Abstract 17801: Subcutaneous Delivery of M-ANP, a Designer Natriuretic Peptide and Guanylyl Cyclase-A Stimulator, Potently Activates Cyclic GMP and Reduces Blood Pressure in Conscious Canines
INTRODUCTION M-atrial natriuretic peptide (M-ANP) is a novel ANP based guanylyl cyclase A (GC-A) receptor activator which is highly resistant to proteolytic degradation and which possesses greater blood pressure (BP) lowering, renal enhancing, and aldosterone suppressing actions compared with native ANP. The current study was designed to determine the bioactivity of subcutaneous (SQ) administered M-ANP compared to ANP as a strategy for chronic delivery.
METHODS A crossover study in which SQ ANP 10 ug/kg, SQ M-ANP 10 ug/kg, and SQ vehicle (0.9% saline) were administered to conscious healthy canines (n=5) in 2-week intervals. BP, ANP immunoreactivity (ANPi), and cGMP (M-ANP's second messenger) were collected before (baseline) and for 5 hours after drug administration.
RESULTS Both M-ANP and ANP resulted in increased (p<0.05) plasma ANPi within 5 minutes of administration. Peak ANPi for M-ANP was 0.38±0.10 pmol/ml and for ANP was 0.25±0.04 pmol/ml (p<0.05). ANPi remained elevated for 150 minutes following M-ANP compared to 45 minutes following ANP. The sustained increase in ANPi following M-ANP resulted in a greater AUC for M-ANP (44.9±12.3 pmol-min/ml) compared to ANP (10.8±2.4 pmol-min/ml) (p=0.02). In addition, the half-life of SQ M-ANP (47 minutes) was greater (p=0.03) than ANP (14 minutes). Maximum cGMP generation was greater and more sustained for M-ANP (43.0±8.7 pmol/ml; 150 minutes) compared to ANP (14.7±1.9 pmol/ml; 60 minutes) (p=0.01). The cGMP AUC was greater following M-ANP (5,095±1,365 pmol-min/ml) compared to ANP (676±211 pmol-min/ml) (p<0.01). Linear regression lines for plasma cGMP for a given level of ANPi following M-ANP or ANP administration demonstrated a greater slope (p<0.05) for M-ANP as compared to ANP. SQ M-ANP resulted in a significant reduction in MAP within 5 minutes, which was sustained for the experimental protocol (300 minutes) (p<0.05). In contrast, there was no significant reduction in MAP following SQ ANP or placebo.
DISCUSSION In conclusion, subcutaneous M-ANP administration represents a chronic delivery strategy for this novel, enhanced GC-A activator. Our findings lay the foundation for future studies, which will assess the therapeutic properties of subcutaneous M-ANP in models of cardiovascular disease.
- © 2012 by American Heart Association, Inc.