title: Specific inhibitors of endopeptidase 24.11 inhibit the metabolism of atrial natriuretic peptides in vitro and in vivo.
abstract: Atrial natriuretic peptides (ANPs) are degraded rapidly by renal brush border membranes in vitro. Here, we report that thiorphan, a specific inhibitor of endopeptidase 24.11, afforded almost complete protection against inactivation of ANPs by a renal brush border membrane preparation. The diastereoisomers of [3-(N-hydroxy)carboxamido-2-benzylpropanoyl]-L-alanine (HCBA) are potent inhibitors of endopeptidase 24.11 and were also tested for their abilities to inhibit ANP-(103-126) degradation. The (S,S)-diastereoisomer was more effective than the (R,S)-diastereoisomer (kelatorphan), but both were less potent than thiorphan. To determine if endopeptidase inhibitors could decrease ANP metabolism in in vivo, thiorphan and (S,S)-HCBA were given to rats with or without a continuous infusion of ANP-(103-126). Both inhibitors induced rapid increases in plasma ANP concentration in rats administered exogenous ANP-(103-126), but had no effect on endogenous ANP levels. Thus, specific inhibitors of endopeptidase 24.11 decrease the degradation of ANPs in vitro, and are effective in reducing the metabolism of ANP-(103-126) in vivo.
authors.affiliation: Searle Research and Development, G.D. Searle & Co., Chesterfield, MO 63198.
authors.forename: G M
authors.initials: GM
authors.lastname: Olins
authors.forename: P A
authors.initials: PA
authors.lastname: Krieter
authors.forename: A J
authors.initials: AJ
authors.lastname: Trapani
authors.forename: K L
authors.initials: KL
authors.lastname: Spear
authors.forename: P R
authors.initials: PR
authors.lastname: Bovy
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D007668:Kidney / Q000502:physiology; D008297:Male; D008871:Microvilli / Q000502:physiology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D015244:Thiorphan / Q000494:pharmacology*
chemical_list: D004151:Dipeptides; D011480:Protease Inhibitors; C042591:kelatorphan; D009320:Atrial Natriuretic Factor; D015244:Thiorphan; D015260:Neprilysin