Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of important degradative pathways of atrial natriuretic peptide (ANP) in vivo could be a valuable therapeutic tool for regulating endogenous levels of ANP. The aim was to investigate the in vivo effects of both blockade of atrial natriuretic peptide clearance receptor and inhibition of neutral endopeptidase 24.11, an enzyme shown to be involved in ANP breakdown. Therefore, we infused a specific neutral endopeptidase inhibitor ((S)-thiorphan) and an ANP-C receptor ligand (AP 811) alone or in combination into anaesthetized beagle dogs. Compared with vehicle controls, coadministration of (S)-thiorphan and AP 811 (100 micrograms/kg/min and 10 micrograms/kg/min, resp.) had greater effects on endocrine and renal parameters than administration of either substance alone. Coadministration of both compounds increased urinary excretion of volume and sodium, cGMP and ANP. We found also increased plasma cGMP, plasma ANP and decreased plasma renin activity. No effects were observed with respect to blood pressure, left ventricular pressure or heart rate during the infusion period of 2 h. We conclude from these investigations, that blocking both degrading pathways of ANP with the ANP-C receptor ligand AP 811 and the neutral endopeptidase inhibitor (S)-thiorphan is more effective than inhibition of either system alone. Such a combination might therefore be a useful therapeutic tool in cardiovascular diseases.
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PMID:Interaction of a neutral endopeptidase inhibitor with an ANP-C receptor ligand in anesthetized dogs. 758 Dec 58

Although many studies have examined the effects of administering natriuretic peptide receptor C (NPR-C) ligands and endopeptidase 24.11 (EP 24.11) inhibitors on clearance and bioactivity of atrial natriuretic peptide (ANP), none have systematically compared their effects on the endogenous levels of both ANP and brain natriuretic peptide (BNP) under physiological conditions. Accordingly, we examined the hemodynamic, hormonal, and renal actions of an EP 24.11 inhibitor, SCH-32615, and an NPR-C ligand, C-ANP-(4-23), both alone and in combination in eight normal conscious sheep. NPR-C blockade and EP 24.11 inhibition induce similar rises in plasma ANP, BNP, and guanosine 3',5'-cyclic monophosphate (cGMP). Synergistic increments in plasma ANP, BNP, and cGMP observed during combined administration are likely to be due to the reduced clearance of C-ANP-(4-23) in the setting of EP 24.11 inhibition, leading to increased inhibition of the receptor pathway. Combined administration was also associated with enhanced hemodynamic actions and diuretic and natriuretic effects. Our findings show that both enzymatic and receptor clearance pathways contribute equally to natriuretic peptide clearance and induce potentially important hemodynamic and renal effects in normal conscious sheep.
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PMID:Clearance receptors and endopeptidase 24.11: equal role in natriuretic peptide metabolism in conscious sheep. 877 Jan 37

The effects of separate and combined endopeptidase inhibition (by SCH-32615) and natriuretic peptide receptor C blockade [by C-ANP-(4-23)] on the clearance and bioactivity of atrial (ANP) and brain (BNP) natriuretic peptides was investigated in eight sheep with heart failure. SCH-32615 and C-ANP-(4-23) administered separately induced significant and proportionate dose-dependent rises in plasma ANP, BNP, and guanosine 3',5'-cyclic monophosphate (cGMP) levels. Associated with these changes were reductions in arterial pressure, left atrial pressure, and peripheral resistance and increases in cardiac output, urine volume, sodium excretion, and creatinine clearance. SCH-32615 induced greater diuresis and natriuresis than C-ANP-(4-23). Combined administration of SCH-32615 and C-ANP-(4-23) induced greater than additive rises in plasma ANP, BNP, and cGMP concentrations, with enhanced hemodynamic effects, diuresis, and natriuresis and reduced plasma aldosterone levels. In conclusion, we find that the enzymatic and receptor clearance pathways contribute equally to the metabolism of endogenous ANP and BNP in sheep with heart failure. Combined inhibition of both degradative pathways was associated with enhanced hormonal, hemodynamic, and renal effects and may have greater potential therapeutic value than either agent separately.
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PMID:Clearance receptors and endopeptidase: equal role in natriuretic peptide metabolism in heart failure. 937 74

