Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The natriuretic peptide system consists of at least three endogenous ligands: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), and three receptors, ANP-A receptor (guanylate cyclase A), ANP-B receptor (guanylate cyclase B) and clearance receptor (C receptor). ANP, the prototype of natriuretic peptides, is mainly produced in the atrium and secreted into the circulation as a cardiac hormone. ANP is also produced in the ventricle and in the central nervous system. BNP, first isolated from the porcine brain, has a marked divergence in its molecular size and sequence among species. In humans and rats, the major site of production of BNP is the ventricle of the heart. BNP is also secreted into the circulation as a cardiac hormone. The plasma BNP level in normal subjects is approximately one sixths of the plasma ANP level; however, the plasma BNP level markedly increases in heart failure, renal failure and hypertension and the augmentation of the BNP secretion is much larger than that of the ANP secretion. In addition, clearance of BNP from the circulation is slower than that of ANP. Furthermore, BNP is secreted more urgently than ANP in acute heart failure. CNP distributes mainly in the central nervous system and pituitary gland. No significant amount of CNP is detectable in the heart and plasma. Thus, CNP is a local regulator rather than a cardiac hormone. Three natriuretic receptors have ligand selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Natriuretic peptide family]. 134 67

Natriuretic peptides family consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), while receptors for these natriuretic peptides comprise at least three subtypes, i.e. A-type (GC-A), B-type (GC-B) and C-type (clearance). ANP and BNP are cardiac hormones mainly synthesized and secreted by atria and ventricles, respectively, but CNP is a neuropeptide synthesized by brain. Both A- and B-type receptors contain particulate guanylate cyclase within their molecule and mediate biological function via cyclic GMP as a second messenger, whereas C-type receptor is involved in clearance and metabolism of natriuretic peptides. In heart failure, cardiac expression of both ANP and BNP is augmented with increased circulating levels as a cardiac compensatory mechanism. Pathophysiological significance of natriuretic peptides system in heart failure is discussed.
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PMID:[Natriuretic peptide family]. 839 34

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

In addition to cardiac myocyte hypertrophy, proliferation and increased extracellular matrix production of cardiac fibroblasts occur in response to cardiac overload. This remodeling of the cardiac interstitium is a major determinant of pathologic hypertrophy leading to ventricular dysfunction and heart failure. Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones produced primarily by the atrium and ventricle, respectively. Plasma ANP and BNP concentrations are elevated in patients with hypertension, cardiac hypertrophy, and acute myocardial infarction, suggesting their pathophysiologic roles in these disorders. ANP and BNP exhibit diuretic, natriuretic, and vasodilatory activities via a guanylyl cyclase-coupled natriuretic peptide receptor subtype (guanylyl cyclase-A or GC-A). Here we report the generation of mice with targeted disruption of BNP (BNP-/- mice). We observed focal fibrotic lesions in ventricles from BNP-/- mice with a remarkable increase in ventricular mRNA expression of ANP, angiotensin converting enzyme (ACE), transforming growth factor (TGF)-beta3, and pro-alpha1(I) collagen [Col alpha1(I)], which are implicated in the generation and progression of ventricular fibrosis. Electron microscopic examination revealed supercontraction of sarcomeres and disorganized myofibrils in some ventricular myocytes from BNP-/- mice. No signs of cardiac hypertrophy and systemic hypertension were noted in BNP-/- mice. In response to acute cardiac pressure overload induced by aortic constriction, massive fibrotic lesions were found in all the BNP-/- mice examined, accompanied by further increase of mRNA expression of TGF-beta3 and Col alpha1(I). We postulate that BNP acts as a cardiocyte-derived antifibrotic factor in the ventricle.
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PMID:Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart. 1155 81

Brain natriuretic peptide is one member of the natriuretic peptide family, including also ANP, CNP, DNP and urodilatin. In human, brain natriuretic peptide is mainly secreted by the cardiac ventricles. BNP is synthetized as pre-proBNP form, secondary cleaved in proBNP, itself equimolarly cleaved in BNP and NT-proBNP. The biological action of BNP is mediated by the NPR-A receptor. This peptide is eliminated from the systemic circulation by a neutral endopeptidase and by a clearance receptor (NPR-C). The BNP and NT-proBNP concentrations are measured using automated rapid immunoassay techniques. Plasma concentrations of the two peptides physiologically increase with age and are found to be higher in women than in men. The action of BNP against fluid expansion is explained by its vascular (vasodilatation), renal (diuretic and natriuretic) and cerebral activities. The measurement of these two peptides contributes to the diagnosis of heart failure. These peptides are prognostic markers both in heart failure and in acute coronary syndromes. In renal insufficiency, the interpretation of the increase in these two peptide concentrations may be difficult, particularly with the NT-proBNP which is mainly excreted by the kidneys.
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PMID:[Brain natriuretic peptide: physiological, biological and clinical aspects]. 1568 9

Natriuretic peptides are a family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. The mammalian members are atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide, and possibly osteocrin/musclin. Three single membrane-spanning natriuretic peptide receptors (NPRs) have been identified. Two, NPR-A/GC-A/NPR1 and NPR-B/GC-B/NPR2, are transmembrane guanylyl cyclases, enzymes that catalyze the synthesis of cGMP. One, NPR-C/NPR3, lacks intrinsic enzymatic activity and controls the local concentrations of natriuretic peptides through constitutive receptor-mediated internalization and degradation. Single allele-inactivating mutations in the promoter of human NPR-A are associated with hypertension and heart failure, whereas homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux. The physiological effects of natriuretic peptides are elicited through three classes of cGMP binding proteins: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. In this comprehensive review, the structure, function, regulation, and biological consequences of natriuretic peptides and their associated signaling proteins are described.
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PMID:Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. 1629 70

