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)

A membrane-bound metallo-endopeptidase that hydrolyzes human parathyroid hormone (1-84) and reduced hen egg lysozyme between hydrophilic amino acid residues was isolated from rat kidney [Yamaguchi et al. (1991) Eur. J. Biochem. 200, 563-571]. In this study, the hydrolyses of various peptide hormones and neuropeptides by the metallo-endopeptidase were examined using an automated gas-phase protein sequencer. The purified enzyme hydrolyzed the oxidized insulin B chain and substance P most rapidly, followed by big endothelin 1, neurotensin, angiotensin 1, endothelin 1, rat alpha-atrial natriuretic peptide and bradykinin, in this order. The enzyme mainly cleaved these peptides at bonds involving a hydrophilic amino acid residue. However, it cleaved bonds between less hydrophilic amino acid pairs in several short peptides, e.g. at the His5-Leu6 bond in oxidized insulin B chain, the Ile28-Val29 bond in big endothelin-1 and the Ile5-His6 and Phe8-His9 bonds in angiotensin 1. The enzyme cleavage sites of oxidized insulin B chain and angiotensin 1 were different from the reported sites cleaved by meprin and by endopeptidase 2, respectively. Kinetic determination of bradykinin hydrolysis by the purified enzyme yielded values of Km = 18.1 microM and kcat = 0.473 s-1, giving a ratio of kcat/Km = 2.62 x 10(4) s-1.M-1. The Km value was about 20-fold lower than that reported for meprin and endopeptidase 2. These results indicate that the membrane-bound metallo-endopeptidase from rat kidney is distinguished from meprin and endopeptidase 2 in its substrate specificity and is not parathyroid hormone specific, but has potential capacities to inactivate various biologically active peptide hormones and neuropeptides in vivo.
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PMID:A membrane-bound metallo-endopeptidase from rat kidney. Characteristics of its hydrolysis of peptide hormones and neuropeptides. 137 51

1. Regional haemodynamic responses to atrial natriuretic peptide (ANP, 0.5 nmol kg-1) or proendothelin-1 [1-38] (1.0 nmol kg-1) were assessed in the same conscious Long Evans rats before and 20 min after administration of the novel neutral endopeptidase (NEP) inhibitor, SQ 28,603 (50 mg kg-1, i.v.). In a separate experiment, responses to endothelin-1 (0.5 nmol kg-1), angiotensin I (0.25 nmol kg-1) and angiotensin II (0.12 nmol kg-1) were measured before and after administration of SQ 28,603. 2. SQ 28,603 alone had no significant cardiovascular effects but caused significant prolongation of the hypotensive, tachycardic and renal and mesenteric vasoconstrictor effects of ANP. However, the early vasodilator and late vasoconstrictor responses in the hindquarters were not affected significantly. 3. SQ 28,603 caused significant attenuation of the pressor effects of proendothelin-1 [1-38] but the associated bradycardia was unchanged. SQ 28,603 caused a significant inhibition of the renal and mesenteric vasoconstrictor effects of proendothelin-1 and also inhibited the initial vasodilator and subsequent vasoconstrictor responses in the hindquarters vascular bed. 4. SQ 28,603 had no significant effects on the haemodynamic responses to endothelin-1, angiotensin I, or angiotensin II. 5. The results are consistent with SQ 28,603 not only inhibiting NEP that is involved in the degradation of ANP, but also suppressing activity of the enzyme involved in the conversion of proendothelin-1 [1-38] to endothelin-1.
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PMID:Effects of the neutral endopeptidase inhibitor, SQ 28,603, on regional haemodynamic responses to atrial natriuretic peptide or proendothelin-1 [1-38] in conscious rats. 138 23

