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 (alpha 1 (sGC alpha 1(-/-)) 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 sGC alpha(-/-) but not in WT and NOS3(-/-)CSTg. Neurologic function score and 24 hrs survival rate was lower in NOS3(-/-) and sGC alpha 1(-/-) compared with WT and NOS3(-/-)CSTg. Detrimental effects of deficiency of NOS3 or sGC alpha 1 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. (Crit Care Med 2009; 37:256-262)