PHARMACOKINETICS OF ANF AND URODILATIN DURING CANF RECEPTOR BLOCKADE AND NEUTRAL ENDOPEPTIDASE INHIBITION

Urodilatin is a new member of the family of natriuretic peptides. It is of renal origin. Previous reports indicate that urodilatin is natriuretic in lower doses than atrial natriuretic factor (ANF)-(99-126) and that it might be more effective than ANF in the treatment of cardiovascular edema. The present study was designed to compare the pharmacokinetics of the hydrolysis and clearance of I-125-labeled urodilatin and I-125-ANF. In control rats, the volume of distribution (V(ss)), metabolic clearance rate (MCR), and distribution half-life (distribution t1/2) of urodilatin in plasma were not significantly different from those of ANF. Infusion of clearance (c)ANF-(4-23), a specific ligand for receptors that clear ANF in excess amounts (i.e., a bolus injection of 100 mug/kg followed by a continuous infusion of 10 mug.kg-1-min-1), increased the amount of intact peptide in the plasma to the same extent for both urodilatin and ANF. In addition, cANF-(4-23) decreased the V(ss) and the MCR and increased the distribution t1/2 of both peptides to about the same degree. Prior treatment of rats with SQ-28,603, a specific neutral endopeptidase (NEP; EN 3.4.24.11) inhibitor, was without significant effect on the metabolic clearance of urodilatin, whereas it decreased the clearance of ANF by 65%. Furthermore, an infusion of SQ-28, 603 suppressed the appearance of the hydrolytic products of ANF in blood but not of urodilatin. Moreover, the inhibitor increased the total amount of ANF recovered in the kidneys to five times the control values, whereas it did not alter the renal uptake of urodilatin. These data demonstrate that urodilatin is removed from the circulation mainly by cANF receptors, whereas circulating ANF-(99-126) is cleared by both cANF receptors and NEP. This may contribute to the differences in the natriuretic potency of these two peptides, despite similar distribution t1/2, MCR, and V(ss).