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Ascorbate Prevents the Interaction of Superoxide and Nitric Oxide Only at Very High Physiological Concentrations
Abstract
The bioactivity of nitric oxide (.NO) depends, in part, on its interaction with superoxide. Usually, superoxide dismutase (SOD) preserves .NO bioactivity by limiting the availability of superoxide. Ascorbic acid also effectively scavenges superoxide, but the extent to which this interaction is necessary for intact .NO bioactivity is not known. Therefore, the present study examined the effect of ascorbic acid on .NO bioactivity with isolated rabbit arterial segments. A steady flux of superoxide (1.15 to 2.3 micromol . L-1 . min-1) produced either by pyrogallol autoxidation or a hypoxanthine/xanthine oxidase system inhibited endothelium-derived .NO-mediated arterial relaxation elicited by acetylcholine. This effect of superoxide was completely blocked by SOD (300 IU/mL) and the manganese SOD mimic EUK-8 (300 micromol/L) and partially inhibited by ascorbic acid (10 mmol/L). Lower concentrations of ascorbic acid were ineffective despite scavenging >90% of superoxide. We increased the endogenous flux of superoxide (3.2+/-0.3-fold) by inhibiting vascular copper-zinc SOD with diethyldithiocarbamate. This increased endogenous flux of superoxide produced an impairment of .NO-mediated arterial relaxation that was reversed by EUK-8 (300 micromol/L) but not ascorbic acid (10 mmol/L) despite equivalent scavenging of the endogenous superoxide flux. We used 3-nitrotyrosine formation (from peroxynitrite) as an indicator of .NO interaction with superoxide and found that SOD and EUK-8 compete more effectively with .NO for superoxide than does ascorbic acid. These data indicate that preservation of .NO bioactivity by superoxide scavengers depends not only on superoxide scavenging activity, but also on the rate of superoxide scavenging. Normal extracellular concentrations of ascorbic acid (30 to 150 micromol/L) are not likely to prevent the interaction of .NO with superoxide under physiological conditions.
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“However, in competition with NO, a concentration of vitamin C about 10 mM is needed to block the interaction of NO with the superoxide by effective scavenging of the latter [167].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [167]
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Schindler, T. H., Nitzsche, E. U., Münzel, T. F., Olschewski, M., Brink, I., Jeserich, M., Mix, M. D., Buser, P. T., Pfisterer, M. E., Solzbach, U., et al. (2003) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(03)00851-9 · Cited by 84
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Novel Therapeutic Strategies for Traumatic Brain Injury: Acute Antioxidant Reinforcement
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Rodrigo, R., Libuy, M., Feliú, F., & Hasson, D. (2013) · BioMed Research International · doi:10.1155/2013/437613 · Cited by 68
“Indeed, superoxide reacts withNO at a rate 10(5)-fold greater than the rate at which superoxide reacts with ascorbic acid [8].”
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“Thus, it has been recently reported that only high physiologic concentrations of ascorbic acid are able to effectively scavenge the superoxide anion, therefore enhancing arterial dilatation [24].”
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“An acute supraphysiologic infusion of ascorbic acid that produced plasma concentrations known to inhibit superoxide production in vitro (23) improved FMDBA in the ADPKD group but not in healthy controls, indicating the presence of vascular endothelial oxidative stress.”
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Linowiecka, K., Foksiński, M., & Brożyna, A. A. (2020) · Nutrients · doi:10.3390/nu12123869 · Cited by 61
“Furthermore, in vitro studies demonstrated that an increased level of ascorbate can act as a stimulus to cooperate with superoxide dismutase in the removal of superoxides [5].”
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“Indeed, superoxide reacts with NO at a rate 105-fold greater than the rate at which superoxide reacts with ascorbic acid (Jackson et al., 1998).”
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“Then, after a 20-min resting period, while maintaining unchanged insulin infusion, infusion of vitamin C (Bracco, Milan, Italy) was started at a dose of 25 mg/min (1 ml/min infusion rate); this dose has previously proven effective to raise vitamin C concentrations in the forearm to levels protecting NO from premature…”
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“Although both azide and ascorbate are efficient singlet O2 scavengers, at the concentrations used here, they are poor scavengers for more highly reactive ROS, NO, and agents such as peroxynitrite (42, 43).”
