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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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“O2 2, but only in the high millimolar range, can also be scavenged by ascorbate (Jackson et al., 1998) Furthermore the reaction with NO is 1000 times faster (Scarpa et al., 1983).”
BackgroundFruits, vegetables, 100% juices, and cognitive function
Lamport, D. J., Saunders, C., Butler, L. T., & Spencer, J. P. E. (2014) · Nutrition Reviews · doi:10.1111/nure.12149 · Cited by 120
Antioxidant therapy for management of oxidative stress induced hypertension
Ahmad, K. A., Yuan, D. Y., Nawaz, W., Hong, Z., Zhuo, C. X., Talal, B., Taleb, A., Mais, E., & Qi-long, D. (2017) · Free Radical Research · doi:10.1080/10715762.2017.1322205 · Cited by 121
“Ascorbic acid may have beneficial outcomes on vasodilation, probably because of its antioxidant actions on NO [42,47,48].”
BackgroundDuffy, S. J., Gokce, N., HOLBROOK, M. M., Hunter, L. M., Biegelsen, E. S., Huang, A., Keaney, J. F., & Vita, J. A. (2001) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2001.280.2.h528 · Cited by 118
“While ascorbic acid is an effective scavenger of superoxide anion, we recently showed in an experimental model that supraphysiological concentrations of extracellular ascorbic acid would be required to enhance NO bioavailability in vivo (25).”
BackgroundMelatonin and vitamin C increase umbilical blood flow via nitric oxide‐dependent mechanisms
Thakor, A. S., Herrera, E. A., Serón‐Ferré, M., & Giussani, D. A. (2010) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2010.00813.x · Cited by 116
“Although this was as much vitamin C as a pregnant woman could ingest on a daily basis, the circulating concentration of vitamin C achieved in these women was substantially more diluted than the 10 mmol/L range estimated to be necessary for vitamin C to act as an antioxidant in vivo [37].”
BackgroundRationale and impact of vitamin C in clinical nutrition
McGregor, G. P., & Biesalski, H. K. (2006) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/01.mco.0000247478.79779.8f · Cited by 115
Mak, S. S., Egri, Z., Tanna, G., Colman, R., & Newton, G. E. (2002) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00947.2001 · Cited by 115
Effect of Vitamin C on the Availability of Tetrahydrobiopterin in Human Endothelial Cells
Baker, T. A., Milstien, S., & Katusic, Z. S. (2001) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-200103000-00012 · Cited by 113
“However, kinetics of the reactions with superoxide anions dictate that NO and superoxide dismutase are the most likely physiologic scavengers of superoxide (7).”
BackgroundInfluentialRodrigo, R., Prieto, J. C., & Castillo, R. L. (2012) · Clinical Science · doi:10.1042/cs20110663 · Cited by 112
Raitakari, O. T., Adams, M. R., McCredie, R. J., Griffiths, K. A., Stocker, R., & Celermajer, D. S. (2000) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(00)00576-3 · Cited by 107
Neurobiology of vitamin C: Expanding the focus from antioxidant to endogenous neuromodulator
Ballaz, S., & Rebec, G. V. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104321 · Cited by 106
Effects of vitamin C infusion and vitamin E-coated membrane on hemodialysis-induced oxidative stress
Yang, C.-C., Hsu, S. P., Wu, M., Hsu, S.-M., & Chien, C. (2006) · Kidney International · doi:10.1038/sj.ki.5000109 · Cited by 106
“VC prevents the interaction of O2 K and nitric oxide only at very high physiologic concentrations.(44) VC overdoses may cause secondary oxalosis via an increase in plasma oxalate levels and the deposition of calcium oxalate in various tissues.”
BackgroundEskurza, I., Monahan, K. D., Robinson, J. A., & Seals, D. R. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00879.2003 · Cited by 106
“Moreover, ascorbic acid can be acutely infused at rates that attain supraphysiological plasma concentrations, which are known to reduce superoxide anions and increase NO bioavailability (29).”
