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:3.4.24.11 (CD10)
9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

These experiments compare the effects of a neutral endopeptidase inhibitor, retrothiorphan, 1-[(1-mercaptomethyl-2-phenyl)ethyl]amino-1-oxopropanoic acid, a converting enzyme inhibitor, enalaprilat, and the combination of the two inhibitors on changes in blood pressure and renal function induced by exogenous and endogenous bradykinin in deoxycorticosterone acetate (DOCA)-salt rats. Enalaprilat potentiated the exogenous bradykinin-induced hypotensive responses while retrothiorphan potentiated the effects on urinary cyclic-GMP (cGMP) and bradykinin. The combination potentiated the exogenous bradykinin-induced hypotensive effects and the bradykinin-induced urinary excretion of cGMP, bradykinin and prostaglandin. The bradykinin B2 receptor antagonist, Hoe 140, had no effect on the enalaprilat- and retrothiorphan-induced changes in blood pressure and renal function. In conclusion, while angiotensin-converting enzyme and neutral endopeptidase are involved in the vascular and renal catabolism of exogenous bradykinin, the effects of the peptidase inhibitors do not appear to depend on the protection of endogenous bradykinin under acute conditions in DOCA-salt rats.
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PMID:Effects of angiotensin-converting enzyme and neutral endopeptidase inhibitors: influence of bradykinin. 890 78

The purpose of this study was to determine whether an aqueous extract of smokeless tobacco (moist snuff) increases clearance of macromolecules from postcapillary venules in the in situ oral mucosa and, if so, whether bradykinin mediated this response. Using intravital microscopy, we found that 20-min suffusion of the extract elicited significant concentration-dependent leaky site formation and increase in clearance of FITC-dextran (molecular mass, 70 kDa) from the hamster cheek pouch (p < 0.05). These responses were associated with a significant increase in bradykinin-like immunoreactivity in the suffusate. Smokeless tobacco extract-induced leaky site formation and increase in clearance of FITC-dextran were significantly attenuated by NPC 17647 and Hoe 140 (p < 0.05), two bradykinin B2 receptor antagonists, but not by desArg9,[Leu8]bradykinin, a bradykinin B1 receptor antagonist. Both bradykinin B2 receptor antagonists had no significant effects on adenosine-induced responses. Indomethacin had no significant effects on smokeless tobacco extract-induced responses. Exposure to smokeless tobacco extract was associated with a significant decrease in angiotensin I-converting enzyme activity and a small, but significant, increase in neutral endopeptidase 24.11 activity in the cheek pouch, two peptidases widely distributed in the microcirculation that cleave and inactivate bradykinin (p < 0.05). Overall, these data suggest that smokeless tobacco elicits plasma exudation in the oral mucosa in vivo in a specific fashion, and that this response is mediated by bradykinin.
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PMID:Mechanisms of smokeless tobacco-induced oral mucosa inflammation: role of bradykinin. 890 42

Kinins, by an autocrine or paracrine hormonal action, are potent modulators of regional vasomotricity. Their effects on the renal circulation are not well defined. The aim of this study was to analyse the renal vascular response induced by bradykinin, to precise the type(s) of receptor involved and to evaluate the contribution of various peptidases in the local catabolism of the kinin. Experiments were performed on the isolated rat kidney, perfused in an open circuit, at a constant flow of 8 mL/min, with a Tyrode's solution. Vasodilator responses were evaluated after renal vascular tone had been restored by a continuous perfusion with prostaglandin F2 alpha. Infusion of bradykinin (0.1-30 nM) induced a concentration-dependent renal vasorelaxation. A maximal response of 39.5 +/- 2.8% (n = 32) reversion of the tone induced by prostaglandin F2 alpha (about 50% of the maximal response induced by acetylcholine on the same kidneys) was obtained at 30 nM. Bradykinin-induced vasodilatation was completely inhibited by HOE 140 (10 nM), a selective bradykinin B2 receptor antagonist. At a supramaximal concentration of 300 nM, bradykinin-induced vasorelaxation was modulated by a concomitant vasoconstriction. A concentration-dependent vasoconstriction was also obtained with desArg9 bradykinin (1-8 microM), a selective agonist of the bradykinin B1 receptor. The inhibition of neutral endopeptidase by phosphoramidon (10 microM) or the inhibition of carboxypeptidase M by MGTPA (10 microM) did not modify the bradykinin-induced renal vasorelaxation. On the other hand, the inhibition of angiotensin I converting enzyme by lisinopril (1 microM) potentiated by about 32% the vasorelaxant response induced by 30 nM bradykinin (52.3 +/- 11.8% relaxation, n = 5, p < 0.05). Present results demonstrate that 1) bradykinin primarily evokes B2 receptor-linked renal vasodilatation, 2) bradykinin B1 receptors appear also to be present on the rat renal vasculature and 3) angiotensin 1 converting enzyme contributes to the local vascular catabolism of the kinin.
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PMID:[Renal vascular responses of bradykinin in the isolated rat kidney]. 940 22

