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)

Vasopeptidase inhibitors are a new class of antihypertensive drugs that are single molecules having dual inhibitory action on angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The best known drug in this class is omapatrilat, which has been proposed to be more efficacious than ACE inhibitors because of its ability to inhibit NEP and prevent the breakdown of atrial peptides and bradykinin. However, survival of endothelin (ET) may also be enhanced and therefore, NEP inhibitors may have limited efficacy under conditions of low renin and high ET production. The purpose of the current study was to contrast the effects of the ACE inhibitor, enalapril, with omapatrilat in a model of established hypertension where ACE inhibitors are ineffective, the deoxycorticosterone acetate (DOCA)-salt-treated rat. Two weeks after starting DOCA-salt treatment, rats were given either enalapril (10 mg/kg/day) or omapatrilat (30 mg/kg/day) for 5 days. Mean arterial pressure (MAP) measured by radiotelemetry in untreated DOCA-salt rats increased from 102 +/- 2 to 181 +/- 12 mm Hg (P<.05) as a result of DOCA-salt treatment for 3 weeks. MAP was unaffected by either enalapril (189 +/- 3 mm Hg) or omapatrilat (184 +/- 8 mm Hg). DOCA-salt treatment significantly increased urinary ET excretion compared to baseline (1.6 +/- 0.2 vs. 0.5 +/- 0.1 pmol/day). Administration of omapatrilat significantly increased urinary ET excretion in DOCA-salt rats (2.9 +/- 0.4 pmol/day) compared to enalapril-treated (1.6 +/- 0.2 pmol/day) or untreated (1.5 +/- 0.1 pmol/day) rats. These results indicate that combined ACE/NEP inhibition does not lower blood pressure in a model of established hypertension with high ET activity. These results also support the hypothesis that combined ACE/NEP inhibition can increase renal ET production.
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PMID:Omapatrilat increases renal endothelin in deoxycorticosterone acetate-salt hypertensive rats. 1525 92

Angiotensin I is a substrate for both the angiotensin converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). The present study examined the hypothesis that a high ACE expression is associated with a low NEP activity. Male Sprague-Dawley rats had two-kidney, one-clip (2K1C), N(G)-nitro-L-arginine methyl ester (L-NAME) or deoxycorticosterone acetate (DOCA)-salt hypertension, which were either angiotensin-dependent or -independent. The expression of ACE and NEP mRNA was determined in the thoracic aorta by a reverse transcription-polymerase chain reaction. The catalytic activity of NEP was measured by fluorometry. The expression of ACE was increased in 2K1C and L-NAME hypertension, and decreased in DOCA-salt hypertension. Conversely, the expression of NEP was decreased in 2K1C and L-NAME hypertension, and increased in DOCA-salt hypertension. The catalytic activity of NEP was altered similarly as its expression. These results suggest that ACE expression is inversely related to vascular NEP activity in certain forms of hypertension.
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PMID:Reciprocal regulation of angiotensin converting enzyme and neutral endopeptidase in rats with experimental hypertension. 1531 94

CGS 26303 is a vasopeptidase inhibitor that simultaneously inhibits endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP). We compared the effects of chronic treatment with CGS 26303 to the selective inhibition of angiotensin-converting enzyme (ACE) and NEP during the transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF) in hypertensive rats. LV geometry and function were assessed in Dahl salt-sensitive rats placed on a high-salt diet from age 6 weeks (hypertensive rats) and in control rats fed a low-salt diet. The hypertensive rats were randomized into groups that received no treatment or were treated with an ACE inhibitor (temocapril), an ECE/NEP inhibitor (CGS 26303), or a NEP inhibitor (CGS 24592) from the LVH stage (11 weeks) to the CHF stage (17 weeks). All treatments decreased the systolic blood pressure equally and significantly improved LV fractional shortening. Both temocapril and CGS 26303 ameliorated LV perivascular fibrosis, reduced mRNA levels of types I and III collagen, and decreased the heart weight/body weight ratio. CHF rats had increased plasma ET-1 levels compared with control rats. Only CGS 26303 reduced ET-1 to normal levels. ET-1 levels were found to correlate with heart/body weight, right ventricle/body weight and perivascular fibrosis ratios. During the transition to CHF, CGS 26303 produces effects that are comparable to temocapril and superior to CGS 24592. The beneficial effects of CGS 26303 are likely caused in part by the greater reduction of plasma ET-1. Dual ECE/NEP inhibitor may provide a new strategy for the treatment of human heart failure.
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PMID:Dual ECE/NEP inhibition on cardiac and neurohumoral function during the transition from hypertrophy to heart failure in rats. 1589 63

