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

Natriuretic peptides play an important role in water and salt homeostasis and in the regulation of the cardiovascular system. In recent years, exogenous administration of natriuretic peptides has primarily been used to improve our understanding of the role of natriuretic peptides. Also, it became evident that natriuretic peptides may be used therapeutically. Because of their peptide character, they cannot be administered orally and, therefore, may be used for short-term intravenous therapy only. In recent years, inhibitors of neutral endopeptidase, which degrades natriuretic peptides to inactive metabolites, have been investigated. This review focuses on the potential benefits of increasing natriuretic peptide levels, either through exogenous administration or inhibiting the degradation of endogenous natriuretic peptides.
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PMID:Therapeutic benefits of increasing natriuretic peptide levels. 1147 41

Calcitonin gene-related peptide (CGRP), a potent vasodilator neuropeptide, plays a counterregulatory role in subtotal nephrectomy-salt (SN-salt)-induced hypertension, reflecting a stimulation of the efferent vasodilator function of perivascular sensory nerves. To determine the effect of omapatrilat, a dual ACE and neutral endopeptidase inhibitor, on blood pressure and the potential antihypertensive role for CGRP, 24 male Sprague-Dawley rats were separated into 4 groups: (1) SN-salt, (2) SN-salt plus omapatrilat (80 mg. kg(-1). d(-1) in the drinking water), (3) sham-operated plus salt, (4) sham-operated plus salt and omapatrilat. After 11 days the mean arterial pressure was higher in the SN-salt group (174+/-10 mm Hg) versus the sham-operated-salt (109+/-4 mm Hg) and sham-operated-salt plus omapatrilat (105+/-3 mm Hg) groups. Omapatrilat treatment of the SN-salt rats significantly decreased the mean arterial pressure to 123+/-7 mm Hg and significantly reduced the heart-to-body weight ratio. Intravenous administration of a specific CGRP receptor antagonist produced a significant 10+/-2 mm Hg mean arterial pressure increase in the untreated SN-salt hypertensive rats but was without effect in the other groups. This indicates that CGRP does not contribute to the antihypertensive actions of omapatrilat. In addition, CGRP mRNA and protein content in dorsal root ganglia were decreased approximately 25% in the SN-salt plus omapatrilat rats. Thus, omapatrilat not only markedly reduces the blood pressure in this model of renal failure-induced hypertension but may also prevent the abnormal compensatory stimulation of the vasodilator activity of the peripheral sensory nervous system.
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PMID:Omapatrilat in subtotal nephrectomy-salt hypertension: role of calcitonin gene-related peptide. 1156 59

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.
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PMID:Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? 1159 26

The botulinum neurotoxin type A (BoNT/A) light chain (LC) acts as zinc endopeptidase. The X-ray structure of the toxin demonstrated that Zn(2+) is coordinated by His(222) and His(226) of the Zn(2+) binding motif HisGluXXHis and Glu(261), whereas Glu(223) coordinates the water molecule required for hydrolysis as the fourth ligand. Recent analysis of a cocrystal of the BoNT/B LC and its substrate synaptobrevin 2 suggested that Arg(362) and Tyr(365) of the homologous BoNT/A may be directly involved in catalysis. Their role and that of Glu(350) which is also found in the vicinity to the active site were analyzed by site-directed mutagenesis. Various replacements of Arg(362) and substitution of Tyr(365) with Phe resulted in 79- and 34-fold lower k(cat)/K(m) values, respectively. These changes were provoked by decreased catalytic rates (k(cat)) and not by alterations of ground state substrate binding as evidenced by largely unchanged K(d) and K(m) values. None of these mutations affected the overall secondary structure or zinc content of the LC. These findings suggest that the guanidino group of Arg(362) and the hydroxyl group of Tyr(365) together accomplish transition state stabilization as was proposed for thermolysin, being the prototypical member of the gluzincin superfamily of metalloproteases. Mutation of Glu(350) dramatically diminished the hydrolytic activity which must partly be attributed to an altered active site fine structure as demonstrated by an increased sensitivity toward heat-induced denaturing and a lower Zn(2+) binding affinity. Glu(350) apparently occupies a central position in the active site and presumably positions His(222) and Arg(362).
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PMID:Arg(362) and Tyr(365) of the botulinum neurotoxin type a light chain are involved in transition state stabilization. 1182 15

