Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several processes participate in the clearance of atrial natriuretic peptide (ANP) from the circulation, one of which is enzymatic degradation. Endoprotease EC 3.4.24.11 (NEP 24.11), present within the kidney in high concentration, has been shown in vitro to degrade ANP. Phosphoramidon and thiorphan, two potent NEP 24.11 inhibitors, have been shown to prevent the enzymatic degradation of ANP. The purpose of the present study was to determine if phosphoramidon or thiorphan would alter the in vivo time course of the pharmacologic effects of ANP. The magnitude and duration of the ANP-induced increase in urine output and sodium and cyclic GMP excretion were examined with and without either thiorphan or phosphoramidon. Six separate groups of anesthetized rats received either a low, medium, or high infusion rate of thiorphan or phosphoramidon. Renal responses to ANP were potentiated and prolonged during the low phosphoramidon infusion (3 Ki) and the medium thiorphan infusion (150 Ki). At high inhibitor infusion rates in the anesthetized rat, ANP elicited a marked depressor response. In the conscious spontaneously hypertensive rat (SHR), a 15-min intravenous (i.v.) infusion of ANP (1 microgram/kg/min) lowered mean arterial pressure (MAP 23 +/- 6 mm Hg), with an approximately 35-min duration of action. A simultaneous i.v. infusion of phosphoramidon (high dose) produced both a potentiation (33 +/- 3 mm Hg) and a prolongation (greater than 65 min to return to baseline) of the depressor response. These data lend support to the hypothesis that enzymatic breakdown of ANP may play an important role in regulating the actions of atrial natriuretic peptide.
 ...
PMID:Degradation of atrial natriuretic peptide: pharmacologic effects of protease EC 24.11 inhibition. 247 3

Neutral endopeptidase (NEP, EC 3.4.24.11), purified from renal brush border, cleaves the Cys7-Phe8 amide bond of rat atrial natriuretic peptide (ANP), to generate the inactive metabolite (ANP cleaved at the Cys7-Phe8 bond; x-ANP). To determine if NEP contributes to the inactivation of circulating ANP, we investigated the degradation of rat ANP (rANP, 1-28) in the vasculature. Formation of x-ANP from exogenous ANP was studied in a mesenteric arterial preparation by perfusion in a single pass system in the presence and absence of the NEP inhibitors, thiorphan or phosphoramidon. In addition, a purified membrane fraction was prepared from mesenteric arterial homogenate and compared with an equivalent renal membrane fraction. Formation of x-ANP was quantified by a specific immunoassay (ELISA). Renal and vascular membranes shared the same pH optima for x-ANP formation (pH 7.5), although x-ANP generation was considerably greater in renal vs. vascular membranes (31.6 and 0.4 nmol min-1 mg-1 of protein, respectively). Both preparations were inhibited in a similar, dose-dependent manner by phosphoramidon, thiorphan or a polyclonal antibody to NEP. In perfused mesenteric arteries, 1.6 +/- 0.8 pmol of x-ANP were generated from 1 microgram of ANP; this formation was inhibited 51% by 10 microM phosphoramidon or thiorphan. Plasma levels of x-ANP after bolus i.v. administration of rANP in rats, were inhibited (70-80%) by thiorphan at comparable doses to those used in perfused mesenteric arteries. These studies indicate that ANP is degraded in the vasculature by NEP or an "NEP-like" enzyme(s).
 ...
PMID:Rat vascular tissue contains a neutral endopeptidase capable of degrading atrial natriuretic peptide. 253 52

The effects of the selective neutral endopeptidase (EC 3.4.24.11, NEP) inhibitor SQ 28,603 on endogenous plasma endothelin (ET) concentration and on the clearance from the circulation of exogenously administered synthetic human ET-1 were examined in Sprague-Dawley rats. Inhibition of NEP by SQ 28,603 (100 mumol/kg intravenously, i.v.) affected neither basal levels of plasma ET nor the circulatory clearance of an i.v. administered bolus dose (3 nmol/kg) of ET-1. ET-1 produced marked, statistically significant increases in plasma atrial natriuretic peptide (ANP) and cyclic GMP concentrations. SQ 28,603 markedly augmented the duration of the increases in plasma concentrations of ANP and cyclic GMP induced by exogenous ET-1. SQ 28,603 alone produced modest but statistically significant increases in plasma ANP and cyclic GMP concentrations that lasted for at least 30 min. These results clearly demonstrate that NEP does not contribute to the in vivo clearance of ET and support the hypothesis that NEP plays an important role in clearance of ANP from the circulation.
 ...
PMID:Effects of neutral endopeptidase inhibition on the clearance of exogenously administered endothelin in Sprague-Dawley rats. 768 10

