Printed in U.S.A. ROLE OF THE ENDOPEPTIDASE 24. 1 1 IN THE DISPOSITION AND METABOLISM OF ENDOGENOUS ATRIAL NATRIURETIC FACTOR IN THE RABBIT

The neutral endopeptidase 24.1 1 (NEP) has been shown to inactivate the atrial natriuretic factor (ANF) by opening the ring structure. To document the role of NEP in the metabolic fate of ANF in vivo, the effects of an infusion of thiorphan (25 ig/min/kg), a specific NEP Inhibitor, on the kinetics and metabolism of endogenous ANF were studied in conscious rabbits. A bolus of [I]ANF(99-126) was in-jected 50 mm after the beginning of the infusion of thiorphan. Plasma samples containing the radioactive peptides were separated by reverse-phase HPLC. The parent compound could be separated from at least two other minor metabolites, corresponding to the elution position of [I]ANF(99-1O5/1O6-126), the inactive ring-opened me-tabolite, and of [1ThI]ANF(103-126), an N-truncated analog. The gen-eration of the N-truncated metabolite was increased by thiorphan. Thiorphan also induced an increase in plasma ANF (29%) that was closely associated with a 32 % reduction in the systemic clearanc