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)

Natriuretic peptide system consists of three endogenous ligands, ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), and three receptor subtypes, natriuretic peptide receptor (NPR)-A or guanylate cyclase (GC)-A and NPR-B or GC-B and C receptor (NPR-C). ANP and BNP are mainly secreted from the atrium and ventricle of the heart respectively to act as cardiac hormones whereas CNP is secreted from the endothelium to act as an endothelium-derived relaxing peptide. ANP and BNP regulate body fluid and blood pressure to reduce cardiac pre- and after-load. Recent molecular biology and developmental biotechnology demonstrated the physiological role of ANP and BNP for the determination of basal blood pressure. CNP can modulate the phenotype of vascular smooth muscle cells to regulate vascular remodeling. Therefore, natriuretic peptide system is implicated in the pathophysiology of hypertension, congestive heart failure atherosclerosis and renal diseases. Clinical application of natriuretic peptide system is actively going on progress. Determination of plasma ANP and BNP levels are useful for the evaluation of congestive heart failure, cardiac hypertrophy and acute myocardial infarction. Infusion of ANP improves acute heart failure. Application of NEP (neutral endopeptidase) inhibitor for the treatment of congestive heart failure and hypertension is under clinical trial.
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PMID:[Natriuretic peptide system]. 928 3

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

The natriuretic peptides are a group of structurally similar but genetically distinct peptides that have diverse actions in cardiovascular, renal, and endocrine homeostasis. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are of myocardial cell origin and C-type natriuretic peptide (CNP) is of endothelial origin. ANP and BNP bind to the natriuretic peptide-A receptor (NPR-A), which, via 3',5'-cyclic guanosine monophosphate (cGMP), mediates natriuresis, vasodilation, renin inhibition, antimitogenesis, and lusitropic properties. CNP lacks natriuretic actions but possesses vasodilating and growth-inhibiting actions via the guanylyl cyclase-linked natriuretic peptide-B receptor (NPR-B). All three peptides are cleared by the natriuretic peptide-C receptor (NPR-C) and are degraded by the ectoenzyme neutral endopeptidase 24.11 (NEP), both of which are widely expressed in the kidneys, lungs, and the vascular wall. Congestive heart failure (CHF) represents a pathological state in which the activation of the natriuretic peptides exceeds those of all other states. In this brief review, we will attempt to provide an update on important issues regarding natriuretic peptides in CHF, with a focus on their functional importance as a beneficial humoral response in asymptomatic left ventricular dysfunction (LVD), the mechanisms of natriuretic peptide hyporesponsiveness in severe heart failure, the diagnostic and prognostic significance of the natriuretic peptides in CHF, and the therapeutic potential of the natriuretic peptides in this multiorgan syndrome.
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PMID:The natriuretic peptides in heart failure: diagnostic and therapeutic potentials. 1051 61

The identification of natriuretic peptides as key regulators of natriuresis and vasodilatation, and the appreciation that their secretion is under the control of cardiac hemodynamic and neurohumoral factors, has caused wide interest. The natriuretic peptides are structurally similar, but genetically distinct peptides that have diverse actions on cardiovascular, renal, and endocrine homeostasis. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are of myocardial cell origin, while cardiac natriuretic peptide (CNP) is of endothelial origin. ANP and BNP bind to the natriuretic peptide receptor (NPR-A) which, via 3' 5'-cyclic guanosine monophosphate (cGMP), mediates natriuresis, vasodialation, renin inhibition, and antimitogenic properties. CNP lacks natriuretic action but possesses vasodilating and growth inhibiting effects via the guanyl cyclase linked natriuretic peptide-B (NPR-B) receptor. All three peptides are cleared by natriuretic peptide-C receptor (NPR-C) and degraded by neutral endopeptidase, both of which are widely expressed in kidney, lung, and vascular wall. Recently, a fourth member of the natriuretic peptide, dendroaspsis natriuretic peptide (DNP) has been reported to be present in human plasma and atrial myocardium.
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PMID:Brain natriuretic peptide: role in cardiovascular and volume homeostasis. 1222 50

