COMPARISON OF CHRONIC NEUTRAL ENDOPEPTIDASE INHIBITION AND FUROSEMIDEIN AN OVINE MODEL OF HEART-FAILURE

The hemodynamic, hormonal, and metabolic effects of chronic neutral en dopeptidase (NEP) 24.11 inhibition and furosemide were compared in the pacing model of ovine heart failure (HF). Intravenous SCH 39370 induc ed a dose-related inhibition of NEP activity during 4-days treatment, in association with a transient increase in plasma atrial natriuretic peptide (ANP) and, at the higher dose, an increased mean level of plas ma cyclic guanosine monophosphate. There was a significant and persist ent decrease in left atrial pressure, a brief increase in cardiac outp ut (GO), and a tendency for arterial pressure to be reduced. Significa nt dose-related diuresis and natriuresis were also observed. Furosemid e induced a similar hemodynamic response, associated with greater diur esis and natriuresis. Both agents significantly reduced plasma aldoste rone levels. Coinfusion of captopril on day 4 of treatment resulted in similar responses in both the SCH 39370- and furosemide pretreated gr oups. Chronic NEP inhibition significantly alters circulatory and rena l function and appears to be as effective as furosemide in reducing ca rdiac preload in this model of congestive HF.