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

Inhibition of the metabolism of endogenous atrial natriuretic peptide (ANP), by continuous infusion of a specific inhibitor of neutral endopeptidase (membrane metalloendopeptidase E.C. 3.4.24.11), UK 73,967 (candoxatrilat), was undertaken in rats, in which chronic hypoxia was used as a stimulus to induce pulmonary hypertension and right ventricular hypertrophy. Inhibition of neutral endopeptidase 24.11 with low-dose and high-dose UK 73,967 (NEI) increased endogenous plasma ANP by greater than 155% during the development of pulmonary hypertension. NEI treatment reduced mean pulmonary arterial pressure in hypoxia as follows: vehicle 26.6 +/- 4.0 mm Hg; low-dose NEI 22.7 +/- 1.9 mm Hg, and high-dose NEI 22.6 +/- 2.5 mm Hg (both p less than 0.01 compared with hypoxic vehicle); however, it was without effect on pulmonary arterial pressure in normoxia (17.6 +/- 2.2 mm Hg) or on systemic blood pressure. The development of right ventricular hypertrophy was also reduced in both groups treated with NEI (right ventricular weight/left ventricular weight: 0.43 +/- 0.03 vehicle; 0.40 +/- 0.02 low-dose NEI and 0.40 +/- 0.02 high-dose NEI, both p less than 0.05 compared with vehicle). Remodelling of the pulmonary vasculature, characterized by extension of the muscle within the small pulmonary arteries toward the periphery of the lung, was reduced by NEI treatment (percentage of thick-walled peripheral vessels; 19.2 +/- 3.1% vehicle; 10.4 +/- 2.3% low-dose NEI and 8.1 +/- 1.8% high-dose NEI, both p less than 0.001 compared with vehicle). In the isolated blood perfused rat lung pulsed doses of NEI had no effect on pulmonary vascular tone in the absence of ANP. Specific inhibition of the enzyme neutral endopeptidase reduces vascular remodelling, the development of pulmonary hypertension, and right ventricular hypertrophy. Endogenous ANP modulates vascular remodelling in vivo. Retarding the metabolism of endogenous ANP through inhibition of neutral endopeptidase 24.11 represents a potential approach toward therapy. g
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PMID:Neutral endopeptidase 24.11 inhibition reduces pulmonary vascular remodeling in rats exposed to chronic hypoxia. 183 25

Basal atrial natriuretic peptide levels and the response to exogenous atrial natriuretic peptide are influenced by dietary sodium intake. In view of interest in the therapeutic potential of elevating plasma atrial natriuretic peptide by inhibition of neutral endopeptidase 24.11, we studied the renal and hormonal effects of 200 mg of the oral endopeptidase 24.11 inhibitor candoxatril in eight patients with untreated essential hypertension on high sodium (350 mmol/day) and low sodium (10 mmol/day) diets. With endopeptidase 24.11 inhibition, plasma atrial natriuretic peptide increased more than twofold on low and high sodium diets (p less than 0.05). Plasma N-terminal pro-atrial natriuretic peptide increased on the high sodium intake but was unaffected by candoxatril. Urinary sodium excretion increased threefold on the low sodium and sixfold on the high sodium diet (p less than 0.05). The absolute increase in urinary sodium excretion during the 24 hours after treatment compared with placebo was 18 +/- 8 mmol on the low sodium and 98 +/- 34 mmol on the high sodium diet (p less than 0.05). Plasma renin activity was suppressed by treatment on the low but not on the high sodium diet (p less than 0.05). Blood pressure did not change in the 6 hours after a single dose of candoxatril. These findings show that sodium intake is a major determinant of the response to endopeptidase 24.11 inhibition. The lack of effect on N-terminal pro-atrial natriuretic peptide suggests that candoxatril does not influence cardiac secretion of atrial natriuretic peptide or catabolism of N-terminal pro-atrial natriuretic peptide, and the latter does not appear to play a role in the response to candoxatril.
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PMID:Dietary sodium and inhibition of neutral endopeptidase 24.11 in essential hypertension. 183 59

