Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study
Open accessAbstract
In addition to vaso-occlusion by sickled erythrocytes, the pathophysiology of sickle cell disease (SCD) is compounded by the diminished bioavailability of nitric oxide (NO), associated with vasoconstriction, endothelial activation and cell adhesion. We tested the ability of sodium nitrite, which can be converted to NO by deoxyhaemoglobin at acid pH and low oxygen tension, to improve blood flow in patients with SCD. In a phase I/II clinical trial, sodium nitroprusside, NG-monomethyl-L-arginine, and sodium nitrite were infused sequentially into the brachial artery in 14 patients at steady state. In a dose-dependent manner, sodium nitrite infusion rates of 0.4, 4 and 40 micromol/min into the brachial artery augmented mean venous plasma nitrite concentrations (P < 0.0001) and stimulated forearm blood flow up to 77 +/- 11% above baseline (P < 0.0001), measured by venous occlusion strain gauge plethysmography. This nitrite response was blunted significantly compared to controls without SCD, as previously seen with other NO donors. Sodium nitrite infusions were well tolerated without hypotension, clinically significant methaemoglobinaemia or other untoward events. The unique pharmacological properties of nitrite as a hypoxia-potentiated vasodilator and cytoprotective agent in the setting of ischaemia-reperfusion injury make this anion a plausible NO donor for future clinical trials in SCD.
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In human subjects with SCD, small doses of sodium nitrite are adequate to provide detectable changes in systemic plasma nitrite levels and augment forearm blood flow.
“Mack et al has shown that in human subjects with SCD, small doses of sodium nitrite were adequate to provide detectable changes in systemic plasma nitrite levels and augment forearm blood flow [187].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [187]
Infusions of sodium nitrite in SCD patients show no indications of nitrite-mediated side effects like methemoglobinaemia or reduced blood pressure.
“there were no indications of nitrite-mediated side effects like methemoglobinaemia or reduced blood pressure with the infusions of sodium nitrite.”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [187]
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Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation
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Self-citationCytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver
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“…injury and infarction in animal models, prevents cerebral vasospasm after subarachnoid haemorrhage in primates and decreases pulmonary hypertension in hypoxic newborn sheep (Hunter et al, 2004; Webb et al, 2004; Duranski et al, 2005; Pluta et al, 2005; Hataishi et al, 2006; Jung et al, 2006).”
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“…injury and infarction in animal models, prevents cerebral vasospasm after subarachnoid haemorrhage in primates and decreases pulmonary hypertension in hypoxic newborn sheep (Hunter et al, 2004; Webb et al, 2004; Duranski et al, 2005; Pluta et al, 2005; Hataishi et al, 2006; Jung et al, 2006).”
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- Authors
- Mack, A. K., McGowan II, V. R., Tremonti, C. K., Ackah, D., Barnett, C., Machado, R. F., Gladwin, M. T., & Kato, G. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Kato, Gregory J.
- Venue
- British Journal of Haematology
- Publisher
- Wiley
- Published
- 2008-08-21
- Volume
- 142
- Issue
- 6
- Pages
- 971-978
- ISSN
- 0007-1048 (ISSN-L)
- 1365-2141
- PMC
- PMC2766260
- OpenAlex
- W2013752873
- Cited by
- 64
- References
- 7
- Citations by year
- 2024: 2 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 7 · 2016: 1 · 2015: 3 · 2014: 9 · 2013: 3 · 2012: 6
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- British Journal of Haematology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (ZIAHL006024)
- NIH Clinical Center (Z01CL008081)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- sickle cell disease, sodium nitrite, nitric oxide donors, regional blood flow, forearm blood flow, vasoconstriction, ischemia-reperfusion injury, brachial artery infusion, L-NMMA, sodium nitroprusside, methemoglobinemia
- MeSH terms
- Adult, Anemia, Sickle Cell, Dose-Response Relationship, Drug, Forearm, Humans, Middle Aged, Nitroprusside, Regional Blood Flow, Sodium Nitrite, Vasodilation, Vasodilator Agents, Nitric Oxide Donors, Young Adult
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