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:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new angiotensin converting enzyme inhibitor, enalaprilic acid (MK-422), was given in a bolus of 0.5 mg/kg i.v., followed by an infusion of 0.25 mg/kg/hr to determine its effects in hemorrhagic shock. MK-422 produced no significant hemodynamic effects in sham shock controls, yet it effectively blocked the pressor effect of exogenously administered angiotensin I throughout the 260-min experimental period and reduced angiotensin converting enzyme activity by 90% as determined by radiochemical assay. In vitro studies on cat papillary muscles and pancreatic homogenates revealed no direct inotropic or antiproteolytic effect of enalaprilic acid. Nevertheless, converting enzyme inhibitor treatment maintained postreinfusion mean arterial blood pressure at a significantly higher value (P less than .01) than that of untreated hemorrhaged animals (66 +/- 5 vs. 27 +/- 10 mm Hg, respectively). Superior mesenteric artery flow for hemorrhaged cats was significantly higher (P less than .05) in the treated group both during the end of the oligemic period (6.1 +/- 0.4 vs. 3.8 +/- 0.8 ml/kg/min) and during the postreinfusion period (6.5 +/- 0.7 vs. 1.9 +/- 1.0 ml/kg/min). Moreover, enalaprilic acid blunted the marked rise in plasma cathepsin D (P less than .01) and myocardial depressant factor activities (P less than .01), and plasma amino-nitrogen concentrations (P less than .05) observed in the untreated hemorrhaged cats. These results indicate that enalaprilic acid improved the hemodynamic and metabolic status of cats in hemorrhagic shock.
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PMID:Anti-shock actions of a new converting enzyme inhibitor, enalaprilic acid, in hemorrhagic shock in cats. 609 95

A highly sensitive and specific enzymatic assay for the quantitative determination of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) and its hydrolysis product Hoe 498-diacid in serum and a GLC method for the simultaneous determination of both compounds in urine are described. Both methods involve extraction from the respective biological fluid using disposable C 18 columns. In serum, the enzyme-inhibiting properties of Hoe 498-diacid (Hoe 498 can readily be converted to its hydrolysis product) are utilized for the determination of both compounds concurrently. The serum extract is dissolved in buffer solution and incubated with human serum as angiotensin converting enzyme (peptidyl-dipeptide-hydrolase, EC 3.4.15.1) source and hip-his-leu substrate. The hippuric acid liberated is quantitated by HPLC. The urine extract is treated with diazomethane followed by trifluoroacetic anhydride to convert Hoe 498 and Hoe 498-diacid to their methylester, trifluoroacetyl derivatives, which are then determined simultaneously by GLC using a nitrogen specific detector.
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PMID:Determination of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) and its hydrolysis product in serum and urine. 609 70

Increased concentrations of angiotensin converting enzyme (ACE) were found in lung lavages from rabbits exposed to hyperoxia for 72 h and the concentrations of ACE were correlated with ratios of extravascular lung water to body weight (r = 0.69, p less than 0.05) and albumin concentrations in lung lavages (r = 0.89, p less than 0.01). In parallel studies, rabbits treated with nitrogen mustard in which granulocytopenia was maintained throughout the 72-h hyperoxic exposure period had less evidence of edematous lung injury and lower concentrations of ACE in their lung lavages than similarly treated rabbits in which granulocytopenia was not maintained. The results suggested that granulocytes contribute to acute edematous lung injury from hyperoxia and that ACE concentrations in lung lavages reflect this process.
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PMID:Angiotensin converting enzyme concentrations in the lung lavage of normal rabbits and rabbits treated with nitrogen mustard exposed to hyperoxia. 626 99