The objective of the present study was to assess the cardioprotective effect of dual NEP-ACE inhibition in relation to endogenous cardiac bradykinin (BK), its active metabolite des-Arg9-BK, endogenous brain natriuretic peptides (BNP), and cGMP. Rats were treated with the dual metallopeptidase inhibitor, omapatrilat, or the ACE inhibitor, ramipril, for 7 d (1 mg.kg(-1).d(-1)). Hearts were then isolated and subjected to a zero-flow ischemia and reperfusion (except controls), in the absence or presence of either a B2-receptor antagonist (Hoe-140), a B1-receptor antagonist (Lys-Leu8-des-Arg9-BK), or the GC-A/GC-B-receptor antagonist (HS-142-1). Chronic omapatrilat and ramipril increased the amount of endogenous BK collected upon reperfusion, but only ramipril increased that of des-Arg9-BK. Only omapatrilat increased both peak BNP and peak cGMP upon reperfusion, those increases being blocked by Hoe-140. Chronic omapatrilat (but not ramipril) decreased the total noradrenaline and lactate dehydrogenase release during the reperfusion period. Importantly, only omapatrilat improved the functional recovery of the ischemic reperfused heart, with a reduced left ventricular end-diastolic pressure, and improved developed left ventricular pressure. All cardio protective effects of omapatrilat were blocked by Hoe-140 and by HS-142-1, but not by the B1-receptor antagonist. In conclusion, a chronic treatment with a dual metallopeptidase inhibitor demonstrated a cardioprotective action not observed with an ACE inhibitor in a context of severe ischemia in rat isolated hearts, which was mediated by both endogenous BK and BNP.
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PMID:The cardioprotective effect of dual metallopeptidase inhibition: respective roles of endogenous kinins and natriuretic peptides. 1579 Dec 90

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

Temporal carbohydrate expression patterns at cell surfaces are thought to be of crucial regulatory significance during developmental processes. Hitherto, however, data on individual membrane proteins undergoing development-associated changes in glycosylation are sparsely. Here, we show that the two natriuretic peptide receptors, guanylyl cyclase-A (GC-A) and GC-B are subject to pronounced size alterations in the rat brain between postnatal day 1 and adult. Comparable size changes were not detectable for GC-A and GC-B in peripheral tissues and for three other membrane proteins (insulin receptor, insulin-like growth factor-II/mannose-6-phoshate receptor, neutral endopeptidase) in brain, indicating remarkable specificity. As revealed by treatments with carbohydrate-digesting enzymes, both GC-A and GC-B are hyperglycosylated at N-linked glycosylation sites in the developing brain. At postnatal day 1, the vast majority of GC-B (but not GC-A) molecules contain additionally an O-linked carbohydrate modification of about 1 kDa in mass and a further modification of similar size which is resistant to enzymatic removal. The glycoforms exhibited functional activity in membrane GC assays, indicating proper folding and signaling capability. These data link recently reported roles of natriuretic peptides during brain development for the first time with specific glycosylation states of their cyclic GMP-generating receptors.
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PMID:The membrane receptors guanylyl cyclase-A and -B undergo distinctive changes in post-translational modification during brain development. 2088 10

Here, we investigated the receptor profile of the newly designed natriuretic peptide (NP) ACNP consisting of the N- and C-terminus of human ANP and the ring structure of CNP, its potency/efficacy in stimulating cGMP generation in primary cells, and its stability towards peptidase activity. ACNP stimulated both human natriuretic peptide receptors (NPRs), NPRA and NPRB, as potent as their native ligands in receptor transfected cells. Consequently, ACNP was more efficient in generating cGMP compared to ANP, BNP, and CNP, in primary cells expressing both NPRs. All NPs have been similarly degraded by neprilysin, except the neprilysin-resistant BNP. However, ACNP was fastest degraded in serum, while CNP was most stable. Congruently, CNP but not ACNP reduced blood pressure most significantly after acute peptide infusion in normotensive mice. Our data identify ACNP as the first compound being able to stimulate both natriuretic receptors with similar potency and efficacy as their respective ligands.
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PMID:Chimeric natriuretic peptide ACNP stimulates both natriuretic peptide receptors, the NPRA and NPRB. 2318 9


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