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Mutation of three amino acids in the disulfide-ring of a CNP based chimeric natriuretic peptide alters its vascular properties

Clinical background

C-type natriuretic peptide (CNP) is a 22-amino-acid peptide produced mainly in the endothelium with potent cardiac unloading and blood pressure lowering actions, but minimal renal actions. Based on our previous knowledge, we recently fused a 6 aa sequence from BNP to the C-terminus and a 5 aa sequence from ANP to the N-terminus of CNP. This novel hybrid peptide, CBA-NP, has cardiac unloading actions and mild hypotensive effects similar to CNP. Importantly however, the N and C terminus alterations resulted in potent renal excretory actions. Here we test the hypothesis that the 3 aa GSM15–17 in the disulfide-ring mediate the vascular and hypotensive actions of CBA-NP. We therefore mutated GSM 15–17 to REA15–17, which we named ABC-NP and compared its in vivo and in vitro actions to CBA-NP.

Methods

We determined the cardiorenal and humoral actions of intravenous bolus administration of CBA-NP (n = 5) and ABC-NP (n = 5) at 25 mg/kg in two separate groups of normal anesthetized dogs. We also assessed the cGMP response of both peptides in human aortic endothelial cells (HAEC), human cardiac fibroblast (HCF) and isolated canine glomeruli. * p < 0.05.

Results

IV bolus administration of CBA-NP and ABC-NP resulted in diuresis* and natriuresis*. There was a significant decrease in mean arterial blood (MAP) pressure with CBA-NP* but no change with ABC-NP. In addition, the reduction in pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) was significantly greater with CBA-NP as compared to ABC-NP. cGMP generation in HAEC and HCF was minimal with ABC-NP and was significantly higher with CBA-NP*. In contrast, cGMP generation was similar in isolated glomeruli between the two peptides.

Conclusion

Our studies demonstrates that mutation of three amino acid (aa) residues within the CNP ring of CBA-NP from GSM 15–17 to REA alters the vascular but not the renal excretory properties. Hence by this minimal mutation within the ring of CBA-NP, we have designed a renal specific peptide ABC-NP resulting in new sequence specific functional information which can be used to design organ specific therapeutic peptides with unique properties tailored for a specific disease state.

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Correspondence to Horng H Chen.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Chen, H.H., Huntley, B.K., Cataliotti, A. et al. Mutation of three amino acids in the disulfide-ring of a CNP based chimeric natriuretic peptide alters its vascular properties. BMC Pharmacol 9, P8 (2009). https://doi.org/10.1186/1471-2210-9-S1-P8

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Keywords

  • Pulmonary Capillary Wedge Pressure
  • Bolus Administration
  • Right Atrial Pressure
  • Human Aortic Endothelial Cell
  • Therapeutic Peptide