It is widely accepted that a high sodium intake triggers blood pressure rise. However, only one-third of the normotensive subjects were reported to show salt-sensitivity in their blood pressure. Many factors have been proposed as causes of salt-sensitive hypertension, but none of them provides a satisfactory explanation. We propose, on the basis of accumulated data, that the reduced activity of the kallikrein-kinin system in the kidney may provide this link. Renal kallikrein is secreted by the distal connecting tubular cells and all kallikrein-kinin system components are distributed along the collecting ducts in the distal nephron. Bradykinin generated is immediately destroyed by carboxypeptidase Y-like exopeptidase and neutral endopeptidase, both quite independent from the kininases in plasma, such as angiotensin converting enzyme. The salt-sensitivity of the blood pressure depends largely upon ethnicity and potassium intake. Interestingly, potassium and ATP-sensitive potassium (K(ATP)) channel blockers accelerate renal kallikrein secretion and suppress blood pressure rises in animal hypertension models. Measurement of urinary kallikrein may become necessary in salt-sensitive normotensive and hypertensive subjects. Furthermore, pharmaceutical development of renal kallikrein releasers, such as K(ATP) channel blockers, and renal kininase inhibitors, such as ebelactone B, may lead to the development of novel antihypertensive drugs.
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PMID:A missing link between a high salt intake and blood pressure increase. 1665 1

We previously reported that CGS 35601, a potent triple inhibitor of angiotensin-converting enzyme, neutral endopeptidase, and endothelin-converting enzyme 1, completely normalized mean arterial blood pressure (MABP) in 36-week-old spontaneously hypertensive rats, a normal renin model. The aim of the present study was to determine the effects of this triple vasopeptidase inhibitor (VPI) on the hemodynamic profile of instrumented, conscious, and unrestrained Dahl salt-sensitive (DSS) rats, a gene-prone, high-salt diet-induced low-renin hypertension model. Male DSS rats (mean weight [+/-SEM], 385 +/- 10 g) were fed a normal diet (Group 1) or a high-salt diet (Groups 2 and 3; 8% NaCl in food) for 6 weeks and then instrumented with a carotid catheter and placed individually in metabolic cages for 30 days. The hemodynamic, hematological, and biochemical profiles were assessed daily. Dose-dependent treatment started after a 7-day stabilization period in Groups 1 and 2 (vehicle dosage, 250 microl/hr) and Group 3 (CGS 35601 dosages of 0.1, 1, and 5 mg/kg/day for 6 days per dose by means of constant intra-arterial infusion), followed by a 5-day washout period. Two additional groups included normotensive Wistar rats (Group 4) and DSS rats that received a double high-salt solid (8% NaCl) and liquid (1% NaCl) diet (Group 5). The MABP in rats receiving CGS 35601 decreased in a dose-dependent fashion toward the baseline level observed in DSS rats receiving a normal diet. The heart rate was unaffected. The hemodynamic profile returned to normal during the washout period. This novel triple VPI is a potent and effective antihypertensive agent with a safe short-term profile that may be of interest for treating hypertension and other cardiovascular diseases. Other hypertensive rat models are being tested.
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PMID:Triple VPI CGS 35601 reduces high blood pressure in low-renin, high-salt Dahl salt-sensitive rats. 1674 Oct 7

