Acute inhibition of
endothelin converting enzyme (ECE) and
neutral endopeptidase (NEP) exerts beneficial hemodynamic effects in chronic
heart failure (CHF). However, the long-term effects of dual ECE-NEP inhibition are unknown. We evaluated, in rats with CHF, the long-term effects of the dual ECE-NEP inhibitor
CGS 26303 (10 mg.kg(-1).day(-1)) on systemic and left ventricular (LV) hemodynamics and LV remodeling, and compared them to those induced by the selective NEP inhibitor
CGS 24592 (10 mg.kg(-1).day(-1)), both administered subcutaneously by mini-pump for 30 days starting 7 days after left coronary artery
ligation. After 30 days,
CGS 26303, but not
CGS 24592, reduced systolic blood pressure, while both drugs never affected heart rate. Echocardiographic studies showed that only
CGS 26303 diminished LV end-diastolic and systolic diameters and increased LV fractional shortening and cardiac output. Moreover,
CGS 26303, but not
CGS 24592, reduced LV end-diastolic pressure, while LV dP/dtmax/min was not affected. Both drugs reduced
collagen accumulation in the 'viable' part of the LV, but only
CGS 26303 reduced LV weight. Thus, long-term treatment with
CGS 26303 decreases both preload and afterload, increases cardiac output, and diminishes LV
hypertrophy, dilatation, and cardiac
fibrosis, suggesting that dual ECE-NEP inhibition might be beneficial in human CHF.