Abstract 371: Cardiorenal and Neurohumoral Actions of a Novel Designer Natriuretic Peptide, CU-NP, in Canine Experimental Heart Failure
CU-NP is a novel designer natriuretic peptide (NP) consisting of the 17-AA ring of human C-type NP (CNP) and the N- and C- termini of urodilatin (URO). CU-NP was designed to preserve the favorable actions of URO, a NP receptor (NPR)-A agonist while minimizing hypotension by replacing the URO ring with that of CNP, a ligand for NPR-B, which is more abundant in veins than in arteries. Here, we assessed CU-NP for the first time in canine heart failure (HF) to test our hypothesis that CU-NP would activate the second messenger cGMP and exert favorable actions without excessive hypotension. Mild HF was induced by pacing (180 bpm for 10 d). CU-NP 75 ng/kg/min was infused iv into 6 anesthetized dogs for 75 min. GFR was measured by inulin clearance. Fractional reabsorption of Na+ (FRNa) was assessed by Li+ clearance. Data were collected at pre-infusion (pre-I), 30 and 60 min I and post-I. Plasma renin activity (PRA), angiotensin II (Ang II), aldosterone (Aldo) and cGMP were measured. Mean±SE, P<.05*,<.01†. CU-NP increased plasma cGMP (17±3 to 41±3† to 43±2† to 21±2 pmol/mL), urinary cGMP excretion (1186±152 to 5066±828† to 5476±876† to 2394±197 pmol/min), net renal cGMP generation (610±66 to 2977±549† to 3255±662† to 1342±200 pmol/min), urine flow (0.09±.01 to 0.50±.15† to 0.56±.11† to 0.19±.03 mL/min) and urinary Na+ excretion (2.9±.9 to 80.5±29.4† to 102.0±22.2† to 22.1±7.9 μEq/min). Proximal (89±2 to 68±5† to 67±3† to 79±3* %) and distal FRNa (99.6±.1 to 96±1† to 96±1† to 99±.3 %) were reduced. Renal blood flow (238±39 to 281±42* to 294±42† to 275±42* mL/min) and GFR (40±5 to 51±9 to 51±3 to 53±7* mL/min) were enhanced with a mild decrease in MAP (108±9 to 100±8† to 96±8† to 107±8 mmHg). Both CO (2.4±.1 to 2.5±.1 to 2.4±.1 to 2.3±.04 L/min) and SVR (42±3 to 39±3 to 39±3 to 45±3 mmHgL−1min) were unchanged. PCWP (11±1 to 9±1† to 8±1† to 10±1 mmHg) and PAP (16±.8 to 15±.6* to 14±.7† to 16±.7 mmHg) were reduced. PRA (9±2 to 3±1† to 2±1† to 9±2 ng/mL/hr), Ang II (32±7 to 9±2† to 9±3† to 19±4 pg/mL) and Aldo (14±5 to 9±2 to 6±2* to 11±3 ng/dL) were suppressed. CU-NP activates cGMP in canine HF and exerts renal-enhancing, cardiac-unloading and RAAS-suppressing actions without excessive hypotension. The therapeutic potential of CU-NP in human HF warrants investigation.