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)

Patients with homozygous beta-thalassemia are chronically transfused and, if not assiduously chelated, are at risk for cardiac dysfunction. Available data suggest that even in optimally chelated patients, cardiac pathology is abnormal secondary to iron deposition, fibrosis, hypertrophy, and the structural effects of chronic anemia. Evidence of myopericarditis may also be found. Cardiac performance is usually only subtly affected, primarily with diastolic abnormalities not routinely detected on echocardiograms or nuclear scan. In poorly chelated patients, severe heart failure occurs and is easily predictable but invariably fatal, despite treatment with diuretics, vasodilators, inotropes, and antiarrhythmics. Based on successful prevention of heart failure with ACE inhibitors in other forms of cardiomyopathy, we suggest multicenter trials to explore methods to stabilize cardiac function in patients at risk for iron-induced heart disease. Long-term adverse effects of iron deposition, diastolic dysfunction, and abnormal hormone regulation need to be quantitated in patients reaching their third and fourth decades when the potential for ischemic cardiac disease could compound cardiac dysfunction.
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PMID:Diagnosis and management of iron-induced heart disease in Cooley's anemia. 966 46

We report a neonate with neonatal hemochromatosis (NH), renal tubular dysgenesis (RTD), and hypocalvaria. NH is a fatal condition of the newborn, characterized by severe idiopathic liver failure of intrauterine onset and siderosis, intra- and extrahepatic, with sparing of the reticuloendothelial system. RTD is characterized by short, abnormally developed cortical tubules that lack proximal tubule differentiation. Although both NH and RTD have been reported as entities with a genetic component, similar findings can be secondary to in utero insults. Hypocalvaria has been reported in association with fetal hypoxia including that secondary to angiotensin converting enzyme inhibitors. This 38-week-old infant died at 8.5 h. The small nodular liver weighed 44 g. Grossly, the kidneys were normal. Hypocalvaria was present. Microscopically, the hepatic parenchyma was distorted by fibrous tracts, proliferation of bile ducts, and abundant iron deposition in hepatocytes. Extrahepatic siderosis in the pancreas, myocardium, and other organs was consistent with NH. Proximal convoluted tubules were not seen on routine stains and markers for proximal tubules were negative. Previous reports have linked NH with RTD and RTD with hypocalvaria. This infant had all three of these rare conditions, which have been hypothesized or shown to be due to genetic factors, hypoxia, or drugs. The etiology in this case is unknown.
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PMID:Neonatal hemochromatosis, renal tubular dysgenesis, and hypocalvaria in a neonate. 968 68

Much attention has been focused in recent years on ways of optimizing the use and cost-effectiveness of erythropoietin therapy. The balance of evidence suggests that the subcutaneous route allows lower doses to be used compared with the intravenous route, and dosing should be two to three times weekly. Concomitant use of intravenous iron potently enhances the response to erythropoietin, and more recently other adjuvant therapies such as ascorbic acid, L-carnitine, folic acid, vitamin D, androgens, and other cytokines and growth factors have been investigated. Many factors can affect the response to erythropoietin, and underdialysis and co-administration of angiotensin converting enzyme inhibitors have attracted much recent interest. Controversy regarding the optimum target hemoglobin concentration in patients with renal failure remains, but three multicenter studies are providing useful data on this issue.
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PMID:Optimizing erythropoietin therapy. 1022 31

In Eisenmenger's syndrome a central left-to-right shunt in the heart, a congenital anomaly, leads to pulmonary hypertension which subsequently causes the shunt to be reversed. The hypoxaemia resulting from a right-to-left shunt is compensated by an increase of the haemoglobin concentration due to a rise of the haematocrit. In adult patients not operated (adequately), the symptoms are the consequence of the erythrocytaemia and an increased haemorrhagic diathesis. In the long run heart failure develops. Phlebotomy is indicated for patients with haematocrits higher than 0.65 with signs of hyperviscosity and is also advised before non-cardiac surgery to improve coagulation parameters. Phlebotomy should be performed slowly (500 ml in 30-45 min) with simultaneous volume replacement. Excessive phlebotomy causes iron deficiency and spherocytosis which increase viscosity as well as the risk of CVA. Treatment consists of iron supplementation. Anticoagulation is indicated only in case of atrial fibrillation or mechanical valves. The use of acetylsalicylacid or NSAIDs is relatively contraindicated, because of abnormal haemostasis in these patients. During treatment with ACE inhibitors and other vasodilators, hypovolaemia should be avoided, because at a lower systemic blood pressure the right-to-left shunt increases and a potentially fatal cyanosis may occur.
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PMID:[Eisenmenger syndrome in adults]. 1032 Dec 57

