Regional Release and Clearance of C-Type Natriuretic Peptides in the Human Circulation and Relation to Cardiac Function

Abstract

Abstract-Production and clearance of plasma C-type natriuretic peptide (CNP) and amino terminal (NT)-proCNP immunoreactivity in the human circulation remain poorly characterized. Accordingly, we have measured arterial and venous concentrations of CNP and NT-proCNP across multiple tissue beds during cardiac catheterization in 120 subjects (age: 64.2Ϯ9.0 years; 73% men) investigated for cardiovascular disorders. The heart, head and neck, and musculoskeletal tissues made the clearest contributions to both plasma CNP and NT-proCNP (PϽ0.05). Net release of NT-proCNP was also observed from hepatic tissue (PϽ0.001). Negative arteriovenous gradients for CNP were observed across renal, hepatic, and pulmonary tissue (PϽ0.05), indicating net clearance, whereas no tissue-specific site of NT-proCNP clearance was identified. Age, mean pulmonary artery pressure, left ventricular end diastolic pressure, Brandt score of myocardial jeopardy, and troponin I were independent predictors of circulating CNP levels in multivariable analysis. Sex and kidney function were independently predictive of arterial NT-proCNP. The proportional step-up of CNP (ϩ60%) across the heart was less than for brain natriuretic peptide (ϩ123%) but greater than for NT-pro-brain natriuretic peptide (NT-proBNP) (ϩ36%) and NT-proCNP (ϩ42%; PϽ0.001 for all). We conclude that cardiac and head and neck tissue are important sources of CNP. Circulating CNP but not NT-proCNP concentrations are related to cardiac hemodynamic load and ischemic burden. Although cardiac release is most evident, multiple additional tissues release NT-proCNP immunoreactivity without evidence for an organ-specific site for NT-proCNP degradation. Taken together, differences in magnitude and direction of transorgan gradients for CNP compared with NT-proCNP suggest net generalized cosecretion with differing mechanisms of clearance. Key Words: natriuretic peptides Ⅲ circulation Ⅲ plasma Ⅲ glomerular filtration rate Ⅲ human C -type natriuretic peptide (CNP), a vasoactive and antiproliferative peptide, 1,2 shares sequence homology and biological actions 3 with the endocrine cardiac peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). After the isolation of CNP from porcine brain tissue, 4 both CNP and CNP mRNA have been identified in vascular endothelium 5,6 and cardiac, 7,8 renal, 9 skeletal, 10 and reproductive 11,12 tissues. Although ANP and BNP activate the guanylate cyclase-coupled natriuretic peptide receptor (NPR)-A and promote natriuresis and diuresis, 3 CNP is the predominant ligand for another NPR, NPR-B, 13 which is also widely distributed in tissues including brain, 14 vascular endothelium, smooth muscle cells, 15 and myocardium. 16 Binding to NPR-B, CNP induces in vitro venodilatation, 17 cardiac inotropy, and chronotropy 18 and inhibits vascular smooth muscle proliferation. 15 Recent studies have shown that CNP exhibits antihypertrophic and antifibrotic properties during ventricular modeling after experimental myocardial infarction. 19 Distinct from ANP a...

Sustained increases in plasma C-type natriuretic peptides fail to increase concentrations in cerebrospinal fluid: Evidence from pregnant sheep

“…It is therefore reasonable to conclude that our findings will have general application -including non pregnant states. It is relevant to note that while plasma CNP values in the current study greatly exceed those likely to be observed in pathophysiological states in humans [20,24,25], they are several orders of magnitude lower than those (1-100 nmol/L) shown to increase BBB permeability in tissue preparations -or achieved after intravenous doses (10 nmol/kg) that increase permeability in mice [12]. Whether equivalent (e.g.…”

Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth

“…Because of the low concentrations of CNP in blood from children [16, 17], larger volumes of plasma (> 0.5 mL) are concentrated 4-fold prior to a radioimmunoassay (RIA) to maximize sensitivity. This requirement introduces the potential for loss of the labile peptide during collection and ­processing and limits the use of CNP measurements to specific settings – for example, in detecting an arteriovenous gradient across organs [18, 19] or where the ratio of NTproCNP to CNP has applications in clinical diagnosis. It should be noted that, unlike NTproCNP, interactions of atrial natriuretic peptide (ANP) or B-type natriuretic peptide (BNP) at high plasma concentrations will raise CNP concentrations by competitive displacement of the ligand from the clearance receptor natriuretic peptide receptor C (NPR3) [20-22], which may confound the interpretation of results in some pathological settings.…”

Furin as proprotein convertase and its role in normal and pathological biological processes

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