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)

Because of the importance of bradykinin in improving heart function in some conditions or in enhancing glucose uptake by skeletal muscle, we investigated kininases in these tissues. In P3 fraction of the heart and skeletal muscles, angiotensin I-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) are the major kininases, as determined first with specific substrates and second with bradykinin. ACE activity was highest in guinea pig heart (2.7 +/- 0.07 mumol.h-1.mg protein-1) but decreased in other species in this order: dog atrium, rat heart, dog ventricle, and human atrium. The specific activity of NEP was lower: 0.45 mumol.h-1.mg protein-1 in cultured neonatal cardiac myocytes and varying between 0.12 and 0.05 mumol.h-1.mg protein-1 in human, dog, rat, and guinea pig heart. In the skeletal muscle P3, ACE was most active in guinea pig and rat (1.2 and 1.1 mumol.h-1.mg protein-1, respectively) but less so in dog (0.09 mumol.h-1.mg protein-1). NEP activity was higher in dog P3 (0.28 mumol.h-1.mg protein-1) but lower in rat and guinea pig (0.19 and 0.1 mumol.h-1.mg protein-1, respectively). Continuous density gradient centrifugation enriched NEP activity in dog and rat (from 0.3 to 1.0 and 0.49 mumol.h-1.mg protein-1, respectively). Immunoprecipitation with antiserum to purified NEP proved the specificity of the rat enzyme. Bradykinin (0.1 mmol/l) was inactivated in the presence and absence of inhibitors by rat skeletal muscle NEP, as measured by high-performance liquid chromatography. Here, 36% of the activity was caused by NEP and 19% by ACE. In radioimmunoassay (bradykinin 10 nmol/l), 46 and 55% of kininase in rat and dog skeletal muscle P3, respectively, was due to ACE; 36 and 28%, respectively, was due to NEP. Aside from these enzymes, an aminopeptidase in rat P3 also inactivates bradykinin. Thus, in conclusion, heart and skeletal muscle membranes contain kininase II-type enzymes, but their activity depends on the species.
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PMID:Kininase II-type enzymes. Their putative role in muscle energy metabolism. 852 98

We have identified angiotensin-converting enzyme, neutral endopeptidase-24.11, and aminopeptidase M in a purified glycoprotein fraction of rabbit skeletal muscle membranes. The identification was based on substrate specificity and sensitivity to selective inhibitors. Angiotensin I metabolism was due to angiotensin-converting enzyme-mediated conversion to angiotensin II and neutral endopeptidase-24.11-mediated conversion to angiotensin(1-7). Bradykinin was degraded by angiotensin-converting enzyme and neutral endopeptidase-24.11; angiotensin II by neutral endopeptidase-24.11; and angiotensin III by neutral endopeptidase-24.11 and aminopeptidase M. Thus, the effects of angiotensins and kinins on skeletal muscle blood flow and metabolism may be regulated by local angiotensin-converting enzyme, neutral endopeptidase-24.11, and aminopeptidase M.
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PMID:Angiotensin and bradykinin metabolism by peptidases identified in skeletal muscle. 853 91

The present study was undertaken to characterize the direct chronotropic effect of bradykinin in isolated spontaneously beating atria of the guinea pig. Bradykinin caused concentration-dependent increases in the beating rate of atria. In contrast, the active metabolite of bradykinin and the typical bradykinin B1 receptor agonist, Des-Arg9-bradykinin, had no effect on the beating rate of atria. Inhibition of converting enzyme or neutral endopeptidase by captopril or SQ-28603, respectively, did not affect beating rate but potentiated bradykinin-induced increase in beating rate. The potent bradykinin B2 receptor antagonist, HOE 140, antagonized bradykinin-induced chronotropic effect. In contrast, the bradykinin B1 receptor antagonist, Lys-[Leu8]Des-Arg9-bradykinin, had no effect. The increase in beating rate caused by bradykinin was not affected by blockade of beta 1-adrenoceptors, cyclooxygenase, or nitric oxide synthesis using atenolol, indomethacin and N omega-nitro-L-arginine, respectively. Unlike bradykinin, angiotensin I and angiotensin II caused very small or no change in beating rate in the presence or absence of captopril and SQ-28603. These results indicate that bradykinin causes a direct positive chronotropic effect which is mediated by activation of bradykinin B2 receptors independently of prostaglandins and beta 1-adrenoceptors.
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PMID:Bradykinin B2 receptor-mediated chronotropic effect of bradykinin in isolated guinea pig atria. 856 11

Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK-1-receptor antagonist. Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580. Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin. It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP. In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of bradykinin are concealed by the effects of the other mediators.
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PMID:Influence of several peptidase inhibitors on the pro-inflammatory effects of substance P, capsaicin and collagenase. 893 67

The influence of some peptidase inhibitors on oedema and plasma extravasation induced by bradykinin and carrageenan in rat paw was evaluate. Bradykinin-induced oedema in normal rats was increased by o-phenanthroline (3.10(-2) M), by captopril (10(-6) M to 10(-4) M), by lisinopril (10(-6) M to 10(-4), or by lisinopril (10(-5) M) in combination with apstatin (8.10(-5) M or 1.4 10(-4) M). It was not modified by phosphoramidon (10(-6) M to 10(-5) M) and by diprotin A (10(-3) M). It was increased by mergepta at high concentrations (2.10(-4) M). Mergepta did not increase the potentiating effect of captopril. Carrageenan-oedema in normal rats was increased by captopril (10(-5) M), lisinopril (10(-5) M) and apstatin (1.4 10(-4) M. It was not modified by mergepta (10(-4) M), phosphoramidon (10 (-5) M) and diprotin A (109-3) M). Des-Arg1-bradykinin and Des-Arg9-bradykinin have low oedema-promoting effects. Captopril (10(-5) M) increased the effects of bradykinin but not those of carrageenan in kininogen-deficit Brown Norway rats. Angiotensin-converting enzyme and aminopeptidase P appear to be main kinin-inactivating enzymes in rat paws. Carboxypeptidase N, neutral endopeptidase 24.11 and dipeptidyl(amino)peptidase IV do not play a significant role in this inactivation.
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PMID:Potentiation of the pro-inflammatory effects of bradykinin by inhibition of angiotensin-converting enzyme and aminopeptidase P in rat paws. 893 68

Prolyl endopeptidase has been predominantly described as a cytosolic activity capable of cleaving a number of important neuropeptides (including TRH, LHRH, Bradykinin, Angiotensin, Substance P, Neurotensin, Oxytocin and Vasopressin) on the carboxy side of proline. In this paper, we report, for the first time, on the complete purification and characterization of a membrane-bound form of prolyl endopeptidase. This novel activity has been isolated from the synaptosomal (plasma membranes) membranes of bovine brain. Following gel filtration, hydroxylapatite and hydrophobic interaction chromatographies, the prolyl endopeptidase activity was purified 1400-fold with a 23% recovery of activity. The enzyme was shown to have a relative molecular mass of 87 kDa and a Km of 60 microM for its specific fluorimetric substrate, Z-GlyProMCA. The purified enzyme demonstrated a relatively broad substrate specificity and a relatively high affinity for proline-containing neuropeptides. It was shown to be inhibited by certain thiol-protease inhibitors and by the metal chelator, 1,10-phenanthroline, thus possibly classifying it as a 'thimet' activity. The purified particular form of proyl endopeptidase displayed a similar substrate specificity to the previously reported cytosolic forms of the enzyme. However, there were differences between the two forms in term of their sensitivity to inhibitors, their affinities for the peptide substrates and their relative molecular masses. The different subcellular location (i.e. the synaptosomal membrane) of the particulate prolyl endopeptidase is also of potential physiological significance given that here it is more likely to come in contact with the vesicle-bound neuropeptides than is its cytosolic counterpart.
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PMID:Purification and characterization of a novel membrane-bound form of prolyl endopeptidase from bovine brain. 902 55