We examined adenosine 5'-triphosphate (ATP), pertussis toxin (PT) and phorbol myristate acetate (PMA), a protein kinase C (PKC) activator, modulation of atrial natriuretic peptide (ANP)-stimulated cell-membrane guanylate cyclase (ANP-s-GC) activity and ANP stimulation of whole-cell cGMP accumulation (ANP-s-cGMP) in an ANP-receptor-transduction cell model, the human renal cell line (SK-NEP-1). Acute and long-term effects of PMA on PKC isotype activity are different: Acute (20-min) PMA activation of PKC inhibits ANP-s-cGMP and ANP-s-GC; whereas, long-term (36-h) PMA treatment inhibits slightly less by only partially down-regulating PKC activity, the type-III PKC isotype being 36-h resistant. Long-term 10(-7)M PMA treatment of cells neither affected membrane basal GC activity nor ANP-s-GC activity but partially inhibited ATP enhancement of ANP-s-GC. This partial inhibition was completely reversed by the PKC inhibitor H7 and a PKC inhibitory antibody but only partially reversed by the antibody to the catalytic domain of PKC type III. The EC50 for ATP and its non-phosphorylating analog ATP gamma S in the presence of acute PMA inhibition of ANP-s-cGMP was similar (approximately 10(-9)). This enhancement of PMA inhibition was two orders of magnitude more sensitive (EC50 10(-7)M) than inhibition of ANP-s-cGMP that we previously reported for acute PMA treatment of whole SK-NEP-1 cells. The three- to four-fold ATP enhancement of cell membrane ANP-s-GC was not blocked by 12-hour preincubation of cells with 150 ng/mL PT but was completely blocked if 2-x-10(-7)M PMA was then added for 20 minutes, indicating that acute activation of PKC by PMA does not require a functional "G-type" protein. Acute PMA inhibition of ANP-s-cGMP was reversed by permeabilizing SK-NEP-1 cells to a specific PKC inhibitory peptide, further confirming that PMA inhibition was mediated through PKC activation. These data demonstrated that ANP-s-GC and ANP-s-cGMP were modified through non-phosphorylating interactions with ATP, by multiple PMA activatable PKC isoforms, and that neither were affected by PT-sensitive guanine-nucleotide-binding (G)-protein(s).
 ...
PMID:Adenosine 5'-triphosphate, phorbol ester, and pertussis toxin effects on atrial natriuretic peptide stimulation of guanylate cyclase in a human renal cell line. 790 11

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.
 ...
PMID:Activation of adenylate cyclase and phosphodiesterase inhibition enhance neutral endopeptidase activity in human endothelial cells. 854 50

1. We assessed the changes of atrial natriuretic peptide and brain natriuretic peptide gene expression associated with progression and regression of cardiac hypertrophy in renovascular hypertensive rats (RHR). 2. Two-kidney, one-clip hypertensive rats (6-week-old male Wistar) were made and studied 6 (RHR-1) and 10 weeks (RHR-2) after the procedure. Regression of cardiac hypertrophy was induced by nephrectomy at 6 weeks after constriction, and the nephrectomized rats were maintained further for 4 weeks (nephrectomized rat: NEP). Sham operation was performed, and the rats were studied after 6 (Sham-1) and 10 weeks (Sham-2). Atrial natriuretic peptide and brain natriuretic peptide gene expression in the left ventricle was analysed by Northern blotting. 3. Plasma atrial natriuretic peptide and brain natriuretic peptide were significantly higher in RHR-1 and RHR-2 than in Sham-1, Sham-2 and NEP. Atrial natriuretic peptide and brain natriuretic peptide mRNA levels in RHR-1 were approximately 7.2-fold and 1.8-fold higher than those in Sham-1, respectively, and the corresponding levels in RHR-2 were 13.0-fold and 2.4-fold higher than those in Sham-2, respectively. Atrial natriuretic peptide and brain natriuretic peptide mRNA levels of NEP were normalized. Levels of atrial natriuretic peptide and brain natriuretic peptide mRNA were well correlated positively with left ventricular weight/body weight ratios. There was a significant positive correlation between the levels of atrial natriuretic peptide and brain natriuretic peptide mRNA (r = 0.86, P < 0.01). 4. We conclude that the expression of atrial natriuretic peptide and brain natriuretic peptide genes is regulated in accordance with the degree of myocardial hypertrophy and that the augmented expression of these two natriuretic peptides may play an important role in the maintenance of cardiovascular haemodynamics in renovascular hypertension.
 ...
PMID:Alteration of atrial natriuretic peptide and brain natriuretic peptide gene expression associated with progression and regression of cardiac hypertrophy in renovascular hypertensive rats. 877 25

