Abstract 9215: Flavonoids Baicalein Mitigates Post-Resuscitation Myocardial Dysfunction and Improves Survival via PI3K-Akt-eNOS Pathway

Abstract

Background: Post-resuscitation myocardial dysfunction is a model of global ischemia-reperfusion (IR) injury that is associated with poor prognosis. Flavonoids baicalein has been shown to reduce myocardial IR injury. We therefore investigated the role of baicalein in mitigating post-resuscitation myocardial dysfunction and the potential protective mechanisms. Methods: Using an established rat model of asphyxia cardiac arrest and CPR, we administered baicalein (20 mg/kg) 2 h before cardiac arrest and compared the left ventricular (LV) function with those of standard CPR control. The arterial blood was sampled for measurement of reactive oxygen species (ROS) using chemiluminescence method. The LV systolic and diastolic functions were assessed by dP/dt max and -dP/dt max. Two hours after return of spontaneous circulation (ROSC), the heart was harvested for measurement of malondialdehyde (MDA), phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). In a subgroup with minimal invasive procedures, the survival and neurological outcomes were monitored up to 3 days. Results: In standard CPR group, the systemic ROS generation and myocardial MDA were increased in the post-resuscitation phase. The dP/dt max and -dP/dt max were significantly compromised. Treatment of baicalein reduced systemic ROS and myocardial MDA (both P <0.001), and improved post-CPR dP/dt max and -dP/dt max ( P <0.05 and 0.01, respectively). The survival and neurological outcomes were also ameliorated (Logrank P < 0.001 and P < 0.01, respectively). In terms of the protective mechanism, the phosphorylated Akt (p-Akt) and eNOS (p-eNOS) of the heart 2 h post-CPR were both increased in baicalein group. If NOS inhibitor N ω -nitro-L-arginine methyl ester (10 mg/kg) was cotreated with baicalein, the improved dP/dt max and -dP/dt max were diminished. The survival and neurological outcomes also became worse. If phosphoinositide 3 kinase (PI3K) inhibitor wortmannin (15 μ g/kg) was cotreated, the increased p-Akt and p-eNOS were reversed. The improvements in LV function and survival/neurological outcomes were also abrogated. Conclusion: Baicalein improves post-resuscitation myocardial dysfunction and prognosis through antioxidant protection and PI3K-Akt-eNOS signaling.