Effects of SCH 34826, an orally active inhibitor of atrial natriuretic peptide degradation, in healthy volunteers

Abstract

Atrial natriuretic peptide is cleared from plasma by clearance receptors and by enzymatic degradation by way of a neutral metalloendopeptidase. Inhibition of neutral metalloendopeptidase activity appears to provide an interesting approach to interfere with metabolism of atrial natriuretic peptide to enhance the renal and haemodynamic effects of endogenous atrial natriuretic peptide. In this study, the effects of SCH 34826, a new orally active neutral metalloendopeptidase inhibitor, have been evaluated in a single‐blind, placebo‐controlled study involving eight healthy volunteers who had maintained a high sodium intake for 5 days. SCH 34826 had no effect on blood pressure or heart rate in these normotensive subjects. SCH 34826 promoted significant increases in excretion of urinary sodium, phosphate, and calcium. The cumulative 5‐hour urinary sodium excretion was 15.7 ± 7.3 mmol for the placebo and 22.9 ± 5, 26.7 ± 6 (p < 0.05), and 30.9 ± 6.8 mmol (p < 0.01) for the 400, 800, and 1600 mg SCH 34826 doses, respectively. During the same time interval, the cumulative urinary phosphate excretion increased by 0.3 ± 0.4 mmol after placebo and by 1.5 ± 0.3 (p< 0.01), 1.95 ± 0.3 (p < 0.01), and 2.4 ± 0.4 mmol (p < 0.001) after 400, 800, and 1600 mg SCH 34826, respectively. There was no change in diuresis or excretion of urinary potassium and uric acid. The natriuretic response to SCH 34826 occurred in the absence of any change in plasma atrial natriuretic peptide levels but was associated with a dose‐dependent elevation of urinary atrial natriuretic peptide and cyclic guanosine monophosphate. These results demonstrate that neutral metalloendopeptidase inhibition with SCH 34826 can produce natriure‐sis and phosphate excretion in volunteers receiving a high‐salt diet maybe by reducing the renal atrial natriuretic peptide metabolism. Clinical Pharmacology and Therapeutics (1991) 50, 181–191; doi:

Renal Hemodynamic and Natriuretic Effects of Concomitant Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibition in Men

“…6 Accordingly, a higher urinary ANP excretion was found with the 2 doses of omapatrilat. This effect of omapatrilat was not observed in the placebo group or in the FOS/HCTZ group.…”

“…3,4 In humans, the administration of exogenous ANP and the inhibition of natriuretic peptide degradation by use of neutral endopeptidase inhibitors have been found to increase sodium and water excretion and to lower blood pressure. [5][6][7][8] Omapatrilat is a member of the new drug class of vasopeptidase inhibitors that possess the ability to inhibit the membrane-bound zinc metalloproteases ACE EC 2.4.15.1 and the neutral endopeptidase EC 3.4.24.11 (NEP). 9 Thus, omapatrilat simultaneously decreases angiotensin II generation by inhibiting ACE activity and reduces the metabolic degradation of natriuretic peptides by inhibiting NEP.…”

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor, omapatrilat in healthy subjects

“…In contrast, ACE inhibitors such as captopril [25] and cilazapril [26] show little effect on BP in healthy volunteers. Similarly, pure NEP inhibitors, such as candoxatril [27] and SCH34826 [28], also produce no changes in BP in normotensive volunteers.…”

Dual inhibition of angiotensin-converting enzyme and neutral endopeptidase by the orally active inhibitor mixanpril: a potential therapeutic approach in hypertension.

“…In the treatment of cardiovascular disease, it could be of therapeutic Interest to associate the hypotensive effects due to the inhibition of lagotensn formation with the diuretic and natriuretic responses induced by the protection of the endogenous atrial natriuretic peptide (ANP) (14)(15)(16)(17) with no potassium loss (14, 16). However, these renal effects are not accompanied by significant changes in blood pressure or left ventricular hemodynamic load (14).…”

“…Selective inhibitors of NEP have been developed with the aim of delaying ANP degradation (9)(10)(11)(12) and their efficiency in protecting endogenous ANP has been demonstrated in various animal models of hypertension (10)(11)(12)(13). In humans they have significant diuretic and natriuretic effects (14)(15)(16)(17) with no potassium loss (14,16). However, these renal effects are not accompanied by significant changes in blood pressure or left ventricular hemodynamic load (14).…”