1. We have studied the contractile activity of the 39 amino acid precursor of endothelin-1 (ET-1), big endothelin-1 (big ET-1), on human isolated bronchi. The contribution of the metalloproteases, neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE), in the presence or absence of the epithelium lining, by use of specific inhibitors, was also evaluated on the effects of big ET-1. 2. Big ET-1 elicited a potent contraction of human isolated bronchus. The -log EC50 value for big ET-1 was 7.53 +/- 0.08 (n = 11) and Emax 78.5 +/- 3.8% (% of ACh 3mM). 3. Incubation of human isolated bronchi with the NEP inhibitor phosphoramidon (10(-5) M) induced a rightward shift of the concentration-response curve induced by big ET-1 (10(-9) M to 3 x 10(-7) M). Similar results were observed when human bronchi were incubated with thiorphan (10(-5) M), but the shift to the right was significantly less (P less than 0.01) than that observed in the case of phosphoramidon (-0.35 +/- 0.05 vs -0.67 +/- 0.07 log unit). 4. The two inhibitors of angiotensin I converting enzyme (ACE), captopril or enalapril diacid, did not affect the concentration-response curve for contraction induced by big ET-1. 5. When the epithelium was removed, a leftward shift of the concentration-response curve of big ET-1 (10(-9) M to 3 x 10(-7) M) was observed. Incubation of human isolated bronchi with phosphoramidon or thiorphan (10-5M) or with enalapril diacid or captopril did not modify the leftward shift of the concentration-response curve for big ET-1 after epithelium removal.6. These results suggest that big ET-1 elicits potent contractile activity in the human isolated bronchus and that its effect is the consequence of the conversion to ET-1 by a phosphoramidon-sensitive metalloprotease which, although different from NEP and ACE, appears to be similar to the endothelinconverting enzyme (ECE) described in other studies in animals.
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PMID:Contractile activity of big endothelin-1 on the human isolated bronchus. 139 87

To study the role of neutral endopeptidase (NEP) on endothelin-1-induced contraction of the airway smooth muscle, we examined the contractile effect of endothelin-1 in the isolated guinea pig trachea and human bronchus in the presence or absence of NEP inhibitor phosphoramidon. After incubation with phosphoramidon (10(-8) to 10(-5) M), we added endothelin-1 cumulatively from 10(-11) to 10(-7) M to the airway tissues in organ baths. Phosphoramidon significantly potentiated the endothelin-1-induced contraction in a concentration-dependent fashion in both guinea pig trachea and human bronchus, and it shifted the concentration-response curves to the left. Because NEP is known to cleave tachykinins, we next studied whether endothelin-1 contracts airway tissues by releasing endogenous tachykinins from bronchial C-fibers. After incubation with phosphoramidon (10(-5) M), we added endothelin-1 cumulatively from 10(-11) to 10(-7) M to the tissues that were treated with capsaicin to deplete the tachykinins. Phosphoramidon significantly potentiated the endothelin-1-induced contraction in the capsaicin-treated tissues, suggesting that endothelin-1 causes the contraction, at least in part, without releasing tachykinins. In contrast to the effect of phosphoramidon, captopril (an angiotensin-converting enzyme inhibitor), leupeptin (a serine protease inhibitor), and bestatin (an aminopeptidase inhibitor) did not modulate the effect of endothelin-1-induced contraction in both guinea pig trachea and human bronchus. From these results, we conclude that NEP plays an important role in regulating endothelin-1-induced contraction in the guinea pig trachea and human bronchus.
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PMID:Neutral endopeptidase inhibitor potentiates endothelin-1-induced airway smooth muscle contraction. 140 23

This study was designed to evaluate the role of neutral endopeptidase (NEP) in modulating the airway smooth muscle contraction induced by endothelin-1 in isolated segments of guinea-pig trachea. Endothelin-1 (10(-9)-10(-6) M) produced a concentration-dependent contraction that reached a maximum by 30 min. The NEP inhibitor leucine-thiorphan (10(-5) M) significantly increased the contractile response to endothelin-1. The addition of leucine-thiorphan to tracheal segments precontracted by 10(-9) and 10(-8) M endothelin-1 increased isometric tension by 181 +/- 65% (mean +/- 1 S.E.M.; P less than 0.05) and by 138 +/- 49% (P less than 0.05), respectively. In contrast, the kininase II inhibitor captopril and the peptidase inhibitors leupeptin and bestatin had no effect. Preincubation of endothelin-1 with 1 microgram recombinant human NEP decreased the contractile activity of endothelin-1 by 72 +/- 9%, whereas no effect was observed using heat-inactivated NEP. We conclude that NEP modulates endothelin-induced contraction of airway smooth muscle in the guinea-pig trachea.
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PMID:Neutral endopeptidase modulates endothelin-1-induced airway smooth muscle contraction in guinea-pig trachea. 143 68

