Concurrent neutral endopeptidase and ACE inhibition in experimental heart failure: Renal and hormonal effects

Abstract

Helin K. Concurrent neutral endopeptidase and ACE inhibition in experimental heart failure: renal and hormonal effects. Scand J Clin Lab Invest 1993; 53: 843-851.

Neutral endopeptidase (NEP) inhibitors have been shown to strengthen the 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 present study, renal and hormonal effects of SCH 34826, an orally active NEP inhibitor, were studied in a coronary-ligation model of experimental 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 (90mgkg⁻¹ sc) elevated plasma ANP from 382 ± 85 to 658 ± 120ngl⁻¹ compared with vehicle (p = 0.002). In sham-operated control rats, plasma ANP also increased slightly from 52 ± 6 to 70±9ngl⁻¹ (p = 0.05). Plasma renin activity did not change in either group. When given orally for 36 h (90mgkg⁻¹ b.i.d.), SCH 34826 enhanced natriuresis in controls but not in rats with CHF. Captropril (0.2mgml⁻¹ in drinking water) enhanced natriuresis in CHF rats and both natriuresis and kaliuresis in controls. When SCH 34826 and captropril were combined, natriuresis was potentiated in control rats 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 not with captopril or combination of the two drugs. Moreover, captopril suppressed aldosterone excretion both in CHF rats and controls when administered alone but not when combined with SCH 34826. The excretion of catecholamine metabolites was practically unaffected by SCH 34826.

It is concluded that, in this model of experimental heart failure, NEP inhibition with SCH 34826 elevates plasma ANP and possibly increases urinary cGMP excretion but lacks any other major beneficial renal or hormonal effect also when combined to ACE inhibition with captopril.

Key Words:

• aldosterone
• angiotensin-I-converting enzyme inhibition
• atrial natriuretic peptide
• catecholamines
• cGMP
• chronic congestive heart failure
• neutral endopeptidase inhibition
• rat
• renal function
• renin