This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (66)  • Contact me when this article is cited  Related Content  • Related letters  • Similar articles in JAMA  Topic Collections  • Neurology  • Cerebrovascular Disease  • Alert me on articles by topic  Social Bookmarking   What's this?

Ryszard M. Pluta, MD, PhD; Andre Dejam, MD, PhD; George Grimes, PhD; Mark T. Gladwin, MD; Edward H. Oldfield, MD

JAMA. 2005;293:1477-1484.

Context  Delayed cerebral vasospasm causes permanent neurological deficits or death in at least 15% of patients following otherwise successful treatment for ruptured intracranial aneurysm. Decreased bioavailability of nitric oxide has been associated with the development of cerebral vasospasm.

Objective  To determine whether infusions of nitrite will prevent delayed cerebral vasospasm.

Design, Setting, and Subjects  A total of 14 anesthetized cynomolgus monkeys had an autologous blood clot placed around the right middle cerebral artery. Cerebral arteriography was performed before clot placement and on days 7 and 14 to assess vasospasm. The study was conducted from August 2003 to February 2004.

Interventions  A 90-mg sodium nitrite intravenous solution infused over 24 hours plus a 45-mg sodium nitrite bolus daily (n = 3); a 180-mg sodium nitrite intravenous solution infused over 24 hours (n = 3); or a control saline solution infusion (n = 8). Each was infused continuously for 14 days.

Main Outcome Measures  Nitrite, S-nitrosothiol, and methemoglobin levels in blood and cerebrospinal fluid and degree of arteriographic vasospasm.

Results  In control monkeys, mean (SD) cerebrospinal fluid nitrite levels decreased from 3.1 (1.5) µmol/L to 0.4 (0.1) µmol/L at day 7 and to 0.4 (0.4) µmol/L at day 14 (P = .03). All 8 control monkeys developed significant vasospasm of the right middle cerebral artery, which was complicated by stroke and death in 1 animal. Sodium nitrite infusions increased the nitrite and methemoglobin levels (<2.1% of total hemoglobin) in the blood and cerebrospinal fluid without evoking systemic hypotension. Nitrite infusion prevented development of vasospasm (no animals developed significant vasospasm; mean [SD] reduction in right middle cerebral artery area on day 7 after subarachnoid hemorrhage of 8% [9%] in nitrite-treated monkeys vs 47% [5%] in saline-treated controls; P<.001). There was a negative correlation between the concentration of nitrite in cerebrospinal fluid and the degree of cerebral vasospasm (P<.001). Pharmacological effects of nitrite infusion were also associated with the formation of S-nitrosothiol in cerebrospinal fluid. There was no clinical or pathological evidence of nitrite toxicity.

Conclusion  Subacute sodium nitrite infusions prevented delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage.

Author Affiliations: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (Drs Pluta and Oldfield), Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases (Dr Dejam), Pharmacy Department, Clinical Center (Dr Grimes), Vascular Therapeutics Section, Cardiovascular Branch, National Heart, Lung, and Blood Institute (Dr Gladwin), and Critical Care Medicine Department (Dr Gladwin), National Institutes of Health, Bethesda, Md.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

RELATED LETTERS

Methodological Standards in Human vs Animal Clinical Trials
Kennon Heard, Vikhyat S. Bebarta, and Steven R. Lowenstein
JAMA. 2005;294(1):40.
EXTRACT | FULL TEXT  

Methodological Standards in Human vs Animal Clinical Trials—Reply
Ryszard M. Pluta, Mark T. Gladwin, and Edward H. Oldfield
JAMA. 2005;294(1):40-41.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation
Cao et al.
Am. J. Physiol. Heart Circ. Physiol. 2009;297:H1494-H1503.
ABSTRACT | FULL TEXT  

Nitrite Therapy After Cardiac Arrest Reduces Reactive Oxygen Species Generation, Improves Cardiac and Neurological Function, and Enhances Survival via Reversible Inhibition of Mitochondrial Complex I
Dezfulian et al.
Circulation 2009;120:897-905.
ABSTRACT | FULL TEXT  

Myocardial protection by nitrite
Calvert and Lefer
Cardiovasc Res 2009;83:195-203.
ABSTRACT | FULL TEXT  