Dendroaspis natriuretic peptide (DNP) is a newly-described natriuretic peptide which lowers blood pressure via vasodilation. The natriuretic peptide clearance receptor (NPR-C) removes natriuretic peptides from the circulation, but whether DNP interacts with human NPR-C directly is unknown. The purpose of this study was to test the hypothesis that DNP binds to NPR-C. ANP, BNP, CNP, and the NPR-C ligands AP-811 and cANP(4-23) displaced [(125)I]-ANP from NPR-C with pM-to-nM K(i) values. DNP displaced [(125)I]-ANP from NPR-C with nM potency, which represents the first direct demonstration of binding of DNP to human NPR-C. DNP showed high pM affinity for the GC-A receptor and no affinity for GC-B (K(i)>1000 nM). DNP was nearly 10-fold more potent than ANP at stimulating cGMP production in GC-A expressing cells. Blockade of NPR-C might represent a novel therapeutic approach in augmenting the known beneficial actions of DNP in cardiovascular diseases such as hypertension and heart failure.
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PMID:Dendroaspis natriuretic peptide binds to the natriuretic peptide clearance receptor. 1747 16

Four major natriuretic peptides have been isolated: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and Dendroaspis-type natriuretic peptide (DNP). Natriuretic peptides play an important role in the regulation of cardiovascular homeostasis maintaining blood pressure and extracellular fluid volume. The classical endocrine effects of natriuretic peptides to modulate fluid and electrolyte balance and vascular smooth muscle tone are complemented by autocrine and paracrine actions that include regulation of coronary blood flow and, therefore, myocardial perfusion; modulation of proliferative responses during myocardial and vascular remodeling; and cytoprotective anti-ischemic effects. The actions of natriuretic peptides are mediated by the specific binding of these peptides to three cell surface receptors: type A natriuretic peptide receptor (NPR-A), type B natriuretic peptide receptor (NPR-B), and type C natriuretic peptide receptor (NPR-C). NPR-A and NPR-B are guanylyl cyclase receptors that increase intracellular cGMP concentration and activate cGMP-dependent protein kinases. NPR-C has been presented as a clearance receptor and its activation also results in inhibition of adenylyl cyclase activity. The wide range of effects of natriuretic peptides might be the base for the development of new therapeutic strategies of great benefit in patients with cardiovascular problems including coronary artery disease or heart failure. This review summarizes current literature concerning natriuretic peptides, their receptors and their effects on fluid/electrolyte balance, and vascular and cardiac physiology and pathology, including primary hypertension and myocardial infarction. In addition, we will attempt to provide an update on important issues regarding natriuretic peptides in congestive heart failure.
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PMID:Natriuretic peptides in vascular physiology and pathology. 1870 4

Heart failure (HF) is a common disease that continues to be associated with high morbidity and mortality warranting novel therapeutic strategies. Cyclic guanosine monophosphate (cGMP) is the second messenger of several important signaling pathways based on distinct guanylate cyclases (GCs) in the cardiovascular system. Both the nitric oxide/soluble GC (NO/sGC) as well as the natriuretic peptide/GC-A (NP/GC-A) systems are disordered in HF, providing a rationale for their therapeutic augmentation. Soluble GC activation with conventional nitrovasodilators has been used for more than a century but is associated with cGMP-independent actions and the development of tolerance, actions which novel NO-independent sGC activators now in clinical development lack. Activation of GC-A by administration of naturally occurring or designer natriuretic peptides is an emerging field, as is the inhibition of enzymes that degrade endogenous NPs. Finally, inhibition of cGMP-degrading phosphodiesterases, particularly phosphodiesterase 5 provides an additional strategy to augment cGMP-signaling.
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PMID:Modulation of cGMP in heart failure: a new therapeutic paradigm. 1908 42

Alternative RNA splicing may provide unique opportunities to identify drug targets and therapeutics. We identified an alternative spliced transcript for B-type natriuretic peptide (BNP) resulting from intronic retention. This transcript is present in failing human hearts and is reduced following mechanical unloading. The intron-retained transcript would generate a unique 34 amino acid (aa) carboxyl terminus while maintaining the remaining structure of native BNP. We generated antisera to this carboxyl terminus and identified immunoreactivity in failing human heart tissue. The alternatively spliced peptide (ASBNP) was synthesized and unlike BNP, failed to stimulate cGMP in vascular cells or vasorelax preconstricted arterial rings. This suggests that ASBNP may lack the dose-limiting effects of recombinant BNP. Given structural considerations, a carboxyl-terminal truncated form of ASBNP was generated (ASBNP.1) and was determined to retain the ability of BNP to stimulate cGMP in canine glomerular isolates and cultured human mesangial cells but lacked similar effects in vascular cells. In a canine-pacing model of heart failure, systemic infusion of ASBNP.1 did not alter mean arterial pressure but increased the glomerular filtration rate (GFR), suppressed plasma renin and angiotensin, while inducing natriuresis and diuresis. Consistent with its distinct in vivo effects, the activity of ASBNP.1 may not be explained through binding and activation of NPR-A or NPR-B. Thus, the biodesigner peptide ASBNP.1 enhances GFR associated with heart failure while lacking the vasoactive properties of BNP. These findings demonstrate that peptides with unique properties may be designed based on products of alternatively splicing.
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PMID:Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide. 1954 13


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