1. Phosphoramidon (10 microM) markedly increased the contractile response to endothelin-3 in human and rabbit bronchus in vitro. In human tissue the contractile response to 0.3 microM endothelin-3 was significantly increased from 54 +/- 12% to 137 +/- 34% (of the response to 1 nM acetylcholine) in the presence of phosphoramidon. Similarly, in rabbit isolated bronchus, the endothelin-3-induced response was increased from 34 +/- 5% to 61 +/- 7%. 2. In addition, the potency (as measured by EC30 values) of this peptide in human and rabbit airways was significantly augmented in the presence of the enzyme inhibitor. The geometric mean EC30 value was decreased from 53 nM (95% CI:15, 190) to 8 nM (95% CI:3, 23) in human bronchus and from 150 nM (95% CI:89, 250) to 23 nM (95% CI:11, 50) in rabbit tissue. 3. Neither the potency nor the response (at 0.3 microM) to endothelin-3 in canine bronchial rings was altered after incubation of the tissue in phosphoramidon. 4. A previous study carried out in human airways has implied that the difference in potency between endothelin-1 and endothelin-3 may be attributed to a heterogeneous endothelin receptor population. The results of our study, while also demonstrating this difference in potency, have shown that this marked difference, as well as that obvious in rabbit airway tissue can be abolished in the presence of phosphoramidon. 5. Phosphoramidon produced no change in the cumulative concentration-response curve for endothelin-1 in airway tissue from the three species studied. 6. These results suggest that a phosphoramidon-sensitive enzyme (probably neutral endopeptidase) found in lung, may be responsible for local degradation of endothelin-3, but not endothelin-l in human and rabbit isolated bronchus.
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PMID:Phosphoramidon potentiates the contractile response to endothelin-3, but not endothelin-1 in isolated airway tissue. 150 19

When big endothelin-1 (big ET-1, 1-39) was incubated with the membrane fraction obtained from cultured endothelial cells (ECs) at pH 7.0 for 6 h, the immunoreactive (ir) ET in the reaction mixture was markedly increased. Phosphoramidon, a metalloproteinase inhibitor, as well as metal chelators specifically suppressed the above increase. Using reverse-phase high-performance liquid chromatography, ir-ET was confirmed to be ET-1[1-21]. In addition, we noted that the alterations in ET-1 correlated with those in the C-terminal fragment (CTF, 22-39) of big ET-1. When cultured ECs were incubated with phosphoramidon, time-dependent secretion of ET-1 and CTF from the cells was markedly suppressed. In contrast, the secretion of big ET-1 was increased by phosphoramidon. Thiorphan, a specific inhibitor of neutral endopeptidase 24.11, was without effect on the secretion of ET-related peptides. Moreover, phosphoramidon potently inhibited the hypertensive effect of big ET-1 without affecting the ET-1-induced hypertension in anesthetized rats. From these findings, it seems reasonable to consider that phosphoramidon-sensitive and membrane-bound metalloproteinase, which is not a neutral endopeptidase 24.11, is the most plausible candidate for big ET-1-converting enzyme in vivo.
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PMID:Conversion of big endothelin-1 to endothelin-1 by phosphoramidon-sensitive metalloproteinase derived from aortic endothelial cells. 172 35