Bovine lung angiotensin I-converting enzyme is rapidly and irreversibly inactivated by p-[N,N-bis(chloroethyl)amino]phenylbutyric acid (chlorambucil) and by the chlorambucil derivative of L-proline (chlorambucyl-proline). Chlorambucil is a nitrogen mustard alkylating agent that is used as an antineoplastic drug. At any one concentration, the inactivation is pseudo-first order with time. Inhibition by both substances is active site directed as suggested by the formation of a reversible enzyme-inhibitor complex prior to the alkylation reaction and by the fact that L-Phe-L-Pro, a reversible inhibitor which is competitive with substrate, is also competitive with both irreversible inhibitors in protecting the enzyme against inactivation. The second order rate constant for inactivation increases in the pH range 5-8 and reaches a value of 3.5 X 10(3) M-1 . min-1 for chlorambucil and 4.8 X 10(2) M-1 . min-1 for chlorambucyl-proline. Chlorambucyl [U-14C]L-proline reacts 1:1 with the converting enzyme and the uptake of radioactivity paralleled the loss of enzyme activity with and without protection by Phe-Pro. Once bound, the radioactive chlorambucyl proline was released (as the dihydroxy derivative) by hydroxide ion with a second order rate constant of 2.2 M-1 . min-1 at 25 degrees C. The radioactive label is also removed by hydroxylamine at pH 10. The lability of the irreversibly bound inhibitor in alkali and in hydroxylamine indicates that an ester bond is formed by the alkylation of an aspartic acid or glutamic acid side chain.
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PMID:Irreversible inhibition of bovine lung angiotensin I-converting enzyme with p-[N,N-bis(chloroethyl)amino]phenylbutyric acid (chlorambucil) and chlorambucyl L-proline and with evidence that an active site carboxyl group is labeled. 627 65

N alpha-Phosphoryl-L-alanyl-L-proline is a reversible competitive inhibitor of angiotensin converting enzyme with a Ki of 1.4 nM. Alkylation of one phosphate oxygen with methyl, ethyl, or benzyl does not change the Ki. The high activity of the O-alkylated inhibitors demonstrates that the two phosphate oxygen anions do not constitute a bidentate ligand of the active site zinc ion. Substitution of valyltryptophan, glycylglycine, or delta-aminovaleric acid for alanylproline in the phosphoramidate raises the Ki to 12 nM, 25 microM, and 178 microM, respectively. Methylation of the alanine nitrogen in phosphorylalanylproline raises the Ki to 29 microM. Polyphosphates inhibit converting enzyme with the following Ki's: phosphate, approximately 300 mM; pyrophosphate, 2 mM; tripolyphosphate, 18 microM; tetrapolyphosphate, 150 microM. The inhibition by tripolyphosphate appears to be competitive and is unaffected by the addition of excess zinc ion. Since the Ki of tripolyphosphate is nearly 10-fold lower than that of N-phosphoryl-delta-aminovaleric acid and is near that of N alpha-phosphorylglycylglycine, its terminal phosphates may bind the zinc site and the cationic site on the enzyme, thus spanning the S1' and S2' sites.
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PMID:Inhibition of angiotensin converting enzyme by phosphoramidates and polyphosphates. 629 38

Mutants of Salmonella typhimurium deficient in dipeptidyl carboxypeptidase have been isolated by screening for clones unable to use N-acetyl-L-alanyl-L-alanyl-L-alanine (AcAla3) as the sole nitrogen source. An insertion of the transposable element Tn10 near dcp (the locus coding for dipeptidyl carboxypeptidase) has been isolated and used to map the locus in the interval between purB and trp, an otherwise genetically silent region of the S. typhimurium map. All dcp mutants could still grow using N-acetyl-L-alanyl-L-alanyl-L-alanyl-L-alanine (AcAla4) as the sole nitrogen source. Crude extracts from the dcp mutants failed to hydrolyze AcAla3 but retained approximately 80% of the wild-type activity toward AcAla4. Several lines of evidence indicate that hydrolysis of AcAla4 in the dcp mutant results from the action of a new peptidase distinct from dipeptidyl carboxypeptidase. A mutant strain lacking dipeptidyl carboxypeptidase in addition to peptidases N, A, B, and D showed reduced protein breakdown during carbon starvation compared with a strain lacking only peptidases N, A, B, and D.
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PMID:Dipeptidyl carboxypeptidase-deficient mutants of Salmonella typhimurium. 633 91

An oligopeptidase that hydrolyzes N-acetyl-L-alanyl-L-alanyl-L-alanyl-L-alanine (AcAla4) has been identified in extracts of Salmonella typhimurium. Mutants lacking this activity have been isolated in dcp mutant strains by screening extracts of mutagenized clones for failure to hydrolyze AcAla4 or by screening colonies for inability to use AcAla4 as a nitrogen source. Double mutants (dcp optA) lacking both oligopeptidase A and dipeptidyl carboxypeptidase cannot use AcAla4 as a nitrogen source, although dcp+ optA and dcp optA+ strains grow on this peptide. The mutations responsible for the loss of activity map at a locus (optA) between asd (75 map units) and xylA (78 map units). Oligopeptidase A hydrolyzes certain N-blocked tetrapeptides, unblocked pentapeptides, and unblocked hexapeptides, usually but not always liberating the C-terminal tripeptide. These two activities seem to be responsible for the production of a large fraction of the dipeptides that accumulate during protein breakdown in a pepN pepA pepB pepD strain.
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PMID:Oligopeptidase-deficient mutants of Salmonella typhimurium. 633 92

