Relation of ANP and BNP to their N-terminal fragments in fetal circulation: evidence for enhanced neutral endopeptidase activity and resistance of BNP to neutral endopeptidase in the fetus

Objectives: To investigate the role of neutral endopeptidase in the turnover of atrial (ANP) and brain (BNP) natriuretic peptides and their N-terminal fragments in human fetal circulation. Design: Retrospective case-control study. Setting: Department of Obstetrics and Gynaecology, University of Leipzig, Germany. Sample: Nine control pregnancies and nine pregnancies with rhesus isoimmunisation before and after intravascular transfusion. Methods: Natriuretic peptides and N-terminal fragments in maternal and fetal blood were measured by radioimmunoassay. Neutral endopeptidase activity was determined by HPLC. Main outcome measures: Maternal and fetal plasma concentrations of ANP, NT-proANP, BNP, NT-proBNP as well as neutral endopeptidase activity. Ratios between mature peptide and N-terminal fragment. Fetomaternal ratio. Results: Plasma NT-proANP concentrations are 11.7 times higher in fetal than in maternal circulation. The ANP concentration is only 1.8 times higher, probably due to doubled neutral endopeptidase activity. In contrast, both NT-proBNP and BNP are doubled in fetal plasma. Fetuses with Rh isoimmunisation had significantly higher NT-proBNP but not NT-proANP and neutral endopeptidase activity than controls. An additional volume load by intravascular transfusion did not influence N-terminal fragments or neutral endopeptidase activity. Conclusions: Our study is the first to determine NT-pro natriuretic peptide concentrations and neutral endopeptidase activity in human fetuses. The results show that increased fetal neutral endopeptidase activity shifts the ANP/NT-proANP but not the BNP/NT-proBNP ratio and that the shifted BNP/NT-proBNP ratio in fetuses with Rh isoimmunisation does not involve increased neutral endopeptidase activity. These findings point to a BNP degradation that is not dependent on neutral endopeptidase.