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Enzymatic inactivation of major circulating forms of atrial and brain natriuretic peptides
J Ozaki1, H Shimizu, Y Hashimoto
1Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Japan.
Abstract:
We compared the enzymatic inactivation of major circulating forms of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Both ANP and BNP induced a significant increase in cyclic GMP (cGMP) formation in cultured epithelial cell line derived from porcine kidney, LLC-PK1. The cGMP formation stimulated by ANP in LLC-PK1 cells was significantly decreased by pre-treatment of the peptide with rat renal brush-border membranes, and the inactivation of ANP was inhibited by neutral endopeptidase inhibitors, phosphoramidon and S-thiorphan. BNP exhibited greater resistance to enzymatic inactivation than did ANP. In addition, phosphoramidon potentiated the natriuresis with a low dose (7.5 pmol min(-1) kg(-1)) of ANP but not of BNP in rats. These results suggest that enzymatic degradation of natriuretic peptides is highly dependent on peptide structure, and that the affinity of BNP to neutral endopeptidase is less than that of ANP.
Insights
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) increase cyclic GMP. ANP is more susceptible to enzymatic inactivation by neutral endopeptidase than BNP, impacting natriuresis.
Area of Science:
- Biochemistry
- Nephrology
- Endocrinology
Background:
- Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are key regulators of cardiovascular and renal function.
- Understanding their enzymatic inactivation is crucial for their therapeutic applications.
Purpose of the Study:
- To compare the enzymatic inactivation of ANP and BNP.
- To investigate the role of neutral endopeptidase (NEP) in their degradation.
- To assess the impact of NEP inhibition on natriuresis.
Main Methods:
- Incubation of ANP and BNP with porcine kidney LLC-PK1 cells to measure cyclic GMP (cGMP) formation.
- Pre-treatment of peptides with rat renal brush-border membranes.
- Use of neutral endopeptidase inhibitors (phosphoramidon, S-thiorphan).
- In vivo assessment of natriuresis in rats following peptide administration and NEP inhibition.
Main Results:
- Both ANP and BNP stimulated cGMP formation in LLC-PK1 cells.
- ANP inactivation by renal brush-border membranes was significant and inhibited by NEP inhibitors.
- BNP showed greater resistance to enzymatic inactivation compared to ANP.
- NEP inhibition potentiated ANP-induced natriuresis but not BNP-induced natriuresis in rats.
Conclusions:
- Enzymatic degradation of natriuretic peptides is highly dependent on their specific structure.
- BNP has a lower affinity for neutral endopeptidase compared to ANP.
- These findings have implications for the development of natriuretic peptide-based therapies.