Omapatrilat, a vasopeptidase inhibitor, inhibits both neutral endopeptidase and angiotensin-converting enzyme with similar potency. The aim of this study was to investigate whether omapatrilat prevents or reverses cardiovascular remodeling and hypertension in deoxycorticosterone acetate (DOCA)-salt rats. Male Wistar rats (313 +/- 2 g, n = 114) were uninephrectomized (UNX) with or without further treatment with DOCA and 1% NaCl in the drinking water. Compared with UNX control rats, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, perivascular and interstitial cardiac fibrosis and inflammation, endothelial dysfunction, and the prolongation of ventricular action potential duration within four weeks. The administration of omapatrilat (40 mg/kg/day po) for two weeks commencing two weeks after surgery attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis, and ventricular action potential prolongation. In contrast, omapatrilat treatment did not lower systolic blood pressure nor improve endothelial dysfunction. This study concludes that the renin-angiotensin-aldosterone, natriuretic peptide, and bradykinin systems are directly involved in the pathogenesis of cardiovascular remodeling in the DOCA-salt model of hypertension in rats, which may be independent of their effects on blood pressure.
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PMID:Attenuation of cardiovascular remodeling in DOCA-salt rats by the vasopeptidase inhibitor, omapatrilat. 1682 Mar 44

The aim of this study was to identify the role of chymase in the conversion of exogenously administered Big endothelin-1 in the mouse in vivo. Real-time polymerase chain reaction analysis detected mRNA of mucosal mast cell chymases 4 and 5, endothelin-converting enzyme 1a, and neutral endopeptidase 24.11 in pulmonary, cardiac, and aorta homogenates derived from C57BL/6J mice, with the latter tissue expressing the highest levels of both chymase isoforms. Furthermore, hydrolysis of a fluorogenic peptide substrate, Suc-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin, was sensitive to the chymase inhibitors Suc-Val-Pro-Phe(P)(OPh)(2) (200 microM) and chymostatin [(S)-1-carboxy-2-phenylethyl]-carbamoyl-alpha-[2-iminohexahydro-4(S)-pyrimidyl]-(S)-Gly-X-Phe-al, where X can be the amino acid Leu, Val, or Ile) (100 microM) in supernatants extracted from the same tissue homogenates. In anesthetized mice, Big endothelin-1, endothelin-1 (1-31), and endothelin-1 triggered pressor responses (ED(50)s, 0.67, 0.89, and 0.16 nmol/kg) that were all reduced or potentiated by selective endothelin ET(A) or ET(B) receptor antagonists, respectively, BQ-123 (cyclo[D-Asp-Pro-D-Val-Leu-D-Trp]) or BQ-788 (N-[N-[N-[(2,6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-l-leucyl]-1-(methoxycarbonyl)-D-tryptophyl]-d-norleucine sodium salt), each at 1 mg/kg. The pressor responses to big endothelin-1 were significantly reduced by the neutral endopeptidase inhibitor thiorphan (dl-3-mercapto-2-benzylpropanoylglycine) (1 mg/kg) or the endothelin-converting enzyme inhibitor CGS 35066 [alpha-[(S)-(phosphonomethyl)amino]-3-dibenzofuranopropanoic acid] (0.1 mg/kg). In contrast, the responses to endothelin-1 (1-31) were abolished by thiorphan but unaffected by CGS 35066. In addition, Suc-Val-Pro-Phe(P)(OPh)(2) (20-40 mg/kg) reduced, by more than 60%, the hemodynamic response to big endothelin-1 but not to endothelin-1 (1-31) and endothelin-1. Finally, intravenous administration of big endothelin-1 induced Suc-Val-Pro-Phe(P)-(OPh)(2)-sensitive increases in plasma-immunoreactive levels of endothelin-1 (1-31) and endothelin-1. The present study suggests that chymase plays a pivotal role in the conversion and cardiovascular properties of big endothelin-1 in vivo.
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PMID:Chymase-dependent conversion of Big endothelin-1 in the mouse in vivo. 1898 1

