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Circulation Research. 2006;99:183-190
Published online before print June 15, 2006, doi: 10.1161/01.RES.0000232322.06633.d3
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(Circulation Research. 2006;99:183.)
© 2006 American Heart Association, Inc.

Cellular Biology

Novel Snake Venom Ligand Dendroaspis Natriuretic Peptide Is Selective for Natriuretic Peptide Receptor-A in Human Heart

Downregulation of Natriuretic Peptide Receptor-A in Heart Failure

Gurminder Singh, Rhoda E. Kuc, Janet J. Maguire, Mark Fidock, Anthony P. Davenport

From the Clinical Pharmacology Unit (G.S., R.E.K., J.J.M., A.P.D.), University of Cambridge, Centre for Clinical Investigation, Addenbrooke’s Hospital, UK; and Pfizer Global Research & Development (M.F.), Sandwich, Kent, UK.

Correspondence to Dr Anthony P. Davenport, Clinical Pharmacology Unit, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. E-mail apd10{at}medschl.cam.ac.uk

The natriuretic peptides are considered to be cardioprotective; however, their receptors have not been identified in human myocardium using radiolabeled analogs. Dendroaspis natriuretic peptide (DNP) has been recently identified as a new member of this peptide family and is thought to be less susceptible to enzymatic degradation. Therefore, we have developed the novel radiolabeled analog [125I]-DNP and used this to localize high-affinity (KD=0.2 nmol/L), saturable, specific binding sites in adult human heart (n=6) and coronary artery (n=8). In competition binding experiments, atrial natriuretic peptide and brain type natriuretic peptide had greater affinity for [125I]-DNP binding sites than C-type natriuretic peptide and the natriuretic peptide receptor (NPR)-C ligand, cANF. This rank order of potency suggested binding of [125I]-DNP was specific to NPR-A. Messenger RNA encoding NPR-A was identified in left ventricle and coronary artery smooth muscle, and expression was confirmed by immunocytochemical studies at the protein level. In addition, fluorescence dual labeling immunocytochemistry localized NPR-A protein to cardiomyocytes, endocardial endothelial cells, and smooth muscle of intramyocardial vessels. Importantly, we demonstrated a significant downregulation in the density of NPR-A in heart and coronary artery of patients with ischemic heart disease that may explain, in part, the attenuated natriuretic peptide response reported in this patient group.


Key Words: Dendroaspis natriuretic peptide • heart failure • downregulation • natriuretic peptide receptor-A


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