Introduction: Cerebral vasoconstriction is usually encountered in the post-resuscitation phase, which adversely affects neurological prognosis. Nitric oxide (NO) is an important signaling molecule mediating vasodilatation and anti-apoptotic protection. S-nitrosoglutathione (GSNO) serves as a NO donor and is neuroprotective by itself.
Hypothesis: Exogenous administration of GSNO improves post-CPR cerebral perfusion and confers anti-apoptotic protection via reciprocating NO signaling.
Methods: Using an established rat model of asphyxia cardiac arrest and CPR, we administrated GSNO (0.25 mg/kg) after return of spontaneous circulation (ROSC). Hemodynamics were continuously monitored and arterial blood regularly sampled for measurement of reactive oxygen species (chemiluminescence method) and NO (demonstrated by nitrate/nitrite). The cerebral perfusion was continuously recorded by OxyFLO probe. Two hours after ROSC, the brain was harvested for measurement of casepase-3, endothelial NO synthase (eNOS) and protein kinase B (Akt). Neuronal apoptosis was indicated by cleaved caspase-3/caspase-3.
Results: After standard cardiac arrest and CPR, the cerebral perfusion was significantly reduced to ~0.5 folds that of baseline. Upon GSNO injection, the cerebral perfusion was significantly augmented from the first few min post-CPR and consistently enhanced in the following 2 h (up to 1.3 folds, P < 0.001 vs. CPR control). The plasma NO measured 2 h post-CPR was significantly increased (P < 0.01) while ROS remarkably abrogated (P < 0.05). This was associated with significantly decreased cleaved caspase-3/caspase-3 of the brain (P < 0.001), suggesting that activation of apoptotic pathway was inhibited. Specifically, not only the downstream NO was increased after GSNO administration, the upstream eNOS was also activated (indicated by increased phosphorylated-eNOS/eNOS). By contrast, phosphorylated-Akt/Akt remained unaffected.
Conclusion: GSNO reduces post-CPR cerebral vasoconstriction and caspase-3 activation not only by direct release of NO but reciprocating activation of upstream eNOS, which altogether lead to substantial increase of NO, continued improvement in cerebral perfusion, and anti-apoptotic protection.