Abstract 2166: Design, Synthesis and Unique Biological Actions of CD-NP: A Novel CNP-like Chimeric Natriuretic Peptide
Background: Recent research has focused on the therapeutic potential of the anti-proliferative, venodilating and minimally hypotensive properties of C-type natriuretic peptide (CNP) which functions via the NPR-B receptor and cGMP. CNP lacks renal actions that may be due to the absence of a C-terminus amino acid (AA) sequence. Our goal was to design and synthesize a novel CNP-like chimeric peptide that possessed cardiac unloading properties of CNP and minimal blood pressure lowering actions together with natriuresis and diuresis.
Methods: Here we designed, synthesized and defined the cardiorenal actions of a novel chimeric peptide CD-NP based on the 22-AA peptide CNP together with the 15-AA C-terminus of the newly discovered natriuretic peptide DNP.
Results: *p<0.05. In normal anesthetized dogs, administration of CD-NP (10, 50 and 100 ng/kg/min) decreased MAP only at high dose (from 137±6 to 134±6 to 128±5 to 118±6* mmHg). PCWP decreased (from 6.4±0.4 to 5.2±0.5* to 4.4±0.6* to 3.6±0.5* mmHg) while GFR increased (from 37±3 to 33±2 to 50±8 to 55±6* ml/min). Sodium excretion increased (from 48±17 to 123±23 to 326±51* to 462±69* μEq/min) while urine flow also increased (from 0.7±0.2 to 1.7±0.3 to 4.0±0.7* to 4.5±0.7* ml/min). At the two lowest doses, CD-NP decreased plasma renin activity (from 8.2±1 to 5.3±1* to 3.9±0.7* to 6.3±1.1 ng/ml/hr). In a second series of experiments in normal dogs we determined that CD-NP (n=8) when used at 50 ng/mg/min is less hypotensive (p<0.05 between groups) than equimolar doses of human BNP (n=8) in association with a greater increase in GFR (p<.0.05 between groups).
Conclusion: Our findings demonstrate the successful transformation of the peptide CNP into a chimera that possesses renal enhancing actions with cardiac unloading and renin suppressing properties. Its minimal hypotensive properties are clinically of high priority as it may suggest a highly safe as well as efficacious peptide for intravenous infusion in cardiorenal disease states warranting further studies.