CLEARANCE RECEPTORS AND ENDOPEPTIDASE - EQUAL ROLE IN NATRIURETIC PEPTIDE METABOLISM IN HEART-FAILURE

The effects of separate and combined endopeptidase inhibition (by SCH- 32615) and natriuretic peptide receptor C blockade [by C-ANP-(4-23)] o n the clearance and bioactivity of atrial (ANP) and brain (BNP) natriu retic peptides was investigated in eight sheep with heart failure. SCH -32615 and C-ANP-(4-23) administered separately induced significant an d proportionate dose-dependent rises in plasma ANP, BNP, and guanosine 3',5'-cyclic monophosphate (cGMP) levels. Associated with these chang es were reductions in arterial pressure, left atrial pressure, and per ipheral resistance and increases in cardiac output, urine volume, sodi um excretion, and creatinine clearance. SCH-32615 induced greater diur esis and natriuresis than C-ANP-(4-23). Combined administration of SCH -32615 and C-ANP-(4-23) induced greater than additive rises in plasma ANP, BNP, and cGMP concentrations, with enhanced hemodynamic effects, diuresis, and natriuresis and reduced plasma aldosterone levels. In co nclusion, we find that the enzymatic and receptor clearance pathways c ontribute equally to the metabolism of endogenous ANP and BNP in sheep with heart failure. Combined inhibition of both degradative pathways was associated with enhanced hormonal, hemodynamic, and renal effects and may have greater potential therapeutic value than either agent sep arately.