Neurohormonal Profile of a Novel Chimeric Natriuretic Peptide, CD-NP, as Compared to C-Type Natriuretic Peptide, in the Normal Dog

Abstract

Background: CD-NP is a novel Mayo-designed chimeric natriuretic peptide (NP) that was synthesized by combining the 22-amino-acid (AA) residues of human C-type natriuretic peptide (CNP) with the 15-AA C-terminus of Dendroaspis NP. In this investigation, we sought to evaluate the effects of CD-NP, as compared to CNP, on plasma neurohormone levels and natriuretic peptide (NP) immunoreactivities (IR). We hypothesized that CD-NP would inhibit the renin-angiotensin-aldosterone system (RAAS) and would enhance endogenous NP levels. Methods: Normal anesthetized dogs received CD-NP 50 ng/kg/min i.v. (n = 10) or an equimolar dose of CNP (29.3 ng/kg/min i.v., n = 6) for 75 min. Four clearances were performed: pre-infusion (I), 30 min and 60 min of infusion (I), post-I. Plasma neurohormones and natriuretic peptide IR were quantified by radioimmunoassays. Comparisons were made within group versus pre-I (mean ± SEM, P < 0.05∗, < 0.01†) and between groups (P < 0.05‡, < 0.001§). Results: CD-NP significantly suppressed plasma renin activity (PRA, 6.1 ± 1.4 to 1.8 ± .7† to 1.1 ± .4† to 7.0 ± 1.6 ng/ml/hr), whereas CNP tended to suppress PRA (3.9 ± 2.1 to 2.4 ± 1.0 to 3.4 ± 0.9 to 4.3 ± 1.3 ng/ml/hr). CD-NP significantly decreased angiotensin II (Ang II, 16.6 ± 3.0 to 7.5 ± 1.8† to 4.4 ± .7† to 14.7 ± 2.8 pg/ml), whereas CNP tended to decrease Ang II (16.4 ± 6.2 to 9.0 ± 1.6 to 14.1 ± 3.1 to 19.3 ± 6.7 pg/ml). CD-NP tended to reduce plasma aldosterone (21.6 ± 5.0 to 18.2 ± 5.5 to 14.3 ± 4.7 to 18.6 ± 6.4 ng/dl) whereas no decrease was observed with CNP (18.7 ± 5.8 to 27.3 ± 3.4 to 26.7 ± 3.7 to 27.8 ± 3.9 ng/dl). Plasma BNP IR in CD-NP-treated versus CNP-treated dogs were 23.7 ± 5.0 to 26.5 ± 2.5 to 40.0 ± 4.1†§ to 29.7 ± 4.2§ pg/ml; 9.8 ± 2.9 to 17.1 ± 1.6† to 17.2 ± 2.2† to 7.5 ± 0.8 pg/ml, respectively. Plasma CNP IR, an estimate of both CD-NP and CNP levels, were significantly increased in both groups (CD-NP 8.7 ± 3.3 to 808 ± 100†‡ to 897 ± 159†‡ to 17.3 ± 1.7 pg/ml; CNP 7.7 ± 3.1 to 413 ± 140∗ to 436 ± 165† to 7.9 ± 3.4 pg/ml). Conclusion: The novel chimeric natriuretic peptide, CD-NP, possesses RAAS-inhibiting properties, and significantly augments endogenous BNP levels to a greater extent as compared to CNP. The greater increase in CNP with CD-NP strongly supports a longer half-life for CD-NP versus CNP. These greater neurohumoral changes in response to CD-NP compared to native CNP support potentially important biological properties for this novel chimeric peptide in the treatment of cardiorenal diseases.