The breakdown of endothelin-1 by crude membrane preparations of human kidney and choroid plexus was investigated. 125I-labeled endothelin-1 was degraded by both tissues in a phosphoramidon-sensitive way, suggesting a role of endopeptidase 24.11 in the in vitro metabolism of this peptide. Identification of the cleavage sites of purified human renal endopeptidase 24.11 in the sequence of endothelin-1 revealed that bonds involving the amino side of the hydrophobic amino acids (Ser4, Leu6, Val12, Phe14, His16, Leu17, Ile19) were susceptible to cleavage. Endothelin-1 appears thus to be degraded at multiple sites by endopeptidase 24.11 in vitro, producing inactive fragments.
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PMID:In vitro degradation of endothelin-1 by endopeptidase 24.11 (enkephalinase). 178 41

Endothelin-1 is a potent endothelium-derived vasoconstrictor and pressor peptide with uniquely sustained activity. We have examined the contribution of endogenously-generated endothelin-1 to the maintenance of basal vascular tone in healthy subjects. In these studies, on separate occasions, a combined inhibitor of endothelin converting enzyme (ECE) and neutral endopeptidase (NEP), phosphoramidon, a selective inhibitor of NEP, thiorphan, and a selective ETA receptor antagonist, BQ-123, were given via the brachial artery. Big endothelin-1, the precursor to endothelin-1, caused a slow onset dose-dependent forearm vasoconstriction, the magnitude of which was consistent with about 10% conversion to mature endothelin-1 in the forearm. Vasoconstriction to big endothelin-1 was abolished by co-infusion of phosphoramidon, whereas vasoconstriction to endothelin-1 was unaffected. Phosphoramidon caused progressive vasodilatation when infused alone, with blood flow increasing by 37% at 90 min (P = 0.02), whereas thiorphan caused vasoconstriction, consistent with NEP inhibition exerting its major effect on degradation of constrictor peptides, such as angiotensin and endothelin-1. Vasoconstriction to endothelin-1 was completely abolished by coinfusion of BQ-123, and BQ-123 alone produced progressive forearm vasodilatation, with blood flow increasing by 64% after 60 min (P = 0.001). These results demonstrate that endogenous production of endothelin-1 acts to sustain vascular tone in humans and indicate that ECE inhibitors and endothelium receptor antagonists may have therapeutic potential as vasodilators.
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PMID:Endogenous endothelin generation maintains vascular tone in humans. 747 28

The purpose of these experiments was to compare the effects of endopeptidase inhibition with oral candoxatril on systemic and forearm hemodynamics and muscle sympathetic nerve activity with responses to a low-dose atrial natriuretic factor infusion. Eleven healthy men received at random on three separate days either intravenous saline, natriuretic factor (1.6 pmol/kg per minute) plus saline, or oral candoxatril (200 mg) plus saline. Measurements were made at baseline and 30, 60, and 90 minutes after interventions. Atrial natriuretic factor lowered diastolic pressure (P < .01), central venous pressure (P < .001), forearm blood flow (P < .05), and forearm vascular compliance (P < .05) but had no effect on systolic pressure, heart rate or its variability, stroke volume, sympathetic nerve activity, plasma norepinephrine, or endothelin-1. Plasma epinephrine increased (P < .01). Candoxatril lowered central venous pressure (P < .001) and increased systolic pressure (from 116 +/- 6 to 120 +/- 7 mm Hg; P < .05), endothelin (from 4.6 +/- 1.1 to 6.8 +/- 3.2 pmol/L; P < .02), and epinephrine (P < .05), without affecting any other variables. Candoxatril and atrial natriuretic factor lowered central venous pressure in healthy men without causing a reflex increase in sympathetic nerve activity or norepinephrine, yet epinephrine rose. This suggests that both interventions may specifically inhibit sympathetic nerve traffic to muscle at physiological plasma atrial natriuretic factor concentrations. However, whereas the peptide lowered blood pressure, candoxatril increased systolic pressure. These contrasting hemodynamic responses may be related to differences in plasma atrial natriuretic peptide concentration and to altered endothelin metabolism by candoxatril.
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PMID:Comparison of candoxatril and atrial natriuretic factor in healthy men. Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin. 749 88


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