Clearance receptor and neutral endopeptidase-mediated metabolism of atrial natriuretic factor.
A novel small linear C-atrial natriuretic factor receptor ligand [C-ANF-(11-15)] and phosphoramidon (PHO) were used to determine the effects of C-ANF receptor blockade alone, or in combination with inhibition of neutral endopeptidase (NEP), on the pharmacokinetics and metabolism of ANF in the rat. C-ANF-(11-15) infusion decreased apparent volume of distribution (Vss) and metabolic clearance rate (MCR) of administered 125I-ANF-(1-28) to one-third of their control values, whereas PHO alone was without effect on these parameters. In combination with C-ANF-(11-15), however, PHO further decreased MCR of 125I-ANF-(1-28) and increased plasma half time by more than threefold. High-performance liquid chromatography analysis revealed that C-ANF-(11-15) inhibited the delayed appearance of free 125I and [125I]monoiodotyrosine but had no effect on the small proportion of NEP metabolites in plasma. The combination of C-ANF-(11-15) and PHO further delayed the appearance of small metabolites, abolished the appearance of NEP metabolites, and markedly prolonged the permanence of intact 125I-ANF-(1-28) in plasma. The results demonstrate that C-ANF receptor blockade by C-ANF-(11-15) impairs clearance and metabolism of ANF, an effect which is synergistically potentiated by concomitant inhibition of NEP. C-ANF-(11-15) alone or in combination with NEP inhibitors may be a potentially useful therapeutic tool in the treatment of cardiovascular and renal diseases.
Okolicany
J
J
Department of Physiology, Cornell University Medical College, New York, New York 10021.
McEnroe
G A
GA
Koh
G Y
GY
Lewicki
J A
JA
Maack
T
T
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism* / Q000494:pharmacology; D011232:Chemical Precipitation; D002851:Chromatography, High Pressure Liquid; D006020:Glycopeptides / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D015260:Neprilysin / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism*; D013997:Time Factors; D014238:Trichloroacetic Acid
D006020:Glycopeptides; D014238:Trichloroacetic Acid; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D017461:Receptors, Atrial Natriuretic Factor; C008890:phosphoramidon