1. This study sought to determine whether neurogenic inflammation occurs in the airways by examining the effects of capsaicin or substance P on microvascular plasma leakage in the trachea and lungs of male pathogen-free C57BL/6 mice. 2. Single bolus intravenous injections of capsaicin (0.5 and 1 micromol kg(-1), i.v.) or substance P (1, 10 and 37 nmol kg(-10, i.v.) failed to induce significant leakage in the trachea, assessed as extravasation of Evans blue dye, but did induce leakage in the urinary bladder and skin. 3. Pretreatment with captopril (2.5 mg kg(-1), i.v.), a selective inhibitor of angiotensin converting enzyme (ACE), either alone or in combination with phosphoramidon (2.5 mg kg(-1), i.v.), a selective inhibitor of neutral endopeptidase (NEP), increased baseline leakage of Evans blue in the absence of any exogenous inflammatory mediator. The increase was reversed by the bradykinin B2 receptor antagonist Hoe 140 (0.1 mg kg(-1), i.v.). 4. After pretreatment with phosphoramidon and captopril, capsaicin increased the Evans blue leakage above the baseline in the trachea, but not in the lung. This increase was reversed by the tachykinin (NK1) receptor antagonist SR 140333 (0.7 mg kg(-1), i.v.), but not by the NK2 receptor antagonist SR 48968 (1 mg kg(-1), i.v.). 5. Experiments using Monastral blue pigment as a tracer localized the leakage to postcapillary venules in the trachea and intrapulmonary bronchi, although the labelled vessels were less numerous in mice than in comparably treated rats. Blood vessels of the pulmonary circulation were not labelled. 6. We conclude that neurogenic inflammation can occur in airways of pathogen-free mice, but only after the inhibition of enzymes that normally degrade inflammatory peptides. Neurogenic inflammation does not involve the pulmonary microvasculature.
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PMID:Neurogenic plasma leakage in mouse airways. 1007 47

Peptide hormones are involved in the paracrine regulation of several physiological processes. A possible function of the kallikrein-kinin system (KKS) in mammalian reproduction has been discussed. To evaluate its putative role in spermatogenesis, we searched for components of the KKS (kallikrein, kininases, kinin receptor) in the rat testis. Specific immunostaining demonstrated that the kininogenase tissue kallikrein was present in round and elongated spermatids. Leydig cells, Sertoli cells, peritubular cells, spermatogonia and spermatocytes were not stained. Bradykinin in the supernatant of Sertoli cell cultures was effectively degraded. The resulting metabolites were analysed by high-performance liquid chromatography (HPLC). Specific protease inhibition in the degrading experiments confirmed the occurrence of several metalloproteases on Sertoli cell membranes, including neutral metalloendopeptidases (NEP 24.11 and NEP 24.15), kininase type II (angiotensin converting enzyme, ACE), and kininase type I (metallocarboxypeptidase). Northern blots hybridized with a bradykinin B2 receptor probe showed the presence of B2 receptor mRNA in testis homogenate and Sertoli cell extract. All components of the kallikrein-kinin system are present within the seminiferous epithelium of the rat. Therefore, this paracrine peptide system may play a role in the regulation of Sertoli cell function or in the Sertoli cell-germ cell crosstalk.
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PMID:Elements of the kallikrein-kinin system are present in rat seminiferous epithelium. 1061 98

