N-terminal pro-C-type natriuretic peptide, but not C-type natriuretic peptide, is greatly elevated in the fetal circulation

Prickett, Timothy C. R.; Kaaja, Risto; Nicholls, M. Gary; Espiner, Eric A.; Richards, A. Mark; Yandle, Timothy G.

doi:10.1042/cs20030307

Cited by 34 publications

(27 citation statements)

References 23 publications

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“…After centrifugation at 4000 rpm and 4°C for 10 minutes, plasma was stored at Ϫ80°C. After extraction using Sep Pak C 18 cartridges, NT-proCNP 29,34 and NT-proBNP 35 levels were determined using our established radioimmunoassays. CNP was measured as described previously.…”

Section: Assaysmentioning

confidence: 99%

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

et al. 2009

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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...

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Section: Assaysmentioning

confidence: 99%

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

et al. 2009

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“…NT-CNP is co-secreted with CNP and provides a sensitive and reliable alternative (53). The NH2-terminal propeptide for CNP (NT-proCNP) was assayed as previously described (52). Two milliliters of plasma were extracted on SepPak C18 cartridges and eluted with 2 ml of 80% isopropanol in 0.1% TFA, dried under air, and reconstituted with 0.5 ml of phosphate buffer.…”

Section: Analytic Measurementsmentioning

confidence: 99%

Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases

Peebles

Richards²,

Celi

et al. 2008

Journal of Applied Physiology

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Evidence from animal studies indicates that various vasoactive factors, including release of norepinephrine, endothelin, adrenomedullin, C-natriuretic peptide (CNP), and nitric oxide (NO), may play a role in arterial blood gas-induced alterations in CBF. For the first time, we directly quantified exchange of these vasoactive factors across the human brain. Using the Fick principle and transcranial Doppler ultrasonography, we measured CBF in 12 healthy humans at rest and during hypercapnia (4 and 8% CO 2), hypocapnia (voluntary hyperventilation), and hypoxia (12 and 10% O 2). At each level, blood was sampled simultaneously from the internal jugular vein and radial artery. With the exception of CNP and NO, the simultaneous quantification of norepinephrine, endothelin, or adrenomedullin showed no cerebral uptake or release during changes in arterial blood gases. Hypercapnia, but not hypocapnia, increased CBF and caused a net cerebral release of nitrite (a marker of NO), which was reflected by an increase in the venous-arterial difference for nitrite: 57 Ϯ 18 and 150 Ϯ 36 mol/l at 4% and 8% CO 2, respectively (both P Ͻ 0.05). Release of cerebral CNP was also observed during changes in CO 2 (hypercapnia vs. hypocapnia, P Ͻ 0.05). During hypoxia, there was a net cerebral uptake of nitrite, which was reflected by a decreased venous-arterial difference for nitrite: Ϫ96 Ϯ 14 mol/l at 10% O 2 (P Ͻ 0.05). These data indicate that there is a differential exchange of NO across the brain during hypercapnia and hypoxia and that CNP may play a complementary role in CO 2-induced CBF changes. cerebral circulation; nitric oxide; endothelium RESPIRATORY-INDUCED CHANGES in arterial PCO 2 (Pa CO 2 ) and, to a lesser extent, PO 2 (Pa O 2 ) play a major role in cerebral blood flow (CBF) regulation (9). Elevations in Pa CO 2 (hypercapnia) lead to vasodilation of cerebral arterioles in the downstream bed and a subsequent increase in CBF, whereas a reduction in Pa CO 2 (hypocapnia) leads to vasoconstriction and a subsequent decrease in CBF (28, 65). A fall in Pa O 2 (hypoxia) below a certain threshold (Ͻ40 Torr) also produces cerebral vasodilation (19). These arterial blood gas-induced changes in CBF are mediated through changes in cerebrovascular resistance via alterations in vascular smooth muscle diameter in response to changes in the level of intracellular calcium and/or calcium sensitivity (for review see Ref. 22). Cerebrovascular tone is influenced by several chemical substances, including nitric oxide (NO). NO, synthesized from the terminal guanidino nitrogen atom(s) of L-arginine in a two-step reaction that is catalyzed by the enzyme NO synthase (NOS) (48), is an important vasoactive factor that dilates the cerebral vasculature. Under normal conditions, two isoforms of NOS are expressed in the brain, endothelium-derived NOS (eNOS) and neuronal-derived NOS (nNOS) (61), although evidence for the role of eNOS vs. nNOS in the control of CBF is controversial (3). Vasodilation evoked by NO is initiated by an increase in cGMP (7).Pharmac...

