Distribution and inhibition of neutral metalloendopeptidase (NEP) (EC 3.4.24.11), the major degradative enzyme for atrial natriuretic peptide, in the rat kidney.

1. Atrial natriuretic peptide (ANP) is degraded by neutral metalloendopeptidase (NEP) (EC 3.4.24.11) and the kidney is a major site of ANP clearance. 2. The regional distribution of NEP in the rat kidney was investigated. 3. The activity of NEP, measured with an enzymatic fluorimetric method employing N-dansyl-D-alanyl-glycyl-L-4-nitrophenylalanyl-glycine as a synthetic substrate, was 18 times and eight times higher in the outer stripe of the medulla and inner cortex than in the outer cortex (OC). 4. Low concentrations of NEP were found in the OC, inner stripe and inner medulla. 5. NEP activity in the rat kidney was inhibited by the specific NEP inhibitors (SCH39370, phosphoramidon and thiorphan) at micromolar concentrations. 6. The present result suggests that degradation of ANP by NEP occurs mainly in the proximal tubules of the juxtamedullary nephrons, rather than cortical nephrons, and that the convoluted tubule in the OC is not a major site of location of NEP. 7. The relationship between NEP activities in the kidney in vitro and plasma clearance of ANP in vivo remains to be clarified.