Inhibition of neutral endopeptidase stimulates renal sodium excretion in patients with chronic renal failure

Abstract

1. The acute effects of a single oral dose of sinorphan (100 mg), an inhibitor of neutral endopeptidase, on the plasma atrial natriuretic factor level and the fractional excretion of sodium were examined in 12 patients with severe chronic renal failure who were not on maintenance haemodialysis and who ingested a normal sodium diet. The drug was administered against placebo by a double-blind cross-over protocol. 2. Basal plasma atrial natriuretic factor level and fractional excretion of sodium were high (23.2 ± 3.7 pmol/l and 2.64 ± 0.38%, respectively). Sinorphan inhibited plasma neutral endopeptidase activity by 68–75% 30 min after ingestion. This effect persisted for at least 4 h. There were simultaneously increases in plasma atrial natriuretic factor and cyclic GMP levels to 1.9 and 1.4 times the basal values, respectively. Fractional excretion of sodium increased during the second and third hour periods after ingestion of the drug with a peak of 1.9 times the basal value in the second period. Changes in fractional excretion of sodium were significantly correlated with those in plasma atrial natriuretic factor and cyclic GMP levels. Plasma aldosterone level, creatinine clearance and mean blood pressure were unchanged, whereas plasma renin activity increased slightly. An increase in urinary cyclic GMP excretion was observed in parallel with the increase in plasma cyclic GMP level. 3. The results of the present study indicate that (i) high basal values of plasma atrial natriuretic factor level and fractional excretion of sodium, as observed in patients with chronic renal failure, are associated with marked effects of neutral endopeptidase inhibition; (ii) fractional sodium excretion increases after protection of endogenous atrial natriuretic factor from degradation independently of any initial change in extracellular fluid volume or sodium intake, which suggests that this hormone may play a role in the control of sodium excretion in chronic renal failure.