1. The permeability response to acutely applied bradykinin and [des-Arg9]-bradykinin on single cerebral venular capillaries has been investigated using the low molecular mass fluorescent dyes Lucifer Yellow and Sulforhodamine B with the single vessel occlusion technique. 2. When bradykinin was applied repeatedly for up to 2 h, the permeability increase was small and reversible for concentrations that ranged from 5 nM to 50 microM. 3. The logEC50 of the permeability response to bradykinin was -5.3 +/- 0.15 (logM; mean +/- s.e.m.). This was reduced to -6.37 +/- 0.24 with the angiotensin-converting enzyme inhibitor captopril, to -6.33 +/- 0.19 with the neutral endopeptidase inhibitor phosphoramidon and to -7.3 +/- 0.20 with captopril and phosphoramidon combined. 4. The permeability response to bradykinin was blocked by the bradykinin B2 receptor antagonist HOE 140, by inhibition of the Ca2+-independent phospholipase A2, by the scavenging of free radicals, or by inhibition of both cyclo-oxygenase and lipoxygenase in combination. Block of Ca2+ entry channels with SKF 96365 had no effect on the response. 5. Application of [des-Arg9]-bradykinin also increased permeability over the concentration range 5 nM to 50 microM, with a logEC50 of -5.6 +/- 0. 37. This response was not affected by free radical scavenging, but was completely blocked by the histamine H2 receptor blocker cimetidine. 6. These results imply that the acute permeability response to bradykinin is mediated via the release of arachidonic acid, which is acted on by cyclo-oxygenase and lipoxygenase resulting in the formation of free radicals, and that the response to [des-Arg9]-bradykinin is mediated via histamine.
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PMID:Acute effects of bradykinin on cerebral microvascular permeability in the anaesthetized rat. 1101 16

Kinins in the circulation are rapidly metabolized by several different peptidases. The purpose of this study was to evaluate the contribution of membrane-bound peptidases to kinin metabolism in the renal circulation. Experiments were performed in vitro, in isolated rat kidneys perfused at a constant flow rate (8 ml/min) with Tyrode's solution. The effects of peptidase inhibitors were evaluated on the functional vasodilator response caused by bradykinin (30 nM) or [Tyr(Me)(8)]bradykinin (10 nM) via activation of bradykinin B2 receptors in kidneys precontracted with prostaglandin F2alpha. Angiotensin converting enzyme inhibitors, enalaprilat (3 microM), ramiprilat (1 microM) or lisinopril (1 microM), increased the bradykinin-induced renal vasodilation by 40% or more. Inhibitors of neutral endopeptidase (thiorphan or phosphoramidon, 10 microM), basic carboxypeptidase (DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid or MGTPA, 10 microM) and aminopeptidase P (apstatin, 20 microM) however did not enhance the renal vasodilator response elicited by kinins, whatever tested alone or in the presence of lisinopril. These findings indicate that angiotensin converting enzyme is the major peptidase whose inhibition potentiates the renal bradykinin B2 receptor mediated vasodilator response of kinins. The relative contribution in this potentiation of inhibition of kinin inactivation and of cross-talk of angiotensin converting enzyme with bradykinin B2 receptor remains however to be clarified.
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PMID:Vascular catabolism of bradykinin in the isolated perfused rat kidney. 1106 29

