Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance: A Human In Vivo Study
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Background—In healthy humans, continuous treatment with nitroglycerin (GTN) causes nitric oxide synthase dysfunction, probably through the reduced bioavailability of tetrahydrobiopterin. Recent studies proposed that folic acid is involved in the regeneration of tetrahydrobiopterin in different disease states. Therefore, we investigated whether folic acid administration would prevent this phenomenon. We also sought to determine if folic acid supplementation could prevent the development of tolerance to GTN. Methods and Results—On the first visit, 18 healthy male volunteers (aged 19 to 32 years) were randomized to receive either oral folic acid (10 mg once a day) or placebo for 1 week in a double-blind designed study. All subjects also received continuous transdermal GTN (0.6 mg/h). On the second visit, forearm blood flow was measured with venous occlusion strain gauge plethysmography in response to incremental infusions of acetylcholine (7.5, 15, and 30 μg/min),N-monomethyl-l-arginine (1, 2, and 4 μmol/min), and GTN (11 and 22 nmol/min). Folic acid prevented GTN-induced endothelial dysfunction, as assessed by responses to intraarterial acetylcholine and N-monomethyl-l-arginine (P<0.01). Moreover, in the subjects treated with folic acid plus transdermal GTN, responses to intraarterial GTN were significantly greater than those observed after transdermal GTN plus placebo (P<0.05). Conclusion—Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous GTN and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.
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Folic acid has been shown to prevent nitroglycerin tolerance in short-term human studies.
“Supplementation of folic acid (5-methyltetrahydrofolate) shows positive effects on eNOS function (900, 978) and has been shown to prevent nitroglycerin tolerance in short-term human studies (375).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [375]
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Self-citation
- Authors
- Gori, T., Burstein, J. M., Ahmed, S., Miner, S. E. S., Al-Hesayen, A., Kelly, S., & Parker, J. D.
- Affiliations
- Mount Sinai Hospital (CA)
- From the Division of Cardiology, Department of Medicine, Mount Sinai Hospital, and the University of Toronto, Toronto, Canada.
- Venue
- Circulation
- Published
- 2001-09-04
- Volume
- 104
- Issue
- 10
- Pages
- 1119-1123
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2165304543
- Cited by
- 178
- References
- 35
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 4 · 2015: 8 · 2014: 8 · 2013: 6 · 2012: 13
- FWCI
- 8.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- folic acid, nitrate tolerance, nitroglycerin, tetrahydrobiopterin, endothelial dysfunction, oxidative stress, nitric oxide bioavailability, forearm blood flow, acetylcholine response, L-NMMA, transdermal nitroglycerin
- MeSH terms
- Acetylcholine, Adult, Blood Flow Velocity, Blood Pressure, Dose-Response Relationship, Drug, Double-Blind Method, Drug Tolerance, Enzyme Inhibitors, Folic Acid, Forearm, Nitroglycerin, Heart Rate, Hematinics, Homocysteine, Humans, Infusion Pumps, Male, Vasodilator Agents, Nitric Oxide Synthase, omega-N-Methylarginine
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