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)

The superoxide radical scavenging effects of the SH group in the captopril molecule has been proposed to be the basis of the "cadioprotective" effect of this angiotensin converting enzyme (ACE) inhibitor in animal models of myocardial injury. We determined the effects of captopril, another ACE inhibitor with an SH group (SQ 26,703), its stereoisomer without ACE inhibitory effect but with an SH group (SQ 14,534), another ACE inhibitor without a SH group (enalaprilat), and N-acetylcysteine on superoxide radical generation by human neutrophils and by the purine-xanthine oxidase reaction. None of the compounds examined decreased superoxide radicals in therapeutic concentrations; however, SH-containing agents directly reduced spectrophotometric absorbance of ferricytochrome C. Thus, SH-containing agents with or without ACE inhibitory effects do not scavenge superoxide radicals.
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PMID:Sulfhydryl group in angiotensin converting enzyme inhibitors and superoxide radical formation. 170 10

Inhibition of glucose-6-phosphate dehydrogenase (G6-PDH) by dithranol (anthralin, CAS 480-22-8) has been studied in the presence of catalase, superoxide dismutase (SOD) and various scavengers of active oxygen species. Most scavengers were found to be either inhibitors of G6-PDH by themselves or simply without effect. The combined addition of catalase and SOD as well as the heat-denatured enzymes and the oxygen radical scavengers alpha-tocopherol and salicylic acid markedly reduced the inhibitory effect of dithranol. The direct exposure of G6-PDH to active oxygen species led to different results. When liberated from a water-soluble naphthalene endoperoxide, singlet oxygen was without effect whereas photosensitization with methylene blue resulted in a total loss of enzyme activity. Experiments under anaerobic conditions revealed that this inhibition was accomplished by the triplet state of the sensitizer. Superoxide anion radical was highly effective at concentrations corresponding to the amount of that produced by a 10 mumol/l dithranol solution. In contrast, hydroxyl, alkylperoxyl and alkoxyl radicals were all less efficient. H2O2 and alkylhydroperoxides did not alter the enzyme activity. The results suggest that .O2- is the potent species towards G6-PDH, if dithranol acts through formation of active oxygen species.
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PMID:Dithranol, glucose-6-phosphate dehydrogenase inhibition and active oxygen species. 181 Feb 65

Selected functions of alveolar macrophages obtained by bronchoalveolar lavage of 12 healthy smokers were examined before and after eight weeks' treatment with an inhaled glucocorticosteroid, budesonide (400 micrograms twice daily). After budesonide treatment spontaneous as well as opsonised zymosan triggered prostaglandin E2 (PGE2) secretion from harvested cells was reduced; no such reduction in opsonised zymosan triggered leukotriene B4 (LTB4) production was observed. Neither the capacity to phagocytose opsonised yeast particles nor the superoxide radical generation triggered by the calcium ionophore A23187, 4 beta-phorbol 12-myristate 13-acetate (PMA), or opsonised zymosan ex vivo were more than marginally affected by the glucocorticosteroid treatment in vivo. Lavage fluid concentrations of angiotensin converting enzyme (ACE), however, after treatment were twice those before treatment and concentrations of fibronectin were reduced to half. Albumin concentrations in lavage fluid were not affected by the glucocorticosteroid treatment. In separate experiments treatment of alveolar macrophages with 10(-7) or 10(-6) M budesonide overnight in vitro did not affect their superoxide radical or PGE2 generation but significantly blocked LTB4 release. These data indicate that inhaled gluco-corticosteroid treatment may affect synthesis or release (or both) of ACE and fibronectin by alveolar macrophages from healthy smokers whereas other functions of these cells, such as the generation of reactive oxygen derived products ex vivo, are only marginally affected.
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PMID:Effects of an inhaled corticosteroid, budesonide, on alveolar macrophage function in smokers. 216 59

Scavenging of superoxide radical by angiotensin converting enzyme (ACE) inhibitor captopril (CAP), a thiol compound, was studied by several investigators and the results were contradictory; while some reported a high superoxide scavenging activity of CAP others found that CAP removed superoxide inefficiently. In this work we show that in the presence of copper ions the apparent rate of superoxide removal by CAP (molar ratio CAP:CuSO4 4:1) was two orders of magnitude higher (approximately 1.5 x 10(5) M-1s-1 at pH 7.4) than the literature value for superoxide scavenging by CAP alone (< 10(3) M-1s-1 at pH 7.4). We presume that in the presence of copper ions a CAP/copper complex with a SOD-mimicking activity is being formed. Similar results were also obtained with another thiol glutathione (GSH). The possible role of the CAP/copper complexes in the anti-inflammatory effect of CAP is discussed.
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PMID:Superoxide scavenging by thiol/copper complex of captopril--an EPR spectroscopy study. 770 83