The aim of this study was to determine whether acute dual angiotensin-converting enzyme (ACE)/neutral endopeptidase 24-11 (NEP) inhibition could improve whole body insulin-mediated glucose disposal (IMGD) more than ACE inhibition alone and whether this effect was mediated by the kinin-nitric oxide (NO) pathway activation. We therefore compared in anaesthetized obese (fa/fa) Zucker rats (ZOs) the effects of captopril (2 mg kg(-1), i.v.+2 mg kg(-1) h(-1)), retrothiorphan (25 mg kg(-1), i.v. +25 mg kg(-1) h(-1)), a selective NEP inhibitor, and mixanpril (25 mg kg(-1), i.v. +25 mg kg(-1) h(-1)), a dual ACE/NEP inhibitor, on IMGD using hyperinsulinaemic euglycaemic clamp technique. The role of the kinin-NO pathway in the effects of mixanpril was tested using a bradykinin B2 receptor antagonist (Hoe-140, 300 microg kg(-1)) and a NO-synthase inhibitor (N(omega)-nitro-L-arginine methyl ester, L-NAME, 10 mg kg(-1) i.v. +10 mg kg(-1) h(-1)) as pretreatments. Insulin sensitivity index (ISI) was lower in ZO controls than in lean littermates. Increases in ISI were observed in captopril- and retrothiorphan-treated ZOs. In mixanpril-treated ZOs, ISI was further increased, compared to captopril- and retrothiorphan-treated ZOs. In ZOs, Hoe-140 and L-NAME alone did not significantly alter and slightly reduced the ISI respectively. Hoe-140 and L-NAME markedly inhibited the ISI improvement induced by mixanpril. These results show that in obese insulin-resistant Zucker rats, under acute conditions, NEP or ACE inhibition can improve IMGD and that dual ACE/NEP inhibition improves IMGD more effectively than does either single inhibition. This effect is linked to an increased activation of the kinin-NO pathway.
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PMID:Acute effect of the dual angiotensin-converting enzyme and neutral endopeptidase 24-11 inhibitor mixanpril on insulin sensitivity in obese Zucker rat. 1139 66

Although prior studies suggest that hypoxia may increase pulmonary vascular permeability, the mechanisms responsible for that effect remain uncertain. Neprilysin (neutral endopeptidase) is a cell surface metallopeptidase that degrades several vasoactive peptides including substance P and bradykinin. We hypothesized that hypoxia could reduce lung neprilysin expression, leading to increased vascular leak. Weanling rats were exposed to normobaric hypoxia (inspired O(2) fraction = 0.1). Lung neprilysin activity was significantly decreased after 24 and 48 h of hypoxia (P < 0.006). The decrease in enzyme activity was associated with decreased lung neprilysin protein content and decreased lung neprilysin mRNA expression. Immunohistochemistry showed a predominantly perivascular distribution of neprilysin, with clear reductions in neprilysin immunoreactivity after exposure to hypoxia. Exposure to hypoxia for 24 h also caused marked increases in vascular leak (P = 0.008), which were reversed by the administration of recombinant neprilysin. The hypoxia-induced increase in leak was also reversed by substance P and bradykinin receptor antagonists. We conclude that in young rats hypoxia decreases lung neprilysin expression, which contributes to increased pulmonary vascular leak via substance P and bradykinin receptors.
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PMID:Hypoxia decreases lung neprilysin expression and increases pulmonary vascular leak. 1155 98

Angiotensin converting enzyme (ACE) was demonstrated to modulate the production of 17beta-estradiol, progesterone and prostaglandin E2 (PGE2) in frog ovary of Rana esculenta. However, the activity was not mediated by angiotensin II (Ang II). In an attempt to identify the peptide involved in the pathway modulated by ACE, bradykinin, another physiological substrate of ACE, was chosen and incubated in the presence of the membrane suspension purified from the frog ovary homogenate. The hydrolytic products were analysed by reverse-phase high-pressure liquid chromatography (HPLC) analysis and the results showed that bradykinin was metabolized by membrane suspension. The presence of the protease inhibitors in the incubation mixture indicated ACE and neutral endopeptidase as being responsible for the bradykinin hydrolysis. Frog ovary was incubated in vitro in the presence of bradykinin (10 microM), bradykinin receptor antagonist NPC 567 (1 mg mL-1), bradykinin fragment (1-7) (10 microM), ACE (2.5 mU mL-1), captopril (0.1 mM) and lisinopril (0.1 mM). The results showed no modulating activity by bradykinin on ovarian 17beta-estradiol and PGE2 production, thus demonstrating that it was not involved in the ACE-modulated pathway.
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PMID:Bradykinin is not involved in angiotensin converting enzyme modulation of ovarian steroidogenesis and prostaglandin production in frog Rana esculenta. 1202 32


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