Neutral endopeptidase (EC3.4.24.11, NEP, enkephalinase) is a zinc-metalloendopeptidase, cleaving a variety of substrates like enkephalins, substance P, and bradykinin. In the brain, NEP is a key enzyme in the degradation of enkephalins. Pharmacological inhibition of NEP-activity causes analgesia resulting from enhanced extracellular enkephalin concentrations. Recently, transgenic mice lacking the enzyme NEP have been developed (Lu, 1995). The present study was designed to investigate the nociceptive behavior of these NEP-knockout mice. Interestingly, NEP-deficient mice did not respond with decreased pain perception, but exhibited hyperalgesia in the hot-plate jump, warm-water tail-withdrawal, and mostnotablyin theacetic-acid writhing test. Inhibition of aminopeptidase N by bestatin reduced writhing in both strains, whereas NEP-inhibition by thiorphan reduced writhing selectively in wild-type mice. Naloxone increased writhing in wild-type but not in knockouts, whereas the bradykinin B2-receptor antagonist HOE140 reduced writhing selectively in NEP-knockouts. Similarly, the nitric oxide synthase inhibitor L-NAME reduced writhing in NEP-knockouts. These results indicate that genetic elimination of NEP, in contrast to pharmacological inhibition, leads to bradykinin-induced hyperalgesia instead of enkephalin-mediated analgesia. Nitric oxide (NO) is suggested to be involved in this process.
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PMID:Neutral endopeptidase knockout induces hyperalgesia in a model of visceral pain, an effect related to bradykinin and nitric oxide. 1193 42

A microdialysis (MD) technique, combined with HPLC-fluorescence (FL) detection, was developed for the evaluation of the tissue-specific renin-angiotensin system (RAS) in the rat renal cortex. An MD probe constructed with a hydrophilic hollow fiber dialysis tubing, AN69, showed high recovery (more than 50%) in vitro for all four angiotensins: angiotensin I (Ang I), Ang II, Ang III, and Ang (1-7). Angiotensins, successfully derivatized with m-BS-ABD-F, a water-soluble fluorogenic reagent that has a 2,1,3-benzoxadiazole (benzofurazan) structure, could be simultaneously determined by coupled-column HPLC. The detection limit for Ang I, Ang II, Ang III, and Ang (1-7) were 94, 44, 47, and 83 fmol, respectively. All these peptides were determined with good linearity (0.0125-3.1 microM, equivalent to 0.25-62 pmol, correlation coefficient >0.99) and good precision (recovery >91%). In the MD studies, generation of Ang (1-7) and Ang II was observed when Ang I was perfused, and Ang (1-7) was the major biologically active angiotensin found in the dialysate samples. The concentration of Ang (1-7) and Ang II in the dialysate samples showed good correlation to that of Ang I in a MD perfusate (20-100 microM). Cleavage of Ang I to Ang (1-7) was drastically suppressed by the co-perfusion of phoshoramidon (0.5-5 mM), an inhibitor of neprilysin, which generates Ang (1-7) from Ang I. These results are consistent with the previously reported characteristics of tissue-specific renal RAS, suggesting that our MD/HPLC-FL system may have the potential to be employed to evaluate tissue-specific RAS in the rat renal cortex.
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PMID:A method to evaluate the renin-angiotensin system in rat renal cortex using a microdialysis technique combined with HPLC-fluorescence detection. 1223 64

The enzyme neutral endopeptidase (NEP; EC 3.4.24.11) cleaves several vasoactive peptides such as the atrial natriuretic peptide (ANP). ANP is a hormone of cardiac origin with diuretic and natriuretic actions. Despite elevated circulating levels of ANP, congestive heart failure (CHF) is characterized by progressive sodium and water retention. In order to elucidate the loss of natriuretic and diuretic properties of ANP in CHF we analyzed activity, protein concentrations, mRNA and immunostaining of NEP in kidneys of different models of severe CHF in the rat.CHF was induced by either aortocaval shunt, aortic banding or myocardial infarction in the rat. All models were defined by increased left ventricular end-diastolic pressure and decreased contractility. The diminished effectiveness of ANP was reflected by reduced cGMP/ANP ratio in animals with shunt or infarction. Renal NEP activity was increased in rats with aortocaval shunt (203 +/- 7%, p < 0.001), aortic banding (184 +/- 11%, p < 0.001) and infarction (149 +/- 10%, p < 0.005). Western blot analysis revealed a significant increase in renal NEP protein content in two models of CHF (shunt: 214 +/- 57%, p < 0.05; infarction: 310 +/- 53 %, p < 0.01). The elevated protein expression was paralleled by a threefold increase in renal NEP-mRNA level in the infarction model. The increased renal NEP protein expression and activity may lead to enhanced degradation of ANP and may contribute to the decreased renal response to ANP in heart failure. Thus, the capacity to counteract sodium and water retention, would be diminished. The increased renal NEP activity may therefore be a hitherto unknown factor in the progression of CHF.
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PMID:Increased expression of renal neutral endopeptidase in severe heart failure. 1238 78