Captopril (D-3-mercapto-2-methylpropanoyl-L-proline) is an angiotensin converting enzyme (ACE) inhibitor, used widely in the treatment of hypertension and congestive heart failure. Captopril also inhibits proliferation of a variety of cell types, including several lacking ACE and renin acitvity. We have previously demonstrated that human mammary ductal carcinoma cells are among the cell types whose mitotic activity is inhibited by captopril. In those cells, captopril also reduces estrogen receptor (ER) and increases progesterone receptor (PR) concentrations. The present study evaluated the mechanism of captopril's antiproliferative action in an ER/PR-negative human mammary ductal carcinoma cell line, Hs578T. Cells grown in a 10% serum medium showed negligible changes in the presence of captopril alone. However, in the presence of subphysiologic concentrations of copper salts or copper-loaded ceruloplasmin, captopril caused a dose-dependent reduction in cell number, thymidine incorporation and mitochondrial dehydrogenase activity. In contrast, iron salts and iron-saturated transferrin had no effect on captopril activity. Catalase and horseradish peroxidase nullified the cytotoxic effects of captopril/Cu++, whereas H2O2 mimicked those effects. These data are consistent with the notion of a copper-catalyzed oxidation of captopril, leading to the generation of H2O2 as the cytotoxin to this clinically important cell type.
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PMID:Mechanism of captopril toxicity to a human mammary ductal carcinoma cell line in the presence of copper. 1051 67

Several factors influence the efficacy of the action of human recombinant erythropoietin during treatment of anaemia in haemodialysis patients. We carried out a six-month prospective study of 23 stable patients who had been on haemodialysis for at least one year to attempt to evaluate those factors modifying the dose of the hormone to attain a similar haematocrit, such as use or not of angiotensin converting enzyme inhibitors, hepatitis C virus positive or negative, age older or younger than 60 years, acquired cystic kidney disease or not, and sex. The patients were treated with subcutaneaous erythropoietin for over a year to attain a haematocrit of 35%, intravenous iron to reach plasma ferritin levels > 250 ng/ml and a transferrin saturation index > 20%, folic acid and group B vitamins. Parameters studied included age, time and duration of haemodialysis, Kt/V, albumin, haematocrit, erythropoietin in U/kg/week, intact PTH, hepatitis C virus, PCR of the hepatitis C virus, transaminases, ferritin, transferrin saturation index, folic acid, vitamin B12, and aluminium. No statistically significant differences were seen between the patients with and without hepatitis or in age or acquired cystic kidney disease and sex in the hormone dose given to achieve similar levels of haematocrit. Higher doses of erythropoietin were necessary in those patients treated with antihypertensive agents (71 +/- 25 vs 44 +/- 25 U/kg/week; p < 0.05). There were no differences between groups in factors known to cause resistance to the action of the hormone. The most important conclusions from this study concern the cost-benefit relation of treating hypertensive patients on haemodialysis with angiotensin converting enzyme inhibitors and erythropoietin.
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PMID:[Study of various factors that could have an impact on the treatment with erythropoietin of hemodialysis anemia]. 1085 98

1. Somatic angiotensin I-converting enzyme (ACE) is a protein that contains two similar domains (N- and C-terminal), each possessing an active site. We have examined the effects of a generator of hydroxyl radicals (g*OH: 2,2'-azo-bis(2-amidinopropane)) and hydrogen peroxide (H2O2) on ACE using an in vitro approach. 2. The generator of hydroxyl radicals inactivated ACE in a time (2-6 h)- and concentration (0.3-3 mmol/L)-dependent manner at 37 degrees C. When ACE was coincubated for 4 h with g*OH (3 mmol/L), its activity decreased by 70%. Addition of dimethylthiourea or mannitol + methionine, two *OH scavengers, resulted in a significant protection of ACE activity. Mercaptoethanol and dithiotreitol, two thiol-reducing agents, also efficiently protected ACE activity. 3. The hydrolysis of two natural and domain-specific substrates was explored. The hydrolysis of angiotensin I, preferentially cleaved by the C-domain, was significantly inhibited (57-58%) after 4 h exposure to g*OH (0.3-1 mmol/L). Under the same conditions of exposure, the hydrolysis of N-acetyl-Ser-Asp-Lys-Pro, a specific substrate for the N-domain, was only slightly inhibited by 1 mmol/L g*OH. 4. Hydrogen peroxide, another source of *OH, was used. After exposure to H2O2 (3 mmol/L; 4 h), an 89% decrease in ACE activity was observed. Pretreatment with the iron chelator deferoxamine (1 mmol/L) attenuated H2O2-mediated ACE inactivation, demonstrating that the effect of H2O2 was partly due to its conversion into *OH (Fenton reaction). 5. In summary, our findings demonstrate that g*OH and H2O2 inhibit ACE activity and suggest a preferential action of g*OH on the C-domain of the enzyme.
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PMID:Inhibitory effect of reactive oxygen species on angiotensin I-converting enzyme (kininase II). 1120 78