Blockade of the renin-angiotensin system was studied in male Sprague-Dawley rats during long-term inhibition of nitric oxide synthase. Nitro-L-arginine-methyl ester (L-NAME) was placed in the drinking water for 4 weeks (approximately 100 mg/kg per day). Separate groups of rats were coadministered the angiotensin II antagonist A-81988 in the drinking water ranging from approximately 0.001 to 1 mg/kg per day. Control groups received only tap water or A-81988 alone. Each week, rats were placed in metabolic cages, and tail-cuff blood pressures and blood samples were taken. L-NAME produced a sustained elevation in tail-cuff pressure that was completely prevented by A-81988. No changes in creatinine clearance, sodium excretion, plasma creatinine concentration, or blood urea nitrogen were observed. Food and water intakes were identical in all groups. Water excretion was significantly increased in L-NAME-treated animals regardless of additional inhibitor treatment, suggesting a possible role for nitric oxide synthase in the control of water excretion; this effect was independent of blood pressure. Although less potent than A-81988, the angiotensin II antagonist losartan and the angiotensin converting enzyme inhibitor enalapril also blocked L-NAME-induced hypertension. In a separate series of experiments, rats were not given A-81988 until 2 weeks after hypertension had fully developed in L-NAME-treated rats. Within 1 week of treatment with the angiotensin II antagonist, tail-cuff pressure returned to normal. We conclude from these studies that long-term inhibition of endogenous nitric oxide production produces an angiotensin II-dependent form of hypertension.
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PMID:Angiotensin blockade reverses hypertension during long-term nitric oxide synthase inhibition. 768 26

The clinical use of nonsteroidal anti-inflammatory drugs is gaining wide acceptance and acute oliguric renal failure in association with the administration of ibuprofen has been reported. This study was designed to evaluate the renal effects of intermittent versus continuous intravenous infusion of ibuprofen (Motrin) over a 24-h period in the anesthetized non-pregnant baboon. A total of 50 mg/kg of ibuprofen was either infused continuously or given as a bolus in four divided doses (intermittent). Control animals received only normal saline. Mean aortic pressure showed a tendency to decrease with time in all groups studied with a significant decrease occurring in the infusion group. There were no significant changes in the renal artery flow, renal resistance, central venous pressure and heart rate within the groups. Serum urea nitrogen decreased and was significantly different from the baseline value at 24 h in the infusion group. Serum creatinine, however, showed no such changes. Although, urinary output and creatinine clearance showed a tendency to decrease in the treated groups, it was not significantly different. Plasma renin activity decreased from 9.95 to 2.3 ng/ml/hr in the control group but showed no significant changes in others. Serum levels of angiotensin converting enzyme were well maintained. The circulating levels of ibuprofen reached a steady state after 2 h in the infusion group. The results of this study demonstrate that continuous infusion of ibuprofen does not possess an advantage over its intermittent administration. Despite the modifications we have observed in renal flow and function, this drug appears to be safe in the dose levels we have used in these experiments.
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PMID:Renal effects of intermittent versus continuous infusion of ibuprofen in the primate. 784 93

For a rigorous assessment of the precise amount of sample loaded, for quantitation purposes, different sample injection systems were evaluated with two commercially available units, Waters Quanta 4000 and Beckman P/ACE 2100. In the first system, sample introduction by hydrostatic means (i.e., placing the sample vial at some height, usually 10.1 cm, above the other capillary end) was evaluated. It was found that in this system there is a constant positive bias, i.e. the amount of sample loaded lies on a curve parallel and above the theoretically predicted loading curve. However, the excess of mass loaded was constant along the injection times explored (covering from 5 to 35 s) and, for a 75 microns capillary, was found to be of the order of +6 nL (above the expected injected value). Thus it is easy to correct for this sample bias. In the electrokinetic mode, a very good correlation between expected and predicted sample loads was obtained for both units. In the pressure system (by positive pressure from a nitrogen tank, Beckman unit) a substantial discrepancy was found between experimental and predicted values (13.5% overload). Since the manufacturer claims a constant pressure of 0.5 psi, i.e. 3447.5 Pa, it would appear that the injection pressure is higher than the given value.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Quantitative studies of different injection systems in capillary electrophoresis. 785 24


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