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(Circulation. 2009;120:888-896.)
© 2009 American Heart Association, Inc.

Resuscitation Science

Hydrogen Sulfide Improves Survival After Cardiac Arrest and Cardiopulmonary Resuscitation via a Nitric Oxide Synthase 3–Dependent Mechanism in Mice

Shizuka Minamishima, MD; Masahiko Bougaki, MD; Patrick Y. Sips, PhD; Jia De Yu, BS; Yoji Andrew Minamishima, MD, PhD; John W. Elrod, PhD; David J. Lefer, PhD; Kenneth D. Bloch, MD; Fumito Ichinose, MD, PhD

From the Anesthesia Center for Critical Care Research, Department of Anesthesia and Critical Care, Massachusetts General Hospital (S.M., M.B., P.Y.S., J.D.Y., K.D.B., F.I.), and Department of Medical Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Harvard Medical School (Y.A.M.), Boston, Mass; Department of Molecular and Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio (J.W.E.); and Department of Surgery, Emory University School of Medicine, Atlanta, Ga (D.J.L.).

Correspondence to Fumito Ichinose, MD, PhD, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 149 13th St, 3405, Charlestown, MA 02129. E-mail fichinose{at}partners.org

Received November 17, 2008; accepted June 15, 2009.

Background— Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. We sought to evaluate the impact of hydrogen sulfide (H₂S) on the outcome after CA and cardiopulmonary resuscitation (CPR) in mouse.

Methods and 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 (Na₂S) (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 Na₂S 1 minute before CPR markedly improved survival rate at 24 hours after CPR (15/15) compared with vehicle (10/26; P=0.0001 versus Na₂S). Administration of Na₂S prevented CA/CPR-induced oxidative stress and ameliorated left ventricular and neurological dysfunction 24 hours after CPR. Delayed administration of Na₂S at 10 minutes after CPR did not improve outcomes after CA/CPR. Cardioprotective effects of Na₂S were confirmed in isolated-perfused mouse hearts subjected to global ischemia and reperfusion. Cardiomyocyte-specific overexpression of cystathionine -lyase (an enzyme that produces H₂S) markedly improved outcomes of CA/CPR. Na₂S 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 Na₂S on the outcome of CA/CPR.

Conclusions— These results suggest that administration of Na₂S at the time of CPR improves outcome after CA possibly via a nitric oxide synthase 3–dependent signaling pathway.

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Clinical Summaries
Circulation 2009 120: 823-824. [Extract] [Full Text]