The study was focused on the role of the penicillin binding protein PBP4* of Bacillus subtilis during growth in high salinity rich media. Using pbpE-lacZ fusion, we found that transcription of the pbpE gene is induced in stationary phase and by increased salinity. This increase was also corroborated at the translation level for PBP4* by western blot. Furthermore, we showed that a strain harboring gene disruption in the structural gene (pbpE) for the PBP4* endopeptidase resulted in a salt-sensitive phenotype and increased sensitivity to cell envelope active antibiotics (vancomycin, penicillin and bacitracin). Since the pbpE gene seems to be part of a two-gene operon with racX, a racX::pRV300 mutant was obtained. This mutant behaved like the wild-type strain with respect to high salt. Electron microscopy showed that high salt and mutation of pbpE resulted in cell wall defects. Whole cells or purified peptidoglycan from WT cultures grown in high salt medium showed increased autolysis and susceptibility to mutanolysin. We demonstrate through zymogram analysis that PBP4* has murein hydrolyze activity. All these results support the hypothesis that peptidoglycan is modified in response to high salt and that PBP4* contributes to this modification.
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PMID:High salt stress in Bacillus subtilis: involvement of PBP4* as a peptidoglycan hydrolase. 1906 62

Although deoxycorticosterone acetate (DOCA)-salt hypertension is a volume dependent model of hypertension, it shows polyuria and natriuresis. It is expected that dysregulation of aquaporin water channels (AQPs) and sodium transporters associated with natriuretic peptide (NP) system may play an escape role in sodium retaining state. One week after left unilateral nephrectomy, rats were subcutaneously implanted with silastic DOCA (200 mg/kg) strips. Physiologic saline was supplied as a drinking water to all animals. 4 weeks after operation, the protein expression of AQPs, sodium transporters, and endopeptidase (NEP) was determined in the kidneys by semiquantitative immunoblotting and immunohistochemistry. The mRNA expression of NP system was determined by real-time polymerase chain reaction. The amount of urinary ANP excretion was measured by radioimmunoassay. In DOCA-salt rats, urine osmolality was decreased while urinary excretion of sodium was increased. The expression of AQP1-3 as well as that of alpha-1 subunit of Na,K-ATPase, NHE3, NKCC2 and NCC was decreased in the kidney. The mRNA expression of ANP, brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) was increased in the kidney. The expression of NEP was decreased, and urinary ANP excretion was increased. Downregulation of AQPs and sodium transporters may contribute to mineralocorticoid escape in DOCA-salt hypertension. Increased expression of natriuretic peptides associated with downregulation of NEP may play a role in natriuresis.
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PMID:Altered regulation of renal sodium transporters and natriuretic peptide system in DOCA-salt hypertensive rats. 1942 59

The objectives of the present study were to assess how the stability of the emulsion recovered from aqueous extraction processing of soybeans was affected by characteristics of the starting material and extraction and demulsification conditions. Adding endopeptidase Protex 6L during enzyme-assisted aqueous extraction processing (EAEP) of extruded soybean flakes was vital to obtaining emulsions that were easily demulsified with enzymes. Adding salt (up to 1.5 mM NaCl or MgCl(2)) during extraction and storing extruded flakes before extraction at 4 and 30 degrees C for up to 3 months did not affect the stabilities of emulsions recovered from EAEP of soy flour, flakes and extruded flakes. After demulsification, highest free oil yield was obtained with EAEP of extruded flakes, followed by flour and then flakes. The same protease used for the extraction step was used to demulsify the EAEP cream emulsion from extruded full-fat soy flakes at concentrations ranging from 0.03% to 2.50% w/w, incubation times ranging from 2 to 90 min, and temperatures of 25, 50 or 65 degrees C. Highest free oil recoveries were achieved at high enzyme concentrations, mild temperatures, and short incubation times. Both the nature of enzyme (i.e., protease and phospholipase), added alone or as a cocktail, concentration of enzymes (0.5% vs. 2.5%) and incubation time (1 vs. 3 h), use during the extraction step, and nature of enzyme added for demulsifying affected free oil yield. The free oil recovered from EAEP of extruded flakes contained less phosphorus compared with conventional hexane-extracted oil. The present study identified conditions rendering the emulsion less stable, which is critical to increasing free oil yield recovered during EAEP of soybeans, an environmentally friendly alternative processing method to hexane extraction.
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PMID:Factors affecting emulsion stability and quality of oil recovered from enzyme-assisted aqueous extraction of soybeans. 1957 Jun 74


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