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“Although acute administration of high concentrations of radical scavengers has been shown to restore endothelial vasodilator function in experimental models and human subjects [8,9], interventions that inhibit the enzymatic sources of reactive oxygen species appear to be a more effective strategy to maintain nitric ox…”
BackgroundIntra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion
Pleiner, J., Schaller, G., Mittermayer, F., Marsik, C. L., MacAllister, R. J., Kapiotis, S., Ziegler, S., Ferlitsch, A., & Wolzt, M. (2007) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2007.06.011 · Cited by 58
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“was assessed by infusing its metabolite GLP-1(9-36) (n = 5).”
BackgroundMethodInfluentialTopical Ascorbic Acid Reduces Myringosclerosis in Perforated Tympanic Membranes a Study in the Rat
Spratley, J. E. F., Hellström, S., Mattsson, C. K., & Pais‐Clemente, M. (2001) · Annals of Otology Rhinology & Laryngology · doi:10.1177/000348940111000615 · Cited by 54
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“Two recent studies reported that high ascorbate concentrations are able to scavenge superoxide anions during oxidant stress in aorta (10, 22) and thus restore the NO-dependent relaxation (10).”
BackgroundAntioxidant Pretreatment and Reduced Arterial Endothelial Dysfunction After Diving
Obad, A., Valić, Z., Palada, I., Brubakk, A. O., Modun, D., & Dujić, Ž. (2007) · Aviation Space and Environmental Medicine · doi:10.3357/asem.2039.2007 · Cited by 52
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“Superoxide reacts readily with NO forming deleterious peroxynitrite, while the Km of vitC precludes efficient scavenging of superoxide until concentrations reach the millimolar range (103), suggesting that this mechanism may only be relevant intracellularly.”
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“Free radicals and organic peroxides also decrease erythrocyte Na+ K+ ATPase levels by affecting the pump activity and antioxidants may prevent this inhibition.”
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“At the millimolar concentrations present in neurons in vivo, ascorbate will effectively scavenge superoxide (Jackson et al., 1998), a major diffusible byproduct of rapid neuronal mitochondrial metabolism (Harrison and May, 2009).”
BackgroundChan, E. C., Drummond, G. R., & Woodman, O. L. (2003) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-200312000-00006 · Cited by 50
“This is probably due to the relatively slow rate of reaction between ascorbate and O2 −• (2 × 10(5) M s)(11) since exogenous SOD did enhance relaxation.(10) Therefore one of the aims of this study was to determine whether DiOHF scavenged O2 −• rapidly enough to enhance endothelium-dependent relaxation in the presence…”
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“However, to compete efficiently with the reaction of NO with superoxide, ascorbate concentrations of 10 mmol/l or even higher would be required, suggesting that this mechanism may only be active in plasma following ascorbate infusion at high doses [22].”
BackgroundKim, E. J., Park, Y. G., Baik, E. J., Jung, S. J., Won, R., Nahm, T. S., & Lee, B. H. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20384 · Cited by 48
“Jackson et al. (1998) reported that AA could inhibit superoxide at a high concentration (10 mM) even though AA could not inhibit it at low concentration (0.1 mM).”
BackgroundInfluentialFree radical biology in neurological manifestations: mechanisms to therapeutics interventions
Tripathi, R. S., Gupta, R. V., Sahu, M., Srivastava, D., Das, A., Ambasta, R. K., & Kumar, P. (2021) · Environmental Science and Pollution Research · doi:10.1007/s11356-021-16693-2 · Cited by 54
“was found to inhibit the interaction between superoxide and nitric oxide in vitro (Jackson et al. 1998).”
BackgroundRodrigo, R., Prieto, J. C., Aguayo, R., Ramos, C., Puentes, Á., Gajardo, A. I. J., Panieri, E., Rojas-Solé, C., Lillo‐Moya, J., & Saso, L. (2021) · Molecules · doi:10.3390/molecules26185702 · Cited by 46
“However, Vit C must reach a plasma concentration of 10 mmol/L to displace the reaction of the superoxide anion radical with nitric oxide, which acts at a rate 105 times greater than the reaction between ascorbic acid and superoxide anion radical [74,75].”
