Sevoflurane postconditioning prevents activation of caspase 3 and 9 through antiapoptotic signaling after myocardial ischemia-reperfusion

Volatile anesthetic postconditioning reduces apoptosis through antiapoptotic signaling. Whether sevoflurane postconditioning prevents activation of caspase 9 and 3, which are implicated in the initiation and execution step of apoptosis, is not known. Isolated perfused guinea pig hearts underwent 30 min global ischemia and 120 min reperfusion [control (CTL)]. Anesthetic postconditioning was elicited with sevoflurane (2%) for 2 min at reperfusion onset (POST). LY294002, phosphatidylinositol-3-kinase (PI3K)/Akt (protein kinase B) inhibitor; and PD98059, extracellular signal-regulated kinase 1/2 (ERK) inhibitor, were administered for 10 min before ischemia and throughout the reperfusion period in POST (POST + LY, POST + PD). Left-ventricular-developed (LVDP) and LV end-diastolic (LVEDP) pressures and infarct size were measured. Western blot analysis determined phosphorylated Akt and ERK expression. Myocardial caspase 3 and 9 were determined immunohistochemically. After ischemia-reperfusion, POST had higher LVDP (57 +/- A 9 vs. 38 +/- A 7 mmHg, p < 0.05) and lower LVEDP (21 +/- A 8 vs. 46 +/- A 15 mmHg, p < 0.05) versus CTL. Infarct size was significantly reduced in POST versus CTL (15 +/- A 3 vs. 41 +/- A 11%, p < 0.001). Phosphorylation of Akt and ERK after reperfusion was significantly increased in POST versus CTL. Immunoreactivity for caspase 3 and 9 was greater in the nucleus of myocytes and endothelial cells in CTL. POST attenuated this increased immunoreactivity. LY294002 and PD98059 abolished the effect of POST on caspase 3 and 9 immunoreactivity. Sevoflurane postconditioning prevents activation of caspase 3 and 9, mediators of apoptosis in ischemia-reperfusion injury. This caspase activation is mediated by phosphorylation of Akt and ERK.