Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00568 (ascorbate)
 23,072 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophages activated with bacterial lipopolysaccharide (LPS) and cytokines produce nitric oxide through the induction of iNOS gene expression. Ascorbate increased NOx (nitrite and nitrate) formation by approximately 40% in a mouse macrophage-like cell line, J774.1, activated with LPS and interferon-gamma. Ascorbate alone exhibited no inductive activity toward NO formation. N(G)-Monomethyl-L-arginine inhibited nitrite formation in cells activated in the presence or absence of ascorbate. Northern and Western blotting analyses showed that both iNOS mRNA and protein steady-state levels were increased approximately twofold in cells activated in the presence of ascorbate compared to in cells activated only with the inducers. These data suggest that ascorbate increased NO production by increasing the amount of iNOS in the activated macrophages.
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PMID:Ascorbate-dependent enhancement of nitric oxide formation in activated macrophages. 985 64

Tolerance to nitroglycerin (NTG) may be due to increased superoxide anion production. Hemodynamic parameters and biochemical markers of free radical production were measured in 20 healthy male subjects at baseline, 3 h after acute transdermal NTG (0.6 mg/h), and after 5 days of continuous therapy. Transdermal NTG therapy was continued, and 2 days later all subjects received 2 g of oral vitamin C, or placebo, in a double-blind, randomized, crossover fashion. In another study of eight male subjects, forearm plethysmography was used to assess the venous responses to sublingual NTG at baseline, after 5 days of sustained transdermal NTG therapy (0.6 mg/h), and after 2 g of oral vitamin C or placebo. Systolic blood pressure decreased in response to acute transdermal NTG therapy but returned to normal after sustained NTG therapy, indicating the development of tolerance. The venous volume responses to sublingual NTG were significantly diminished after sustained therapy with transdermal NTG. Plasma lipid peroxidation products, 8-iso-PGF2 alpha, and vitamin C were unchanged by acute and sustained therapy with transdermal NTG. Vitamin C failed to restore either the hemodynamic or venous effects of NTG. These results do not support the hypothesis that nitrate therapy and tolerance is associated with increased free radical production.
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PMID:Biochemical, hemodynamic, and vascular evidence concerning the free radical hypothesis of nitrate tolerance. 1022 53

Glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) are among the most known organic nitrates that are used in cardiovascular therapy as vasodilators. However, anti-ischemic therapy with organic nitrates is complicated by the induction of nitrate tolerance. When nitrates are metabolized to release nitric oxide (NO), there is considerable coproduction of superoxide radicals in vessels leading to inactivation of NO. However, nitrate-induced increase of superoxide radical formation in vivo has not been reported. In this work, the authors studied the in vivo formation of superoxide radicals induced by treatment with PETN or GTN and determined the antioxidant effect of vitamin C. The formation of superoxide radicals was determined by the oxidation of 1-hydroxy-3-carboxy-pyrrolidine (CP-H) to paramagnetic 3-carboxy-proxyl (CP) using electron spin resonance spectroscopy. CP-H (9 mg/kg intravenous bolus and 0.225 mg/kg per minute continuous intravenous GTN or PETN 130 microg/kg) were infused into anesthetized rabbits. Every 5 min, blood samples were obtained from Arteria carotis to measure the CP formation. Both PETN and GTN showed similar vasodilator effects. Formation of CP in blood after infusions of GTN and PETN were 2.0+/-0.4 microM and 0.98+/-0.23 microM, respectively. Pretreatment with 30 mg/kg vitamin C led to a significant decrease in CP formation: 0.27+/-0.14 microM (vitamin C plus GTN) and 0.34+/-0.15 microM (vitamin C plus PETN). Pretreatment of animals with superoxide dismutase (15,000 units/kg) significantly inhibited nitrate-induced nitroxide formation. Therefore, in vivo infusion of GTN or PETN in rabbits increased the formation of superoxide radicals in the vasculature. PETN provoked a minimal stimulation of superoxide radical formation without simultaneous development of nitrate tolerance. The data suggest that the formation of superoxide radicals induced by organic nitrate correlates with the development of nitrate tolerance. The effect of vitamin C on CP formation leads to the conclusion that vitamin C can be used as an effective antioxidant for protection against nitrate-induced superoxide radical formation in vivo.
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PMID:Comparison of glyceryl trinitrate-induced with pentaerythrityl tetranitrate-induced in vivo formation of superoxide radicals: effect of vitamin C. 1044 33

In 1998, nitric oxide (NO) was extensively explored. First studies demonstrating a beneficial effect of inhaled NO in patients with pulmonary hypertension, right ventricular dysfunction and intractable heart failure were published. It was further shown, that, in patients with essential hypertension, impaired vasodilatation can be improved by vitamin C as an antioxidant, an effect that can be reversed by NO-synthase inhibition. Unlike arotinolol, which has no antioxidat effect, carvedilol is a beta- and alpha-blocker with antioxidative properties that may prevent the development of nitrate tolerance. In clinical cardiology, the main focus is on the prevention and therapy of coronary heart disease, heart failure and hypertension: a Task force report on the prevention of coronary heart disease in clinical practice. Proceedings on anticoagulant therapy and Guidelines for antithrombotic management were published in 1998. There is an agreement that in mild hypertension the decision how to treat should be based on the estimate of cardiovascular risk and not on an arbitrary blood pressure threshold. Diuretics and betablockers should be preferred unless they are contraindicated, or there are positive indications for other drug classes. Studies also strongly suggest that therapy with relatively small doses of two different classes of drugs is the effective way to treat the majority of patients and minimize side effects. In heart failure, the evidence for the current treatment with diuretics, ACE-inhibitors and digoxin, in selected patients, is well established.
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PMID:[Cardiology 1998]. 1051 May 45

Enhanced oxidant stress occurs under many pathophysiologic conditions (e.g., inflammation) and can be induced and mimicked by continuous nitrate therapy, eliciting increases in platelet activity, enhanced formation of reactive oxygen species (ROS), and impaired nitrate-induced vasorelaxation. Analysis was performed of effects of coinfusion of glycerol trinitrate (GTN) either with a carvedilol metabolite with antioxidant properties or with antioxidant vitamin C (Vit-C) on various hemodynamic parameters during enhanced oxidant stress associated with nitrate tolerance. Carvedilol metabolite (BM910228: 4.5 microg/kg/min) or Vit-C (55 microg/kg/min) was coadministered with GTN (1.5 microg/kg/min) for 5 days in chronically instrumented dogs. Changes in coronary diameters (CD) and other hemodynamic parameters were continuously monitored, as well as changes in platelet function. At the beginning of GTN treatment, CD increased by 9.8 +/- 0.4% and progressively declined to basal control values within 3 days. However, with additional antioxidant protection either with BM910228 or with Vit-C, the GTN-induced increase in CD was maintained (8.6 +/- 0.4% or 10.5 +/- 0.6%) and remained elevated for the entire infusion period. The thrombin-stimulated intracellular Ca2+ concentrations of platelets remained nearly unchanged during Vit-C or BM910228 in contrast to the increase with GTN. The basal cyclic guanosine monophosphate (cGMP) contents of platelets after GTN coadministered with BM910228 or with Vit-C increased on day 1 to 233 or to 250% versus control and remained at that level. Additional in vitro tests with xanthine oxidase-induced oxidant stress resulted in a more or less pronounced scavenging of O2- radicals by BM920228, Vit-C, or superoxide dismutase (SOD). Coadministration of carvedilol metabolite BM910228 or of Vit-C along with GTN suppressed noxious effects of GTN-induced oxidant stress such as increased platelet activity and impaired nitrate-induced vasorelaxation.
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PMID:Tolerance to nitrates with enhanced radical formation suppressed by carvedilol. 1059 22

The present study investigates the pharmacological activity of the nitric oxide (NO) donor S-nitrosoglutathione (GSNO) on the plasma glucose and insulin levels in healthy normoglycemic dogs. The plasma nitrate and nitrite concentrations were measured by a commercial autoanalyzer and taken as the biochemical markers of in vivo nitric oxide formation. Plasma glucose levels were measured by the glucose oxidase method, while the insulin levels were determined by radioimmunoassay. The possible effect of the coadministration of ascorbic acid (vitamin C) and GSNO on plasma glucose levels was also examined. In healthy normoglycemic dogs, administration of 35 and 50 mg/kg of GSNO caused a dose-dependent increase in postprandial plasma glucose levels. The plasma glucose levels were significantly elevated at the 1.5-, 2.0-, and 2.5-h time intervals of the oral glucose tolerance test at both concentrations of GSNO (P < 0.05). These values were significantly higher than those obtained using captopril (control). Furthermore, coadministration of 35 mg/kg of GSNO and 50 mg/kg ascorbic acid enhanced the postprandial hyperglycaemic effect observed for the administration of only 35 mg/kg of GSNO. There was a 35-100% increase in plasma nitrate concentration on administration of both doses of GSNO. Intravenous administration of GSNO (35 mg/kg) and captopril (20 mg/kg) significantly decreased the mean arterial blood pressure and increased the heart rate. The blood pressure-lowering effect of these drugs was more pronounced on systolic than on diastolic blood pressure (P < 0.05). These results suggests that in healthy normoglycaemic dogs: (a) nitric oxide released from GSNO increases postprandial plasma glucose levels and inhibits glucose-stimulated insulin secretion, (b) ascorbic acid enhances the postprandial hyperglycaemic effect of GSNO, probably by increasing the release of NO, and (c) GSNO decreases mean arterial blood pressure and increase heart rate in normotensive dogs.
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PMID:The hyperglycemic effect of S-nitrosoglutathione in the dog. 1063 27

