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


METHODS
Prospective, randomized, controlled study.


METHODS
Animal research laboratory.


METHODS
Mice.


METHODS
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.


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.
Nishida
Takefumi
T
Anesthesia Center for Critical Care Research, Department of Anesthesia and Critical Car), Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Yu
Jia De
JD
Minamishima
Shizuka
S
Sips
Patrick Y
PY
Searles
Robert J
RJ
Buys
Emmanuel S
ES
Janssens
Stefan
S
Brouckaert
Peter
P
Bloch
Kenneth D
KD
Ichinose
Fumito
F
D000818:Animals; D016887:Cardiopulmonary Resuscitation; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology*; D006323:Heart Arrest / Q000628:therapy*; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D016896:Treatment Outcome
D018160:Receptors, Cytoplasmic and Nuclear; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase