Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The reduced ability of inhaled compared with intravenous atrial natriuretic peptide (ANP) to modify bronchial reactivity and tone may be due to degradation of the peptide by neutral endopeptidase (NEP) within the airways. To test this hypothesis, we have examined the effect of thiorphan, an NEP inhibitor, on the protection afforded by inhaled ANP against histamine-induced bronchoconstriction in 10 mildly asthmatic patients. Pretreatment with ANP alone attenuated the bronchoconstrictor response to histamine with a mean (SEM) maximum percent fall in FEV1 after histamine of 15.9 (2.9) (p < 0.05) compared with 24 (2.9) after placebo and 24 (4) after pretreatment with thiorphan alone. Prior inhalation of thiorphan greatly enhanced the ANP effect: the mean maximum percent fall after this combination was 5.1 (2.3) (p < 0.01, compared with ANP alone). Our results suggest that airway NEP is important in modulating the effect of inhaled ANP. It may be possible to exploit the guanylyl cyclase pathway, by which ANP acts, in the treatment of asthma by the administration of ANP analogues stable to neutral endopeptidase.
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PMID:Effect of inhaled atrial natriuretic peptide and a neutral endopeptidase inhibitor on histamine-induced bronchoconstriction. 776 51

1. The effects of sodium supplements on the renal responses to human atrial natriuretic peptide (hANP 99-126) and to the selective inhibitors of neutral endopeptidase 3.4.24.11 (NEP) SQ 28,603 and candoxatrilat were determined in conscious monkeys. 2. When the monkeys' diet was changed from 0.55% sodium to 1.1% sodium, the natriuretic response to 100 mumol/kg intravenous of SQ 28,603 increased from 665 +/- 64 to 1015 +/- 224 mu Eq/3 h. An acute oral load of 25 mEq sodium significantly increased the natriuresis stimulated by 300 mumol/kg, p.o., of SQ 28,603 from 700 +/- 332 mu Eq/3 h in normal monkey to 2437 +/- 841 mu Eq/3 h. Therefore, the non-human primate model was appropriate for investigating the effects of sodium loads on the urinary ANP and cGMP responses to exogenous ANP in the presence and absence of NEP inhibitors. 3. Graded intravenous infusions of saline increased basal urine volume and excretion of sodium and ANP. Salt supplements enhanced the diuretic, natriuretic and ANP responses to 0.3 nmol/kg intravenous of hANP 99-126 in monkeys treated with vehicle or 10 mumol/kg intravenous of candoxatrilat. The sodium and ANP excretions stimulated by hANP 99-126 were positively correlated with each other and with the calculated intravenous sodium load in the presence or absence of candoxatrilat. 4. SQ 28,603 and candoxatrilat (0.3 to 10 mumol/kg intravenous) each produced significant, dose-related potentiation of the natriuretic, cGMP and ANP responses to 0.3 nmol/kg intravenous of hANP 99-126 in monkeys receiving 5 mL/kg+0.2 mL/min saline. In addition, the highest dose of SQ 28,603 produced significant depressor activity. 5. In conclusion, the increased natriuretic activity of hANP 99-126 in sodium loaded monkeys was mediated, in part, by increased ANP delivery to the guanylate cyclase linked ANP receptors in the distal renal tubules.
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PMID:Sodium loads enhance the natriuretic responses to atrial natriuretic peptide and neutral endopeptidase inhibitors in conscious cynomolgus monkeys. 788 75

Endothelial neutral endopeptidase (EC 3.4.24.11, NEP) contributes to the inactivation of vasoactive and inflammatory peptides such as f-Met-Leu-Phe, substance P, atrial natriuretic peptide, and bradykinin. The aim of the present study was to investigate the cellular regulation of NEP expression in human endothelial cells, focusing on the role of cyclic nucleotides and cellular phosphodiesterases (PDE). Activation of adenylate cyclase by forskolin or prostaglandin E1 (PGE1) induced an increase of NEP activity and NEP protein after 24 h of incubation. This effect was mimicked by two activators of protein kinase A, dibutyryl-cAMP and 8-bromo-cAMP. The nonspecific PDE inhibitor, 3-isobutyl-1-methylxanthine (200 microM), increased NEP activity up to 192%. The activator of guanylate cyclase, sodium nitroprusside (SNP), did not affect NEP activity but completely inhibited the 3-isobutyl-1-methylxanthine-mediated increase of NEP activity. The PDE-III inhibitors motapizone (100 microM) and enoximone (100 microM) enhanced NEP activity up to 188% and 213%, the PDE-IV inhibitor rolipram (3 microM) up to 162%, and the combined PDE-III/IV inhibitor zardaverine (1 microM) up to 176% of control values. The present data provide evidence for a cAMP-mediated increase of NEP activity in human endothelial cells.
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PMID:Activation of adenylate cyclase and phosphodiesterase inhibition enhance neutral endopeptidase activity in human endothelial cells. 854 50