The present study was aimed at investigating whether the regulation of vascular renin-angiotensin and endothelin (ET) systems is altered by a chronic blockade of nitric oxide (NO) synthesis. Male Sprague-Dawley rats were supplemented with N(G)-nitro-L-arginine methyl ester (L-NAME, 100mgl(-1)) in drinking water for 4 weeks to inhibit the endogenous synthesis of NO. The mRNA expressions of renin, angiotensin converting enzyme (ACE), type-1 angiotensin II receptor (AT1R), ET-1, type-A ET receptor (ET(A)), and neutral endopeptidase (NEP) were determined in the thoracic aorta by reverse transcription-polymerase chain reaction. The treatment with L-NAME significantly increased the blood pressure, while it decreased the tissue levels of nitrite/nitrate. The mRNA expression of renin, ACE, and AT1R was increased in the aorta. The protein expression of AT1R assessed by Western blot analysis was also increased. The expression of ET-1 and ET(A) mRNA was increased, whereas that of NEP mRNA decreased. The increased expression of renin-angiotensin and ET system genes and the decreased expression of NEP may in part be causally related with the development of hypertension induced by a chronic blockade of NO synthesis.
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PMID:Upregulation of vascular renin-angiotensin and endothelin systems in rats inhibited of nitric oxide synthesis. 1241 41

The byssal threads of marine mussels represent a peculiar case of extraorganismic extracellular material. The threads consist of fibrous chimeric collagens such as preCol-P (with collagenous, elastin-like and histidine-rich domains) embedded in a microfibrillar matrix. We report here on the extraction, purification, and characterization of water-soluble proximal thread matrix protein 1 (PTMP1), which is preferentially located in the proximal portion of each byssal thread and decreases in a proximal to distal direction. PTMP1 has a mass of about 50 kDa as determined by matrix-assisted laser desorption-ionization with time-of-flight (MALDI-TOF) mass spectrometry. Glycine is the most common residue at 12.2 mol %, followed by asparagine/aspartic acid and glutamine/glutamic acid at 11.4 and 9.9 mol %, respectively. Glycosylation has been detected by Western blotting with biotinylated concanavalin A and neutral sugar analysis. With degenerate primers designed from the N-terminal sequence and an additional internal peptide derived by Lys-C endopeptidase digestion, a complete cDNA sequence for this protein was obtained by polymerase chain reaction (PCR) amplification of a Mytilus edulis foot cDNA library. Two variants with minor sequence differences limited to the N-terminus were found. The cDNA-deduced protein sequence reveals two symmetric internal repeats that together account for >85% of the protein. Sequence and epitope similarity of PTMP1 to the A domains of von Willebrand factor and integrin alpha(1)I suggest a capacity for collagen binding. Enzyme-linked immunosorbent assay (ELISA)-based measurement of PTMP1 binding to immobilized type I collagen shows high affinity (apparent K(D) = 0.25 microM), but the binding exhibits no dependence on metals. Using primers designed from M. edulis, we also found a PTMP1-like cDNA in a related species, M. galloprovincialis, with a deduced protein sequence having 97% identity with one M. edulis variant and 99% identity with the other. The corresponding cDNA sequences have 94% and 96% identity, respectively.
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PMID:Collagen-binding matrix proteins from elastomeric extraorganismic byssal fibers. 1242 61

A salt-fermented sauce from shrimp processing byproducts (heads, shells, and tails) was prepared and characterized. Three types of sauces were prepared; sauce C, with 30 g of salt/100 g of byproduct (high salt); sauce E, with 30 g of salt and 0.2 g of sodium erythorbate (high salt); and sauce L, with 20 g of salt, 0.2 g of sodium erythorbate, 6 g of sorbitol, 0.5 mL of lactic acid, and 5 mL of ethanol (low salt). Sauces C and E showed higher exopeptidase activities than sauce L, whereas sauce L showed the highest endopeptidase activity. After 3 months of fermentation, the amino N content of sauce increased from 150-200 to 500-600 mg/100 g and the nonprotein nitrogen content increased from 300 to 950-1050 mg/100 g. Volatile basic nitrogen content increased significantly from 18 to 60 mg/100 g. The total carotenoids retained in sauces C, E, and L were 26.3, 76.2, and 73%, respectively, thus indicating that the addition of sodium erythorbate to sauces E and L retarded oxidation. Water activities of sauces C, E, and L were 0.753, 0.751, and 0.773, respectively. According to the omission test, the taste of sauces was influenced by the content of free amino acids, mainly glutamic acid and aspartic acid. All three sauces examined showed a 35% higher total amino acid content than commercial salt-fermented shrimp sauces. Therefore, shrimp processing byproducts may lend themselves to the preparation of high-quality salt-fermented sauces.
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PMID:Characteristics of salt-fermented sauces from shrimp processing byproducts. 1253 58


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