Hydrogen sulfide improves survival after cardiac arrest and cardiopulmonary resuscitation via a nitric oxide synthase 3-dependent mechanism in mice.
BACKGROUND
Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. We sought to evaluate the impact of hydrogen sulfide (H(2)S) on the outcome after CA and cardiopulmonary resuscitation (CPR) in mouse.


RESULTS
Mice were subjected to 8 minutes of normothermic CA and resuscitated with chest compression and mechanical ventilation. Seven minutes after the onset of CA (1 minute before CPR), mice received sodium sulfide (Na(2)S) (0.55 mg/kg IV) or vehicle 1 minute before CPR. There was no difference in the rate of return of spontaneous circulation, CPR time to return of spontaneous circulation, and left ventricular function at return of spontaneous circulation between groups. Administration of Na(2)S 1 minute before CPR markedly improved survival rate at 24 hours after CPR (15/15) compared with vehicle (10/26; P=0.0001 versus Na(2)S). Administration of Na(2)S prevented CA/CPR-induced oxidative stress and ameliorated left ventricular and neurological dysfunction 24 hours after CPR. Delayed administration of Na(2)S at 10 minutes after CPR did not improve outcomes after CA/CPR. Cardioprotective effects of Na(2)S were confirmed in isolated-perfused mouse hearts subjected to global ischemia and reperfusion. Cardiomyocyte-specific overexpression of cystathionine gamma-lyase (an enzyme that produces H(2)S) markedly improved outcomes of CA/CPR. Na(2)S increased phosphorylation of nitric oxide synthase 3 in left ventricle and brain cortex, increased serum nitrite/nitrate levels, and attenuated CA-induced mitochondrial injury and cell death. Nitric oxide synthase 3 deficiency abrogated the protective effects of Na(2)S on the outcome of CA/CPR.


CONCLUSIONS
These results suggest that administration of Na(2)S at the time of CPR improves outcome after CA possibly via a nitric oxide synthase 3-dependent signaling pathway.
Minamishima
Shizuka
S
Anesthesia Center for Critical Care Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Bougaki
Masahiko
M
Sips
Patrick Y
PY
Yu
Jia De
JD
Minamishima
Yoji Andrew
YA
Elrod
John W
JW
Lefer
David J
DJ
Bloch
Kenneth D
KD
Ichinose
Fumito
F
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000503:physiopathology; D016887:Cardiopulmonary Resuscitation / Q000009:adverse effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006323:Heart Arrest / Q000201:enzymology* / Q000401:mortality / Q000503:physiopathology / Q000628:therapy*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000201:enzymology; D009420:Nervous System / Q000187:drug effects / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013440:Sulfides / Q000494:pharmacology; D015996:Survival Rate; D015854:Up-Regulation
D002316:Cardiotonic Agents; D013440:Sulfides; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D003542:Cystathionine gamma-Lyase; C033479:sodium sulfide; D006862:Hydrogen Sulfide
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