Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers
Open accessAbstract
BACKGROUND: Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. METHODOLOGY: Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21-56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. FINDINGS: The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. CONCLUSION: Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov; NCT00103025.
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The decrease in haemoglobin oxygen saturation following nitrate consumption is a consequence of methaemoglobin formation.
“We note a decrease in haemoglobin oxygen saturation (SaO2) following nitrate consumption which we propose is a consequence of methaemoglobin (mtHb) formation (Pluta et al. 2011).”
From Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure (2016) · cites this paper as Pluta et al. 2011
Acute infusions of sodium nitrite increase forearm blood flow under normoxic and hypoxic conditions in healthy adults and in patients with heart failure.
“acute infusions of sodium nitrite increase forearm blood flow under normoxic (32, 74, 122, 151) and hypoxic (77, 122) conditions in healthy adults and in patients with heart failure (121).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [151]
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- Authors
- Pluta, R. M., Oldfield, E. H., Bakhtian, K. D., Fathi, A. R., Smith, R. K., DeVroom, H. L., Nahavandi, M., Woo, S., Figg, W. D., & Lonser, R. R.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Pluta, Ryszard M.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-01-10
- Volume
- 6
- Issue
- 1
- Pages
- e14504
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3018414
- OpenAlex
- W2073027308
- Cited by
- 112
- References
- 51
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 16 · 2016: 8 · 2015: 12 · 2014: 15 · 2013: 10 · 2012: 12
- FWCI
- 8.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (123454)
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke
- National Institute of Child Health and Human Development
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- sodium nitrite, intravenous infusion, nitric oxide, dose-limiting toxicity, methemoglobin, blood pressure reduction, S-nitrosothiols, maximum tolerated dose, cerebral vasospasm, ischemia, pulmonary hypertension, organ transplantation
- MeSH terms
- Adult, Feasibility Studies, Female, Half-Life, Humans, Infusions, Intravenous, Male, Middle Aged, Sodium Nitrite, Time Factors, Maximum Tolerated Dose, Drug-Related Side Effects and Adverse Reactions
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