Abstract 264: Beneficial Effects of Therapeutic Hypothermia After Cardiac Arrest and CPR in Mice Require Nitric Oxide Synthase 3
Background: Therapeutic hypothermia (TH) improves neurological outcomes after ventricular fibrillation (VF)-induced cardiac arrest (CA), but the mechanisms by which TH elicits its beneficial effects are incompletely elucidated. Recently, we reported that inhaled nitric oxide (NO) improves outcomes after CA and CPR in mice. In this study, we tested the hypothesis that NO signaling is required for TH to improve outcomes after CA/CPR. We also sought to determine whether inhaled NO remains beneficial in mice treated with TH after CA and CPR.
Methods: Adult male wild-type (WT) and NO synthase 3-deficient (NOS3-/-) mice were subjected to potassium-induced CA at 37°C for 8 and 6.5 minutes, respectively, at which time, CPR was performed with chest compression and mechanical ventilation. Body temperature was maintained at 37°C or reduced to 33°C starting 30 min after return of spontaneous circulation (ROSC) for 24h. TH-treated mice contemporaneously breathed air without or with NO (40 ppm). T2-weighted magnetic resonance imaging (MRI) was performed in live WT mice at 24h after CA/CPR.
Results: Normothermic (NT) WT mice exhibited 100% mortality within 24h after CA/CPR. TH markedly improved the survival rate at 10 days in WT mice (43%; P<0.05 vs NT). In WT mice treated with TH, breathing NO (NO+TH) further improved the survival rate after CA/CPR (88%, P<0.05, NO+TH vs TH). NT NOS3-/- mice exhibited 100% mortality within 24h after CA/CPR. TH failed to improve survival rate in NOS3-/- mice, suggesting that NOS3 is required for the beneficial effects of TH after CA/CPR. NO breathing combined with TH improved the survival rate in NOS3-/- mice after CA/CPR (67%, P<0.01 vs NOS3-/-TH). T2-weighted MRI in live mice showed hyperintense areas in the brainstem and ventral hippocampus of mice that were treated with TH alone consistent with development of vasogenic edema. NO+TH largely prevented the development of brain hyperintense regions (P<0.05, NO+TH vs TH).
Conclusions: The ability of TH to improve survival in mice subjected to CA/CPR requires NOS3 suggesting that NO signaling plays a critical role in the beneficial effects of TH. Inhaled NO can improve survival and reduce brain injury after CA/CPR even in mice treated with TH.
- © 2012 by American Heart Association, Inc.