BackgroundInfluentialVasorelaxant and Antioxidant Activity of Flavonols and Flavones: Structure-Activity Relationships
Woodman, O. L., Meeker, W. F., & Boujaoude, M. (2005) · Journal of Cardiovascular Pharmacology · doi:10.1097/01.fjc.0000175431.62626.07 · Cited by 103
“For example ascorbate, an effective antioxidant, does not improve responses to ACh in the presence of oxidative stress caused by pyrogallol or hypoxanthine/xanthine oxidase, apparently because of the known slow rate of reaction between ascorbate and superoxide.(37) In this study the observed relationship between struc…”
BackgroundHirashima, O., Kawano, H., Motoyama, T., Hirai, N., Ohgushi, M., Kugiyama, K., Ogawa, H., & Yasue, H. (2000) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(00)00616-1 · Cited by 103
“reported that normal extracellular concentrations of ascorbic acid (30 to 150 mmol/liter) are not likely to prevent the interaction of NO with superoxide under physiological condition (41).”
BackgroundVirdis, A., Colucci, R., Fornai, M., Blandizzi, C., Duranti, E., Pinto, S., Bernardini, N., Segnani, C., Antonioli, L., Taddei, S., et al. (2005) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.077644 · Cited by 102
“To address this issue, we first used ascorbic acid, an antioxidant compound capable of scavenging superoxide anions at high concentrations (Jackson et al., 1998).”
MethodOxidative Stress Contributes to Renovascular Hypertension
Oliveira‐Sales, E. B., Dugaich, A. P. C., Carillo, B. A., Abreu, N. P., Boim, M. A., Martins, P. J. F., D’Almeida, V., Dolnikoff, M. S., Bergamaschi, C. T., & Campos, R. R. (2007) · American Journal of Hypertension · doi:10.1038/ajh.2007.12 · Cited by 101
Nitric oxide has a regulatory effect in the germination of conidia of Colletotrichum coccodes
Wang, J., & Higgins, V. J. (2005) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2004.12.006 · Cited by 100
Inflammatory Response in Microvascular Endothelium in Sepsis: Role of Oxidants
Cepinskas, G., & Wilson, J. X. (2008) · Journal of Clinical Biochemistry and Nutrition · doi:10.3164/jcbn.2008026 · Cited by 101
“injection of 2 g vitamin C in human subjects does not alter superoxide production by neutrophils [98].”
BackgroundQin, C. X., Chen, X., Hughes, R. A., Williams, S. J., & Woodman, O. L. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm070352h · Cited by 99
Augmented oxidative stress of platelets in chronic smokers
Takajo, Y., Ikeda, H., Haramaki, N., Murohara, T., & Imaizumi, T. (2001) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(01)01583-2 · Cited by 97
“(26) showed that impaired endotheliumderived NO release by superoxide was not prevented by vitamin C at concentrations 150 mol/l.”
BackgroundInflammation-induced vasoconstrictorhyporeactivity is caused by oxidative stress
Pleiner, J., Mittermayer, F., Schaller, G., Marsik, C. L., MacAllister, R. J., & Wolzt, M. (2003) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2003.06.002 · Cited by 96
“Vitamin C is an effective scavenger of reactive species at this high local concentration (29) and has been used to assess the bioactivity of endogenous O2.”
Ascorbic Acid Selectively Improves Large Elastic Artery Compliance in Postmenopausal Women
Moreau, K. L., Gavin, K. M., Plum, A. E., & Seals, D. R. (2005) · Hypertension · doi:10.1161/01.hyp.0000165678.63373.8c · Cited by 96
Oxidative Stress and Endothelial Nitric Oxide Bioactivity
Thomas, S. R., Chen, K., & Keaney, J. F. (2003) · Antioxidants and Redox Signaling · doi:10.1089/152308603764816541 · Cited by 93
Crecelius, A. R., Kirby, B. S., Voyles, W. F., & Dinenno, F. A. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00614.2010 · Cited by 91
Possible application of high-dose vitamin C in the prevention and therapy of coronavirus infection
Hoang, B. X., Shaw, G., Fang, W., & Han, B. (2020) · Journal of Global Antimicrobial Resistance · doi:10.1016/j.jgar.2020.09.025 · Cited by 93
Jablonski, K., Seals, D. R., Eskurza, I., Monahan, K. D., & Donato, A. J. (2007) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00533.2007 · Cited by 90
“However, the strongest, most direct experimental evidence supporting the involvement of oxidative stress is that infusion of supraphysiological concentrations of ascorbic acid, an intervention known to reduce the bioavailability of reactive oxygen species and thus decrease oxidative stress (3, 4, 27), selectively incr…”
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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