Brain natriuretic peptide (BNP) is a cardiac hormone with a spectrum of activities quite similar to those of atrial natriuretic peptide (ANP), including diuretic, natriuretic, hypotensive and smooth muscle relaxant activities. These effects are due to the stimulation of guanylate cyclase-linked natriuretic peptide receptors, leading to an increase in cyclic GMP concentration in target cells. BNP has a lower affinity than ANP for C (clearance) receptors, and is less susceptible to degradation by neutral endopeptidase-24.11, resulting in a longer half-life. In the kidney, BNP increases the glomerular filtration rate and inhibits sodium reabsorption in the distal tubule. It also inhibits the release of renin and aldosterone. Unlike ANP, produced by the atria, BNP is mainly synthesized and released into circulation by the left ventricle and is therefore influenced by stimuli involving this cardiac chamber, such as an increase in arterial pressure, left ventricular hypertrophy and dilation. Plasma BNP levels are very low in healthy subjects, and respond modestly, although significantly to physiological stimuli such as changes in posture or sodium intake. In contrast, plasma BNP concentrations increase in disease states such as cirrhosis with ascites, hypertension, chronic renal failure, acute myocardial infarction and congestive heart failure. In the latter condition, plasma BNP concentration is a reliable prognostic index. Evidence obtained by administering BNP to healthy subjects and hypertensive patients suggests that BNP, at physiological and pathophysiological plasma concentrations, markedly influences cardiovascular homeostasis, mainly due to its effects on sodium excretion and the renin-aldosterone axis.
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PMID:[Brain natriuretic peptide]. 871 58

The present studies were done to determine if the attenuation of the natriuretic and diuretic effects of atrial natriuretic factor (ANF) during rat pregnancy was caused by an increase in its metabolism. It was found that the plasma half-life (min), plasma clearance (ml.kg-1.min-1), and volume of distribution (ml/kg) of ANF were, respectively, 2.5 +/- 4, 115 +/- 19, and 371 +/- 44 in pentobarbital-anesthetized virgin rats (n = 6) and not different from the corresponding values of 3.1 +/- 0.5, 124 +/- 26, and 526 +/- 120 in 20-day gravid animals (n = 6). Rates of metabolism of ANF (pmol.min-1.microgram protein-1) by renal cortical membranes from virgin (n = 5) and gravid (n = 5) rats were, respectively, 45 +/- 0.6 and 45 +/- 0.5; likewise, cortical membrane neutral endopeptidase activities in virgin and 20-day gravid rats (n = 7) did not differ. It is concluded that the attenuation of the renal effects of ANF during pregnancy is not caused by changes in its systemic or renal metabolism but might be due to a decrease in guanylate cyclase-linked renal ANF receptors and/or receptor-mediated effects.
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PMID:Pharmacokinetics and renal metabolism of atrial natriuretic factor during rat pregnancy. 876 Feb 60

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

Although guanosine 3',5'-cyclic monophosphate (cGMP) acts as a relaxant second messenger, the regulation of intracellular cGMP has not been comprehensively studied in human airway smooth muscle. We studied the production of cGMP by cultured human airway smooth muscle cells (HASMC) after stimulation with activators of soluble guanylyl cyclase [sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP)] and particulate guanylyl cyclase [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and Escherichia coli heat stable enterotoxin (STa)]. cGMP was measured by enzyme-linked immunosorbent assay. Both SNP (10(-6) to 10(-3) M) and SNAP (10(-6) to 10(-3) M) caused concentration-dependent elevation of cGMP in the presence of the nonselective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (10(-3) M), with cGMP increasing 6- and 15-fold in response to SNP and SNAP, respectively, at the highest concentration tested (10(-3) M). The increases in cGMP in response to SNP (5 x 10(-5) M) and SNAP (10(-5) M) were inhibited by hemoglobin (Hb; 5 x 10(-5) M), a nitric oxide scavenger, and methylene blue (MB; 5 x 10(-4) M), an inhibitor of guanylyl cyclase. cGMP accumulation after SNAP was abolished by both Hb and MB. The response to SNP was inhibited by 79% with Hb and was abolished with MB. ANP, BNP, and CNP (10(-9) to 10(-5) M) + phosphoramidon (10(-6) M) caused a concentration-dependent elevation in cGMP with an order of potency ANP > BNP > CNP. cGMP formation in the presence of the highest concentration of the most potent natriuretic peptide (10(-5) M ANP) was two- to threefold greater than with the highest concentration of SNAP. The increase in cGMP seen with natriuretic peptides was similar in the presence or absence of phosphoramidon, a neutral endopeptidase (NEP) inhibitor, suggesting that NEP is not playing a role in modulating the effect of natriuretic peptides in HASMC. STa (400 IU/ml) had no effect on cGMP levels. SNAP- and ANP-induced cGMP accumulation was increased by the selective type V PDE inhibitors SKF-96231 and zaprinast, suggesting that type V PDE is responsible for cGMP breakdown in HASMC. These results suggest that cultured HASMC contain both soluble and particulate guanylyl cyclases. The order of potency of the natriuretic peptides ANP > BNP > CNP suggests that type A particulate membrane-bound guanylate cyclase predominates.
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PMID:Regulation of cGMP by soluble and particulate guanylyl cyclases in cultured human airway smooth muscle. 935 56

