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Cardiorenal actions of a novel chimeric natriuretic peptide, CD-NP, as compared to C-type natriuretic peptide, in the normal dog

  • 1Email author,
  • 1,
  • 1 and
  • 1
BMC Pharmacology20077 (Suppl 1) :P37

https://doi.org/10.1186/1471-2210-7-S1-P37

  • Published:

Keywords

  • Natriuretic Peptide
  • Inulin
  • Pulmonary Capillary Wedge Pressure
  • Decompensated Heart Failure
  • Acute Decompensated Heart Failure

Background

The novel chimeric natriuretic peptide, CD-NP, is a Mayo-designed cGMP-activating synthetic peptide that consists of the 22-amino-acid (AA) residues of C-type natriuretic peptide (CNP) and the 15-AA C-terminal extension of Dendroaspis natriuretic peptide (DNP) [1]. The rationale for the design of CD-NP was to transform CNP, which activates natriuretic peptide receptor-B (NPR-B) and is natriuretic, diuretic and less hypotensive than ANP and BNP which activate NPR-A into a CNP-like peptide with added renal actions. The goal of this investigation was to directly compare the cardiorenal profile of CD-NP to that of CNP.

Materials and methods

Normal anesthetized dogs were given CD-NP 50 ng/kg/min i.v. (n = 10) or an equimolar dose of CNP (29.3 ng/kg/min i.v., n = 7) for 75 min. Four 30-min clearances were performed at the following time points: pre-infusion (pre-I), at 30 and 60 min of I, and post-I. Blood and urine samples were collected for each clearance. Glomerular filtration rate was determined by inulin clearance. Comparisons were made within group vs pre-I (mean ± SEM, P < 0.05*, <0.01) and between groups (P < 0.05, <0.01§, <0.001) using repeated measures ANOVA.

Results

CD-NP significantly increased plasma cGMP (7 ± .4 to 25 ± 3 to 36 ± 3 to 23 ± 3 pmol/ml) and urinary cGMP excretion (978 ± 145 to 3170 ± 205†‡ to 5919 ± 616 to 3077 ± 298 pmol/min) versus CNP (7.8 ± .8 to 9.1 ± .3 to 10.1 ± .6 to 8.1 ± .6 pmol/ml; 1099 ± 101 to 1193 ± 119 to 1301 ± 142 to 1003 ± 146 pmol/min, respectively). CD-NP significantly increased urinary sodium excretion (19 ± 4 to 168 ± 24†§ to 237 ± 26 to 96 ± 12 μeq/min) versus CNP (39 ± 14 to 68 ± 12 to 85 ± 31 to 81 ± 29 μeq/min). Urine flow (ml/min) was augmented by CD-NP (0.2 ± .06 to 1.3 ± .2 to 1.8 ± .3 to 0.8 ± .2) and CNP (0.5 ± .1 to 1.0 ± .2 to 1.3 ± .3* to 1.0 ± .3). Glomerular filtration rate was enhanced by CD-NP (37 ± 2* to 48 ± 3 to 51 ± 3 to 53 ± 4 ml/min) and was preserved by CNP (55 ± 5 to 57 ± 6 to 52 ± 4 to 50 ± 6 ml/min). Pulmonary capillary wedge pressure was significantly reduced by CD-NP (5.7 ± .7 to 4.1 ± 1* to 3.2 ± .7†‡ to 4.3 ± .8 mmHg), but not by CNP (5.8 ± .7 to 5.7 ± .8 to 6.7 ± .7 to 7.4 ± .9 mmHg). Right atrial pressure was significantly reduced by CD-NP (1.8 ± .4 to 1.1 ± .4 to 0.9 ± .5†§ to 1.3 ± .5 mmHg), but not by CNP (2.7 ± .3 to 2.6 ± .3 to 3.2 ± .3 to 3.9 ± .4 mmHg). Neither CD-NP nor CNP induced systemic hypotension (mean arterial pressure 127 ± 4 to 124 ± 5 to 122 ± 6 to 126 ± 7 mmHg; 121 ± 5 to 126 ± 4 to 127 ± 5 to 126 ± 4 mmHg, respectively).

Conclusion

This study demonstrates the successful transformation of CNP to a CNP-like peptide, which is cGMP-activating, natriuretic, diuretic, GFR-enhancing, and cardiac unloading, and has minimal blood pressure lowering effects. This cardiorenal profile of CD-NP is highly attractive as a drug for the treatment of acute decompensated heart failure, warranting further investigation.

Declarations

Acknowledgements

Supported by the National Institutes of Health (HL36634; PO1 HL76611 and HL80732), the Mayo Foundation, and the Canadian Institutes of Health Research.

Authors’ Affiliations

(1)
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN, USA

References

  1. Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett JC: Design, synthesis and unique biological actions of CD-NP: A novel CNP-like chimeric natriuretic peptide [abst]. Circulation. 2006, 114 (18 Suppl II): II-440-Google Scholar

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