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. 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 (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.

Protective effects of nitric oxide synthase 3 and soluble guanylate cyclase on the outcome of cardiac arrest and cardiopulmonary resuscitation in mice.

OBJECTIVES: Despite advances in resuscitation methods, survival after out-of-hospital cardiac arrest remains low, at least in part, due to postcardiac arrest circulatory and neurologic failure. To elucidate the role of nitric oxide (NO) in the recovery from cardiac arrest and cardiopulmonary resuscitation (CPR), we studied the impact of NO synthase (NOS3)/cGMP signaling on cardiac and neurologic outcomes after cardiac arrest and CPR. DESIGN: Prospective, randomized, controlled study. SETTING: Animal research laboratory. SUBJECTS: Mice. INTERVENTIONS: Female wild-type (WT) mice, NOS3-deficient mice (NOS3-/-), NOS3-/- mice with cardiomyocyte-specific overexpression of NOS3 (NOS3-/-CSTg), and mice deficient for soluble guanylate cyclase alpha1 (sGCalpha1-/-) were subjected to potassium-induced cardiac arrest (9 min) followed by CPR. Cardiac and neurologic function and survival were assessed up to 24 hrs post-CPR. MEASUREMENTS AND MAIN RESULTS: Cardiac arrest and CPR markedly depressed myocardial function in NOS3-/- and sGCalpha1-/- but not in WT and NOS3-/-CSTg. Neurologic function score and 24 hrs survival rate was lower in NOS3-/- and sGCalpha1-/- compared with WT and NOS3-/-CSTg. Detrimental effects of deficiency of NOS3 or sGCalpha1 were associated with enhanced inflammation of heart and liver and increased cell death in heart, liver, and brain that were largely prevented by cardiomyocyte-restricted NOS3 overexpression. CONCLUSIONS: These results demonstrate an important salutary impact of NOS3/sGC signaling on the outcome of cardiac arrest. Myocardial NOS3 prevented postcardiac arrest myocardial dysfunction, attenuated end-organ damage, and improved neurologic outcome and survival. Our observations suggest that enhancement of cardiac NOS3 and/or sGC activity may improve outcome after cardiac arrest and CPR.