C-type natriuretic peptide (CNP) is a 22-amino-acid peptide, structurally related to but genetically distinct from atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Whereas ANP and BNP are ligands for a guanylyl cyclase-coupled receptor, the NPR-A receptor, CNP is a specific ligand for the NPR-B receptor. In addition to clearance by the NPR-C receptor, CNP is subject to degradation by the ectoenzyme neutral endopeptidase 24.11 (NEP), which is widely distributed in the kidney, lung, heart, and endothelial cells. Although initially identified in porcine brain, CNP immunoreactivity has been found in human vascular endothelial cells, plasma, and kidney. CNP has potent systemic cardiovascular actions, which include reductions in cardiac filling pressures and output, secondary to vasorelaxation and decreases in venous return, but has minimal renal actions. Unlike ANP, CNP is a selective endothelium-independent venodilator. However, it is also a potent coronary vasodilator. Expression of the CNP gene by the endothelial cells, the presence of CNP receptors on vascular smooth muscle cells (VSMCs), and the antimitogenic effect of CNP on VSMCs suggest that CNP is produced by the endothelium and acts on adjacent VSMCs serving as an autocrine/paracrine endothelium-derived vasoregulatory system.
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PMID:C-type natriuretic peptide: the endothelial component of the natriuretic peptide system. 988 43

The expression of the natriuretic peptide system in the human ocular ciliary epithelium (CE) and in cultured nonpigmented (NPE) ciliary epithelial cells was examined. By RT-PCR and DNA sequencing, we demonstrated that the CE and NPE cells express mRNA for (i) ANP; (ii) BNP; (iii) NPR-A, NPR-B, and NPR-C receptors; and (iv) the neutral endopeptidase 24.11. Radioimmunoassay results indicate that BNP is secreted by cultured NPE cells at much higher levels than ANP. NPR-A and NPR-B receptors elicited a cGMP response to ANP, BNP, and CNP, in a rank order of potency (CNP >> ANP >/= BNP), indicative that the NPR-B receptor is predominant in NPE cells. A71915, an inhibitor of NPR-A activity, attenuated (65-75%) cGMP response to ANP and BNP, but not to CNP. C-ANP4-23 elicited an inhibitory effect (30-37%) on basal levels of cAMP in NPE cells and on forskolin NPE-treated cells, indicative that the NPR-C receptor is functional in these cells. PMA induced, in NPE cells, a long-term downregulation (75-85%) of NPR-C receptor mRNA, but not of NPR-A or NPR-B receptor mRNA, suggesting a differential regulation of NPR-C receptor mRNA via activation of PKC. Collectively, our data provide molecular evidence that all the components of the natriuretic peptide system with the exception of CNP are coexpressed in the ocular NPE ciliary epithelial cells, where they may function as local autocrine/paracrine modulators to influence eye pressure.
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PMID:Functional expression of components of the natriuretic peptide system in human ocular nonpigmented ciliary epithelial cells. 1022 28

Metabolism of natriuretic peptides is regulated by two degradative pathways: uptake by the clearance receptor (natriuretic peptide receptor C--NPR-C) and hydrolysis by neutral endopeptidase (NEP). Affinity studies favour a dominant role of NPR-C in hormone degradation in several species but do not account for the efficacy of NEP inhibitors in vivo, nor the uniquely prolonged half life (t((1/2))) of human brain natriuretic peptide (hBNP). Postulating that (1) delayed metabolism of hBNP reflects resistance to NEP and (2) interactions between NPR-C and NEP increase enzyme activity, we have used purified ovine and human NEP, plus ovine lung plasma membranes to study the relative importance of receptor and enzyme pathways. We have also related the findings to hormone metabolism in vivo. Binding affinities of atrial natriuretic peptide (ANP), hBNP and ovine BNP (oBNP) to oNPR-C were similar (K(d)=8-16 pM). In contrast, unlike ANP and oBNP, hBNP was not significantly degraded by purified oNEP or plasma membranes. Despite similar (and high) affinity of oNPR-C for oBNP and hBNP, the t((1/2)) of hBNP (12.7 min) was more than fourfold that of oBNP (2.6 min). Although we found no evidence for receptor-enzyme interaction, our results show that the delayed metabolism of hBNP reflects resistance to NEP. These findings have important implications for future treatment strategies in human disease.
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PMID:Delayed metabolism of human brain natriuretic peptide reflects resistance to neutral endopeptidase. 1105 37

