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

Takefumi Nishida, Jia De Yu, Shizuka Minamishima, Patrick Y. Sips, Robert J. Searles, Emmanuel S. Buys, Stefan Janssens, Peter Brouckaert, Kenneth D. Bloch, Fumito Ichinose

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

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 (NOS3CSTg), and mice deficient for soluble guanylate cyclase α1 (sGCα1) 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 sGCα1 but not in WT and NOS3CSTg. Neurologic function score and 24 hrs survival rate was lower in NOS3 and sGCα1 compared with WT and NOS3CSTg. Detrimental effects of deficiency of NOS3 or sGCα1 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.

Original languageEnglish
Pages (from-to)256-262
Number of pages7
JournalCritical care medicine
Volume37
Issue number1
DOIs
Publication statusPublished - 2009 Jan

Keywords

  • Apoptosis
  • Myocardial dysfunction
  • Neurological dysfunction

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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