Abstract 13955: M-Atrial Natriuretic Peptide, a Novel Anti-Hypertensive Therapeutic Peptide, is Markedly Resistant to in vivo Intra-Nephron Degradation
Introduction M-atrial natriuretic peptide (M-ANP) is a novel 40 amino acid peptide based on the native 28 amino acid cardiac hormone atrial natriuretic peptide (ANP). In vitro studies suggest M-ANP is highly resistant to degradation by neutral endopeptidase (NEP) as well other degradation enzymes (including insulin-degrading enzyme) when compared to native ANP. Further, we have reported that M-ANP has greater and more sustained in vivo blood pressure lowering, aldosterone inhibiting, vasodilatation, and renal enhancing properties compared to native ANP. The objective of the current study was to determine, in vivo, the intra-nephron degradation of M-ANP compared to native ANP with the hypothesis that M-ANP would be more resistant to degradation in vivo translating into greater renal actions compared to native ANP.
Methods Studies were performed in normal canines (n=7 for both groups). M-ANP and ANP were administered intravenously (33 pmol / kg / min). After achieving a steady state concentration intranephron degradation of M-ANP and ANP were calculated. Intra-nephron degradation = (GFR, ml/min * plasma concentration, pg/ml) - (urinary excretion, pg/min). *P<0.05 versus ANP by unpaired t-test.
Results Intra-nephron degradation for M-ANP isreported in the figure and issignificantly reduced compared to ANP.
Discussion Our results support the concept that the previously reported enhanced blood pressure lowering, natriuretic, and aldosterone inhibiting actions of M-ANP compared to native ANP are likely due to reduced degradation within the nephron where there are high concentrations of NEP. This resistance to degradation increases the bioavailability of M-ANP both in the kidney. These results offer novel insight into the mechanistic actions of M-ANP which is being developed as therapeutic for severe hypertension.
- © 2011 by American Heart Association, Inc.