Systemic clearance of atrial natriuretic peptide (ANP) is in part due to neutral endopeptidase (NEP) proteolysis and natriuretic peptide receptor-C (NPR-C) mediated endocytosis. Biological responses to ANP are primarily mediated by the membrane guanylyl cyclase-A/natriuretic peptide receptor-A (NPR-A). Analogs of ANP selective for NPR-A and/or resistant to NEP may have increased activity in those tissues where NPR-C and NEP are coexpressed with NPR-A. The analog of ANP termed vANP; [(R3D, G9T, R11S, M12L, G16R)ANP] is selective for human NPR-A with at least 10,000 fold reduction in affinity for human NPR-C. We report that rat NPR-A is insensitive to 10 nM vANP, demonstrating the limitations of this species in evaluating human therapeutic candidates. As an alternative approach we tested the binding and potency of receptor-selective and NEP-resistant ANP analogs in rhesus monkey tissues. Competition binding studies with a simplified version of vANP, sANP [(G9T, R11S, G16R)rANP], in rhesus monkey kidney and lung membrane preparations shows displacement of 125I-ANP from only a fraction of the total ANP receptor population, 30 and 85%, respectively. The remaining ANP binding sites can be occupied with the NPR-C selective ligand cANP(4-23). These data strongly suggest that only two classes of ANP receptor are present in these membrane preparations, NPR-A and NPR-C. The NEP resistant sANP derivative called sANP(TAPR) was 8 fold more potent (ED50 = 0.6 nM) than rANP (ED50 = 5 nM) in stimulating cGMP production in the lung membrane preparation. Our results demonstrate that the rhesus monkey natriuretic peptide receptors reflect the pharmacology of the human receptors, and that this species may be suitable to determine the role of NPR-C and NEP in peptide clearance and attenuating functional responses.
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PMID:Receptor-specific ligands distinguish natriuretic peptide receptors-A and -C in primate tissues. 954 16

Insofar as neutral endopeptidase inhibition has afforded evidence for a tubular luminal action of atrial natriuretic peptide (ANP), the present study was undertaken to investigate a possible effect of the peptide on chloride reabsorption (JCl) in thick ascending limb (TAL). Luminal addition of ANP to in vitro microperfused cortical TAL (CTAL) significantly decreased JCl with a threshold and a maximum concentration of 10(-12) M and 10(-9) M, respectively. A similar effect of 10(-9) M ANP was observed in medullary TAL (MTAL). The effect of luminal ANP was significantly reduced by HS-142-1, a specific inhibitor of guanylyl cyclase receptor, and by H-8, a protein kinase G inhibitor, but was not affected by the protein kinase C inhibitor bisindolylmaleimide I. Unexpectedly, the effect of ANP was not additive with that of endothelin (ET), a peptide that was previously shown to decrease JCl in TAL through a calcium-independent, protein kinase C-mediated pathway. Indeed, ET-1 (10(-8) M in the lumen) significantly decreased JCl and prevented a further effect of ANP on the same tubule. Similarly, the decrease of JCl induced by simultaneous addition of ET and ANP was not higher than that obtained with each agent alone. Conversely, the inhibitory effect of ANP was enhanced in the presence of cyclic guanosine monophosphate (cGMP; 10(-6) M in the lumen). ET-1 significantly attenuated the ANP-stimulated generation of cGMP in microdissected CTAL and failed to prevent a further decrease of JCl promoted by a permeant cGMP analogue. It is concluded that luminal ANP decreased Cl reabsorption in mouse CTAL and MTAL. This effect was abrogated by ET-1 as a result of the inhibition of ANP-stimulated cGMP generation.
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PMID:Effect of luminal atrial natriuretic peptide on chloride reabsorption in mouse cortical thick ascending limb: inhibition by endothelin. 1100 8

Two natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), are found principally in the heart. In preliminary experiments with mouse kidney cells or slices, we found mouse BNP1-45 much more potent than ANP1-28 in causing elevations of cGMP (>50-fold). The guanylyl cyclase-A (GC-A) receptor has been suggested to represent the primary means by which both peptides signal. In cultured cells overexpressing GC-A, BNP and ANP were almost equivalent in potency, suggesting that a receptor unique for BNP exists in the kidney. However, in mice lacking the GC-A gene, neither BNP nor ANP significantly elevated cGMP in kidney slices. Phosphoramidon, a neutral endopeptidase inhibitor, shifted the apparent potency of ANP to values equivalent to that of BNP, suggesting these kidney cell/slices rapidly degrade ANP but not BNP. Mass spectroscopic analysis confirmed that ANP is rapidly cleaved at the first cysteine of the disulfide ring, whereas BNP is particularly stable to such cleavage. Other tissues (heart, aorta) failed to significantly degrade ANP or BNP, and therefore the kidney-specific degradation of ANP provides a mechanism for preferential regulation of kidney function by BNP independent of peripheral ANP concentration.
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PMID:Apparent B-type natriuretic peptide selectivity in the kidney due to differential processing. 1155 80


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