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 125I-labeled urodilatin and 125I-ANF. In control rats, the volume of distribution (Vss), 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 micrograms/kg followed by a continuous infusion of 10 micrograms.kg-1 x 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 Vss 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Abassi
Z A
ZA
Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Tate
J
J
Hunsberger
S
S
Klein
H
H
Trachewsky
D
D
Keiser
H R
HR
D000409:Alanine / Q000031:analogs & derivatives*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D009318:Natriuresis; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010446:Peptide Fragments / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors*
D010446:Peptide Fragments; C065359:SQ 28603; C065367:atrial natriuretic factor (4-23)NH2, de-Gln(18)-de-Ser(19)-de-Gly(20,22)-de-Leu(21)-; C056452:Ularitide; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D017461:Receptors, Atrial Natriuretic Factor; D000409:Alanine