Abstract P140: A Novel New Generation Designer Natriuretic Peptide, CBB-NP, Exerts Favorable Cardiorenal and Neurohumoral Actions
Background: Resuscitated cardiac arrest is characterized by multiorgan ischemia-reperfusion injuries to which there is a dearth of therapy. CBB-NP is a novel synthetic natriuretic peptide (NP) consisting of the ring of human C-type NP (CNP), a NP receptor (NPR)-B agonist, and both the N- and C-termini of human B-type NP (BNP), a NPR-A agonist. CBB-NP was designed to retain the favorable actions of BNP while minimizing hypotension by replacing the BNP ring with that of CNP, a known structural determinant for NPR-B activation. We hypothesized that CBB-NP would activate cGMP via both NPRs and exert favorable actions in vivo.
Methods: In human aortic endothelial cells (HAEC), cGMP response to CBB-NP was assessed by RIA with or without an NPR-A antagonist (A71915, 1 ìM) or an NPR-B antibody (ab) against the NPR-B ligand binding domain (1:100). In 7 normal anesthetized dogs, CBB-NP 14 pmol/kg/min was infused iv for 75 min. GFR was assessed by inulin clearance. Renal, hemodynamic and neurohumoral data at 30 and 60 min of infusion (I) were compared vs pre-I. Mean±SEM, P<.05*,<.01†,<.001‡.
Results: In HAEC, CBB-NP 10−6 M increased cGMP: 0.11±.02‡ vs control 0.001±.001 pmol/mL. In the presence of A71915 or the NPR-B ab, cGMP response was attenuated to 0.09±.01 and 0.05±0.002* pmol/mL, respectively. In vivo, CBB-NP increased plasma cGMP (8±1 to 18±1† to 19±2† pmol/mL), urinary cGMP excretion (1178±159 to 3091±631† to 3337±361† pmol/min), net renal cGMP generation (797±146 to 2167±647* to 2323±310* pmol/min), urine flow (0.30±.08 to 0.75±.13† to 0.89±.15† mL/min) and urinary Na+ excretion (29±11 to 121±23† to 152±28† ìEq/min). PCWP was reduced (5.1±0.6 to 4.2±0.5* to 3.9±0.5† mmHg); CO (3.1±0.2 to 2.7±0.1 to 2.8±0.2 L/min), MAP (121±5 to 116±5* to 119±5 mmHg) and GFR (47±4 to 51±3 to 52±5 mL/min) were preserved. RBF was augmented (270±29 to 288±35 to 299±37* mL/min). Plasma renin activity (5.3±0.6 to 1.7±0.3† to 1.8±0.5† ng/mL/hr) and Ang II (11.6±2.2 to 5.0±0.8† to 5.0±0.5† pg/mL) were reduced.
Conclusions: CBB-NP activates cGMP and exerts favorable cardiorenal and neurohumoral actions with minimal effects on blood pressure. Its cGMP-stimulating action involves NPR-B and possibly NPR-A. The therapeutic potential of CBB-NP in models of resuscitation warrants investigation.