BackgroundAscorbic acid blunts oxidant stress due to menadione in endothelial cells
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Redox Control of Vascular Nitric Oxide Bioavailability
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“It is more likely that plasma concentrations of vitamin C achieved with oral dosing are not sufficient to affect markers of oxidative stress or interfere with the endothelial interaction of superoxide and nitric oxide [36].”
Prooxidative inhibition against NF-κB-mediated inflammation by pharmacological vitamin C
Du, Y., Long, Y., Tang, W., Liu, X., Dai, F., & Zhou, B. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.01.007 · Cited by 41
Matsumoto, T., Kobayashi, T., Wachi, H., Seyama, Y., & Kamata, K. (2006) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2006.06.005 · Cited by 41
Protective effects of ascorbic acid on arterial hemodynamics during acute hyperglycemia
Mullan, B. A., Ennis, C. N., Fee, H. J. P., Young, I. S., & McCance, D. R. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00153.2003 · Cited by 40
“Proposed mechanisms include reduced NO degradation by free radicals (16), increased endothelial NO synthase activity (2), or augmented vascular smooth muscle sensitivity to NO”
BackgroundRimoldi, S. F., Sartori, C. S., Rexhaj, E., Bailey, D. M., de Marchi, S. F., McEneny, J., von Arx, R., Černý, D., Duplain, H., Germond, M., et al. (2014) · European Journal of Preventive Cardiology · doi:10.1177/2047487314535117 · Cited by 40
Targeting Oxidative Stress Component in the Therapeutics of Epilepsy
Azam, F., Prasad, M. V. V., & Thangavel, N. (2012) · Current Topics in Medicinal Chemistry · doi:10.2174/156802612800229224 · Cited by 40
“At the millimolar concentrations present in neurons in vivo, ascorbic acid effectively scavenges superoxide [166], a major diffusible byproduct of rapid neuronal mitochondrial metabolism.”
BackgroundChang, C., Chen, J., Wu, M., & Hu, M. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.05.015 · Cited by 40
Li, Y., Zheng, Y., Zheng, D., Zhang, Y., Song, S., Su, W., & Liu, H. (2020) · Molecules · doi:10.3390/molecules25235678 · Cited by 40
“Vitamin C has been proved to scavenge superoxide and help the regeneration of vitamin E and glutathione [4,7].”
BackgroundCamm, E. J., Tijsseling, D., Richter, H. G., Adler, A., Hansell, J. A., Derks, J. B., Cross, C. M., & Giussani, D. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021142 · Cited by 40
“Ascorbate regenerates a-tocopherol from atocopheroxyl radicals, thus preserving the antioxidant role of atocopherol [38,39].”
BackgroundMatsumoto, T., d’Uscio, L. V., Eguchi, D., Akiyama, M., Smith, L. A., & Katušić, Z. S. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.049163 · Cited by 40
“Several other mechanisms may account for the observed improvement in endothelial function, including scavenging of superoxide anions (Jackson et al., 1998) and stabilization of eNOS cofactor tetrahydrobiopterin (Huang et al., 2000; Baker et al., 2001; Heller et al., 2001; d’Uscio et al., 2003).”
Li, C. G., Karagiannis, J., & Rand, M. J. (1999) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0702540 · Cited by 39
“Recent study suggests that normal extracellular concentrations of ascorbic acid (30 ± 150 mM) are not likely to prevent the interaction of NO. with superoxide under physiological conditions (Jackson et al., 1998).”
BackgroundSystems biology of antioxidants
Andriantsitohaina, R., Duluc, L., Rodríguez, J., del Valle, L. G., Guevara-García, M., Simard, G., Soleti, R., Su, D., Velázquez‐Pérez, L., Wilson, J. X., et al. (2012) · Clinical Science · doi:10.1042/cs20110643 · Cited by 42
Rodrigo, R., Hasson, D., Prieto, J. C., Dussaillant, G., Ramos, C., León, L., Gárate, J., Valls, N., & Gormaz, J. G. (2014) · Trials · doi:10.1186/1745-6215-15-192 · Cited by 38
“Indeed, superoxide reacts with NO at a rate 10(5)-fold greater than the rate at which superoxide reacts with ascorbic acid [68].”