Calcium antagonists are well accepted in the prevention of ischaemia in patients with chronic stable angina, unstable angina, variant angina, and silent ischaemia, and in the treatment of hypertension. Although all of these compounds increase myocardial oxygen supply by reducing coronary tone and decrease myocardial oxygen demand by reducing systolic pressure and myocardial contractility, the magnitude of these effects may differ from one agent to another. Some calcium antagonists, such as verapamil and diltiazem, reduce heart rate and attenuate heart rate increases in response to stress, while in contrast, dihydropyridine calcium antagonists such as nifedipine may cause reflex increases in heart rate. These differences may be of importance in light of epidemiologic evidence that lower heart rates are associated with a reduced long-term risk of cardiovascular mortality, and experimental data showing that a lower heart rate may protect against the development of atherosclerosis. Calcium antagonists also inhibit platelet aggregation and thrombus formation which may contribute to their anti-ischaemic effects. Clinical trial data suggest that calcium antagonists may stay the progression of atherosclerosis. Mechanisms underlying an anti-atherosclerotic effect may include attenuation of endothelial dysfunction, prevention of LDL, peroxidation, stimulation of LDL receptor activity, inhibition of superoxide radical generation, and inhibition of vascular smooth muscle cell growth. Heart-rate-controlling calcium antagonists, such as verapamil and diltiazem, may reduce reinfarction rates following acute myocardial infarction and thus may have a role in post-infarction patients who do not show evidence of heart failure. Their use in heart failure patients receiving an angiotension-converting enzyme inhibitor (ACE-I) is under investigation in several large trials. Because calcium antagonists have a mechanism of action different from ACE-I, the pairing of a heart-rate-controlling calcium antagonist with an ACE-I might be expected to offer additive cardioprotective and vascular protective effects.
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PMID:The role of calcium antagonists in ischaemic heart disease. 884 1

Alacepril is an inhibitor of the angiotensin converting enzyme (ACE), and is commonly used as an antihypertensive. In this study, the effects of alacepril, its metabolites, desacetylalacepril and captopril, and also lisinopril, which has no sulfhydryl group in the structure, on free radicals were examined in vitro, using an ESR method. Superoxide and hydroxyl radical scavenging activities of alacepril metabolites, desacetylalacepril and captopril, were observed, whereas lisinopril hardly scavenged the superoxide or the hydroxyl radicals. Alacepril and its metabolites did not scavenge nitric oxide, but lisinopril showed slight scavenging activity. These findings suggest that the biological action of alacepril may be partly due to the antioxidant effect of its metabolites, having a sulfhydryl group.
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PMID:Free radical scavenging properties of alacepril metabolites and lisinopril. 922 47

Oxygen radicals and reactive oxygen species (ROS) are known to be generated in large amounts under inflammatory conditions and in the first few minutes of postischemic organ reperfusion. Due to the interaction of ROS with nitric oxide (NO), formed constitutively by endothelial cells, two alternatives are feasible. On the one hand, reaction with superoxide radicals may induce toxification (formation of peroxynitrite), and, on the other hand, by reacting with superoxide and hydroxyl radicals, NO can serve as a radical scavenger (formation of the innocuous anions, nitrate and nitrite, respectively). However, NO is considered to play a pivotal role in numerous physiological and pathophysiological processes, with effects arising from both lack and surfeit of this easily diffusible and chemically very reactive molecule. Physiologic contributions to vascular dilatation and inhibition of platelet and leukocyte activation, e.g., are infringed by enhanced inactivation of NO. Such inactivation occurs readily due to spontaneous reaction of NO with the superoxide radical, formed, e.g., by stressed endothelial cells and activated leukocytes. Conversely, overproduction of NO by induced NO synthase (iNOS) may lead to circulatory shock, cell apoptosis or even cell necrosis. Caution would, thus, seem to be warranted when attempting to interfere with homeostasis of NO. We have investigated the ability of NO to act as a radical scavenger during myocardial reperfusion in experimental and clinical settings. In the former, inhibition of angiotensin converting enzyme was employed to generate more endogenous NO (via bradykinin), in the latter, low-dose sodium nitroprusside was used as the donor of exogenous NO in patients undergoing coronary bypass grafting. Inhibition of leukocyte adhesion, attenuation of platelet activation and mitigation of redox-stress and inflammation were observed in both instances. Accordingly, modest enhancement of NO levels should afford cardioprotection during reperfusion.
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PMID:Reactive oxygen species and nitric oxide in myocardial ischemia and reperfusion. 1115 3

