CLEARANCE RECEPTORS AND ENDOPEPTIDASE-24.11 - EQUAL ROLE IN NATRIURETIC PEPTIDE METABOLISM IN CONSCIOUS SHEEP

Although many studies have examined the effects of administering natri uretic peptide receptor C (NPR-C) ligands and endopeptidase 24.11 (EP 24.11) inhibitors on clearance and bioactivity of atrial natriuretic p eptide (ANP), none have systematically compared their effects on the e ndogenous levels of both ANP and brain natriuretic peptide (BNP) under physiological conditions. Accordingly, we examined the hemodynamic, h ormonal, and renal actions of an EP 24.11 inhibitor, SCH-32615, and an NPR-C Ligand, C-ANP-(4-23), both alone and in combination in eight no rmal conscious sheep. NPR-C blockade and EP 24.11 inhibition induce si milar rises in plasma ANP, BNP, and guanosine 3',5'-cyclic monophospha te (cGMP). Synergistic increments in plasma ANP, BNP, and cGMP observe d during combined administration are likely to be due to the reduced c learance of C-ANP-(4-23) in the setting of EP 24.11 inhibition, leadin g to increased inhibition of the receptor pathway. Combined administra tion was also associated with enhanced hemodynamic actions and diureti c and natriuretic effects. Our findings show that both enzymatic and r eceptor clearance pathways contribute equally to natriuretic peptide c learance and induce potentially important hemodynamic and renal effect s in normal conscious sheep.