Our aim was to evaluate the role of maternal nutritional habits during the period of gestation and of children subsequent diet in the etiology of pediatric brain tumors. All cases of incident nervous system tumors under age 18, diagnosed between 1984 and 1993 (n = 300) in Israel were identified. Two matched population controls per case were selected (n = 574). Personal interviews, using a semi-quantified three-step food frequency questionnaire, were performed. Univariate analysis showed that increased child consumption of vegetable fat [p trend 0.01; 95% confidence interval (CI) 1.1-3.2], carbohydrates (p trend 0.05; CI 1.0-5.9), and vitamin E (p trend 0.05; CI 1.0-3.3), were significantly associated with brain tumor risk. No associations were found with nitrate, nitrite or vitamin C. A significant positive association with potassium consumption (p trend 0.01; CI 1.1-3.7) was noted during gestation. Results of multivariate analysis showed that the only persisting associations were with vegetable fat (OR = 1.36; CI 1.06-1.73) in the child diet and potassium intake during gestation (OR = 1.44; CI 1.04-1.99). In conclusion, nutritional associations with pediatric brain tumor etiology, remain unsubstantiated.
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PMID:The role of nutritional habits during gestation and child life in pediatric brain tumor etiology. 1072 8

Several recent studies have shown that certain forms of genetic or acquired hypertension are associated with oxidative stress and that animals with those types of hypertension respond favorably to antioxidant therapy. We hypothesize that oxidative stress may cause hypertension via (among other mechanisms) enhanced oxidation and inactivation of nitric oxide (NO). To test this hypothesis, Sprague-Dawley rats were subjected to oxidative stress by glutathione (GSH) depletion by means of the GSH synthase inhibitor buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for 2 weeks. The control group was given drug-free drinking water. In parallel experiments, subgroups of animals were provided vitamin E-fortified chow and vitamin C-supplemented drinking water. The BSO-treated group showed a 3-fold decrease in tissue GSH content, a marked elevation in blood pressure, and a significant reduction in the urinary excretion of the NO metabolite nitrate plus nitrite, which suggests depressed NO availability. These characteristics were associated with a significant accumulation in various tissues of nitrotyrosine, which is the footprint of NO inactivation by reactive oxygen species. Administration of vitamin E plus vitamin C ameliorated hypertension, improved urinary nitrate-plus-nitrite excretion, and mitigated nitrotyrosine accumulation (despite GSH depletion) in the BSO-treated animals but had no effect in the control group. In conclusion, GSH depletion resulted in perturbation of the NO system and severe hypertension in normal animals. The effects of BSO were mitigated by concomitant antioxidant therapy despite GSH depletion, which supports the notion that oxidative stress was involved in the pathogenesis of hypertension in this model.
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PMID:Induction of oxidative stress by glutathione depletion causes severe hypertension in normal rats. 1090 27

Salivary nitrite arises from nitrate and is the main source of gastric nitrite, a precursor of carcinogenic N-nitroso compounds. We examined nitrate and nitrite levels in unstimulated saliva from subjects consuming low-nitrate low-vitamin C diets. When saliva was collected from six men at nine times of the day (Experiment 1), night time nitrite levels were significantly higher than day time values and nitrite varied more than nitrate. When saliva was collected from 29 subjects aged 19-37 or 60-84 years at four times of the day during 1991-1993 (Experiment 2), all older subjects and older men had significantly higher nitrite levels than the corresponding younger subjects, night time nitrite levels in men were significantly raised, and nitrate and nitrite levels in the same samples were closely correlated. Saliva was collected at 6.00 a.m. on two successive days in 1997 from 16 subjects who had collected saliva in 1991-1993 (Experiment 3). Nitrate and nitrite levels on day 1 of experiment 3 were closely correlated with those on day 2. Nitrate and nitrite levels on days 1 and 2 of Experiment 3 were correlated with the corresponding parameters in Experiment 2 with P = 0.04 and 0.08 for day 1, and 0.10 and 0.28 for day 2, respectively. Hence, saliva nitrite levels rose at night and were higher in older people, especially older men, and saliva nitrate and nitrite levels varied little from day to day, but varied more after 4-6 years.
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PMID:Nitrate and nitrite concentrations in human saliva for men and women at different ages and times of the day and their consistency over time. 1107 87

Human prostate cancer cells (DU145) implanted into nude mice are deficient in DNase activity. After administration of a vitamin C/vitamin K(3) combination, both alkaline DNase (DNase I) and acid DNase (DNase II) activities were detected in cryosections with a histochemical lead nitrate technique. Alkaline DNase activity appeared 1 hr after vitamin administration, decreased slightly until 2 hr, and disappeared by 8 hr after treatment. Acid DNase activity appeared 2 hr after vitamin administration, reached its highest levels between 4 and 8 hr, and maintained its activity 24 hr after treatment. Methyl green staining indicated that DNase expression was accompanied by a decrease in DNA content of the tumor cells. Microscopic examination of 1-microm sections of the tumors indicated that DNase reactivation and the subsequent degradation of DNA induced multiple forms of tumor cell death, including apoptosis and necrosis. The primary form of vitamin-induced tumor cell death was autoschizis, which is characterized by membrane damage and the progressive loss of cytoplasm through a series of self-excisions. These self-excisions typically continue until the perikaryon consists of an apparently intact nucleus surrounded by a thin rim of cytoplasm that contains damaged organelles.
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PMID:In vivo reactivation of DNases in implanted human prostate tumors after administration of a vitamin C/K(3) combination. 1111 83


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