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)

1. We have estimated potencies of tachykinin receptor agonist and antagonist analogues in order to determine the recognition characteristics of tachykinin receptors mediating phasic contractile responses of the rat isolated urinary bladder in vitro. 2. The NK1-selective synthetic agonists, substance P methyl ester and GR73632, the synthetic NK2-selective agonists [beta-Ala8]-NKA(4-10) and GR64349, and the mammalian tachykinins, neurokinin A and neurokinin B, were assayed relative to substance P and were found to be approximately equipotent. The NK3-selective agonist, senktide, was inactive (10 microM). 3. Potencies of all these agonists were not significantly different (P > 0.05) when experiments were carried out in the presence of the neutral endopeptidase inhibitor, phosphoramidon, and the kininase II inhibitor, enalaprilat (both 1 microM). 4. The NK1-selective antagonist, GR82334, inhibited responses to substance P methyl ester in a competitive manner in the rat urinary bladder and the rat ileum, and also in the guinea-pig ileum. Markedly different pKB estimates were obtained in the rat bladder (6.38) and rat ileum (6.56) compared to the guinea-pig ileum (7.42). GR82334 (3 microM) was inactive against responses of the rat bladder to [beta-Ala8]-NKA(4-10). 5. The NK1-selective antagonist (+/-)-CP-96,345 also inhibited responses of the rat bladder and guinea-pig ileum to substance P methyl ester; however, in the rat bladder at 1 microM, this antagonist reversibly inhibited responses both to the NK2-selective agonist [beta-Ala8]-NKA(4-10) and to the muscarinic agonist carbachol (P < or = 0.01), thus showing evidence of some non-selective depressant actions. 6. The NK2-selective antagonists, MEN10207 and L-659,874, competitively inhibited responses of the rat bladder to the NK2-selective agonist [P-Ala5]-NKA(4-10) giving pKB estimates of 5.75 and 6.68,respectively. Both antagonists (1O microM) were inactive against responses to the NKI-selective agonist substance P methyl ester.7. These results support the proposal of a mixed population of NKI and NK2 receptors mediating contraction of the rat isolated urinary bladder. The NK2 receptor is characterized by a relatively low affinity for the NK2-selective antagonist MEN10207 but a high affinity for L-659,874. The NKImediated responses are inhibited by (+/-)-CP-96,345: this compound however, has non-specific depressant effects in the rat bladder at high concentration (1 microM). In contrast, the NK,-receptor peptide antagonist GR82334, did not have non-specific depressant effects and competitively inhibited NK, responses in the rat bladder and rat ileum with an affinity significantly lower than at the NK,-receptors in the guinea-pigileum.
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PMID:A pharmacological study of NK1 and NK2 tachykinin receptor characteristics in the rat isolated urinary bladder. 128 72

The role of angiotensin-converting enzyme (ACE), neutral endopeptidase 24.11 (NEP), and other peptidases in the endothelial degradation of bradykinin was investigated in cultured human umbilical vein endothelial cells (HUVEC). The major part of the kininase II activity on intact cells was attributed to ACE activity, the minor part to NEP activity. Amastatin, as aminopeptidase inhibitor, and DL-2-mercaptomethyl-3-guanidinoethyl-thiopropionic acid (MGTA), an inhibitor of kininase I, did not affect endothelial kininase activity. The decline of the bradykinin concentrations in the supernatant of intact endothelial monolayer indicated a total kininase activity of 289 +/- 27 fmol/min/dish. The calculated activity of ACE was 223 fmol/min/dish and the neutral endopeptidase activity was 51 fmol/min/dish. Thus, ACE and neutral endopeptidase are the main kininases in the degradation of bradykinin by intact endothelial cells. In contrast to the intact endothelial monolayers, in homogenates additional kininase activity was found which was not affected by either ACE and NEP inhibitors nor by amastatin and MGTA.
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PMID:Bradykinin degrading activity in cultured human endothelial cells. 128 24

