Abstract 2493: Design, Synthesis, and Pharmacologic Actions of a Novel Designer Natriuretic Peptide: CU-NP
Introduction: Designer natriuretic peptides (NPs) hold promise for optimizing pharmacologic profiles of native NPs. We recently designed and synthesized a novel NP, named CU-NP, based on the ring structure of human CNP and both C- and N-termini of urodilatin (URO). Our rationale was that a CNP-based designer NP may induce less hypotension, given the venodilating effects of CNP via NPR-B receptor but with the fused URO sequences would have renal actions via NPR-A.
Methods: CU-NP was custom-synthesized using solid phase methods (ABI 431A Peptide Synthesizer, PE Biosystems). Synthesis was confirmed by HPLC/MS. Its molecular weight is 3535.09. Its amino acid sequence is TAPRSLRRSSCFGLKLDRIGSMSGLGCNSFRY with a disulfide bond joining the C residues. Cardiorenal function was defined in 3 normal anesthetized dogs. Clearances were obtained at pre-infusion (pre-I), during CU-NP infusion (10, 50, 100 ng/kg/min i.v. for 45 min each), and post-I. Tubular Na+ reabsorption and GFR were assessed by clearance of Li+ and inulin, respectively. Neurohormones were quantified by radioimmunoassays. Data were analyzed by repeated measures ANOVA followed by Dunnett’s test.
Results: Conclusions: CU-NP represents a novel fusion peptide of CNP (an NPR-B agonist) and the C- and N-termini of URO (an NPR-A agonist). It dose-dependently increases natriuresis, diuresis, GFR; decreases cardiac filling pressures, and inhibits the renin-angiotensin system without inducing significant hypotension. Its tubular effects are consistent with actions at the level of the proximal tubule and inner medullary collecting duct cells. Future studies are needed to define its