RENAL EFFECTS OF NEUTRAL ENDOPEPTIDASE INHIBITION IN EUVOLEMIC AND HYPERVOLEMIC RATS

Candoxatrilat is a potent and selective inhibitor of neutral endopepti dase (EC 3.4.24.11), the enzyme responsible for the degradation of atr ial natriuretic factor (ANF). In these studies, the renal effects of c andoxatrilat were investigated in euvolemic and hypervolemic anaesthet ised rats. In euvolemic rats, candoxatrilat (675 mug/kg per h) had no effect on urine output, sodium and potassium excretion or urinary cycl ic GMP excretion. However, in hypervolemic rats, the natriuretic and d iuretic responses to volume expansion were markedly potentiated by the candoxatrilat infusion, with a concomitant increase in urinary cyclic GMP. Acute volume expansion was characterised by natriuresis, diuresi s and increased levels of plasma ANF and cyclic GMP (1.5-fold and 2-fo ld increases respectively, when compared to cuvolemic rats). The resul ts presented suggest that plasma ANF levels and volume status modulate responses to neutral endopeptidase inhibition. The development of the neutral endopeptidase inhibitor, candoxatrilat, provides the opportun ity to exploit endogenous ANF effectively in disease states with eleva ted ANF.