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.
BACKGROUND
Three-fourths of cardiac arrest survivors die before hospital discharge or suffer significant neurological injury. Except for therapeutic hypothermia and revascularization, no novel therapies have been developed that improve survival or cardiac and neurological function after resuscitation. Nitrite (NO(2)(-)) increases cellular resilience to focal ischemia/reperfusion injury in multiple organs. We hypothesized that nitrite therapy may improve outcomes after the unique global ischemia/reperfusion insult of cardiopulmonary arrest.


RESULTS
We developed a mouse model of cardiac arrest characterized by 12 minutes of normothermic asystole and a high cardiopulmonary resuscitation rate. In this model, global ischemia and cardiopulmonary resuscitation were associated with blood and organ nitrite depletion, reversible myocardial dysfunction, impaired alveolar gas exchange, neurological injury, and an approximately 50% mortality. A single low dose of intravenous nitrite (50 nmol=1.85 micromol/kg=0.13 mg/kg) compared with blinded saline placebo given at cardiopulmonary resuscitation initiation with epinephrine improved cardiac function, survival, and neurological outcomes. From a mechanistic standpoint, nitrite treatment restored intracardiac nitrite and increased S-nitrosothiol levels, decreased pathological cardiac mitochondrial oxygen consumption resulting from reactive oxygen species formation, and prevented oxidative enzymatic injury via reversible specific inhibition of respiratory chain complex I.


CONCLUSIONS
Nitrite therapy after resuscitation from 12 minutes of asystole rapidly and reversibly modulated mitochondrial reactive oxygen species generation during early reperfusion, limiting acute cardiac dysfunction, death, and neurological impairment in survivors.
Dezfulian
Cameron
C
Pulmonary and Critical Care Medicine, Department of Medicine, and Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. cdezfulian@med.miami.edu
Shiva
Sruti
S
Alekseyenko
Aleksey
A
Pendyal
Akshay
A
Beiser
D G
DG
Munasinghe
Jeeva P
JP
Anderson
Stasia A
SA
Chesley
Christopher F
CF
Vanden Hoek
T L
TL
Gladwin
Mark T
MT
D000818:Animals; D016887:Cardiopulmonary Resuscitation; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006323:Heart Arrest / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009420:Nervous System / Q000187:drug effects / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors*; D012977:Sodium Nitrite / Q000008:administration & dosage* / Q000378:metabolism; D015996:Survival Rate; D013997:Time Factors
D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I; D012977:Sodium Nitrite
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