Long-Term Survival and Hemodynamics After Endothelin-A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition in Rats With Chronic Heart Failure

Abstract

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. Methods and 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 Ϫ1 per day Ϫ1 ), the ET A antagonist LU 135252 (LU, 30 mg/kg Ϫ1 per day Ϫ1 ), or their combination starting 7 days after ligation. After 3 months, the combination decreased LV systolic-and end-diastolic pressures (Ϫ32% and Ϫ80%, respectively) more markedly than Tr (Ϫ21% and Ϫ61%, respectively) or LU alone (Ϫ14% and Ϫ48%, 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.

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

“…ET1 was shown to be elevated in blood samples of HF patients, to predict outcome and to play a crucial role for adverse cardiac remodeling (6). In 1996, it was demonstrated that endothelin receptor inhibition is cardioprotective in a preclinical model of HF (7), which was supported by others (8)(9)(10). However, despite convincing preclinical data, unspecific ET1 receptor and specific ET A inhibitors (ET A i) showed no beneficial effects in clinical HF trials (11,12).…”

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

“…We produced MI by ligation of the left coronary artery in 11 week-old male Wistar rats, anesthetized with Ketamine and Xylazine (60 and 5 mg/kg, respectively, intraperitoneally) [33]. MI resulted in a mean 41% infarct size ( Table 1).…”

“…Transthoracic Doppler echocardiographic studies, using an echocardiographic system (HDI 5000, ATL, USA) equipped with an 8.5 MHz probe, were performed in anesthetized rats (Brietal™; 50 mg.kg -1 , intraperitoneally) [33]. LV diameters were measured by the American Society of Echocardiology leading-edge method from at least 3 consecutive cardiac cycles [34].…”

“…Infarct size was calculated as (endocardial + epicardial circumference of the infarcted tissue)/(endocardial + epicardial circumference of the LV). as previously described [33]. Results obtained from 4 to 6 hearts were expressed as a percentage ± sem.…”

“…We have chosen the model of post-myocardial infarction (MI) rat, displaying a cardiac disease relevant with that of elderly and/or established CHF patients [33]. We show that total cardiac left ventricle (LV) glutathione is depleted in CHF patients and CHF post-MI rats.…”