The neutral endopeptidase 24.11 (NEP) also called 'enkephalinase' thanks to its inactivation of enkephalins in the brain, was also recently shown to be involved in the degradation of the circulating atrial natriuretic peptide (ANP). Inhibitors of NEP are therefore under clinical trials as new analgesics or antidiarrheal agents, protecting centrally or peripherally released opioid peptides and as novel antidiuretics and anti-hypertensives in prolonging the renal and vascular actions of NEP. It was therefore important from a clinical point of view to investigate the distribution in peripheral tissue of a systemically administered NEP blocker. Different concentrations of the radiolabelled inhibitor [3H]HACBO-Gly have been intravenously injected in rat and the distribution studied using whole-body sections at different times by 'ex vivo' and 'in vitro' autoradiography to investigate differences in tissue accessibility of NEP to a circulating inhibitor. In vivo [3H]HACBO-Gly binding was fully prevented by an excess of unlabelled inhibitor and disappeared rapidly mainly through renal elimination. NEP labelling was prominent in kidney, liver, lung, fat deposits in the neck region, the flat bones of the skull, the mandibula, the vertebrae, the long bones of the limbs, articular cartilages and synoviae. A lower labelling was found in the intestine, the glomeruli and the submaxillary glands. [3H]HACBO-Gly binds also to a limited number of peripheral tissues in which the presence of NEP was yet unknown (bones, parts of adipose tissues. Some tissues, not labelled in vivo, exhibited various degrees of labelling under in vitro conditions (the brain, some portions of the gut, the testes, the prostate). Interestingly, few lobules of the submaxillary glands were much more densely labelled suggesting the possible occurrence of NEP heterogeneity. Except for the brain, the physiological function of NEP in various tissues remains largely unknown, but this ectoenzyme is likely involved in inactivation of regulatory peptides such as: ANP (partially in the kidney), SP in the lung and possibly somatostatin and ANP in bone, ANP in adipose tissue, enkephalin in testes, immune peptidic factors in bone marrow. A part of NEP in bone marrow corresponds probably to the common acute lymphoblastic antigen, CALLA, densely expressed on pre-B cells. Finally, it is important to notice that several tissues containing important concentrations of NEP (brain, testes, prostate, eye, gut, brush border) are inaccessible to the i.v. injected inhibitor thanks to the presence of functional barriers.
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PMID:Neutral endopeptidase 24.11 in rat peripheral tissues: comparative localization by 'ex vivo' and 'in vitro' autoradiography. 188 86

Neutral endopeptidase (EC 3.4.24.11, NEP) is a Zn-metallopeptidase involved in the degradation of biologically active peptides, notably the enkephalins and atrial natriuretic peptide. Recently, the structure of the active site of this enzyme has been probed by site-directed mutagenesis, and 4 amino acid residues have been identified, namely 2 histidines (His583 and His587), which act as zinc-binding ligands, a glutamate (Glu584) involved in catalysis, and an arginine residue (Arg102), suggested to participate in substrate binding. Site-directed mutagenesis has now been used to investigate the role of 4 other arginine residues (Arg408, Arg409, Arg659, and Arg747) that have been proposed as possible active site residues and to further analyze the role of Arg102. In each case, the arginine was replaced with a methionine, and both enzymatic activity and the IC50 values of several NEP inhibitors were measured for the mutated enzymes and compared to wild-type enzyme. The results suggest that 2 arginines, Arg102 and Arg747, could both be important for substrate and inhibitor binding. Arg747 seems to be positioned to interact with the carbonyl amide group of the P'1 residue and can be modified when the enzyme is treated with the arginine-specific reagents phenylglyoxal and butanedione. Arg102 could be positioned to interact with the free carboxyl group of a P'2 residue in some substrates and inhibitors and can be modified by phenylglyoxal but not by butanedione. The results could explain the dual dipeptidylcarboxypeptidase and endopeptidase nature of NEP.
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PMID:Evidence that both arginine 102 and arginine 747 are involved in substrate binding to neutral endopeptidase (EC 3.4.24.11). 198 94