All four components of the kallikrein-kinin system--kininogens, tissue kallikreins, kinins, and kininases--have been found in human male genital secretions. Kinins are continuously released from seminal plasma kininogens through limited proteolysis by kininogenases like tissue kallikrein from prostate and sperm acrosin. Kinins are the terminal effectors of the kallikrein-kinin system and increase sperm motility and sperm metabolism at nanomolar concentrations. Recent investigations indicate that these effects are possibly mediated by a specific sperm membrane integrated bradykinin receptor, subtype B2. The two major kininase that are present in seminal plasma are kininase II and neutral metallo-endopeptidase. Kininase II, which is identical with angiotensin-converting enzyme, is also involved in the renin-angiotensin system as it converts angiotensin I into angiotensin II and thus is the connecting enzyme of both systems. Apart from the observed effects of kinins on sperm motility, the kallikrein-kinin system is thought to be involved in the regulation of spermatogenic functions of the testis: in the rat, kallikrein activates Sertoli cell function, increases the relative number of spermatocytes and the [3H] thymidine incorporation of testicular tissue, enhances glucose-intake, and increases testicular blood flow. Clinical trials showed that systemic administration of kallikrein may be particularly useful for treatment of infertile men suffering from asthenozoospermia and/or oligozoospermia. During kallikrein therapy, the number of spermatozoa and both quantitative and qualitative sperm motility increased, and a significant improvement of the conception rate was achieved. An increased sperm number was also observed after application of the specific kininase II inhibitor captopril.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible effects of the kallikrein-kinin system on male reproductive functions. 131 46

Aminopeptidase activities were identified in extracts of kidney, ovotestis, head ganglia, heart and haemolymph of Aplysia californica. These enzyme preparations hydrolysed [3H][Leu]enkephalin at the Try-1-Gly-2 bond as determined by h.p.l.c. analysis of cleavage products. In all these tissues, enkephalin-degrading aminopeptidase activities were present both in membrane-bound and cytosolic fractions. The bivalent-cation-chelating agent, 1,10-phenanthroline, inhibited kidney membrane aminopeptidase activity with an IC50 of 30 microM, suggesting that this enzyme is a metalloproteinase. The aminopeptidase inhibitor amastatin was the most potent inhibitor of [Leu]enkephalin degradation (IC50 25 nM) by membrane-bound aminopeptidase, and bacitracin, bestatin and puromycin were about 100-1000 times less potent. In contrast with membrane-bound aminopeptidase, the cytosolic form is sensitive to puromycin. Angiotensin-converting enzyme inhibitor had no effect on [Leu]enkephalin degradation by kidney membranes, while the neutral endopeptidase inhibitors were poor inhibitors of the enzymes in this preparation. The Km values of the aminopeptidase in the kidney membranes and cytosolic fractions for the [Leu]enkephalin substrate were 2.4 and 7.4 microM respectively. The aminopeptidase present in the kidney membranes also hydrolysed endogenous Phe-Met-Arg-Phe-amide peptide at the Phe-1-Met-2 bond as well as synthetic alanine p-nitroanilide and leucine p-nitroanilide. When used in a competition assay, these substrates inhibited hydrolysis of [3H][Leu]enkephalin, suggesting that the same enzyme degraded all these substrates. Taken together, these results suggest that Aplysia tissues contain both a membrane-bound aminopeptidase related to the mammalian aminopeptidase N and a cytosolic puromycin-sensitive aminopeptidase.
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PMID:Identification and characterization of aminopeptidases from Aplysia californica. 141 57

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

We contrasted the effects of D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg-TFA (kinin receptor antagonist), of aprotinin (kallikrein inhibitor), and of combined treatment with captopril (kininase II inhibitor) and phosphoramidon (neutral endopeptidase 24.11 inhibitor) on renal function of rats with and without 14-day deoxycorticosterone pretreatment (DOC, 25 mg.kg-1.wk-1 sc). Neither the kinin antagonist nor aprotinin affected renal function in rats with and without DOC pretreatment. Combined treatment with captopril and phosphoramidon caused in rats with and without DOC pretreatment augmentation (P less than 0.05) of kinin excretion (50-64%), glomerular filtration rate (12-11%), and sodium excretion (46-48%). In DOC-pretreated rats undergoing infusion of captopril and phosphoramidon, the superimposed administration of either the kinin antagonist or aprotinin caused the lowering of renal plasma flow, glomerular filtration rate, and sodium excretion. These effects of the kinin antagonist and aprotinin in rats infused with kininase inhibitors may be the consequence of blockade, respectively, of the renal actions and synthesis of kinins that, when in excess, elicit renal vasodilation and increase glomerular filtration rate and sodium excretion. Collectively, these observations suggest regulatory influence of kinins during conditions featuring increased renal kinin levels.
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PMID:Effects of a kinin antagonist on renal function in rats. 169 May 17

