INHIBITION OF NEUTRAL ENDOPEPTIDASE, THE DEGRADATIVE ENZYME FOR NATRIURETIC PEPTIDES, IN RAT-KIDNEY AFTER ORAL SCH-42495

1. Inhibition of neutral endopeptidase (NEP), the degradative enzyme f or atrial natriuretic peptide, was studied in vitro and in vivo using a previously characterized NEP inhibitor radioligand, I-125-labelled R B104. 2. SCH 42354, the active di-acid of the ethylester prodrug, SCH 42495, caused a concentration-dependent displacement of I-125-labelled RB104 from rat renal NEP. The concentration of SCH 42354 that displac ed 50% of radioligand bound to the enzyme NEP (IC50) was 3.3+/-0.1 nmo l/l (mean+/-SEM), Enalaprilat, an angiotensin converting enzyme inhibi tor, did not displace I-125-labelled RB104 in concentrations up to 10 mu mol/l. 3. In adult normotensive Sprague-Dawley rats, oral SCH 42495 (3-300 mg/kg) caused significant inhibition of renal NEP (P<0.001). S CH 42495 had no effect on renal or plasma angiotensin converting enzym e activity, but high-dose SCH 42495 (300 mg/kg) caused a significant i ncrease in plasma renin activity (P<0.01),4. In a time course study, o ral SCH 42495 (30 mg/kg) caused rapid (within 30 min) and significant inhibition of renal NEP for up to 48 h (P<0.001). No changes in plasma atrial natriuretic peptide or plasma angiotensin converting enzyme ac tivity were seen. 5. These data provide evidence that short-term admin istration of the NEP inhibitor SCH 42495 results in inhibition of rena l NEP and does not inhibit the circulating or the tissue renin-angiote nsin system, The NEP inhibitor radioligand I-125-labelled RB104, is a useful tool to study tissue NEP inhibition after administration of NEP inhibitors.