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“…In contrast, the ovine placenta does not seem to contribute to circulating fetal CNP concentrations, which are much lower than maternal concentrations (12). Nonetheless, as in the human fetus (13), fetal CNP synthesis is likely to be high, as shown by the very high concentrations of NTproCNP in fetal plasma. Fetal CNP forms are clearly regulated independently of maternal concentrations (10), but the sites of synthesis and the source of NTproCNP in the fetal circulation remain to be determined.…”

Section: -Type Natriuretic Peptide (Cnp) Is An Important Growthmentioning

confidence: 93%

“…Reduced fetal concentrations of NTproCNP during fetal stress (10,13) or across parturition (6) are likely to be cortisol induced. …”

Section: Discussionmentioning

confidence: 99%

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Effect of Cortisol on C-Type Natriuretic Peptide in Ovine Pregnancy: Differential Responses in Fetal and Placental Tissues

et al. 2010

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ABSTRACT:We have used aminoterminal pro C-type natriuretic peptide (NTproCNP)-a stable marker of CNP secretion-to study the effect of cortisol on CNP secretion and fetal growth. In ovine pregnancy, maternal plasma NTproCNP (largely sourced from the placenta) increases at the end of the first trimester and then decreases abruptly preterm during the phase of fetal surge in cortisol secretion. Postulating that increases in cortisol, as occurs in the fetal or maternal circulation in late pregnancy, will reduce CNP secretion, we studied the fetal and maternal responses in NTproCNP to sustained low-dose infusions of cortisol (1.2 mg/d/kg for 11 d) delivered to the fetus from d 117 gestation. Fetal plasma NTproCNP was progressively reduced during fetal cortisol infusions, whereas fetal girth growth was unchanged. In contrast, maternal NTproCNP was unaffected by cortisol. We conclude that fetal but not placental tissue production of CNP is reduced by small increments in fetal cortisol. Failure to reduce maternal NTproCNP may relate to the continuing presence of the placental barrier to cortisol at this stage of pregnancy. (Pediatr Res 68: 462-465, 2010) C -type natriuretic peptide (CNP) is an important growth factor expressed in a wide range of tissues (1) during development (2) and postnatal life (3). Although shown to be essential to postnatal linear growth in both rodents (4) and humans (5), CNP production has also been found to correlate strongly with linear growth velocity in lambs and throughout all phases of linear growth in humans (6 -8). In rapidly growing lambs, catabolic interventions such as caloric restriction (9) and high doses of glucocorticoids (7), well-recognized inhibitors of linear growth, rapidly and reversibly reduce circulating forms of CNP and markers of bone formation. Similar reductions in CNP forms occur in the fetus during maternal caloric restriction (10) or glucocorticoid administration (6). However, the effect of physiological increments in fetal cortisol on CNP synthesis is unknown.Recent studies of ovine pregnancy show that both CNP and the bio inactive aminoterminal fragment of pro CNP 1-103 (NTproCNP) (11) are secreted by the placenta and circulate at high concentrations in maternal plasma from the end of the first trimester (12). In contrast, the ovine placenta does not seem to contribute to circulating fetal CNP concentrations, which are much lower than maternal concentrations (12). Nonetheless, as in the human fetus (13), fetal CNP synthesis is likely to be high, as shown by the very high concentrations of NTproCNP in fetal plasma. Fetal CNP forms are clearly regulated independently of maternal concentrations (10), but the sites of synthesis and the source of NTproCNP in the fetal circulation remain to be determined.A striking feature of the pattern of maternal plasma CNP forms in healthy pregnant ewes is the sudden decline in both NTproCNP and CNP within the last week of pregnancy (12)-a phase of rapidly increasing fetal cortisol production (14). Mindful of the inhibitory effects o...

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N-terminal pro-C-type natriuretic peptide, but not C-type natriuretic peptide, is greatly elevated in the fetal circulation

Cited by 34 publications

References 23 publications

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

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

Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases

Effect of Cortisol on C-Type Natriuretic Peptide in Ovine Pregnancy: Differential Responses in Fetal and Placental Tissues

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