Cardiorenal actions of a unique chimeric peptide to CNP and BNP in experimental chronic heart failure

Abstract

Background: CNP, a member of the natriuretic peptide system (NPS) of endothelial origin, is a potent venodilator with minimal natriuretic actions. CNP exerts venodilating actions via generation of cGMP after binding to the NPR-B receptor. BNP, a member of the NPS of myocardial origin, is the most potent natriuretic peptides and mediates its natriuretic properties via the NPR-A receptor. Both CNP and BNP possess a 17-amino acid ringed structure while BNP has a 6-amino acid COOH-terminus that CNP lacks. We recently designed and synthesized a novel 28-amino acid chimeric peptide termed “CBNP” which possesses the natriuretic actions of BNP and the venodilating actions of CNP. This chimeric protein possesses the 22-amino acid structure of CNP and the 6-amino acid COOH-terminus of BNP. To date its biological actions in experimental chronic heart failure (HF) are undefined. Methods: In 5 anesthetized dogs with experimental chronic HF produced by rapid ventricular pacing at 180 beats/min for 10 days, cardiorenal function was assessed in response to CBNP (50 ng/kg/min IV). Results: CBNP increased urinary sodium excretion (41±23 to 108±25 μEq/min∗), fractional sodium excretion (0.3±0.1 to 1.3±0.7 %∗) and glomerular filtration rate (29±5 to 39±4 ml/min∗), with a decrease in proximal fractional reabsorption of sodium (85±5 to 79±6 %∗). These renal responses were paralleled by increases in plasma cGMP (27±3 to 32±3 pmol/ml∗) and urinary cGMP excretion (1532±278 to 2344±589 pmol/min∗). In addition, CBNP also decreased right atrial pressure (5.8±0.4 to 3.4±0.8 mmHg∗), pulmonary capillary wedge pressure (18.9±0.9 to 15.6±0.5 mmHg∗) and cardiac output (2.7±0.3 to 2.0±0.2 l/min∗) consistent with a decrease in cardiac preload. Conclusion: These cardiorenal actions were unassociated with increases in plasma renin activity. The current study suggests that CBNP possess the venodilating actions of CNP and the natriuretic actions of BNP in experimental chronic HF. Thus, CBNP may have therapeutic potential as a venodilating and natriuretic agent in heart failure. (∗p<0.05 vs baseline)