Biochemical analysis of neutral endopeptidase activity reveals independent catabolism of atrial and brain natriuretic peptide.
Recent reports presented contradictory results regarding the catabolism of mature atrial (ANP) and brain (BNP) natriuretic peptides in circulation. Especially the role of neutral endopeptidase (NEP) in BNP degradation was conversely discussed. Our present in vitro-studies characterize the NEP-dependent metabolism of ANP and BNP in different tissues via HPLC-analysis using NEP-deficient mice and specific NEP inhibitors. Our results show a strong tissue-dependent degradation pattern of both peptides, which are not only due to the different NEP activities in these tissues. Whereas NEP rapidly degraded ANP, it had no influence in BNP-metabolism. Additional experiments with purified NEP confirmed this result. Moreover, we describe a degradation of ANP and BNP in NEP-deficient- and NEP-inhibited membranes. Consequently, we postulate the existence of at least one further natriuretic peptide (NP) degrading enzyme, which has not been characterized yet. Thus, the commonly accepted model of the natriuretic peptide system with NEP as the central degrading peptidase has to be partly revised. Moreover, the NEP-independent BNP degradation provides an effective means for achieving a beneficial BNP increase in cardiovascular pathology by inhibiting the assumed novel NP-degrading peptidase(s).
Walther
Thomas
T
Department of Cardiology, Medical Center Benjamin Franklin, Free University of Berlin, D-12200 Berlin, Germany. thomas.walther@charite.de
Stepan
Holger
H
Pankow
Kristin
K
Becker
Matthias
M
Schultheiss
Heinz-Peter
HP
Siems
Wolf-Eberhard
WE
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*
D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D020097:Natriuretic Peptide, Brain; C060942:candoxatrilat; D009320:Atrial Natriuretic Factor; D015260:Neprilysin