Experiments were performed on anesthetized rats to determine whether inhibition of endopeptidase 24.11 (EP) potentiates the biological activity of atrial natriuretic peptide, ANP-(99-126), and to examine the mechanisms that underlie this effect. Thiorphan (30 mg/kg iv), an inhibitor of EP, produced a modest increase in urinary sodium excretion when administered alone but did not affect urine flow, mean arterial pressure (MAP), or the endogenous level of plasma ANP. The infusion of ANP-(99-126) alone (67 ng.kg-1.min-1 iv) produced a modest natriuresis and decrease in MAP while increasing plasma ANP levels fivefold. When thiorphan (30 mg/kg iv) was administered during the ANP infusion, urine flow and urinary sodium excretion increased markedly but no further decrease in MAP or increase in plasma ANP levels was observed. This potentiation of the renal actions of ANP was not mediated by inhibition of angiotensin-converting enzyme, an increase in glomerular filtration rate, or an increase in renal blood flow but was completely abolished by a specific antagonist of the bradykinin receptor [( DArg0, Hyp3, Thi5, DPhe7, Thi8]bradykinin, 30 micrograms.kg-1.min-1 iv). These data suggest that inhibitors of EP can potentiate the renal activity of ANP by a mechanism which is independent of altered ANP catabolism and which may involve the accumulation of bradykinin, another substrate for EP, within the kidney.
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PMID:Interaction of ANP and bradykinin during endopeptidase 24.11 inhibition: renal effects. 214 18

An elevated plasma concentration of atrial natriuretic peptide (ANP) is characteristic of congestive heart failure (CHF) in both humans and animals. One strategy for facilitating the biological actions of this circulating hormone is to inhibit its metabolism. Neutral endopeptidase 24.11, an enzyme known to degrade ANP, has been implicated in the metabolic clearance of this hormone. Inhibition of endopeptidase 24.11 may produce increases in the local concentrations of ANP in organs rich in the enzyme, such as the kidney, thereby enhancing local actions, e.g. natriuresis. Exogenous administration of ANP to CHF patients produces limited natriuresis, perhaps because of the associated fall in arterial pressure. This approach of blocking endopeptidase 24.11 activity in CHF could offset the general effects of exogenous administration of ANP and result in enhanced natriuresis. We therefore undertook studies to determine if thiorphan, an endopeptidase 24.11 inhibitor, would increase circulating ANP levels and enhance natriuresis in conscious cardiomyopathic hamsters with CHF. Cardiomyopathic hamsters had significantly lower (P less than .05) basal mean arterial pressures in comparison to normal hamsters (90 +/- 2 vs. 135 +/- 3 mm Hg). Treatment with thiorphan (10 mg/kg i.v. bolus followed by 10 mg/kg/hr i.v. infusion) did not change arterial pressure in either group and produced a 3-fold increase in urinary sodium excretion in the cardiomyopathic group but not in the normal hamsters. This natriuretic response in the cardiomyopathic hamsters was associated with a doubling of the plasma concentration of ANP. These results indicate that inhibition of endopeptidase 24.11 increases natriuresis and circulating ANP concentrations in this model of CHF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of endopeptidase 24.11 inhibition in conscious cardiomyopathic hamsters. 214 19

Hormonal, renal and blood pressure effects of SCH 39370, a selective inhibitor of neutral metalloendopeptidase (endopeptidase 24.11, NEP), were studied in a chronic, congestive heart failure (CHF) model produced by coronary artery ligation in the rat. Sham-operated control rats and rats with CHF were treated either with vehicle or SCH 39370, 30 mg/kg s.c. b.i.d. for 2.5 days. Plasma levels of atrial natriuretic peptide (ANP) and urinary excretion of cyclic GMP (cGMP) were clearly raised in rats with CHF as compared with controls during vehicle treatment. SCH 39370 caused a further increase in plasma ANP in CHF rats but not in control rats. Urinary excretion of immunoreactive ANP and cGMP increased during SCH 39370 treatment both in CHF rats and in controls. SCH 39370 treatment resulted in an initial increase in urine volume in rats with CHF whereas urine sodium excretion did not change significantly. No changes in renal function due to SCH 39370 treatment were seen in control rats. Systolic blood pressure, plasma renin activity and urine excretion of catecholamine metabolites (4-hydroxy-3-methoxyphenyl acetic acid and metanephrines) did not change during SCH 39370 treatment either in controls or in CHF rats. We conclude that the NEP-inhibitory compound SCH 39370 is capable of increasing plasma ANP concentration and urinary excretion of cGMP in rats with chronic CHF. In this severe heart failure model, the possible beneficial effects of additional ANP increments may be blunted, however. NEP inhibitors offer a novel approach to study the significance of ANP elevation in chronic CHF.
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PMID:Elevation of plasma atrial natriuretic peptide in rats with chronic heart failure by SCH 39370, a neutral metalloendopeptidase inhibitor. 214 36

