limited LV dilatation and increased LV fractional shortening and cardiac index. All treatments equally reduced left ventricular collagen density, whereas only Tr or the combination reduced LV weight. Finally, although LU did not modify long-term survival, Tr and the combination of Tr with LU induced a similar improvement of survival.


CONCLUSIONS
In this rat model, long-term combined administration of an ET(A) antagonist and an ACE inhibitor induces additional effects in terms of systemic and cardiac hemodynamics; however, this is not associated with an additional increase in long-term survival.
Rouen University Medical School, Rouen, France.
Paul
P
Mulder
Houssaine
H
Boujedaini
Vincent
V
Richard
Jean-Paul
JP
Henry
Sylvanie
S
Renet
Klaus
K
Münter
Christian
C
Thuillez
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002908:Chronic Disease; D003331:Coronary Vessels / Q000503:physiopathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004452:Echocardiography; D065128:Endothelin Receptor Antagonists; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D008026:Ligation; D008297:Male; D009206:Myocardium / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D015996:Survival Rate; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects; D014851:Wakefulness
D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C107831:darusentan; D007703:Peptidyl-Dipeptidase A