BackgroundAscorbic acid prevents VEGF-induced increases in endothelial barrier permeability
Ulker, E., Parker, W. H., Raj, A., Qu, Z., & May, J. M. (2015) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-015-2609-6 · Cited by 38
“At the concentrations measured in the current studies, ascorbate can neutralize intracellular superoxide [29] as well as its highly reactive downstream product peroxynitrite [30].”
BackgroundAscorbic acid prevents high glucose-induced apoptosis in human brain pericytes
May, J. M., Jayagopal, A., Qu, Z., & Parker, W. H. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.08.057 · Cited by 37
“However, ascorbate loss during RAGE activation due to both high glucose and RAGE agonists, as well as the need for relatively high intracellular ascorbate concentrations to prevent apoptosis, suggest that it still may be scavenging superoxide [46] or its toxic byproducts.”
BackgroundAscorbic Acid Decreases the Binding Affinity of the AT1 Receptor for Angiotensin II
Leclerc, P. C., Proulx, C. D., Arguin, G., Belanger, S., Gobeil, F., Escher, E., Leduc, R., & Guillemette, G. (2007) · American Journal of Hypertension · doi:10.1038/ajh.2007.1 · Cited by 36
Buttros, J. B., Bergamaschi, C. T., Ribeiro, D. A., Fracalossi, A. C. C., & Campos, R. R. (2009) · Pharmacology · doi:10.1159/000222245 · Cited by 36
“Therefore, the second aim of this study was to analyze whether vitamin C offers protection from myocardial infarction, using the ISO-induced myocardial infarction model in rats. The analyses of the myocardial tissue and immunohistochemistry for iNOS, COX2 and p53 were performed. MethodsAll animal procedures were condu…”
InfluentialKar, S., & Kavdia, M. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.04.024 · Cited by 35
Sepsis-associated encephalopathy: Evolving concepts
Wilson, J. X., & Young, G. B. (2003) · Cited by 34
Ca2+‐mediated ascorbate release from coronary artery endothelial cells
Davis, K. A., Samson, S. E., Best, K., Mallhi, K. K., Szewczyk, M. M., Wilson, J. X., Kwan, C., & Grover, A. K. (2005) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706492 · Cited by 34
“…McMaster University, Hamilton, Ontario, Canada L8N 3Z5; E-mail: groverak@mcmaster.ca British Journal of Pharmacology (2006) 147, 131–139 & 2006 Nature Publishing Group All rights reserved 0007–1188/06 $30.00 www.nature.com/bjp higher than those present in the plasma (Jackson et al., 1998).”
BackgroundInfluentialKarlıdağ, T., İlhan, N., Kaygusuz, İ., Keleş, E., & Yalçn, Ş. (2003) · The Laryngoscope · doi:10.1097/00005537-200401000-00014 · Cited by 33
“Superoxide dismutase indirectly preserves the activity of nitric oxide.(25) When compared with the group without tympanosclerosis, the patients with tympanosclerosis had lower superoxide dismutase and catalase activity levels in their erythrocytes.”
Moreau, K. L., DePaulis, A. R., Gavin, K. M., & Seals, D. R. (2006) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00877.2006 · Cited by 33
“In the present study, we chose to use ascorbic acid because it is one of the most potent water-soluble antioxidants in humans, and it can be acutely infused at rates that attain supraphysiological plasma concentrations known to reduce the bioavailability of superoxide anions (23).”
MethodSchmitt, C. A., Handler, N., Heiß, E. H., Erker, T., & Dirsch, V. M. (2007) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2007.02.024 · Cited by 35
Rocchitta, G., Migheli, R., Esposito, G., Marchetti, B., Desole, M. S., MIELE, E., & Serra, P. A. (2005) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2005.00299.x · Cited by 33
“Autoxidation of l-DOPA and DA generates quinones and superoxide anion (O 2 ), which is scavenged by AsAc [29] and melatonin [13].”