The hydrolysis of the porcine 26-residue brain natriuretic peptide (BNP-26) and its counterpart human 28-residue atrial natriuretic peptide (alpha-hANP) by pig membrane preparations and purified membrane peptidases was studied. When the two peptides were incubated with choroid plexus membranes, the products being analysed by h.p.l.c., alpha-hANP was degraded twice as fast as BNP. The h.p.l.c. profiles of alpha-hANP hydrolysis, in short incubations with choroid plexus membranes, yielded alpha hANP' as the main product, this having been previously shown to be the result of hydrolysis at the Cys7-Phe8 bond. In short incubations this cleavage was inhibited 84% by 1 microM-phosphoramidon, a specific inhibitor of endopeptidase-24.11. BNP-26 was hydrolysed by choroid plexus membranes, kidney microvillar membranes and purified endopeptidase-24.11 in a manner that yielded identical h.p.l.c. profiles. In the presence of phosphoramidon, hydrolysis by the choroid plexus membranes was 94% inhibited. Captopril had no effect and, indeed, no hydrolysis of BNP-26 by peptidyl dipeptidase A (angiotensin-converting enzyme) was observed even after prolonged incubation with the purified enzyme. The stepwise hydrolysis of BNP-26 by endopeptidase-24.11 was investigated by sequencing the peptides produced during incubation. The initial product resulted from hydrolysis at Ser14-Leu15, thereby opening the ring. This product (BNP') was short-lived; further degradation involved hydrolysis at Ile12-Gly13, Arg8-Leu9, Gly17-Leu18, Val22-Leu23, Arg11-Ile12 and Cys4-Phe5. Thus endopeptidase-24.11 is the principal enzyme in renal microvillar and choroid plexus membranes hydrolysing BNP-26 and alpha-hANP.
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PMID:The hydrolysis of brain and atrial natriuretic peptides by porcine choroid plexus is attributable to endopeptidase-24.11. 214 50

Endopeptidase-2, the second endopeptidase in rat kidney brush border [Kenny & Ingram (1987) Biochem. J. 245, 515-524] has been further characterized in regard to its specificity and its contribution to the hydrolysis of peptides by microvillar membrane preparations. The peptide products were identified, after incubating luliberin, substance P, bradykinin and angiotensins I, II and III with the purified enzyme. The bonds hydrolysed were those involving a hydrophobic amino acid residue, but this residue could be located at either the P1 or P1' site. Luliberin was hydrolysed faster than other peptides tested, followed by substance P and bradykinin. Human alpha-atrial natriuretic peptide and the angiotensins were only slowly attacked. Oxytocin and [Arg8]vasopressin were not hydrolysed. No peptide fragments were detected on prolonged incubation with insulin, cytochrome c, ovalbumin and serum albumin. In comparison with pig endopeptidase-24.11 the rates for the susceptible peptides were, with the exception of luliberin, much lower for endopeptidase-2. Indeed, for bradykinin and substance P the ratio kcat./Km was two orders of magnitude lower. Since both endopeptidases are present in rat kidney microvilli, an assessment was made of the relative contributions to the hydrolysis of luliberin, bradykinin and substance P. Only for the first named was endopeptidase-2 the dominant enzyme; for bradykinin it made an equal, and for substance P a minor, contribution.
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PMID:The metabolism of neuropeptides. Hydrolysis of peptides by the phosphoramidon-insensitive rat kidney enzyme 'endopeptidase-2' and by rat microvillar membranes. 246 6

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.
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PMID:Degradation of atrial natriuretic peptide: pharmacologic effects of protease EC 24.11 inhibition. 247 3


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