Enzymes that hydrolyze kinins are known under the collective term of "kininases." This short review surveys kininase I- and II-type enzymes. For the sake of simplicity, we call carboxypeptidases that remove the C-terminal arginine of kinins kininase I-type enzymes. Plasma carboxypeptidase N and the cell membrane-bound carboxypeptidase M belong here. Kininase II enzymes release the C-terminal dipeptide Phe-Arg; angiotensin I-converting enzyme and neutral endopeptidase 24.11 (enkephalinase) are prominent members of this subgroup of proteins. The primary sequence of five proteins of the four human kininases (including the catalytic and regulatory subunits of carboxypeptidase N) were deduced from the nucleotide sequence of their cDNAs. The structure and properties of these enzymes are briefly discussed.
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PMID:Some old and some new ideas on kinin metabolism. 169 56

Glucocorticoids inhibit plasma extravasation induced in the rat tracheal mucosa by substance P and other tachykinins released from sensory nerves. This study was performed to determine whether this antiinflammatory effect of glucocorticoids is mediated by the tachykinin-degrading enzymes neutral endopeptidase (NEP) and kininase II (angiotensin converting enzyme, ACE). In addition, we studied the effect of dexamethasone on a nonpeptide inflammatory mediator, platelet-activating factor (PAF), which is not degraded by NEP or ACE. Adult male pathogen-free F344 rats were treated for 2 d with dexamethasone (0.5 mg/kg per d i.p.), or with the vehicle used to dissolve the steroid. The magnitude of plasma extravasation produced by an intravenous injection of substance P (5 micrograms/kg) or PAF (10 micrograms/kg) was then assessed by using Monastral blue pigment as an intravascular tracer. The role of NEP and ACE activities in the changes produced by dexamethasone was investigated by examining the effect of the selective inhibitors of these enzymes, phosphoramidon and captopril. Dexamethasone reduced the substance P-induced extravasation by 57% but did not affect the PAF-induced extravasation. The suppressive effect of dexamethasone on substance P-induced extravasation was completely reversed by simultaneously inhibiting NEP and ACE activities, but the inhibition of these enzymes had no effect on PAF-induced extravasation, regardless of whether the rats were pretreated with dexamethasone or not. These results suggest that NEP and ACE mediate a selective inhibitory effect of glucocorticoids on neurogenic plasma extravasation.
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PMID:Neutral endopeptidase and kininase II mediate glucocorticoid inhibition of neurogenic inflammation in the rat trachea. 171 45

Bradykinin is a potent vasodilator peptide; however, its half-life in vivo is very short because of various plasma and tissue peptidases that hydrolyze bradykinin to inactive fragments. We studied the role of kininase II (angiotensin converting enzyme) and neutral endopeptidase 24.11 (enkephalinase) in the catabolism of bradykinin in vascular tissue by determining the effect of inhibitors of kininase II (captopril) and of endopeptidase 24.11 (phosphoramidon) on the action of bradykinin on rat isolated mesenteric arteries. Because bradykinin may induce prostaglandin formation and release, we also studied the effect of a cyclooxygenase inhibitor, indomethacin, on the action of bradykinin. The mesenteric bed was isolated from rats (250-300 g) with rats under either anesthesia and was perfused with Krebs' solution (4 ml/min) containing phenylephrine (0.5-1.0 microgram/ml) to produce a mean perfusion pressure of 120-130 mm Hg. Bradykinin (2.5-40.0 ng), injected as a bolus, produced a dose-dependent decrease in perfusion pressure. In the presence of indomethacin (1.0 microgram/ml), the amplitude of the vasodilator responses to bradykinin was not significantly affected, although the duration of the responses was increased approximately two to four times. In the presence of captopril (1.0 microgram/ml), bradykinin elicited either a vasodilator or a biphasic effect. The vasodilator effect was greatly potentiated by captopril, whereas the duration of the response was unchanged when compared with control experiments. When present, the pressor responses were also dose related. In the presence of indomethacin plus captopril, bradykinin produced only a fall in perfusion pressure that lasted five to six times longer than without any treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of bradykinin on isolated mesenteric arteries of the rat. 173 87

An endopeptidase generating a peptide comprised of the first five amino acids of luteinizing hormone-releasing hormone (LHRH) was isolated form the membranes of glioma C6 cells by a procedure including Brij extraction, p-mercuribenzoate-Sepharose chromatography, and Mono Q high-performance liquid chromatography. The molecular weight of the enzyme was estimated to be 64,000. The glial enzyme shows a similar inhibitor susceptibility to that of the enzyme of neuronal origin, and also to that of endopeptidase-24.15 (EC 3.4.24.15). Angiotensin-converting enzyme (EC 3.4.15.11) is suggested to be involved in the secondary cleavage of LHRH by the glioma cells.
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PMID:Evidence for thiol-dependent metallo-endopeptidase involved in degradation of luteinizing hormone-releasing hormone in glioma cells. 179 38


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