1. Bradykinin (BK) has been shown to exert cardioprotective effects which are potentiated by inhibitors of angiotensin I-converting enzyme (ACE). In order to clarify the significance of ACE within the whole spectrum of myocardial kininases we investigated BK degradation in the isolated rat heart. 2. Tritiated BK (3H-BK) or unlabelled BK was either repeatedly perfused through the heart, or applied as an intracoronary bolus allowing determination of its elution kinetics. BK metabolites were analysed by HPLC. Kininases were identified by ramiprilat, phosphoramidon, diprotin A and 2-mercaptoethanol or apstatin as specific inhibitors of ACE, neutral endopeptidase 24.11 (NEP), dipeptidylaminopeptidase IV and aminopeptidase P (APP), respectively. 3. In sequential perfusion passages, 3H-BK concentrations in the perfusate decreased by 39% during each passage. Ramiprilat reduced the rate of 3H-BK breakdown by 54% and nearly abolished [1-5]-BK generation. The ramiprilat-resistant kininase activity was for the most part inhibited by the selective APP inhibitor apstatin (IC50 0.9 microM). BK cleavage by APP yielded the intermediate product [2-9]-BK, which was rapidly metabolized to [4-9]-BK by dipeptidylaminopeptidase IV. 4. After bolus injection of 3H-BK, 10% of the applied radioactivity were protractedly eluted, indicating the distribution of this fraction into the myocardial interstitium. In samples of such interstitial perfusate fractions, 3H-BK was extensively (by 92%) degraded, essentially by ACE and APP. The ramiprilat- and mercaptoethanol-resistant fraction of interstitial kininase activity amounted to 14%, about half of which could be attributed to NEP. Only the product of NEP, [1-7]-BK, was continuously generated during the presence of 3H-BK in the interstitium. 5. ACE and APP are located at the endothelium and represent the predominant kininases of rat myocardium. Both enzymes form a metabolic barrier for the extravasated fraction of BK. Thus, only interstitial, but not intravascular concentrations of BK are increased by kininase inhibitors to the extent that a significant potentiation of BK effects could be explained. NEP contributes less than 5% to the total kininase activity, but is the only enzyme which is exclusively present in the interstitial space.
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PMID:Intravascular and interstitial degradation of bradykinin in isolated perfused rat heart. 940 84

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

Bradykinin is a substrate for both neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE). Our previous studies showed that ACE inhibitors can stimulate nitric oxide production in coronary microvessels, which is mediated by local kinins. Whether inhibition of NEP also can affect local vascular NO production has not been established. To determine the role of NEP in the control of NO production, coronary microvessels were isolated from seven mongrel dogs. Two NEP inhibitors, phosphoramidon and thiorphan, and an ACE inhibitor, ramiprilat, were used. Nitrite, the metabolite of NO in aqueous solution, was measured by using the Griess reaction. Phosphoramidon and thiorphan (10(-6) M) increased nitrite production from 80 +/- 6 to 136 +/- 6 and 144 +/- 7 pmol/mg, respectively. Ramiprilat (10(-8) M) increased nitrite production from 78 +/- 6 to 155 +/- 7 pmol/mg wet weight. The effect of these agents on nitrite release was blocked by L-NAME, which inhibits NO synthase, HOE-140, which blocks bradykinin B2-receptor, and dichloroisocoumarin, which blocks kinin-forming enzymes. These results clearly indicate that inhibition of kinin metabolism by using neutral endopeptidase inhibitors increases NO production from coronary microvessels. Thus neutral endopeptidase plays an important role in local kinin-modulated NO production in the coronary microcirculation and NEP inhibitors may be useful clinical tools in treatment of cardiovascular disease.
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PMID:Neutral endopeptidase and angiotensin-converting enzyme inhibitors increase nitric oxide production in isolated canine coronary microvessels by a kinin-dependent mechanism. 955 14

Tissue kallikrein and low molecular weight kininogen are localized in the particular cells of the connecting tubules, indicating that kinin is immediately generated in the lumina of the lower nephrons. The role of the renal kallikreinkinin system was studied using mutant kininogen-deficient Brown NorwayKatholiek (BN-Ka) rats, and compared with that in normal BN-Kitasato rats of the same strain. Mutant BN-Ka rats showed no visible changes, but they were very sensitive to excess sodium ingestion and to the tendency of sodium to accumulate in the body by aldosterone released by angiotensin II, so that sodium was accumulated in erythrocytes and cerebrospinal fluid in BN-Ka rats and hypertension was induced. After four days infusion of 0.3 M NaCl solution to conscious and unrestrained mutant BN-Ka rats, the sensitivity of the vascular smooth muscle to norepinephrine and angiotensin II increased 30-fold and 10-fold, respectively. Bradykinin was degraded by neutral endopeptidase (NEP) and carboxypeptidase Y-like exopeptidase (CPY) in rat and human urine. Daily oral administration of a selective inhibitor of CPY, ebelactone B, or that of NEP, BP1O2, prevented development of deoxycorticosterone acetate-salt hypertension in Sprague-Dawley rats. These results indicate that: 1) the renal kallikrein-kinin system allows excretion of excess sodium in the body, 2) decreased sodium excretion due to reduced excretion of urinary kallikrein in patients with essential hypertension or in genetically hypertensive rats may cause hypertension, and 3) urine kininase inhibitors such as ebelactone B may emerge as a new antihypertensive drug.
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PMID:Crucial suppressive role of renal kallikrein-kinin system in development of salt-sensitive hypertension. 983 May 1


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