BackgroundOxidative Stress Genes, Antioxidants and Coronary Artery Disease in Type 2 Diabetes Mellitus
Tibaut, M., & Petrovi, D. (2016) · Cardiovascular & Hematological Agents in Medicinal Chemistry · doi:10.2174/1871525714666160407143416 · Cited by 34
“For vitamin C to be effective in O2, scavenging 10 mmol/L concentrations are necessary, otherwise O2 reacts with NO since the rate of reaction with NO is 10(5) fold greater [51].”
BackgroundAntioxidants and CVD in diabetes: Where do we stand now?
Yim, S., Malhotra, A., & Veves, A. (2007) · Current Diabetes Reports · doi:10.1007/s11892-007-0003-9 · Cited by 34
“Because high concentrations of vitamin C are needed to compete for superoxide, the failure to achieve these high levels was proposed as a reason of the failure of vitamin C in this group of patients [ 30 ].”
BackgroundGeorge, T. W., Niwat, C., Waroonphan, S., Gordon, M. H., & Lovegrove, J. A. (2009) · Proceedings of The Nutrition Society · doi:10.1017/s0029665109001165 · Cited by 32
“However, it has been found that high physiological concentrations of vitamin C (>1 mM) are needed to effectively scavenge superoxide and enhance endothelium-dependent vasodilation((42)).”
BackgroundVascular Dysfunction, Oxidative Stress, and Inflammation in Chronic Kidney Disease
Nowak, K. L., Jovanovich, A., Farmer-Bailey, H., Bispham, N., Struemph, T., Malaczewski, M., Wang, W., & Chonchol, M. (2020) · Kidney360 · doi:10.34067/kid.0000962019 · Cited by 30
“(17, 20, 24) The plasma concentrations with this dose have been shown to inhibit superoxide production in vitro.(23) A priming bolus of 0.”
BackgroundMethodFerlitsch, A., Pleiner, J., Mittermayer, F., Schaller, G., Homoncik, M., Peck‐Radosavljevic, M., & Wolzt, M. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000178173.27923.eb · Cited by 31
“Vitamin C is an effective scavenger of reactive species (27, 28).”
BackgroundMachha, A., & Mustafa, M. R. (2006) · Vascular Pharmacology · doi:10.1016/j.vph.2006.05.001 · Cited by 30
Wang, K., Wang, H., Chen, H., Liliang, P., Liang, C., Tsai, Y., Cho, C.-L., & Lu, K. (2014) · BioMed Research International · doi:10.1155/2014/910260 · Cited by 31
Hao, W., Cha, R., Wang, M., Li, J., Guo, H., Du, R., Zhou, F., & Jiang, X. (2023) · ACS Nano · doi:10.1021/acsnano.3c01656 · Cited by 30
Metadata
- Authors
- Jackson, T. S., Xu, A., Vita, J. A., & Keaney, J. F.
- Affiliations
- Boston University (US)
- Venue
- Circulation Research
- Published
- 1998-11-02
- Volume
- 83
- Issue
- 9
- Pages
- 916-922
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2155603952
- Cited by
- 400
- References
- 48
- Citations by year
- 2025: 9 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 18 · 2020: 15 · 2019: 13 · 2018: 9 · 2017: 7 · 2016: 14 · 2015: 12 · 2014: 17 · 2013: 17 · 2012: 21
- FWCI
- 11.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (5r01hl059346-02, HL59346, HL55854, 1r01hl053398-01a1)
- National Heart, Lung, and Blood Institute (HL59346, HL 53398, P01HL055854, HL-55854)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- vitamin C, superoxide, nitric oxide, superoxide dismutase, peroxynitrite, nitrotyrosine, endothelium-derived nitric oxide, acetylcholine-induced relaxation, diethyldithiocarbamate
- MeSH terms
- Animals, Ascorbic Acid, Endothelium, Vascular, Female, Male, Nitric Oxide, Pyrogallol, Rabbits, Superoxides, Vasodilation
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