Oxygen free radical formation has been implicated in dopaminergic toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron. Although MPTP produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP+) by type B monoamine oxidase (MAO-B) in the brain, the etiology of this disease remains obscure. MPP+ is one of the most potent dopamine (DA)-releasing agents. Iron-catalyzed DA autoxidation and oxidative stress may be involved in the pathogenesis of Parkinson's disease. If indeed the effect of MPP+ on hydroxyl radical (.OH) formation is due to DA release, reserpine-induced DA depletion may reduce MPP(+)-induced .OH formation. Imidapril, an angiotensin converting enzyme (ACE) inhibitor, can resist MPP(+)-induced .OH formation via suppression of release of DA by angiotensin. Histidine, a singlet oxygen (1O2) scavenger, protects MPP(+)-induced .OH formation. Fluvastatin, an inhibitor of low-density lipoprotein (LDL) oxidation, can resist MPP(+)-induced .OH formation. The inhibitory effect on the susceptibility of LDL oxidation can reduce .OH generation. These drugs may be applied as antiparkinsonian agents. Further clinical investigation is necessary in the future.
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PMID:[Parkinsonism induced by MPTP and free radical generation]. 1123 1

Dry cough is the most common limiting factor of ACE inhibitor (ACEI) use. Generation of NO, a proinflammatory substance on bronchial epithelial cells, is increased by ACEI. Using a randomized, double-blind, placebo-controlled trial, we tested the hypothesis that supplementing iron, an inhibitor of NO synthase, may reduce the cough associated with ACEI use. The subjects were 19 patients who had developed ACEI-induced cough. After a 2-week observation period, they were randomized to a daily morning dose of either 256-mg ferrous sulfate as a tablet or placebo for a treatment period of 4 weeks. The subjects were requested to fill out a cough diary by scoring the daily severity of the cough on a scale of 0 to 4. Mean daily cough scores for the last week of the observation and treatment period were compared. Changes in blood cell count and serum iron and ferritin concentration between the 2 periods were evaluated. Mean daily cough scores during the observation and treatment periods were 3.07+/-0.70 and 1.69+/-1.10, respectively, for the iron group and 2.57+/-0.80 and 2.35+/-1.22, respectively, for the placebo group, showing a significant reduction in cough scores with iron supplementation (P<0.01) but not with placebo. Three subjects in the iron group showed almost complete cough abolition. No significant changes in laboratory data were observed in either group. In conclusion, iron supplementation successfully decreases ACEI-induced cough. This effect may be related to the decrease of NO generation associated with the inhibition of NO synthase activity in bronchial epithelial cells.
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PMID:Iron supplementation inhibits cough associated with ACE inhibitors. 1175 45

The increase of radical forms of mitochondrial respiratory chain compounds (MRCC) is an indicator of an increased risk of the formation of oxygen radicals. Using electron paramagnetic resonance (EPR), we found an increase of signals corresponding to ubisemichinone radical (.QH) and ironsulfur proteins radical forms (-FeS) of these respiratory chain compounds during ischemia in the isolated perfused rat heart (.QH increased from 1.51 to 3.08, .FeS1 from 1.14 to 2.65 arbitrary units). During the 5-min reperfusion, the signals returned to normoxic levels. In isolated mitochondria exposed to anoxia and reoxygenation the radical forms of .QH and FeS2 changed in a similar manner as in the intact heart. A combination of in vivo captopril treatment and in vitro L-arginine administration significantly decreased the levels of MRCC radicals in the isolated myocardium (.QH from 2.61 to 1.72 and .FeS, from 1.82 to 0.46 under normoxia; .QH from 4.35 to 2.66 and .FeS1 from 1.93 to 1.35 during ischemia). This decrease in MRCC radical forms was associated with increased NO levels in the perfusate, determined as NO2- / NO3-, as well as tissue NO levels determined using EPR as the dinitrosyl iron complex (DNIC). These results provide new information about the cardioprotective effects of ACE inhibitors and L-arginine.
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PMID:The effect of captopril on nitric oxide formation and on generation of radical forms of mitochondrial respiratory chain compounds in ischemic rat heart. 1170 52


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