Protection of atrial natriuretic factor against degradation: diuretic and natriuretic responses after in vivo inhibition of enkephalinase (EC 3.4.24.11) by acetorphan.
Atrial natriuretic factor (ANF) might be beneficial in several cardiovascular disorders, but its poor oral absorption and rapid inactivation in vivo have so far prevented its use in therapeutics. We have assessed the role of enkephalinase (membrane metallo-endopeptidase, EC 3.4.24.11) in the in vivo inactivation of ANF in mice and healthy human volunteers by evaluating the effects of acetorphan, a potent inhibitor. In mice, the degradation of 125I-labeled ANF was markedly delayed, as shown by the levels of the intact peptide in the plasma and the kidney, a major target organ. The effect of acetorphan was due to the inhibition of enkephalinase activity, since it occurred at an ED50 very close to this drug's ID50 for the inhibition of the specific binding of radioactive material to the kidney or lung peptidase that was measured after administration of [3H]acetorphan. The effects of acetorphan were also studied in eight healthy human volunteers by using a randomized double-blind, placebo-controlled design. Oral administration of acetorphan elicited a lasting elevation of plasma ANF-like immunoreactivity, with a time course parallel to that of the inhibition of plasma enkephalinase activity. These effects were accompanied by significant increases in urinary volume and sodium excretion, two well-established renal responses to ANF peptides. These results indicate that enkephalinase plays a critical role in ANF degradation in vivo and that its inhibition enhances the levels of circulating endogenous ANF, which, in turn, results in diuresis and natriuresis. Enkephalinase inhibition may constitute another therapeutic approach to the treatment of cardiovascular diseases, such as congestive heart failure or essential hypertension, on which ANF is postulated to have a beneficial effect.
Gros
C
C
Unité de Neurobiologie et Pharmacologie (Unité 109), Institut National de la Santé et de la Recherche Médicale, Paris, France.
Souque
A
A
Schwartz
J C
JC
Duchier
J
J
Cournot
A
A
Baumer
P
P
Lecomte
J M
JM
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects*; D006801:Humans; D006868:Hydrolysis; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D009318:Natriuresis / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000097:blood; D015244:Thiorphan / Q000494:pharmacology / Q000031:analogs & derivatives
C049331:racecadotril; D009320:Atrial Natriuretic Factor; D015244:Thiorphan; D015260:Neprilysin