Tumor Necrosis Factor-{alpha} Mediates Hemolysis-Induced Vasoconstriction and the Cerebral Vasospasm Evoked by Subarachnoid Hemorrhage
Vecchione et al.
Hypertension 2009;54:150-156.
ABSTRACT | FULL TEXT  

Increased nitrite reductase activity of fetal versus adult ovine hemoglobin
Blood et al.
Am. J. Physiol. Heart Circ. Physiol. 2009;296:H237-H246.
ABSTRACT | FULL TEXT  

Evolution of Novel Small-Molecule Therapeutics Targeting Sickle Cell Vasculopathy
Kato and Gladwin
JAMA 2008;300:2638-2646.
ABSTRACT | FULL TEXT  

Mechanisms Underlying Erythrocyte and Endothelial Nitrite Reduction to Nitric Oxide in Hypoxia: Role for Xanthine Oxidoreductase and Endothelial Nitric Oxide Synthase
Webb et al.
Circ. Res. 2008;103:957-964.
ABSTRACT | FULL TEXT  

Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury
Hendgen-Cotta et al.
Proc. Natl. Acad. Sci. USA 2008;105:10256-10261.
ABSTRACT | FULL TEXT  

Nitrite Anion Provides Potent Cytoprotective and Antiapoptotic Effects as Adjunctive Therapy to Reperfusion for Acute Myocardial Infarction
Gonzalez et al.
Circulation 2008;117:2986-2994.
ABSTRACT | FULL TEXT  

The Acidic Tumor Microenvironment Promotes the Reconversion of Nitrite into Nitric Oxide: Towards a New and Safe Radiosensitizing Strategy
Frerart et al.
Clin. Cancer Res. 2008;14:2768-2774.
ABSTRACT | FULL TEXT  

Hypoxic Modulation of Exogenous Nitrite-Induced Vasodilation in Humans
Maher et al.
Circulation 2008;117:670-677.
ABSTRACT | FULL TEXT  

Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury
Bryan et al.
Proc. Natl. Acad. Sci. USA 2007;104:19144-19149.
ABSTRACT | FULL TEXT  

Nitrite Infusion in Humans and Nonhuman Primates: Endocrine Effects, Pharmacokinetics, and Tolerance Formation
Dejam et al.
Circulation 2007;116:1821-1831.
ABSTRACT | FULL TEXT  

A novel method of measuring reduction of nitrite-induced methemoglobin applied to fetal and adult blood of humans and sheep
Power et al.
J. Appl. Physiol. 2007;103:1359-1365.
ABSTRACT | FULL TEXT  

Hemoglobin oxygen fractional saturation regulates nitrite-dependent vasodilation of aortic ring bioassays
Isbell et al.
Am. J. Physiol. Heart Circ. Physiol. 2007;293:H2565-H2572.
ABSTRACT | FULL TEXT  

In vitro and in vivo kinetic handling of nitrite in blood: effects of varying hemoglobin oxygen saturation
Blood and Power
Am. J. Physiol. Heart Circ. Physiol. 2007;293:H1508-H1517.
ABSTRACT | FULL TEXT  

Early Intravenous Infusion of Sodium Nitrite Protects Brain Against In Vivo Ischemia-Reperfusion Injury
Jung et al.
Stroke 2006;37:2744-2750.
ABSTRACT | FULL TEXT  

Nitrite therapy for protection against ischemia-reperfusion injury
Lefer
Am. J. Physiol. Renal Physiol. 2006;290:F777-F778.
FULL TEXT  

Unraveling the Reactions of Nitric Oxide, Nitrite, and Hemoglobin in Physiology and Therapeutics
Kim-Shapiro et al.
Arterioscler. Thromb. Vasc. Bio. 2006;26:697-705.
ABSTRACT | FULL TEXT  

Effects of sodium nitrite on ischemia-reperfusion injury in the rat kidney
Basireddy et al.
Am. J. Physiol. Renal Physiol. 2006;290:F779-F786.
ABSTRACT | FULL TEXT  

Nitric Oxide Metabolites and Cardiovascular Disease: Markers, Mediators, or Both?
Lundberg
J Am Coll Cardiol 2006;47:580-581.
FULL TEXT  

Methodological Standards in Human vs Animal Clinical Trials
Heard et al.
JAMA 2005;294:40-40.
FULL TEXT