We have investigated the effects of the neutral endopeptidase inhibitor, SCH 42354, on the vasoreactivity of atrial natriuretic peptide (ANP) in rat isolated pulmonary resistance vessels (PRV) and isolated perfused lungs (IPL). PRV (n = 37) were mounted onto the jaws of a myograph and precontracted with PGF2alpha (100 mu M). Concentration-responses to ANP (0.17 to 340 nM) were determined before and after the addition of SCH 42354 (10, 30 and 100 nM). Each concentration of SCH 42354 caused a significant increase in potency (- log EC50) of ANP in isolated PRV. Lungs from normoxic rats (n = 13) were isolated and perfused with whole blood. An increase in pulmonary artery pressure was achieved by ventilating with an hypoxic gas mixture and concentration-responses obtained by incremental additions of ANP (40 nM to 12 mu M), before and after the addition of SCH 42354 (100 nM). SCH 42354 significantly increased the potency (- log EC50) of ANP in the rat IPL. ANP is partly metabolized by NEP. That an inhibitor of NEP increased the potency of ANP in isolated pulmonary vessels, and in isolated perfused whole lungs, suggested that SCH 42354 may be having a local action within the pulmonary vasculature.
 ...
PMID:Neutral endopeptidase inhibition increases the potency of ANP in isolated rat pulmonary resistance vessels and isolated blood perfused lungs. 882 Feb 54

To evaluate the interaction between renal nerves, the atrial natriuretic peptide (ANP), and the renin-angiotensin system (RAS), electrical stimulation of renal nerves was performed in spontaneously hypertensive rats (SHR) and in their normotensive controls, Wistar Kyoto rats (WKY), before and after pharmacologic treatment with (a) a neutral endopeptidase inhibitor (NEP-i) to enhance the intrarenal ANP activity; (b) an ACE inhibitor (ACE-i) to block RAS; (c) both NEP-i and ACE-i; and (d) the vehicle of the drugs. Renal nerve stimulation did not change arterial pressure (AP) but reduced renal blood flow (RBF), glomerular filtration rate (GFR), and urinary sodium excretion (UNa+V) in both WKY and SHR. NEP-i treatment in WKY and SHR had no systemic or renal hemodynamic effects but increased GFR and urinary cyclic guanosine monophosphate (GMP) excretion; UNa+V increased (+2.78 +/- 0.31 microEq/min) in WKY, whereas it did not change in SHR (+0.83 +/- 0.79 microEq/min). In both strains, ACE-i treatment reduced AP, increased RBF, and did not change GFR and UNa+V. The combined treatment with NEP-i and ACE-i did not modify the natriuretic effect observed in NEP-i treated WKY (+4.29 +/- 1.25 microEq/min), but it elicited a natriuretic effect in SHR (+3.98 +/- 1.29 microEq/min). Pharmacologic treatment did not change the hemodynamic and excretory responses to renal nerve stimulation in both WKY and SHR. In conclusion, NEP-i treatment increased UNa+V in normotensive rats without changing AP. In hypertensive rats, the natriuretic effect of NEP-i became evident only after block of RAS by ACE-i. Neither NEP-i nor ACE-i, even in combination, could modify the renal responses to sympathetic stimulation.
 ...
PMID:Excretory responses to renal nerve stimulation during inhibition of neutral metalloendopeptidase and angiotensin-converting enzyme in the rat. 894 80

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.
 ...
PMID:[Natriuretic peptide system]. 928 3

Recently high immunoreactive atrial natriuretic peptide (ir-ANP) levels have been found in the pericardial fluid of patients undergoing cardiac surgery. The present study was designed to characterize pericardial fluid ANP in anesthetized dogs. Pericardial fluid ir-ANP levels were 3.4-fold higher than plasma levels and the molecular form, revealed by high performance liquid chromatography, was indistinguishable from ANP[99-126]. Elimination of [125I]ANP was 5-fold slower in the pericardial space than in plasma. Activity of the major ANP degrading enzyme, neutral endopeptidase (NEP, EC 3.4.24.11), was 15-times higher in the pericardial fluid than in plasma. Right atrial balloon distension and rapid right ventricular pacing induced maximally 2.3-fold and 1.5-fold increases of pericardial fluid ir-ANP, respectively. Pericardial fluid ir-ANP concentrations and right atrial pressure values showed significant correlation during the stimuli. Our present results show that high concentrations of ir-ANP can be found in the dog pericardial fluid even under unstimulated conditions. Slow elimination of ANP from the pericardial fluid compartment may contribute to the high peptide levels. However this slow elimination cannot be attributed to a lower NEP activity. High basal levels of ANP in the pericardial fluid could be further increased by atrial balloon stretch and rapid ventricular pacing. The increase of pericardial fluid ir-ANP appeared to be a stretch-dependent response. ANP released into the pericardial fluid may be involved in the regulation of cardiac function and coronary vascular tone.
 ...
PMID:Characterization and stimuli for production of pericardial fluid atrial natriuretic peptide in dogs. 933 24


<< Previous 1 2 3 4 5 6 7 8 Next >>