Specific inhibitors of endopeptidase 24.11 inhibit the metabolism of atrial natriuretic peptides in vitro and in vivo.
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.
Olins
G M
GM
Searle Research and Development, G.D. Searle & Co., Chesterfield, MO 63198.
Krieter
P A
PA
Trapani
A J
AJ
Spear
K L
KL
Bovy
P R
PR
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*
D004151:Dipeptides; D011480:Protease Inhibitors; C042591:kelatorphan; D009320:Atrial Natriuretic Factor; D015244:Thiorphan; D015260:Neprilysin