CONCURRENT NEUTRAL ENDOPEPTIDASE AND ACE-INHIBITION IN EXPERIMENTAL HEART-FAILURE - RENAL AND HORMONAL EFFECTS

Neutral endopeptidase (NEP) inhibitors have been shown to strengthen t he effects of endogenous atrial natriuretic peptide (ANP). It has been well documented that angiotensin I-converting enzyme (ACE) inhibitors act beneficially in chronic congestive heart failure (CHF). In the pr esent study, renal and hormonal effects of SCH 34826, an orally active NEP inhibitor, were studied in a coronary-ligation model of experimen tal CHF in the rat. The effects were compared to those of captropril. The drugs were also administered in combination. In anaesthetized rats with CHF, SCH 34826 (90 mg kg(-1) sc) elevated plasma ANP from 382 +/ - 85 to 658 +/- 120 ng 1(-1) compared with vehicle (p = 0.002). In sha m-operated control rats, plasma ANP also increased slightly from 52 +/ - 6 to 70 +/- 9ngl(-1) (p = 0.05). Plasma renin activity did not chang e in either group. When given orally for 36h (90 mg kg(-1) b.i.d.), SC H 34826 enhanced natriuresis in controls but not in rats with CHF. Cap tropril (0.2mg ml(-1) in drinking water) enhanced natriuresis in CHF r ats and both natriuresis and kaliuresis in controls. When SCH 34826 an d captropril were combined, natriuresis was potentiated in control rat s as compared with captopril alone; in rats with CHF, however, a brisk kaliuresis was seen. The excretion of cyclic guanosine monophosphate was enhanced in CHF rats by 52% during treatment with SCH 34826 but no t with captopril or combination of the two drugs. Moreover, captopril suppressed aldosterone excretion both in CHF rats and controls when ad ministered alone but not when combined with SCH 34826. The excretion o f catecholamine metabolites was practically unaffected by SCH 34826.