Endothelial function is abnormal in a variety of diseased states such as hypercholesterolemia and atherosclerosis. This may be secondary to decreased synthesis of nitric oxide (NO) and/or increased degradation of NO due to interaction with superoxide anions. More recent experimental observations demonstrate increased production of superoxide in hyperlipidemia, suggesting that endothelial dysfunction in these states is in part secondary to increased NO metabolism. Enzymes proposed to be involved in increased superoxide production may include xanthine oxidase, the NO synthase, and the NAD(P)H oxidase. Superoxide rapidly reacts with NO to form peroxynitrite (ONOO-), a highly reactive intermediate with cytotoxic properties. Despite experimental evidence for the oxidative stress concept in causing endothelial dysfunction, the results of recent randomized trials to test the influence of antioxidants on coronary event rates and prognosis in patients with coronary artery disease were very disappointing. In all of these studies the use of vitamins such as vitamin E failed to improve the prognosis. In contrast, treatment with angiotensin converting enzyme inhibitors or cholesterol- lowering drugs improved endothelial dysfunction, prevented the activation of superoxide-producing enzymes in cholesterol-fed animals, reduced coronary event rates, and improved prognosis in patients with coronary artery disease. Therefore, inhibition of superoxide production at the enzymatic level rather than symptomatic superoxide scavenging may be the better choice of treatment.
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PMID:Antioxidants and endothelial dysfunction in hyperlipidemia. 1117 9

Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. However, intervention studies with classic antioxidants, such as vitamin E, failed to demonstrate any beneficial effect. Recent studies demonstrate that a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications. These include increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein kinase C, and increased hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide generation, due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) polymerase. Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, and produces an ADP-ribosylation of the GAPDH. These processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of diabetic complications. These new findings may explain why classic antioxidants, such as vitamin E, which work by scavenging already-formed toxic oxidation products, have failed to show beneficial effects on diabetic complications and may suggest new and attractive "causal" antioxidant therapy. New low-molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, which work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such a strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34, and FP15, which block the protein kinase beta isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. While waiting for these focused tools, we may have other options: thiazolinediones, statins, ACE inhibitors, and angiotensin 1 inhibitors can reduce intracellular oxidative stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to this property.
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PMID:New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy. 1271 23

In the present study, electron paramagnetic resonance coupled with spin-trapping technique was used, with alpha-phenyl-N-tert-butylnitrone (PBN) as a spin-trapping agent, to investigate free radical generation in freshwater fish with acute 2,4-dichlorophenol (2,4-DCP) poisoning. The PBN-radical adducts were detected in fish liver samples following treatments of 2,4-DCP (0.025, 0.05, 0.5, 5, or 25 mg/kg) 24 h after intraperitoneal (i.p.) injection and 2,4-DCP (0.5 mg/kg) at 2, 4, 8, 24, or 72 h after i.p. injection in Carassius auratus. The hyperfine splitting constants for the PBN-radical adducts are aN = 13.7 G, aH = 1.8 G, and g = 2.0058, which is consistent with those of PBN/hydroxyl radical (*OH). The results indicate that the hydroxyl radical is probably produced during acute intoxication of 2,4-DCP. The relative similarity in the kinetics (from 2 to 72 h) of superoxide dismutase activity induction and *OH generation implies that the generation of *OH possibly depends on the superoxide anion (O2*-). Superoxide anion (O2*-) might be the precursor radical undergoing the Haber-Weiss reaction to form *OH. Possible pathways for radical chain reactions in the formation of the hydroxyl radical in vivo after 2,4-DCP administration are proposed. Other parameters with respect to antioxidant defense (e.g., superoxide dismutase and catalase) and oxidative damage (lipid peroxidation level) indicate that the fish were subjected to oxidative stress induced by 2,4-DCP and that the mechanisms of oxidative stress possibly involve the in vivo stimulation of hydroxyl radical formation.
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PMID:Electron paramagnetic resonance investigation of in vivo free radical formation and oxidative stress induced by 2,4-dichlorophenol in the freshwater fish Carassius auratus. 1619 40


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