C-type natriuretic peptide (CNP), a local regulator of vascular tone and cell proliferation, is eliminated from the circulation via NPR-C receptors and neutral endopeptidase enzyme (NEP, EC. 3.4.24.11). The increased contractility of coronary arteries in different cardiovascular diseases made us study the possible enhancement of vasodilator capacity of exogenously added CNP with concomitant NEP inhibition on porcine coronary arteries in vitro. CNP (0.006-1.4 microM) concentration dependently relaxed the U46619 (0.07-0.4 microM) precontracted preparations in an almost equally effective manner in the presence and absence of functional endothelium with maximum effects of about 40%. The combined NEP/endothelin-converting enzyme inhibitor (NEP/ECE inhibitor), phosphoramidon (10 microM) or the specific inhibitor of the NEP, thiorphan (10 microM) resulted in an enhanced magnitude of CNP-induced relaxation without significant change in the EC50 both on endothelium intact and endothelium deprived preparations. The inhibition of endothelin receptors by PD 142893 (10 microM) enhanced the relaxing effect of CNP in the presence but not in the absence of functional endothelium indicating a functional antagonism between CNP and endothelin. Our results suggest that inhibition of CNP degradation may endue this endogenous peptide with therapeutic potency in cardiovascular diseases.
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PMID:NEP inhibitors enhance C-type natriuretic peptide-induced relaxation in porcine isolated coronary artery. 1616 83

Natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide) are cardiac and vascular peptides with vasodilatory, diuretic, natriuretic, anti-inflammatory, antifibrotic and antimitogenic actions. Natriuretic peptides are implicated in normal pressure and volume homeostasis and in the defence against excessive increases in overload-related factors, vasopressive and cardiotoxic factors and their impact on the heart, blood vessels and brain. Genetic manipulation studies confirmed the importance of natriuretic peptides in these functions. Natriuretic peptides are metabolised by NPR-C (clearance receptors) and by enzymatic degradation by neutral endopeptidase. Natriuretic peptide levels (mainly brain natriuretic peptide) correlate with left ventricular hypertrophy and with the severity of heart failure, and are reduced by effective treatment, thus used as diagnostic and prognostic tools. Based on the multiple protective effects of natriuretic peptides, pharmacological therapy has been approved and includes potentiating natriuretic peptide levels by intravenous infusion or by inhibition of endogenous natriuretic peptide degradation. Because each approach has its limitations, the field remains open for improvement.
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PMID:Natriuretic peptides as therapeutic targets. 1654 73

Natriuretic peptides belong to a family of small proteins that play a major role in modulation of natriuresis, diuresis and vasodilatation. They counteract the activity of renin-angiotensin-aldosterone system. They are also involved in the regulation of homeostasis, fat metabolism and long bone growth. Natriuretic peptides family in mammals consists of three main members: atrial natriuretic peptide (ANP) - secreted by the atrial myocardium; brain natriuretic peptide (BNP)--secreted mainly by the ventricular myocardium, and C-type natriuretic peptide (CNP)--produced and released by endothelial cells. Secretion of these peptides is stimulated by atrial and ventricular distension, increased blood pressure, hypoxia or renal dysfunction. Natriuretic peptides play their roles via interactions with NPR-A and NPR-B receptors which are transmembrane guanylyl cyclases. Their local concentrations, regulated by internalization and degradation, are mediated by the NPR-C receptor and by neutral endopeptidase. The paper presents the current knowledge of structure and biological function of natriuretic peptides.
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PMID:[Natriuretic peptides--their receptors and role in cardiovascular system]. 1861 May 80

A heterozygous frameshift mutation causing a 12-amino acid extension to the C terminus of atrial natriuretic peptide (ANP) was recently genetically linked to patients with familial atrial fibrillation (Hodgson-Zingman, D. M., Karst, M. L., Zingman, L. V., Heublein, D. M., Darbar, D., Herron, K. J., Ballew, J. D., de Andrade, M., Burnett, J. C., Jr., and Olson, T. M. (2008) N. Engl. J. Med. 359, 158-165). The frameshift product (fsANP), but not wild-type ANP (wtANP), was elevated in the serum of affected patients, but the molecular basis for the elevated peptide concentrations was not determined. Here, we measured the ability of fsANP to interact with natriuretic peptide receptors and to be proteolytically degraded. fsANP and wtANP bound and activated human NPR-A and NPR-C similarly, whereas fsANP had a slightly increased efficacy for human NPR-B. Proteolytic susceptibility was addressed with novel bioassays that measure the time required for kidney membranes or purified neutral endopeptidase to abolish ANP-dependent activation of NPR-A. The half-life of fsANP was markedly greater than that of wtANP in both assays. Additional membrane proteolysis studies indicated that wtANP and fsANP are preferentially degraded by neutral endopeptidase and serine peptidases, respectively. These data indicate that the familial ANP mutation associated with atrial fibrillation has only minor effects on natriuretic peptide receptor interactions but markedly modifies peptide proteolysis.
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PMID:A familial mutation renders atrial natriuretic Peptide resistant to proteolytic degradation. 1945 86


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